FDA Form 483 and Warning Letter, How do differ from each other?

Self-Inspections

FDA Form 483 and Warning Letters:

It is very important to know how the Warning Letter and FDA Form 483 are issued by the Food and Drug Administration (FDA) after an inspection of a particular drug manufacturing site.

FDA Form 483 and Warning Letters are often confusing for many pharmaceutical professionals, who cannot properly differentiate between the two. Both communications are issued by the Food and Drug Administration (FDA), usually after a regulatory inspection and never before a regulatory inspection.

 

FDA Form 483

FDA Form 483:

Form 483 lists observations in order of importance that FDA inspectors record during manufacturing site inspections. Each observation noted on the FDA Form 483 is clear, specific and significant and FDA investigators are specially trained in the matter.

FDA officials communicate their inspection observations on Form 483, and it is usually issued to the manufacturing site after the FDA audit is completed. Observations are not generally made until the investigator’s judgment, conditions or practices observed that any food/drug/device/cosmetic has been adulterated/changed intentionally to its standard practice.

After completion of the Inspection, FDA Form 483s, are discussed with a company’s senior management, regarding the observations of the inspections. To get a full understanding each observation is read and discussed with the company’s senior management so that they get the actual situation regarding inspection observations.

 

 

An FDA Form 483, is a report, it does not contain any observations of questionable, or unfamiliar significance at the time of the inspection of a specific firm. It only reports on familiar objectionable conditions. which are observed during the inspection. even if it can’t report other objectionable conditions which didn’t notice during the inspection. The company/Firm is only responsible. to correct the objectionable conditions which are noticed after the completion of the inspection on the due date.

 

How to handle FDA Form 483?

Upon completion of the FDA inspector’s manufacturing site inspection, the manufacturing site authority should discuss all findings with the FDA inspector and make every effort to resolve negative observations before the inspector leaves the site.

If errors and miscommunications occur, it is best to consult with inspectors.

Try to understand the positive or negative mood of the regulatory body; Their mood can be negative for various reasons or for no reason at all.
Without any hesitation ask any questions to the inspector regarding confusion found during observations.

 

 

If you think, you can convince the inspector. Try to convince the inspector/inspectors regarding observations found during inspection with the help of related information. Your convincing power may help to delete some observations from FDA 483.

 

The purpose of an FDA Form is to notify the company’s senior management regarding objectionable conditions. The FDA Form 483 is presented and discussed with the company’s senior management after the completion of the inspection. Senior management of the Companies is encouraged to respond to the FDA Form 483 with a corrective action plan within the due date.

 

See Practical Example of

Form 483:

Form 483 for Stryker Craniomaxillofacial Division. Portago, MI.

Form 483 for Teva Parenteral Medicines, Inc. Irvine, CA. Form 483.

Form 483 for Cipla Limited Compliance Record.

Form 483 for Ranbaxy Laboratories Limited.

Form 483 for Lupin Limited.

 

Warning Letter

Warning Letter for Cipla Limited.

Warning Letter for BioMD Plus LLC.

Warning letter for Walmart inc.

Warning letter for Elements brands inc.

Warning Letter for Alber GmbH.

 

It is mandatory to respond to the FDA Form 483 within 15 days otherwise regulatory agency will not consider your response regarding the final observation of your company.

FDA Form 483 is not the final decision maker. It just considers along with a written report known as Establishment Inspection Report. All evidence or documentation collected from the manufacturing site, response made by the company/firm. The agency considers all of the information and then they made the final decision for further action.

You may avoid the issuance of a Warning Letter if you respond to FDA Form 483 within due time with appropriate justification.

 

Form FDA 483 content

 

Header information

It contains the following information:
[] FDA district office Address and phone number
[] Date(s) of inspection
[] Facility’s FEI [FDA Establishment Identification number].
[] Name and title of the individual to whom the 483 is issued
[] Address of the facility that was inspected and
[] Brief description of the type of facility

 

Observations

This section presents all the listed observations made by FDA investigators [Number of Investigators may be one to three persons or as per FDA policy]. This section contains all of the inspectional observations and this is not the final agency decision. You can consult with the FDA investigator regarding the observations and also can share your plan and implementation regarding observations. If you have any questions you can contact with FDA with the header section and contact number.

 

Annotation

During the final discussion, the actual annotation of the 483 occurs with the firm’s management. If the firm management prefers no annotation, then it will not happen. Annotations may be placed at the end of each page or at the last page of the observations where the investigators generally put their signatures. In 1997 FDA introduces an annotation policy for medical device inspections.

 

Signatures

For multiple pages, the FDA investigator’s signatures have on the first page and the last page only other pages only initialed. All investigators’ names are printed and signed, & issue date is recorded in this section. FDA investigator’s title may be included there.

 

Reverse side

This side contains some instructional text regarding Food, Safety, and device cosmetics. And also contains some instructions regarding FDA investigators to their nature of work in the inspected site. All the instructions mention these sections are backed by their specific reference such as

-Pursuant to Section 704(b) of the Federal Food, Drug, and Cosmetic Act
-Section 704(b) of the Federal Food, Drug, and Cosmetic Act

 

FDA Warning Letter

Warning Letter:

The next step after issuing FDA Form 483 is Warning Letter. FDA may issue a Warning Letter to the manufacturing site which has already been visited and inspected by FDA Inspector. Serious violations of the quality of the product may lead to the issuance of a Warning Letter. Generally, Warning Letter is issued by the higher officials of the FDA after the review of the inspection observations and especially reviewing the product quality matters.

After the issuance of FDA Form 483 and completion of the inspection, a regulatory agency may issue a Warning Letter to the manufacturing site. When any serious issue is found regarding the quality of the product, a Warning Letter is issued by the higher officials of the FDA after the review of the inspection observations. It contains evidence and detailed explanations for the observations. FDA high officials generally concentrate on the quality of the product and do not compromise with it.

 

A Warning Letter should be replied to within the given time because a delay can lead to an import ban. It may be asked for an extension of the time to justify the things. Most of the Warning Letter issued by FDA high officials has the quality or cGMP issues of the product or facility.

You may easily find both FDA Form 483 and Warning Letters on their website due to these are published immediately publically on fda.gov. and anyone can get it.

 

Type of warning letter

General FDA Warning Letters
Tobacco Retail Warning Letters
Drug Marketing and Advertising Warning Letters

 

General FDA Warning Letters

This type of warning letter is issued when FDA found that the manufacturer has significantly violated FDA regulations. Poor manufacturing practices, problems with claims for what a product can do, or incorrect directions for use lead to the issuance of General FDA Warning Letters. The problem mentioned in the warning letter must correct by the company and the action plan to be shared with FDA and subsequent interaction may change the status of the issues mentioned in the letter.

 

Tobacco Retail Warning Letters

tobacco retailers occur periodically face Compliance check inspections under the Family Smoking Prevention and Tobacco Control Act (Tobacco Control Act) and the Regulations Restricting the Sale and Distribution of Smokeless Tobacco and Cigarettes to Protect Children and Adolescents. Cigarettes and smokeless tobacco also include in compliance check inspections.

 

Drug Marketing and Advertising Warning Letters

Letters are collected and sorted by month and only cover drug marketing activities. Some of the letters may be edited to remove confidential information. Letters sent electronically may be engaged in illegal activities.

 

Close-Out of Warning Letter

Warning Letter “close-out letter” issued by FDA. Once the agency completed the evaluation of corrective actions taken by the manufacturing site in response to the Warning Letter and the agency found the corrective action satisfactory then the agency may issue a close-out letter. A ‘close-out letter’ will not be issued depending on some action taken by the firm. The corrective action must be verified by FDA. The agency expects that corrections have been implemented and verified by follow-up inspection.

If any violations exist that can’t be corrected then no “close-out letter” will issue. Future FDA inspection may further assess the violations and enforcement action may be taken without prior notice.


user requirement specification of Equipment

Documentation, Engineering, Product Development, Production

User Requirement Specification is a specific document where end user generally defines needs, target, goal and their expectation for a system, service and product. This is actually blueprint for the development personnel and it help to ensure that the product meet the target for the specific group.

 

A standard User Requirement Specification includes information about the user group, targeted use of the product, functional requirements, Operational requirements, and performance requirements. It also contains constraints or limitations.

A standard User Requirement establishes a better understanding between the stakeholders regarding a defined outcome; also sets a specific goal for the end-user and helps to save the project, and product delivery time the best thing is its budget-friendly; the user can previously estimate the cost of the specific project.

URS is generally developed by the buyer defining all listed requirements. After the development of a URS, the user sent it to the equipment manufacturer to prepare it as per predefined criteria.

A poorly developed URS is always creating confusion for the manufacturer, you can see the poorly written URS at the manufacturer’s end and If you don’t know how to write URS then you can ask standard URS template from the manufacturer, they are happy to help you. If supplied Template is found near your requirements then you can go with a modified version.

 

User Requirement Specification when disregarded?

A confusing URS is always disregarded. If the manufacturer can’t read you then the faulty or wrong machine can be developed which can destroy your project and A meaningful and well-written user requirement specification saves time and money; also reduce misunderstanding among the manufacturer.

A series of emails may generate to explain your requirement to the manufacturer which may express your poor level of understanding of the specific requirement also create of the high chance of wrong specification delivery and You have to express the requirement what exactly you are looking for in your User Requirement Specification (URS).

Keep it simple, Specific, and Better user requirement specification creates better outcomes.

Requirements of user and support design, qualification activities, operations, commissioning, and maintenance are mainly present on the URS. It’s good to set your mind at the start of your dream project.

According to Mark R. Smith, MD, Realtech,

“A standard URS shall be clear, jargon-free, easily readable, not hard to understand which helps to software engineer and Designer clearly readable and understandable of the user requirement with minimum cost and maximum output”.

 

Types of Requirements

There are several types of requirements that are depicted here.
[] Business Requirements
[] Functional Requirements
[] Stakeholder Requirements
[] Non-Functional Requirements
[] Transition Requirements

 

What thing to consider for user requirement specification (URS)?
Two main things shall be considered during the writing of URS, number one: What shall be included and number two what shall not be included.

 

What to include:

During the writing of the URS, the actual information shall be included in the URS. More information may require for big projects and less for a small project the basic of all URS shall be specific. Unknowingly including a feature that is not available in the market is the same as knowingly ruining your project.

Knowing then any feature should be included in the URS. The most important thing is to include only those specifications that are necessary. Features that will never be used need not be included but the facility to use updated features can be retained.

 

What not to include:

Ambiguous words or terms, Features that are not easy to understand, and that no one has yet used, features that are not user-friendly and will never be used, and features that are overpriced but less important shall be avoided.

 

How to proceed with your User Requirement Specification?

Before proceeding with your URS, define the responsibility of the stakeholders in your URS then collect all stakeholders’ signatures with designation and date. An approved URS shall be procced to the manufacturer to avoid any wanted circumstances. To sign a document means that you are responsible for it.

 

What should be included in the Introduction section?

In this section, you should describe more briefly about yourself and why this URS has been raised. Give a short description of your organization. Like “We are Startech is a startup organization in west Virginia. We want to install a high tech tablet compression machine to produce almost 6000K tablets per hour. This user requirement specification (URS) documents the user requirements for producing tablet dosage forms in a tablet compression machine.

 

The objective of the User Requirement Specification

They clearly describe the goal of the project so that anyone understands it. A brief overview of the project shall be included. Mention the actual purpose of the URS.

 

Who will write the User Requirement Specification?

Anyone can write URS, who has a thorough knowledge of the system, service, product, or machine in question. But you don’t let someone write something they don’t know about, for example, production personnel can’t write the URS of quality control equipment and vice versa.

 

How to document a User Requirement Specification?

The user will prepare the URS and another SEM will check the URS and Engineering personnel and the head of the user department will Review the document, finally Head of Quality will approve the URS. Always documented hierarchy shall be maintained.

To write user requirement specifications for a pharmaceutical company equipment following points should be included

1. Front Page: URS no., Revision no., Addendum no., Using Facility shall be mentioned.
2. List of revisions: Revision number shall be mentioned (if required).
3. List of addendums: Addendum to be mentioned (if required).
4. Table of Contents: Write the list content of the URS.
5. List of abbreviations: All abbreviations shall be mentioned.
6. Signature page: Signatory page contains all signatures including Approval authority.
7. Scope: The scope of the URS is to define the specific Equipment/Instrument.

 

8.0 Procedural Document Requirements:

This part gives information about the Equipment / Instrument including the Purpose of the Equipment, Specification, Qualification, etc.
8.1 Name of the Equipment: Name of the equipment to be mentioned here, if possible, and Model No. to be defined here.
8.2 Purpose of the Equipment: Purpose of the Equipment shall be clearly defined here.
8.3 Number of Equipment Required: Require quantity of the Equipment/Instrument shall be defined here.
8.4 Qualification: A list of qualification documents shall be mentioned here.
8.5 Specification of Equipment: All major specifications of the Equipment/Instrument shall be mentioned here.

 

9.0 Operational Requirements:

9.1 Vendor Scope: The Vendors scope shall include the Supply, Installation, and Documentation including calibration certificates, User training, and Details of service/maintenance contracts available.
9.2 Operation: Basic operative characteristics including Data logging (21 CFR part 11), controlling system, capacity, safety, and protection, the capacity of basic function, etc.
9.3 Options and Ancillaries: The vendor should identify, where applicable, their standard equipment that fits this specification. The vendor shall (where possible) also provide costs including, A range of additional maintenance support and services., Any additional accessories to fulfill the requirements indicated in section 9.2.
9.4 Interfaces: A user-friendly control system is required, that can allow system operation with a minimal amount of training.
9.5 Data and Security: If required, data and security articles are to be clearly defined here.
9.6 Environment: Instruments/Equipment’s operating environment should be clearly defined here. The operating area must fit with the specific Instruments/Equipment in such a way that it can be operated without any difficulty.

 

10.0 Constraints

10.1 Milestones and Timelines: A projected timeline and milestone may be set here.
10.2 Compatibility and Support: The internal components of the system must be compatible with, and resistant to, the materials used during operation. Operating power to be mentioned here.
10.3 Maintenance Requirements: The manufacturer should supply details of any maintenance/breakdown packages available.
10.4 Procedural Constraints

 

11.0 Life Cycle

11.1 Development Procedures: Future development procedures are to be mentioned here.
11.2 Testing Requirements: See Section 11 for a detailed matrix of the validation testing requirements.
11.3 Delivery Requirements: On supply, the following documentation should be supplied: Operation and maintenance manual (including manufacturer’s recommendations for maintenance schedules). Calibration certificates. Parts list and spare requirements. System specifications.
11.4 Support: The vendor must supply details of all service and maintenance requirements of the equipment. The vendor must also supply details of any service and maintenance support that they can supply.

 

12.0 GMP Requirement: A list of cGMP requirements shall be mentioned here.
13.0 Utilities Available at The Site of Installation: Utilities shall be described here including the power supply for the machine/equipment.
14.0 Documentation Requirement: A list of documents shall be described here such as Operation, cleaning, and maintenance manuals for equipment as well as the operation, Installation instructions/ guideline, other drawings (such as Mechanical, electrical, instrumentation, etc.), IQ/OQ documents & operating manual., Instrument calibration / Qualification certificates traceable to the national reference standards, Guaranty/ warranty certificates for the equipment, Shipping checklist, and Hardware design specification.
15.0 Terms and Conditions to Be Included in The Quotation: All the terms and conditions shall be described here.
16.0 All the discussion shall be noted here and contact personnel details shall be mentioned at the end of the discussion details.
17.0 Annexures: Mention annexures if there are any.
18.0 Validation Requirements:
The following details the test requirements for documentation, testing, and the stage of the project at which they must be provided/performed. These requirements are a minimum tariff, and the vendor is required to include any documentation, not already requested here, which is considered necessary to support the successful validation of the system.

 

 

Which things to follow to write a Modern User Requirement Specification?

From the discussion till now we know what to add to our URS and what not to add. Ambiguity to be avoided as much as possible should be written clearly so that anyone who reads it can understand it. Ambiguity is the enemy of any project’s success and expressing yourself as accurately as possible is possible. Communication must be done in an unambiguous manner to achieve good results; Your project will be successful when you are able to convey your message to others.

To write a best User Requirement Specification you need to keep the following points in mind:

 

 

user requirement specification
user requirement specification

1. Focus on Single Requirement:

Check each requirement to be developed and how it is tested. Project success depends on each effective requirement which is really a demand to the project. Avoid unnecessary requirements which really not essential to the project.

 

2. Avoid Haziness

Your URS must be clearly written. Use a Simple Sentence. No confusing word. Just say what you want and what not.

A user requirement specification should be clearly written, using simple sentences, and without ambiguity. Examples of ambiguous words are:

[] Easy
[] Strong
[] Improve
[] Fast
[] Slow
[] Enough
[] User friendly

What exactly are you meaning “Fast”? this term is theoretical; you can’t actually express your requirement using the word “Fast”. It is hard to measure. Avoid any abbreviations, acronyms, and jargon words (words and phrases, that are not generally understood).

 

3. Go with the SMART Approach

[] S for Specific
[] M for Measurable
[] A for Achievable
[] R for Realistic
[] T for Time-bound

SMART [Specific, Measurable, Achievable, Realistic, Time-bound) targets offer a decent way to confirm your URS is well-defined and supportable.
Specific: All requirements mentioned in the URS must be specific, clear, and jargon-word-free. Don’t add any unnecessary requirements like easy and fast. Mention the actual specification.

Measurable: Reequipment must be measurable, don’t state anything which can’t confirm by testing or examination. Always avoid theoretical statements like rapid and swift. It can’t measure, you can’t prove that your requirements just met the specification until it is measurable.

Achievable: Never set a requirement which is can’t achieve with help of current technology. A feasibility study shall be done before setting any requirements. You can’t set any requirement which is technically impossible to achieve. It is wise to study well before adding features that you have no idea about. If even then you cannot be confirmed, then seek an expert for help. It is not right to add any feature without knowing it.

Realistic: It’s important to be realistic when determining the list of requirements. Sometimes technically achievable requirements may not be realistic due to regulatory requirements, time restrictions, Budget constraints, or other limitations.

Time-bound: A specific time frame shall be fixed to obtain your project. Even after finishing everything and if the specified time is not fixed, then any project may fail.

 

4. Organize

Organize your word choice and think carefully about it. Generally, the word “Shall” and “will” define the actual requirement which must be met. Word like “May” and “Could” use to define goals than are expected but not necessarily requirements. So, when you want the requirement must be met then use shall/will and use may/could for not mandatory cases.

 

5. Control Changes to the Requirements

Any type of changes may require during creating your list of requirements. Changes to the specification of the specific requirement shall be controlled. If any type of change directly affects the requirement, then the requirement shall be updated and a new version shall be created.

 

6. Requirements Must be Testable

Requirements shall be written in a such way that they can be tested and Specific requirements shall be traceable through the life cycle of the system/service/equipment/instruments.

 

7. Structural Products

Two types of products may be used as structural products & custom applications; for custom applications, the manufacturer must describe every process step to the user. For structural products, the process steps must be aligned with their predefined specification.

 

8. Vendor Audit

Most of the cases Regulated companies are most aware of their vendor for periodic assessment. All types of assessment/re-assessment perform in accordance with the Quality Management System (QMS).

 

9. Specifications

It is essential for the supplier to thoroughly document both the functionality and design of the system which is a prerequisite to ensure successful product development. Documentation must cover all aspects of the system, including software, hardware, and configuration, to meet all requirements to be established.

 

10. Training & Documentation

The supplier must agree to provide comprehensive system management documentation and provide instructions for both maintenance and use by the supplier and related issues must be agreed upon prior to system purchase.

 

11. Eliminate Requirement Redundancy

Avoid overcomplicating the system requirements and there is no need to bulk it up by duplicating it. Avoid duplication. Duplicating your documents may require more testing, documentation, and review time, making the project and time progressively longer Don’t include anything which is related to money or finance.

 

What is the difference between data and information

 

12. Embrace the Opportunity to Evaluate Vendors

Conducting audits on suppliers may include asking the following questions:
[] Security
[] Product support
[] End User training
[] Company Overview
[] Use of sub-contractors
[] Service delivery process
[] QMS application at the company
[] Development product life cycle
[] Key products development plans
[] Organization, roles, responsibilities, & training

 

13. Don’t be intimidated by your vendor comparisons

Utilize your URS to evaluate different vendors & note their advantages and disadvantages. If new information is found during the initial stage, feel free to revise your approved URS accordingly through the change control process. It is acceptable to make modifications or adjustments to the requirements to fit your needs until the final approval of the URS and it shall be revised the approved User Requirement Specification accordingly maintaining proper documentation.

 

14. What ought to be included in the URS?

The contents of a URS naturally include the following (but are not limited):
[] Functional requirements
[] Operational requirements
[] Technical requirements
[] Interface requirements
[] Data requirements
[] Security requirements
[] Regulatory requirements
[] Maintenance requirements
[] Availability requirements
[] Migration of any electronic data
[] Environmental requirements
[] Constraints to be observed
[] Life cycle requirements

 

15. Categorize Your Requirements

Categorize Your Requirements as-
[] Mandatory (High)
[] Beneficial (Medium)
[] Good to have it (Low)

 

16. Subjective Knowledge and Processing Step

To ensure that requirements, your professional knowledge is essential but not mandatory; if require you can seek help from an SME [Subject Matter Expert]. To identify key requirements of the system Process knowledge is required which are related to the manufacturing/servicing process. Look for the following key points-
[] Experience
[] Knowledge
[] Documentation

 

17. The requirements may be incomplete or not fully specified

Sometimes the requirements are not fully understood at the beginning of the project; Requirements evolve over time. URS shall be developed as per requirements when information is available. Don’t share incomplete User Requirement Specifications to the manufacturer to avoid any unwanted requirements.

 

Frequently Asked Questions

Are URS always required for validation?

At the initial stage of system/service/equipment/instruments, then URS is a valuable tool for ensuring the asking requirements. When an existing system is being validated then URS consider as a functional requirement. These two documents can’t be considered as single documents.

 

What is the benefit of good User Requirement Specification?

Requirements gathering is an important part of a good software/hardware/service/product development project. Good estimation, improved customer satisfaction, reduced cost, and project duration can all fail if good requirements are not selected and sufficient knowledge is not introduced in the selection If you are unclear about what you are delivering, no one can expect anything better from you.

There are Five main questions that shall be asked to develop any project:
[] Why we are doing it?
[] What do we need to do it?
[] What is the benefit?
[] How do we do it?
[] What is the timeframe?

If we fail to estimate project requirements or are unable to assume what is the requirement, can lead to a poor outcome of the project, and also lead to extra manpower, longer duration, and project costing.

 

Download Your

User Requirement Specification (URS) Template


What is the difference between Mass and Weight?

FAQ, Viva

What is the difference between Mass and Weight? Generally, people, treat them same term in practical life but in physics, they are very much different. One is in practical matter another is variable place to place, Hight to Hight depends gravity. What is gravity? force that exists among all material objects in universe. Express as g & it change place to place, Hight to Hight but one thing that is not change, this is it. It is Mass.

If you in Australia your mass is 59kg, if you in UK you are in 59kg if you in USA you are in almost 59kg, if you in Mars, obviously you are in 59kg. It can’t be change. This is just like your personality which never change other is your attitude which always chance place to place.

 

So, what is the definition of Mass?

Thousands of types of definition you will find in web but I like the following-

Mass can be defined as amount of matter present in you. No matter at what place you are may be in Africa or Europe its value remains constant.

What is the definition of Weight?

Weight is the force by which you are being attracted by this amazing planet. This is very much changeable from planet to planet & height to height. Gravity on Mars is 38 percent of Earth’s gravity, so a 100kg person on Earth would weight 38kg on Mars.

On the other hand, we can say that Mass is actually a physical quantity which measures amount of matter in a body whereas weight is actually the force with which earth pulls our body towards its own center.

How can we express them?

Generally, Mass is express by “m” and its S.I. unit is kg where as Weight is Expressed by “W” and its SI unit is N[Newton].

Weight is mainly the amount of forces force exerted by earth on a mass of any substance. Weight can be calculated as Weight=Mass x g, where g is acceleration due to gravity and its value is 9.8.

Mass & Weight

 

Let me explain,

If want to something buys from supermarket or any place where you prefer, may be online, they will mention mass of the Object not weight in practical though some of the company mention weight of the object but actually that it the mass of the object not weight of the object.

You will only get the weight of the object, when you multiply the value with “g”. So, if your weighing machine gives the reading for a object as 100kg then it weight will be 100×9.8=980N. Hope you got it.

Value of the weight is negligibly change in the earth surface as the value of the “g” is not significantly change on our planet surface but a little amount change in poles of the earth as the value of “g” slightly increase inversely in equator area the value decrease.

 

Evaluation of Mass & Weight

From the very beginning, people are involving their goods for trading. 2-pan balance scale and some reference weights were the primary transaction method to determine the quantity of item. Balance was achieved by placing unknown amount of goods to one pan and another pan contains reference weight. The main problem of the two pan scale was it can’t measure the force only measure the mass.

At the time of the advent of English, the traders referred their known item to compare to the another unknown item as “weights”, and this process known as weighing and thus the result ,mentions as weights at a little before 1000AD.

In late 1600, famous laws of motion developed by Isaac Newton’s but this is not quite accurate in extremely high speeds where theory of special relativity [Albert Einstein’s at 20th-century] is required. Mass depends on how much matter-atoms is an object.

Lot of research on relationship between the quantity of matter & effect of force on that matter, especially with the concept of gravity was performed by Newton & Hooke at 1600s. After the completion of the research, they publish their research paper in Latin as that time it was major communication medium in scientific research.

At 1700s, the Newton and Hooke works start to publish in English and in this process the decided the take the word “Weight” as amount of material which is already use for the centuries and its related to gravity and taking the word “Mass” [ which was unrelated meaning in that time] and having it mean to the amount of material [Similar meaning of Weight as that was using in that time]. So, the great confusion starts then. This was the fault of physicists & their translators.

Mass can be defined as the measurement of an object’s tendency to resist changing its own state of motion, well known as inertia. Left a football on a field will stay put or move in a straight line unless some force like friction, touch by foot or hand or creating obstacle to the line, it will keep moving forward. So much is the measure of force which will require to change its path.

Weight, can be defined as the measure of amount of downwards force that gravity exerts on a specific object. If the mass of the object increases then force increases, the more inertia it contains, then harder gravity pulls. On our Earth’s surface, force of gravity is almost 9.8 newtons per kg.

As the two term was confusing so people involve in trade, law, commerce had no interest to change the long use term “Weight” and continue it. Weight to them, physicists started calling mass already and this practice continue still today.

People who are involving in commerce & Law use the word “Weight” to define the amount of material where never involve the meaning of force and never implement the word “Mass”. At the year of 1750, spring scale was invented and it calibrated to read out the mass which surprisingly works very fine until it moved to significantly different strength of gravity. In our planet, the change of gravity is almost same until it Moves to poles or equator, if do so then change of gravity is not significant. So the traders continue to use the word “Weight” as they are using this term for a long period of time to define the word “Mass”.

At the period of time, physicists start proclaiming that the effectiveness of the Word “Weight” and “Mass” is correct and anyone who used them otherwise is very much incorrect and such shall be obsolete. This is totally insane as the physicists were violating the long-term usage of word “Weight”. They also emphasize the usage of word “Weight” referring forces. But this didn’t reflect the practical life. In practical life, in Commerce and Law, it is very much considered that the Weight is the synonyms of Massa and its correct is kilograms not newtons.

In this context, this is very much meaningful that “I weigh 99 kg” or “My weight is 99 kg” but as per Physics weight is the result of Mass and associated with gravity on its which unit is Newton not kilogram. As discussed, it can’t say forcefully that they are using the terminology incorrectly, moreover in some context the answer of the question is “There is no difference between “Weight and Mass” due to they are synonyms to each other and measured in kilogram.

But there is a clear distinction between the two terminologies where Mass is the amount of material which measured in kilogram and Weight is type of force with Mass measured in Newton. In technical field all of the measurements are associated with the Organization titled as “Weights and Measures”.

As per Scientists “Weight is measured in Newton[N] which is 9.8 times larger than Mass[m] in earth surface and this may vary from place to place [Earth to Moon, Earth to Mars, Earth to Saturn etc.] 10kg of Mass has Weight of 98N and this has the Weight in Moon has 10.6N in Moon.

To simply understand the difference between Weight & Mass is” Mass is the Personality of Matter and Weight is its own attitude which is variable to place to place”.

Attitude

 

Mass is actually the intrinsic property of matter which is just like the like personality is of a man and weight is the gravitational pull on the specific object which depends on the other body which is employing on it which is similar to attitude depends on another party.

Expression of Weight and Mass
As per Physical Science, the Mass and Weight are the totally different and their expression is “m” for Mass and unit is kg where Weight express as m x g [g, acceleration due to gravity] and its unit is Newton.

Let consider Mass is m, then
Weight= m[Mass] x g[acceleration due to gravity]

 

What Is the Difference Between Weight and Mass?

In ordinary conversation, “mass” and “weight” are used interchangeably but they are very much different to each other. Mass is defined as the amount of material present in the matter where Weight is measured as how force of gravity acts on that mass. Amount of matter in a body is measured by mass and Express by “m” or “M”. The amount of force acting on a mass due to the acceleration due to gravity is measured by Weight and it’s the result of Mass multiplied by acceleration of gravity (g).

The values for mass and weight are the same if it does not move on Earth. If you change your location from low to or high to low gravity then the Weight of the Object shall be change but its mass remain same in any location as mass is not location dependent. You can think that your mass of the body is always same but your Weight shall be different on Mars compare to Earth.

Difference Between Mass and Weight

Sl. No.Differentiating PropertyMassWeight
1DefinitionMass is the measure of the amount of matter in a body.It is the measure of amount of force acting on a mass due to acceleration due to gravity.
2CriteriaMass of an object is same in everywhere as Mass is a property of matter.Weight always increases or decreases with higher or lower gravity as Weight depends on effect of the gravity.
3ValueMass is a constant Value and Mass can’t be zero in any place.If no gravity acts upon an object, as in space then Weight can be zero as 0 [Zero] gravity acts on the mass.
4LocationAs per location, Mass does not changeDepends on location, Weight varies accordingly.
5DenotationMass is denoted by “M”.Weight is denoted by “W”.
6MeasurementAn ordinary balance can be used to measure Mass.A spring balance is used to measure Weight.
7UnitMass generally is measured in grams and kilograms.Weight measured in newtons which is a unit of force.
8FormulaMass is always constant value for a body and there are several formulas to calculate the mass.
Mass can be calculated as:
Mass = Volume × Density
Weight is the measure of the gravitational force acting on a body.
Weight can be calculated as:
Weight = mass × acceleration due to gravity[g]
9Gravitational EffectMass does not depend upon gravity and is constant everywhere in the universe.Weight is dependent on gravity and so, it varies from place to place in the planet.
10Measuring InstrumentMass can be easily measured using any ordinary balance like beam balance, lever balance, pan balance, etc.Weight can be measured by a spring balance or by using its formula.

If I go other Planets then How Much I Weigh on there?

Due to acceleration to gravity the weight varies dramatically but person’s mass doesn’t change elsewhere in the solar system. The “surface” distance from the center of gravity plays a major role to calculate the gravity on the mass. When you travel on the top of the mountain [The Himalayas] your weight shall be slightly lower than the sea level. Always mass is not the major as mentioned before, distance plays a significant role.

Suppose, If I in Saturn, my weight will not increase Saturn 95.2 times as Saturn is 95.2 times heavier than earth due to its surface is so much far [1.4075 billion km from Earth] from the center of the earth. To get the actual weight of a person just multiply the appropriate number of Earth Gravity. For Example, 100-pound person shall be weight on 113.9-pound on Saturn or 1.139 times weight on Earth.

 

Different Surface Gravity on different Planet

ParticularsMultiple of
Earth Gravity
Surface Gravity
(m/s2)
Earth1 (defined)9.8226
Jupiter2.64025.93
Mars0.38953.728
Mercury0.37703.703
Moon0.1651.625
Neptune1.14811.28
Sun27.90274.1
Saturn1.13911.19
Uranus0.9179.01
Venus0.90328.872

 

Above the explanation, your weight will be same in Venus as the planet has the same size and mass as Earth. You feel slightly higher weight in Neptune and Saturn but less feel in gas giant Uranus. Almost same weight shall be assumed in Mercury and Mars though Mercury is much smaller than Mars[30% wider than Mercury].

If sun become cold [not possible in near future as assumed] you will feel 28 times much weight compare to Earth surface as it’s the more massive in our solar system.


Data Integrity and Why Is It So Important?

GMP, Pharma Operations, Quality Assurance

Data Integrity can be defined as it is critical part to the plan, execution & practice of system that processes, stores & or retrieves data and maintenance & assurance of data accuracy and consistency throughout its life cycle.

Another best alternative term is Data quality which is sometimes defined as the proxy term of data integrity. It is the wide term & it can be used in different meaning depending on the framework. For data integrity, data validation is prerequisite. Data corruption is the just opposite term of Data integrity.

Also Read

What is the difference between Data and Information?

Confirm that data is recorded exactly as projected and most of the cases Data Integrity technique is the same for all type of probable data source.
The main target regarding is to prevent any type of alteration of the exact data recorded during collection of data and it can’t change at any cost. At the time of retrieval of data, it must be same as collected before.

Data Integrity denote the accuracy & consistency of data over its lifecycle. Sensitive data may loss upon uses of Negotiated data. Under this consideration, continuing it is a main focus of many enterprise security solutions. During replicated or transferred of data, it shall be intact and unaltered. To ensure the integrity of data, Error checking methods and validation procedures are typically best way to serve the same.

 

Data integrity

 

Don’t confuse with Data Integrity and Data security, it is process to prevent unauthorized entry to the projected data or protecting data from unauthorized expert.
Any unintended changes to data as the consequence of a storage, retrieval or processing operation, including malicious intent, unexpected hardware failure, and human error, is failure of data integrity.

Failure of Data Integrity means any unplanned changes to data as the consequence of storage, unexpected hardware failure, retrieval or human error or processing operation malicious intent etc. If you unable to protect your data from unauthorized change then it can define as data security failure.

 

Data Integrity denote that it is a state as well as process, so a confusion may arise. Data Integrity is a state as it denotes a data set is both valid and accurate. Validation methods & Error checking are considered as Data Integrity processes.

 

Study of Data Integrity

Data Integrity is significant for several reasons & need to maintain the same. Data Integrity confirms searchability, recoverability, connectivity, & traceability. To increases stability & performance as well as improving reusability & maintainability; need to protect validity & accuracy of data. Data plays a major role to drive enterprise decision-making and data undergo several stages of changes to form raw to format to become more practical and identifying relation between them. In modern enterprises Data Integrity consider the top most priority.

In a database system, Data Integrity may be Compromised in various type of ways. In the following ways, Data Integrity may be compromised-
[][]Compromised hardware, like device or disk crash
[][]Compromise of Physical devices
[][]Cyber threats, Bugs, Viruses/Malware, Hacking, & other unfamiliar process
[][]Human error, whether unintentional or malicious

Transfer errors, unintended alterations or data compromise during transfer from one device to another device.
Most of the cases, some type of data security may protect this data compromises. Data duplication is the critical para meter for data security as well as data backup process.

 

Data Integrity & Databases

Data Integrity encompasses strategies for data specifying, retention, or guaranteeing the length of time data. Any lessening of enforcement could cause errors in the data; all of the rules shall be consistently & regularly implemented to all data entering the system.

At time of data input, checking system shall be implement which will lessen up the number of data error for the system. Data Integrity rules shall be strictly implemented to the system which will save troubleshooting time, erroneous data subsequently errors to algorithms.

A standard Data Integrity rules must have the strict definition regarding data relation; as which type data shall link with which type of data. A selling record of a item of certain product may be linked with the specific product but is shall not be related to unrelated data such as company asset, policy, loan, promotion etc. Based on predefined rules, it may be included check & correction system for the invalid a data.

Data derivation rules shall be applicable, mentioning data derivation procedure that how a data value shall be derived based on contributors, conditions and algorithm of the system. Re-derived procedure for data value shall be mention on which condition shall be considered for this process.

 

Types of Data Integrity

Organizations can maintain Data Integrity through integrity constraints, which define the rules and procedures around actions like deletion, insertion, and update of information. The definition of Data Integrity can be enforced in both hierarchical and relational databases, such as enterprise resource planning (ERP), customer relationship management (CRM), and supply chain management (CRM) systems.

Organizations can achieve it through the following:

 

classification of Data Integrity

Physical Integrity

Physical integrity deals with challenges which are associated with correctly storing and fetching the data itself.

Physical integrity indicates the right storing & fetching the data itself & its associated series of challenges. Various types of Challenges are involved with it such as Physical flaws, design flaws, power outages, electromechanical faults, corrosion, material fatigue, natural disasters, environmental hazards such as ionizing radiation, high temperatures, pressures & g-forces [the force of gravity].

Various methods are available to maintain the physical integrity such as UPS [uninterruptible power supply], redundant hardware, various type of RAID arrays, error-correcting memory, radiation hardened chips, clustered file system, watchdog timer & cryptographic hash function for critical system.

 

Error-correcting codes is extensively use as error detecting algorithms in Physical integrity of data management systems. Simpler checks & algorithms as the Damm algorithm or Luhn algorithm is use to detect Data Integrity errors. This system is use to uphold Data Integrity at manual transcription from one computer system to another computer system through a human intermediary such as credit card numbers. Hash functions are more beneficial to detect Computer-induced transcription errors.

These techniques are used together to ensure various degrees of Data Integrity in production systems such as a fault-tolerant RAID array may be use to configured a computer system but in silent data corruption block-level checksums might not provide.

In a nutshell, Physical integrity means protecting the accuracy, correctness, and wholeness of data when it is stored and retrieved. This is typically compromised by issues like power outages, storage erosion, hackers targeting database functions, and natural disasters, which prevent accurate data storage and retrieval.

 

Logical Integrity

It is concerned with correctness or rationality of a piece of data provide a particular context. It denotes the topic such as Entity integrity & referential integrity in a relational database system. Design flaws, software bugs, and human errors are the major challenges. Foreign key constraints, check constraints, program assertions, and other run-time sanity checks are the common methods to ensure logical integrity.

 

Design flaws & Human errors, both are the common problems for physical and logical integrity which must be properly deal with the contemporaneous requests to record and retrieve data. Physical error for a specific data system is more critical than logical error. If a data system suspected to logical error, it can be reused by overwriting with the new one but if it faces physical error then the data sector is totally used of its own condition.

Logical integrity ensures that data remains unchanged while being used in different ways through relational databases. This approach also aims to protect data from hacking or human error issues but does so differently than physical integrity.

Logical integrity comes in four different formats:

 

Entity Integrity

Entity integrity is a feature of relation systems that store data within tables, which can be used and linked in various ways. It relies on primary keys and unique values being created to identify a piece of data. This ensures data cannot be listed multiple times, and fields in a table cannot be null.

Referential Integrity

Referential integrity is a series of processes that ensure data remains stored and used in a uniform manner. Database structures are embedded with rules that define how foreign keys are used, which ensures only appropriate data deletion, changes, and amendments can be made. This can prevent data duplication and guarantee data accuracy.

Domain Integrity

Domain integrity is a series of processes that guarantee the accuracy of pieces of data within a domain. A domain is classified by a set of values that a table’s columns are allowed to contain, along with constraints and measures that limit the amount, format, and type of data that can be entered.

User-defined Integrity

User-defined integrity means that rules and constraints around data are created by users to align with their specific requirements. This is usually used when other integrity processes will not safeguard an organization’s data, allowing for the creation of rules that incorporate an organization’s Data Integrity measures.

 

Types of Integrity Constraints

A set of integrity constraints or rules are followed to implement Data Integrity in a database system. Relational data model suggests the three types of integrity constraints such as domain integrity, entity integrity, & referential integrity.

First of all, Entity integrity denote the concept of a primary key. As per this system, Entity integrity states that every table shall contain a primary key and existing column or columns of the table shall be identified by the primary key & it shall be inimitable and not null.

 

Concept of a foreign key denote Referential integrity. As per referential integrity rule, any foreign-key value can only be in one of two states. In general condition, foreign-key value refers to a primary key value of some table in the database system. Sporadically, a foreign-key value can be null and this will rest on on the rules of data owner. Under these circumstances, it can be stated here that this relationship is unknown or there is no relationship between the objects represented in the database system.

All columns in a relational database must be stated upon a defined domain is the main concern of the Domain integrity. In the relational data model, the primary unit of data is the data item. This type of data items is known as atomic or non-decomposable. A set of values of the same type is defined as domain. Actual values appearing in the columns of a table are drawn from the Domains which are considered as pools of values.

As the User-defined integrity are set by the specific user with a set of rules which is not related to domain, entity, and referential integrity classes. The database which supports these features, it is the sole responsibility of the database to confirm Data Integrity and reliability model for the data storage & retrieval system. The database which does not support these features then it is the accountability of the applications to confirm Data Integrity though the database supports the consistency model for data storage & recovery process.

 

A well-controlled single and well managed data-integrity system increases.

[][]Maintainability
=>All Data Integrity administration commences from a single centralized system.

[][]Performance
=>As a single operation unit, all Data Integrity operations perform as consistency model.
[][]Re-usability
=>A single centralized Data Integrity system provides the all applications benefit.
[][]Stability
=>As avoid the multiple system, so Data Integrity operation performs sound as well as better retrieval on a one centralized system.

Examples
Data-integrity mechanism is often considered as the parent-and-child connection of interrelated records. When one or more related child records exist for a parent record then all of referential integrity methods are handled by database itself & inevitably ensures accuracy & integrity of data, so no child record can exist without parent record and subsequently no parent drops their child records. In this system if the parent record owns any child records, then no parent record can be deleted and all of the process handled by the database system.

 

File systems

File system including Ext, JFS, UFS, XFS, and NTFS or hardware RAID solutions can’t provide satisfactory protection against Data Integrity problems. Some special file system such as BTRFS and ZFS use for silent data corruption can provide extra protection for data integrity. Upon provide this protection and being chance raise to corrupt the data then such file system can construct the data is widely known as end-to-end data protection.

Data Integrity as applied to various industries
[][]FDA has created the draft guidance for Data Integrity system as per 21 CFR Parts 210–212.[12] for pharmaceutical manufacturers. Same guideline has been developed by UK [2015], Switzerland [2016], and Australia [2017].
[][]Data Integrity also addressed by ISO as per ISO 13485, ISO 14155, and ISO 5840.
[][]FINRA [Financial Industry Regulatory Authority], implement the Data Integrity system on 2018 under technology change management policies and procedures” and Treasury securities reviews as Data Integrity problem found in 2017 on automated trading and money movement surveillance systems.

 

Why Data Integrity Matter?

Now a days Data are becoming more available, a smart business strategy which are using to make decision are obtaining the several times benefits.
According to recent research, a data driven organization is more than 23 times better performer in customer acquisition, nine times more performer to retain their customer and more than 19 times profitable to their competitor.

As the power of data is increasing day by day, so Data Integrity shall be valued properly and its importance can’t be denied at current situation. Presence of any type of error in data can spoil the total organization goal. A data driven organization must protect their database system at any cost to provide better security solution.

Threats involve in Data Integrity

[][]Human error:
It may arise in such case of transferring of data manually from one share drive to another, copying data from one spreadsheet to another and subsequently deleting of row or column of a spreadsheet. Storing data on excel sheet may cause formatting problem during manually data transferring process. Updating of excel sheet from old version to new one may cause formatting problem of subsequent data.

[][]Inappropriate format:
Stored data on Microsoft excel based on cell referencing may not accurate in different format. Failure to determine the same may case Data Integrity problem.

[][]Collection error:
During collecting any type of data, proper precaution shall be taken. Collecting of data on wrong method may cause storing of incomplete data and actual data may not represent the total situation.

[][]Internal security breaches:
If the database system hacked by third part or internal or external competitor may cause serious Data Integrity failure.

 

Why is Data Integrity Important?

Generally, a specific individual or group of people are involved in database system of a organization. Problem arises when multiple people are responsible to operate the database system. Anyone of the team member may not aware about Data Integrity of the organization, then all of the individual shall educate regarding protection of the database system and tech them the importance of data quality, accuracy, completeness etc. & they must learn how to combat when potential data security threat arises.

If all of the team member are aware about the Data Integrity and know its importance then it is very much effect to maintain the database system.

 

A better Data Integrity system can save company effort, time as well as valuable overhead cost. Wrong decision may take place based on inappropriate data. Data driven organization always take critical decision based on available data, if Data Integrity of that organization are compromised by any situation, then inappropriate result may arise and the organization suffer in long run.

Data always help to make important decision additionally it protect your company image. If you are collecting your customer information then protect the collect data which you have collect from your individual customer, failure to protect the customer data in proper database system may leak your customer information to another one cause image problem of the company and also mispresent your customer to other party.

Any type of customer information may be tracked and may be asked or run a campaign over them to collect specific target data. All type of collected information may not be sensitive as SSN [Social Security number]. To protect your valuable customer, you have to take a proper step regarding Data Integrity of your existing system.

 

a company staff always demand to data access to the database to trace any type of data on time manner upon request. He needs to uninterrupted access to the data system. For this reason, Data Integrity is so important for the organization. Data Integrity confirm the traceability & searchability of the data from its mother source.

 

Effective data accuracy and data protection shall be confirmed to increase Data performance and its stability. It is very much crucial to confirm the completeness & integrity of data. Compromised data always carry the wrong value for the organization & is of no use for most companies.

 

Same scenario arises for big data management. It is very much important to secure the big data management system as well as to maintain the total database system. All type data is totally worthless Without integrity & accuracy. Your data can be compromised If you fail to do the same. Under this circumstances, awkward & expensive data audit trails shall be mandatory to find out error & recover the total database system.

 

Most companies have set specific goals for their data & it is now more important than ever. But if integrity is not assured then data is not of much use. If data loss, corrupted or compromised then data can considerably damage any type of business. To maintain it, data security shall be confirmed using proper tools.

Compromised Data is the big challenge to maintain data integrity. There are several ways to compromised the valuable data. Todays almost all of the data are digital and store then in the same than traditional method and its transferred vary rapidly in different places of the globe. So, security shall be considering first & also the collection data is main concert maintain its integrity.

Data can be unaltered if data transferring occur maintaining valid system. Every time Data is moving from one place to another and it is not static, every user of the specific system is using the data and transferring the same in different way.

 

Management of Data Integrity

A group of steps are available where you can maintain & achieve better Data Integrity for your organization.

Collection of Accurate, Complete, and High-Quality Data

Quality of data depends on the collecting process of the projected data; a collection process is crucial and collection depends on the proper collection method. Failure to select proper data collection technic may cause collection of erroneous data. Sourcing is prerequisite to collect data. Ensure the high-quality data source may provide one step forwards to competitor.

Meticulously Check for Errors

To make common error during collection of data is the main problem of manual collection of error but it can be rectified successfully to involve the second one to the same project. Various type of error can be overcome if proper checking process can be initiate by appropriate body. For most critical data double check or triple check can be initiate. Growing continuous attention during data collection may reduce the data error. Sometime a review of the related data may decrease the data error. A color shading on projected excel sheet in the alternative row may help to track the mentioned data.

 

Cybersecurity Threats

Most of the time you can’t realize that a hacker or third party is trying to access your database. Person or individual who are trying to control your data send a short link with attractive or recent hot topics or similar to company email address link. Thousand of ways a hacker can try to damage or control your database system, so a strong security system shall be established to protect Data Integrity of the system.

Data Science Course

Failure to know the technical framework of database system, you can’t protect your data properly. If you are capable to handle the system then you need not to collect data science but if you want to update your existing your practice and eagerly want to update your team capability then you can involve your team in any data science course which are already available online which help your organization as well as development of self-confidence.

Devotion to Data Integrity

To keep subjects’ information safe & giving organization’s stakeholders the highest quality, accurate, complete, most data on which to base decisions need daily commitment for your Data integrity. A proper security system and group of trained individuals can support the organization in this situation to continue the company progress.

 

Data Integrity vs. Data Quality

Data quality is a crucial piece of the Data Integrity puzzle. It enables organizations to meet their data standards and ensure information aligns with their requirements with a variety of processes that measure data age, accuracy, completeness, relevance, and reliability. Data quality goes a step further by implementing processes and rules that govern data entry, storage, and transformation.

 

Data Integrity vs. Data Security vs. Data Quality

Data security involves protecting data from unauthorized access and preventing data from being corrupted or stolen. Data Integrity is typically a benefit of data security but only refers to data accuracy and validity rather than data protection.

Data Integrity & data security are more relevant to each other. Each of them plays a vital role for each other for their individual achievement. Data Integrity only refers to validation and accuracy of data but didn’t involve to protect data. On the other hand, data security confirms the protection against corruption or unauthorized access.

Data security plays a crucial role to maintain data integrity, on the other hand, Data Integrity is the end result of data security. To maintain data integrity, data security is the vital point and this situation may arise when accidental compromise occurs for data integrity.

 

Data Integrity is the essential component for the modern business procedure while making decision based on accuracy and efficiency of database. The main focus of the data security leads to Data Integrity and various type of procedure are applied to achieve the same.

Data quality can be defined that the data stored in database is compliant with the organization’s standards & requirements. It maintains integrity in a database. A set of rules to a specific or whole dataset and stores it in the target database shall be implement to do the same. Data Integrity shall be considered as data accuracy as well as correctness of data.

 

How to Protect Your data?

Validate Input

To ensure data accuracy data entry must be validated & verified input is significant when data is provided by familiar or unfamiliar sources, such as end-users, applications, & malicious users.

Remove Duplicate Data

Sensitive data stored in secure databases cannot be duplicated & it important to ensure that publicly available spreadsheets, emails, documents, & folders. To prevent unauthorized access to business-critical data or personally identifiable information duplicate shall be remove as soon as possible with the help of authorized personnel.

 

Back Up Data

To confirm data security & integrity data backups are crucial. To prevent the valuable data from permanent lost data backup shall be perform on regular manner at the end of everyday work. Organizations that suffer ransomware attacks, Data backups are especially important for them to protect their potential resources.

Access Controls

To maintaining data integrity, appropriate access controls shall be introduced in the organization. Data privileged option shall be implemented for specific user to control the database access procedure. This process will help the user understand their limitation to use the database system as well as to maintain the whole system.

Audit Trail

An audit trail is the standard practice to trace the unfavorable event. Data breach may occur at anytime in a renowned organization. If audit trail facility are available for the organization then it is very much to find out when and how data breached where. If proper information is available then it is easy to trac the source of attack. So audit shall be introduce at your organization for your database management system.

 

Assurance of Data Quality

It is the part of the Data Integrity process. Regular shall be conduct so that data can meet the certain standard. The processes of data accessibility, data cleaning, , data standardization is the main concern of the Data quality assurance. Data cleaning deal with inputting missing data, removing invalid entries, update same on timely manner.

 

Data accessibility deal with availability of the data to the stakeholders in secure and appropriate manner. For encoding and entering data, business shall be maintained and unauthorized data entry or transfer shall be prohibited. All type of company rule shall be implemented increase of transfer access of data to potential sector.

 

Data Corruption vs Data Integrity

Data corruption shall be considered as the serious Data Integrity failure. Based on the current practice, data corruption may be occurred through multiple channels. Most of them a very common problem is human error occur during collection or transferring of data. Malware and physical damage are another potential cause of data corruption.

Most human error often cause in wrong entry of collected data, unauthorized entry of database system, involving newcomer to sensitive practice with our prior training, programming etc.

It can be traced with appropriate data validation checks & restricting access to database system. Extensive & systematic use of backups can support restore databases in case of improper data entries.

Malware is another common cause of data corruption and this is basically occurred from external source which main purpose is to stole the data from potential data server. Cyberattacks are almost always unpredicted and instantly can’t recognized the source on the most of the cases. So here come the data encryption, always try to encrypt the critical and sensitive data and if possible tight security system shall be introduced though cost may be high to do the same.

 

To ensure organizational network security, regular penetration testing shall be done, this will help you to secure the organizational network system. A physical damage is may cause the data lose which mainly cause by accident and disasters. To protect data, data may be store in different physical location will protect from accident and natural disasters.


What is the difference between affect and effect?

FAQ, Pharma Operations

Affect & Effect

These two words are verbs & nouns and their meanings overlap. It is not possible that whose word come first in English language. In general, Affect is used as Verb and effect as a Noun.

Meaning of Affect

[][]Affect means Change in something, to act on.
“The hot weather affected the iceberg.”[The hot weather produced a change in the iceberg.]

[][]To amaze the mind or move the feelings of,”
“Billie Eilish song ‘lovely’ deeply affected her.” [The music changed his moods or thoughts].

[][]You can also change the word Affect with Right word
“The hot weather damage the iceberg.”
“Billie Eilish song ‘lovely’ deeply moved her.”

To express a change or to describe an action, the word “Affect” shall be use.

 

classification of affect

Meaning of Effect

Effect means “result” or “consequence.” & Most commonly used as a noun. Effect can be replace with another noun.

“His high market share value was an effect of ownership change of the company” Another way to say it is, “His high market share value was a result of ownership change of the company”

Remember Difference Between Affect & Effect

[][]Memorize the word RAVEN; you can easily differentiate them_

R = Remember
A = Affect is a
V = Verb
E = Effect is a
N = Noun

There is another way to remember when to use affect and effect:
[][]A is for action (affect); E is for end result (effect).

 

Example

Affect

[][]Almost always used as a verb to mean to influence someone or something.

How does one’s creativity affect success on the project?
These songs will affect the number of people who will come to the outdoor concert.

[][]Affect can be used as a noun in one particular situation.
The old man’s facial expressions had a humorous affect.

Effect

[][]Most often used as a noun. It denotes an event or a thing. Often used when result is being discussed.

What effect did the job of company on his family?
Did his sudden retirement have any effect on his family?

[][]Effect can words like : on, the, any, into, , take, an, or.
The prescribed pill had an effect on the patient’s symptoms.
We have to consider the changes time to take effect.

[][]Effect can be used as a verb in one particular situation.
The new management is responsible to effect negative changes in the office.


What is the difference between Data and Information?

Documentation, Pharma Operations, Viva

Most of the cases we think that “data” and “information” are same but they actually aren’t the same though they are often used interchangeably. There are elusive differences between these two components & their purposes of use. information is organization & interpretation of group of facts where Data is defined as individual facts. To identify and solve problems, you can use the data & information together. To drive a successful business, we can use these two components to accelerate the ultimate mission to reach the goal.

What Is Data?

Collection of individual facts or statistics is defined as data (Data is plural form of ”datum” but the term didn’t use in for daily expression. Data has its various type of form such as figures, text, observations, numbers, images, graphs, or symbols. Individual dates, prices, weights, addresses, ages, temperatures, distances, names, etc. can the example of data.

Data is simply defined as “facts & figures”. Each piece of data is a tiny fact that doesn’t mean abundant of its own. Data can be defined for singular fact or collection of facts. It comes from the Latin word ”datum”, mean “something given”. “datum” is technically correct singular form of data but is hardly used in public language. Its early usage dates back to 1600s. Over time “data” has become plural of “datum”.

Data doesn’t carry any significance or purpose, it’s the raw form of knowledge. To make it meaningful you have to interpret data. Bits & bytes are used to measured data which are units of information in context of computer storage & processing the same.

Data without analyzed, organized, and interpreted may even seem useless & data can be simple. Two types of data are depicted here-
[][]Quantitative data is in numerical form, like volume, weight, cost of an item. Its not descriptive.
[][]Qualitative data is descriptive, like sex, name, or cloth color of a person. It’s not but non-numerical.

 

What Is Information?

It can be defined as act of knowledge gaining process through research, study, communication, or instruction. Information is the totality of group of analyzed and interpreting data. A data is always the individual numbers, figures, or graphs whereas information is considering the perception of those items. In this era, we can mention that most of the sophisticated modern industry always maintain environmental monitoring through recording of Temperature & Relative Humidity, through out the year of the year and achieve it in a suitable position.

Information can be defined as “news or knowledge received or given”. Processed, interpreted & organized facts is information. It comes from the Latin word īnfōrmātiō, mean “formation or conception.”

This type of recoding doesn’t bear any significant meaning but if you organize, analyze the recoded data then you can easily realize the Environmental condition changes in specific season. You can trend the data to sort out the best matching, minimum maximum data etc. which useful to set up or install the best quality BMS [Building Management System] parameter. Without analyzing and organizing the data, it is the just piece of recording doesn’t denote any significant value. A well-organized data can help the others.

In basic terms, it can be concluded that data is unorganized explanation of raw facts from which information can be take out.

 

Significant Differences Between Data vs Information

[][]collection of facts is considered as Data where information puts all of those facts into context.
[][]Data is always raw & unorganized where information is processed and organized.
[][]Data points are individual & most of the time it is unrelated. Information relates these points and show the actual behind it.
[][]Without analyzed and interpretation data is totally meaningless, when it organized then it became meaningful information.
[][]Data is always independent but Information depends on data due to you can’t get any information without processing data.
[][]Numbers, graphs, figures, or statistics is the form of data. Information generally appears as language, words, thoughts, ideas etc.
[][]To base on data, you can’t make any decision but when information available at your hand you can make any decision. So, data are not enough to make any decision, information require to do the same.
[][]Data always defines figures & facts. It comprises of one entry or collection of diverse values. Information defines values & context together, resulting in approximately meaningful. It forms an organized & interconnected structure, from data, to interpret or link the whole.

[][]Example
=>For data examples, we can use Lance, M. Kiely, 4590 Neville Street, Terre Haute, IN 47807. The separator [commas] characterize each distinct fact that may or may not be linked to others.
=>In this example of information, Each fact narrates to other facts to form a concept, known as Lance M. Kiely. Creating this Lance M. Kiely entity allows people to reason, calculate, & do other influences.
Lance M. Kiely
4590 Neville Street
Terre Haute, IN 47807

difference between data and information

Data vs. Information in Computers

If we consider computers, Data can be considered as INPUT on anything that instruct to computer to do or store. The OUTPUT of the computer which exhibit your computer after your instruction to computer.

As per statistics, data defined as raw information but term statistics is often used in place of information. Statistics interpret & summarize data.
In business, data are often raw numbers & information is a collection of separate data points which you use to realize what you’ve restrained.

[][]1.0
Data: typing the words “Dog videos” in your computer web search engine (INPUT).
Information: The list of search results which includes a variability of dog videos on the resulted browser page (OUTPUT).

[][]2.0
Data: 9994565566
Information: phone number (555)456-5566 of a person.

[][]3.0
Data: 46.07 & 789
Information: Molar mass & Density of Ethanol in g/mol & kg/m³

[][]4.0
Data: 70%
Information: Isopropyl alcohol in percentage

[][]5.0
Data: -16
Information: Freezing points of Vodka in Fahrenheit

 

Difference Between Data and Information

ParametersDataInformation
ContentUnrefined raw factors.Refined in a meaningful way.
CharacteristicData is considered property of a specific organization & is not offered for sale in the public.Information is offered for sale to public.
Decision MakingRaw data is insufficient to make any decision.Information is enough to make any decision.
DependencyData depends upon the sources for collecting method.Information always depends upon data.
Design of Data Data is never designed for specific need of user.Information is always explicit to requirements & expectations because all extraneous facts & figures are detached, during transformation process.
Dependency levelData never depends on Information.Information constantly depended on Data.
DescriptionHelps to develop ideas or conclusions based on Qualitative or Quantitative Variables.It is group of data which carries news and meaning.
EtymologyData has comes from Latin word, datum, means “To give something.” The word “data” become plural of datum.It comes from the Latin word īnfōrmātiō, mean “formation or conception.”
Example1.0 During word Tour Ticket sales on a specific Band.1.0 Sales report generate by region & venue gives information which venue perform best.
Example2.0 An example of data is a student’s Eye Color.2.0 The average Eye Color of a class is the information derived from the given data.
FormatData found in the form of letters, numbers, or a set of characters.Ideas and inferences
FeatureData is a single unit & raw. It doesn’t have any meaning alone.Information is artefact & group of data which jointly carry a logical meaning.
InterrelationCollected Information.Processed Information.
Knowledge levelLow-level of knowledge.Second level of knowledge.
MeaningData does not have any definite persistence.It conveys meaning that has been allocated by interpreting data.
Measuring unitMeasured in bits & bytes.Measured in different meaningful unit like time, quantity, etc.
Meaning of baseData is based on records & explanations and, which are deposited in computers or remembered by a individual.Information is considered more consistent than data. It helps investigator to conduct a appropriate analysis.
Support for Decision makingData can’t be used for decision makingIt is extensively used for decision making.
SignificanceData collected by the researcher, may or may not be useful in different situation.Information is useful & appreciated as it is readily accessible to the researcher for use.

 

List of Examples of Data vs Information

differences between data and information, how these examples turn data into insights:

[][]An individual customer’s bill amount is data at a specific restaurant but after a certain period of time or after one day collection when the restaurant Manager or owner collect all the customer bill of that day or time, it can produce valuable information of the restaurant as it can produce which item of the restaurant is hot cake or what item is running well and what are not. After that the restaurant, can realize how they can maintain the inventory of a specific item and how to continue their service as well as to minimize the overhead, wadges, supplies etc.

[][]An individual customer service survey of a restaurant is a data but after a period of time when compile the all the survey, then it can produce valuable data regarding area of improvement of the restaurant such as customer service, price, cleaning, mannerism, hospitality, space, location, viewpoint etc.

[][]A single social media like on a media post is a data but when multiple social media item like comments, share, statistics etc. are compiled then the specific company can focus on the specific social media where they are performing best and where they are in worst condition. Comments from a social post of multiple social media is very useful to do the same. It helps the company to set their goal based on the comments collect from customer and it help to find out multiple idea from multiple customers.

[][]On their own, inventory levels are data. However, when companies analyze and interpret that data over a range of time, they can pinpoint supply chain issues and enhance the efficiency of their systems.

[][]Inventory management of the company for the different item is the data but when it collects for certain period of time it can be valuable information regarding the inventory item which can help the supply chain management system to run their activity appropriately.

[][]A Price of a specific item is a valuable data but when processing the data from multiple company can produce valuable information regarding market gap, advantage of the competitor, profit margin, bonus, discount, policy etc. for the specific item.

[][]Taste of Azithromycin Suspension is a data but when you collect different taste from different company product you can produce valuable information regarding taste that which taste is more acceptable to the end user i.e., mango/orange/strawberry/pineapple etc. from this activity you can collect valuable information and implement the same for your company product.

[][]Temperature readings all over the world for the past 10 years can be consider as data. When this data is organized, analyzed to find out global temperature condition is raising over the period of time, then this data changed to information.

[][]Number of visitors to a specific website by country of the word is an example of data. Finding out that the traffic source from Canada is decreasing while that from Austria is increasing is meaningful information.

[][]Often data essential to back up a claim or supposition consequent or inferred from it. Such as before a drug is approved by FDA, manufacturer must conduct clinical trials & must have submit lot of data to reveal that the drug is safe.

 

“Misleading” Data

[][]Due to the processing of data, interpreted & analyzed, this is very possible that it can be interpreted incorrectly. When this leads to specious conclusions, it can be said that data are misleading. Often this is the consequence of imperfect data or a lack of framework. Such as your investment in a mutual fund may be up by 7% & you may accomplish that fund managers did a great job. Nevertheless, this could be misleading if major stock market indices are up by 10%. In this case, the fund has floundered the market pointedly.

[][]In the year of 2007, Famous toothpaste company Colgate ran an ad campaign & stating that 80% of the dentists recommend Colgate Toothpaste for safe dental health. From this promotion, many consumers assumed that Colgate was the best choice for their safe dental health for daily use. But in practical, this wasn’t inevitably true. In reality, this is the well-known example of misleading data & information.

[][]Anchor Tucker Carlson presented a graph saying, number of Americans recognizing as Christians had distorted over last decade during one of Fox News’s broadcasts. Over the image above, a graph showing in 2009, Christian Americans is 77%, number decreased to 65% in the year of 2019. Now, if issue here is not noticeable enough, here the Y-axis in that chart starts from 58% & ends at 78%, making the 12% drop from 2009 to 2019 look way more substantial than it really is.
Sample size is the vital point to make any key decision for the organization. Making any decision data collected from 100 sample is more accurate data collect from 10,000 sample. Data collect from 100 sample is misleading compare to 10,000. A key decision shall be make from vast amount of sample.

[][]Federal Trade Commission (FTC) filed a lawsuit against car company Volkswagen , which claimed that car company had betrayed customers with advertising campaign it used to promote its allegedly “Clean Diesel” vehicles, according to a press release.

In the year of 2015, it was uncovered that Volkswagen had been cheating emissions tests for its diesel cars in US in the past 7 years. The Federal Trade Commission, alleged that “Volkswagen cheated consumers by selling or leasing more than 550,000 diesel cars based on the false claims that cars were low-emission & environmentally friendly.” For their false claim, the company was remarkably fine up to $61 billion for the violation of Clean Air Act.

[][]Red Bull, Energy drinks company was sued in 2014 their slogan “Red Bull gives you wings.” The company settled case by agreeing to pay out maximum of $13 million — including giving $10 to every US consumer who had bought their drink since 2002.

They claim that the caffeinated drink could improve consumer’s concentration & reaction speed; the tagline company use for last two decade went alongside marketing claims. One of the regular customers of Red Bull drink claim that that he had not developed “wings,” or shown any signs of enhanced intellectual or physical capabilities.

[][]In 2010, Kellogg’s widespread Rice Krispies cereal had a crisis when it was defendant of misleading consumers about product’s immunity-boosting properties. The Federal Trade Commission [FTC] ordered Kellogg to close all advertising which claimed, cereal enhanced a child’s immunity with “25 percent Daily Value of Antioxidants and Nutrients -Vitamins A, B, C and E,” affirming the claims were “dubious.”

[][]New Balance, the famous show making company [Owner, Jim Davis, own almost 95% total share of this company] was defendant of false advertising in 2011 over a sneaker range which claimed that it could help wearers to burn calories but it was subsequently found that there were no health assistances from wearing this sneaker range. From New Balance, they explain that using hidden board technology & it was advertised as calorie burners which activated the quads, glutes, hamstrings & calves. New Balance agreed to pay a settlement of $2.3 million on August 20, 2012.

 

How Businesses Can Leverage Data & Information

Is it come to the point to distinction between data vs information really matter for businesses? If any company that company collect accurate data then interpreting it and generate information and implement the same on right time on right place can realize the actual benefit for the company.
For example, a company might gather data about the performance of their ads or content. Running a successful add or content to the various platform can produce valuable data. From the data they can produce right information regarding product design, brochure generation, promotional activity, product awareness, customer demand and customer buying capacity.

This can also help to develop target customer, future offering, promotion, branding and developing multiple products for the company.
Right data can lead the organization to the right goal but to maintain the right set of data is very difficult. There are several blockades to create a data dependent better smart organizational culture. Different team of an organization may collect & maintain disparate sets of information. Hence a central database system is crucially need for the organization. Without a central database system, none one can earn the actual benefit and interpretation of data may fail. Data need to supervise by someone, without proper supervision data may not maintain its proper quality and generate poor data mislead the organization.

Any business depends on expressive data patterns to get information. There are dissimilarities between data and information. Business relies on meaningful data patterns to get information, in this article let’s explore the differences and similarities between data and information. Misinterpretation the difference between “data” & “information” sets up the stage for slip-ups. Like the six blind men in an Indian legend, trying to define an elephant, end up puzzling discrete facts, or data, as information or meaning.

In six blind men’s dilemma, individually complicates data (trunk or legs) for information (an elephant is like giant cow or an elephant is like a giant snake). Likewise, anyone can collect customer data & think they have the full customer information when they are actually not. Data & Information have specific implementation. To correctly recognize & use either one, you need to understand the change between data & information is.

To create an effective data driven organization, then you need to maintain the data source which must available across the group of qualified people who are technically sound to generate information from processed data maintaining appropriate protocol to assure the proper data quality.
Data is very critical to generate information and both these two items is crucial to make any decision for the organization.

 

DIKW [Data Information Knowledge Wisdom] Model

DIKW is the model used for discussion of data, information, knowledge, wisdom & their interrelationships. It denote functional or structural relationships between data, information, knowledge & wisdom.

DIKW-Data Information Knowledge Wisdom Model

Are data and information the same thing?

Data is based on observation & records which frequently store in computers or simply memorize it by individual. On the other hand, information denotes to be more consistent than data. In other words, it is a proper analysis which researchers or investigators conduct for converting data into information.

Data and information may be the same thing, From a content & format perspective. For example, you can point same values in two diverse columns on a spreadsheet. Nevertheless, data & information contents & formats do not have to match. In any case, you use data & information very in a different way.
If you want to sort out the value “New York, United States” You will filter data named “New York” under city and “United States” under country.

On the same spreadsheet, If you want to know if the Lance M. Kiely records mean the identical person. Then look at the information in both rows & see, across the columns:
Lance M. Kiely
4590 Neville Street
Terre Haute, IN 47807
You determine both Lance M. Kiely, living in New York, United States, mean the same customer thing from the information provided.

 

How do data and information differ?

Though Data & information may have the same values but from the creation & business usage they may differ. Data generally includes entries whereas Information contains context. Information comprise data with different contents & formats & be the same thing.

As per data perspective point, “United States,” “UNITED STATES,” and “U.S.A.” represent entirely different facts based on number of characters & formatting varies. Therefore, Lance M. Kiely, who lives in U.S.A., is not same customer as Lance M. Kiely, who lives in United States.

If we consider information viewing platform, the “United States,” “UNITED STATES,” & “U.S.A.” represent the same thing for geographical reason because someone with understanding of geography can point to the “United States” or the “U.S.A.” on a American Map.

The correct data and accompanying context make the United States and the U.S.A. contain meaning about a shared concept of that region, like culture, sports, and government. From the shared concept of that region, like culture, sports, and government make the data more accurate. Lance M. Kiely, who lives in U.S.A., with Lance M. Kiely lives in the United States, and consider creating the same object. Comparing with the other people lives in United States using additional data points like cultural activities in U.K.

 

Frequently Asked Questions

What is data? Explain with example.

Raw, unorganized, unprocessed facts are known as Data. All of the facts consider as data until it processed, organized such as all information writing on the paper is data until its processed & organized in suitable manner.

What is information?

Processed, organized data which is advantageous in providing useful facts is known as Information. For Ex. It can be concluded that if data are processed and organized in right way generate valuable piece of information.

What is valid information?

A reliable fact is considered as Valid information. Checked & verified information that is ready for use in a specific purpose.

 

What is the classification of Data?

Classification of Data

Data classification is a critical element of any information security & compliance program, especially if any organization stores big volumes of data. To understand the data security strategy, classification of data plays an important role providing information that where the sensitive data shall be stored. It provides valuable information regarding unused data & elimination of the same type reduce the maintenance cost for the organization.

Types of Data Classification

[][]Content-based classification inspects & interprets files to classify sensitive information.
[][]Context-based classification looks at location, application, creator tags & other variables as secondary indicators of subtle information.
[][]User-based classification depends on manual selection of each document by an individual.

Basic Classification Scheme

The modest scheme is three-level classification:

[][]Public data
Data that can be freely revealed to the public. Examples include any company contact information & any browser cookie policy.

[][]Internal data
Data that has low security level but is not for public expose, like marketing research for a product.

[][]Restricted data
Highly subtle internal data. Expose to public platform create negative impact on operations and put the company at financial or legal risk. Restricted data entails the highest level of security protection at any cost.

Classification of Data

Government Classification Scheme

Government agencies use three levels of sensitivity as top secret, secret and public but based on situation can be classified into five types

[][]Top secret-Cryptologic & communications intelligence
[][]Secret-Selected military plans
[][]Confidential-Data signifying the strength of ground forces
[][]Classified-Data labelled “For Official Use Only”
[][]Unclassified-Data that may be publicly released after authorization of respective body.

Commercial Classification

Typically, organizations that store & process commercial data use 4 levels to classify data: 3 private levels and one public level.

[][]Sensitive- Intellectual property, Secrete Formulation, PHI
[][]Confidential-Vendor contracts, employee reviews, Contract, Special Allowance
[][]Private-Customer names or images, Sensitive Video promotion
[][]Proprietary-Organizational processes, Quality System
[][]Public-Information that may be disclosed to anyone

What is the meaning of the two types of data?

The two types of data are qualitative & quantitative. Qualitative data is non-numerical data like eye color, skin texture, Hair color, Shoe color, Clothing color and more. On the other hand, quantitative data is in the form of numbers like the weight of books, number of apples, number bird and more.


Forced Degradation Study or Stress Testing Procedure

GMP, Pharma Operations, Product Development, R&D

What is Degradation?

Forced Degradation Study before proceeding on it ,first of all  ”Degradation’‘ to be discuss first, This is the act of lowering to some degree or someone to a less respected state or position. A CEO of a multinational company resigning from his office is a degradation. It’s also a downcast state.

The word degradation is very much related to the degrade, which comes from Latin word Degradare. The word “Degradare” comes from “de”-, meaning “down,” & gradus, meaning “Step.” So, it is very much clear that the degradation as a step down, or feeling as though you’re a step below.

Degradation products

It is the unwanted chemicals which can generate during manufacturing, transportation & storage of pharmaceutical drug products & can affect efficacy of pharmaceutical drug products. A small amounts of pharmaceutical degradation products can affect crucial safety because of the potential to cause adverse effects in end user.

Subsequently, it is crucial to focus on formulation, storage conditions, transportation, distribution channel and packaging to prevent the formation of degradation products which can negatively affect quality, safety and efficacy of the pharmaceutical drug products.

To find out the main cause of degradation of the pharmaceutical product is the crucial point, various software and data tracking system can help in this matter. This system can provide useful information during transportation and storage of pharmaceutical products, the route shall be determined to estimate the main cause.

Presence of a genotoxic degradation product shall tend to more assessment if it identified on due time. The chemical structure of the substance shall be determined to identify the toxic alerting structures associated toxic products, products [Compound] without active structure is marked as ordinary impurities.

 

A risk/benefit analysis shall be done to evaluate the levels of degradation products and most of the nest pharmaceutical call its mandatory. During the development of any type of product either critical or non-critical drug, critical variable of the drug products shall be follow-up which will control the degree of degradation of impurities.

 

Now a days the impurity profile has been considered as the key point of the product quality. It is the essential part of the quality parameter for the various competent regulatory authority. The toxicological evaluation and impurity profile become the key point of the degradation products to confirm its certain level of efficacy. Various types of test method have been identified to investigate the degradation products, all of them assay method consider the best to all and it’s highlighted to prove its effectivity.

 

The purity, safety and efficacy of the product depend on the stability of the product and it is the critical parameter of all the parameter. A product must be stable at a certain period of time to prove its efficacy, potency and safety.

A less stable or changes of stability can create serious toxicological effect by forming toxic degradation products and deliver less active or less effective or less potent drugs to the end user. Under these circumstances, this is very crucial to known the actual behavior of the drug products in various surrounding or environmental conditions.

 

Dissolution test are considering the most quality control tool for the commercial batch to batch product to monitor its consistency over a certain period of time. It also provides significant information during post approval changes of the certain product as changes made in formulation, manufacturing process and different scale up procedure.

 

To confirm the quality, safety and efficacy, the chemical stability is very important for a pharmaceutical product. This is very important to know the environmental influences of a certain developed product in specific condition such as Heat [Temperature], Humidity [Relative Humidity] & Light [Photostability] and this also regulatory [ICH & FDA] requirements.

Data acquire from stability study denote the shelf life and storage condition of the specific tested drugs, the container closure system [Protective packaging system] also require to satisfy the regulatory expectation.

Different types of method/instruments are available to determine the degradant compounds which are readily present during the forced degradation study period. HPLC-UV [HPLC with UV detector] and HPLC-PDA [ HPLC with Photodiode Array Detector] is the renowned method and extensively used in pharmaceutical company at the time of degradation study and validation and development of various type of method.

 

LC-MS [HPLC with Mass Detector], GC-MS [Gas Chromatography with Mass Detector] and NMR [Nuclear Magnetic Resonance] spectroscopy are significant methods to detect the degradants’ structure.

 

What is Forced Degradation Study?

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Exposure of specific sample at the unfavorable/stress condition of Heat [Temperature], Humidity [Relative Humidity], Light [Photostability], Oxidation and Acidic/Basic condition; observe/detect the changes of those sample or measure the rate of changes/degradation, mainly in Efficacy, Safety and Potency parameter of drug substance. Forced degradation study is the key point during the development of a specific drug. Determination of the type changes denote the modification or changes of the development process.

Now a days Force Degradation Study become the prerequisite to submit the NDA to regulatory authority and it became the quality parameter for the new product. During the regulatory submission, the Force Degradation Study data shall be submitted to get satisfactory result from FDA. Some of the best application of Force Degradation Study is depicted here-

 

[][]Developing and validating stability study indicating method as per regulatory guidelines [ICH Guidelines].
[][]To set up specification of degradants or impurities and to identify structure and toxicity.
[][]To set propose shelf life the specific product without performing Realtime stability data.
[][]To avoid incompatibility of drug products and excipients.
[][]Determination of the process related degradation products or impurities.
[][]Provide supporting data to lab investigations/OOS [out-of-specification] analysis.
[][]To provide regulatory compliance documents during submitting of ANDA/NDA to FDA.

 

It is a useful tool to predict the stability of any Active Pharmaceutical Ingredient (API) or formulation product. It helps to know about the impurities developed during the storage of drug products in various environmental conditions.

Forced degradation is performed by applying artificial methods and a drug is degraded forcefully. It is also known as stress testing. To assume the stability condition of API [Active Pharmaceutical Ingredient] and formulated product Forced degradation study plays an important role. It also helps to identify the impurities generated during storage of drug products in different environment stage.

process flow diagram of forced degradation study

Why Forced degradation study carried out?

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Its play a vital role to develop and validating of stability study signifying method. At the time of developing phase of a new drug product, force degradation study performs to determine the degradation pathways of drug products & drug substances. It is very important to determine impurities of the degradant product, Forced degradation study quantify the number of impurities present on the specific drug substance. It helps to determine the molecular chemistry. Forced degradation study assure the more stable product. Help to develop the degradation profile. Stability related problem can be solved through Forced degradation study. Forced degradation study also highlight the following point of view-

[][]Evaluation of drug products & drug substance in solution.
[][]Determination of structural transformation of drug product & drug substance.
[][]Determination of the concentration of the degradation products.
[][]To identify the non-relevant impurities in the existence of the desired product.
[][]Separation of the product related degradants derived from intact placebo & excipients.
[][]Describe the degradation pathways of the specific drug substance.
[][]To categorize the degradation products which generate spontaneously during storage & use of products.
[][]To generate product related variants & develop analytical methods Forced degradation studies are performed during accelerated and long-term studies.

 

During the Forced degradation study, the degradation products may or may not be generate but it will show the degradation pathway of the product. This process will help them develop the analytical method of the relevant product and stability indicating analytical procedure. If any degradation occurs during performing of Forced degradation study, the degradation product shall be evaluated if it significant or minute, to robust the developed formulation.

 

How Forced degradation Study Conducted?

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This study of the drug products or substances is generally conducted on the solid and solution stages at the high temperature exceeding accelerated stability condition which is above 40°C. Various condition are consider here as oxidation, hydrolysis, photolysis, polymerization and thermolysis. In Solution hydrolysis condition are investigated in broader pH range and in solid stage high relative humidity taken under consideration.

Control exposure of molecular oxygen or addition of oxidizing agents such as peroxides is use during investigating Oxidation in solution.
Applying heat in solid state effects of thermolysis are usually assessed. Light with wavelengths in the 300-800 nm range are use in Photolysis investigation in solution or the solid state. In an oxygen atmosphere photooxidation can be investigated with light under oxygen atmosphere. Measuring the rate of degradation, Drug substance polymerization can be investigated at the various drug substance concentrations in solution.

List of Analytical Tools to perform Separation & Identification of degradant

A. Sophisticated Techniques

[][]Capillary Electrophoresis- Mass Spectrometry [CE-MS].
[][]Gas chromatography–mass spectrometry [GC-MS].
[][]Liquid chromatography–mass spectrometry [LC-MS].
[][]Liquid Chromatography- Nuclear magnetic Resonance [LC-NMR].
[][]Liquid chromatography-Fourier Transfer Infrared [LC-FTIR].

B. Conservative Techniques:

[][]Thin layer chromatography [TLC].
[][]Solid phase extraction [SPE].
[][]Accelerated solvent extraction [ASE].
[][]Low-pressure LC [LPLC].
[][]Supercritical fluid extraction [SFE].
[][]Mass Spectrometry [MS].
[][]Nuclear Magnetic Resonance [NMR].
[][]High Performance Liquid Chromatography [HPLC].

 

Extend of degradation

For validation of a chromatographic purity assay, degradation level of 10-15% is adequate to perform the activities. Forced degradation studies are not considered part of the formal stability program though forced degradation studies are a regulatory requirement & scientific necessity during development of a specific product. For conducting studies at the various phases of development the guidance gives various recommendations.

Selection of Forced Degradation Condition

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In common industry practice, forced degradation is generally performed in different stress conditions, i.e., thermal, acid, alkali, peroxide, and UV, along with a control sample which also comply with ICH guidelines. There no specific range or rate of degradation in current industry practice but 5 to 30 percent degradation shall be taken into consideration and this can be achievable on any one of the above stress conditions.

 

Through stress testing, the aim of the degradation to be achieved to implement the control room temperature for the stability conditions. The conditions or concentrations of reagent shall be optimized if higher or lower degradations are observed.

During the degradation study Mass balance shall be demonstrated & it shall be around 100%, taking into attention margins of analytical errors. During mass balance evaluations, all the degradants /impurities must be calculated.

Any batch which is not be the part of regulatory submission can be used for the forced degradation study. For multiple strengths of the same placebos and different amounts, the highest ratio of placebo vs. API [Active pharmaceutical ingredient] shall be use.

 

Forced degradation of all the strengths shall demonstrate if placebos are different. Placebo & API [Active Pharmaceutical Ingredient] must be demonstrated to identify actual degradation pathways during the drug product force degradation study. All the placebos shall be considered for force degradation study if placebos are different for different strengths of drug product.

Various degradation conditions are depicted on the following table which is accepted by the regulatory authority [FDA] at the time of DMF/ANDA/NDA submission-

Degradation TypeReagent ConcentrationConditions to be appliedTimeRemarks
Acid5N HCL80deg.C1 HourConcentration, condition and time can change to optimize degradation
Alkali5N NaOH80deg.C1 HourDo
Peroxide10% H2O280deg.C1 HourDo
Heat/Thermal80deg.C80deg.C1 HourDo
UVExpose under UV light at 254nm wavelengthAmbient Temperature24 HoursTime can change to optimize degradation
ControlN/AN/AN/AN/A

 

Force Degradation shall be performed in solid or solution form though it is recommended that Force Degradation shall be executed in solution form using the mobile phase/diluent to get a homogeneous effect with better result. Force Degradation studies shall be started with harsh conditions (i.e., high temperature with high concentration of reagent) to shorten time of study.

Milder conditions shall be applied by reducing concentration of reagent with lowering temperature, etc. when degradation found 30% or above. Based on the initial degradation outcome, Degradation conditions can be optimized to achieve a target range.

To extend shelf life of chromatographic column, pH shall be adjusted about 7.0 for acid & alkali degradation. Different reagents & conditions shall be applied, e.g., Zn, H2SO4, etc. If degradation did not find in any of above conditions. A few numbers of molecule designated rock stable molecules as these molecules didn’t degrade any of the above stress condition. During a stability study This kind of molecule will not engender any additional impurities/degradant peaks.

 

If drug substance or product shows stability for two years at 30 ±2⁰C & 65 ±5% RH & Six months at 40 ±2⁰C & 75 ±5%RH, then the drug substance or product declared stable.
Concentration of the drug that is being tested for the degradation is a great point. For the degradation study 1 mg/ml of drug concentration is recommended though some degradation studies are done at concentration of drug in the final product. Main cause for this type of study is that precise amount of the degradation can be found in final product & their impact can be scrutinized.

types of forced degradation studies

Factors Affecting Forced Degradation Studies

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Hydrolytic Degradation:

The reaction of chemical with water at different pH values occur in Hydrolysis degradation. In this degradation drug react with water in acidic & basic conditions. According to the stability of the drug substance concentration of the acid or base is selected where pH is 0.1 to 1.0 M HCl [Hydrochloric Acid] or H2SO4[Sulfuric Acid].

HCl & H2SO4 is used to maintain acidic conditions and 0.1 to 1.0M NaOH [Sodium hydroxide] or KOH [Potassium Hydroxide] used to generate basic conditions. Some materials are not readily dissolve/soluble in water freely; in that case other solvent are use to dissolve the water insoluble materials. Solvent shall be selected carefully so that it can’t degrade the selected drug substance.

Descriptive termPart of the solvent require per part of solute
Very solubleLess than 1
Free SolubleFrom 1 to 10
SolubleFrom 10 to 30
Sparingly solubleFrom 30 to 100
Slightly solubleFrom 100 to 1000
Very Slightly solubleFrom 1000 to 10,000
Practically insoluble10,000 and over

Reference: British Pharmacopoeia [BP]

 

Generally Chemical degradation shall be conduct in room temperature but if no sign of Chemical degradation occur at room temperature then room temperature shall be increase up to 50-60 ⁰C. A seven days timeframe shall be selected to perform the study. To prevent further degradation, Chemical degradation should be terminated using acid, base or buffer solution. Chemical analysis shall be done as soon as possible after completion of the test.

Oxidation Degradation:

in the forced degradation study, H2O2 (Hydrogen peroxide) is a widely used oxidizing agent. Hydrogen peroxide at 0.1% to3.0% solution is used at room temperature for 7 days is the suitable range to perform the activities. When more then20% degradation occur for a certain product, it can be considered abnormal cases.

Photolytic Degradation:

To determine the effect of light on the product during storage in the market Photostability testing of any drug take into consideration. light conditions shall be described during photostability. light source shall be cool white fluorescent lamp & wavelength of light shall be 200-800 nm (UV+ visible) which is also comply ICH guideline. The and the light intensity shall be not less than 200 watt-hours per sq meter and exposure time shall be not less than 1.2 million lux hours. To monitor the condition, a calibrated lux meter shall be use in place.

Result of forced degradation studies

[][]Forced degradation studies help to determine_
[][]Likely/Probable degradants
[][]Degradation paths
[][]Inherent stability of the drug molecule
[][]Validated stability indicating analytical method

forced degradation studies condition

When forced degradation studies to be performed?

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This is the best practice to perform forced degradation studies at the time of development of new drug substance and new drug product. FDA prefer to perform it at phase III of the regulatory submission which is the best time to do the same. To establish the regular stability study, forced degradation studies can be prerequisite. This study can be done in different pH solution in the presence of light & Oxygen with high temperature & Humidity Level.

Generally, degradation study performs on single batch. There are two types of timeframes are use to perform stability study which Long Term [12 Months] & Short Term [6 Months]. 6 Months are performed at accelerated condition. Moreover, Intermediate Stability Study performed in a condition lesser than accelerated condition.

Force degradation studies are performed at pre-clinical phase or phase I of clinical trial so that sufficient time provides to identifying structure elucidation, degradation products. If forced degradation studies are performed properly, manufacturing process of the new product can be developed properly and stability-indicating analytical procedures can be select more effectively.

 

What is the regulatory obligation regarding Force Degradation Studies?

Following ICH [International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use] Guidelines has been depicted regarding forced degradation studies but it covers only marketing applications for new products but not for during clinical development.

[][]ICH Q1A: Stability Testing of New Drug Substances and Products.
[][]ICH Q1B: Photo stability Testing of New Drug Substances and Products.
[][]ICH Q2B: Validation of Analytical Procedures: Methodology.

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What actually says this guideline?

[][]ICH Q1A (Stress testing): Stability Testing of New Drug Substances and Products.

It implies for the performing of forced degradation studies for drug substances and drug products. The recommended condition is that the result shall be observe temperature above accelerated condition [Temperature>500C) and Humidity [75% relative humidity] including oxidation and photolysis. pH range may be wide for the testing of solution or suspension.

[][]ICH Q1B: Photo stability Testing of New Drug Substances and Products.

It implies the photo stability of drug substances and drug products. Section II and Section III describe the forced degradation conditions condition for drug substance and drug product. Exposure levels are not defined in Forced degradation studies. Photo stability testing can be performed both in Solid or in solution/suspension. Stability indicating method is developed based on this sample result. Some non-experiential degradation products may be formed during stability studies which may not be taken under consideration.

[][]ICH Q2B: Validation of Analytical Procedures: Methodology.

Provide guideline regarding analytical meth validation. Gives guidance to validate the analytical methodology. To demonstrate specificity, in section B1.2.2 (impurities not available) there is a recommendation to utilize samples from the forced degradation studies.

Verdict

to develop degradation pathways, Forced degradation studies are the prominent way & Forced degradation studies are the prominent way to develop degradation pathways and to detect degradation products of API [Active pharmaceutical Ingredients], further it simplifies elucidation of degradants structure. Forced degradation studies also simplify the chemical & physical stability analysis of drug substances & drug products. To develop manufacturing conditions, storage conditions & determine expiry date of a new drug formulation Forced degradation studies is considered as key studies.


Comparative Dissolution Study procedure

Pharma Operations, Protocol, Quality Assurance, Quality Control

Comparative Dissolution, General Overview

[][]Comparative Dissolution, Oral dosage form like Table & Capsule are more popular than IV/IM(Intravenous/Intramuscular) Injection formulation. From the very beginning, people are most familiar with oral solid dosage form (Tablet, Capsule, Powder etc.) and becoming more popular till today as no special technique or device is not require to administer these products and associated pain is not involved here.

[][]In the period of time its are considered as the most effective and efficient method to treat the patient. This orally taken drugs are dissolved in GI (Gastro Intestinal) fluid and then bioavailable at the systemic circulation as it absorbed here. To measure the bioavailability of a certain drugs (in vivo Analysis, vivo is Latin for “within the living, test perform in living organism) is not accurately possible due to its complex nature.

[][]For this reason, in vitro (vitro is Latin for “within the glass, test perform outside the living organism) methods are followed to measure the dissolution rate of a certain drugs. This method is officially recognized by certain regulatory authority and it(in vitro study) considered most convenient way to develop new formulation of oral solid dosage form.

Comparative Dissolution Consideration

[][]Dissolution method is the best option for the lower strength drug where different strength is proportionally formulated to acquire the biowaiver of certain formulated drug. For a certain product which higher strength bioequivalence study has been carried out and found proportional to the concentration then biowaiver is conceivable to the lower strength.

Dissolution test are considering the most quality control tool for the commercial batch to batch product to monitor its consistency over a certain period of time. It also provides significant information during post approval changes of the certain product as changes made in formulation, manufacturing process and different scale up procedure.

 

[][]The most physiological factor is considered as the dissolution and solubility of the API and its permeability through the membrane of the GI[Gastro Intestinal] tract. As this measurement is so prone to error due to its complex nature then in vitro study consider the most convenient and reliable procedure to achieve the required target. During development of a certain solid dosage form, dissolution is considered as the best option to determine its quality parameter which have the great impact on the bioavailability of the formulated product.

Comparative Dissolution, Waiver of in vivo bioavailability

[][]BCS system applied in this case so that waiver for in vivo analysis can be assured. BCS [Biopharmaceutical Classification System] is a system which measure the permeability and solubility of drugs in a certain prescribed condition.

[][]The actual aim of BCS is to aid the post approval changes and arranging approval activities based on in vitro data studies.

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This system has been optimized based on the oral solid dosage unit as most of the market products are available at oral dosage form [More than 50% total market share, US$23.4 Bn in 2021, US$24.7 Bn in 2022 as estimated, growth rate 5.9%).

 

[][]Waivers[ means giving permission to skip in vivo bioequivalence study] is actually reserved for those products that meet the specific requirements of solubility & permeability & most of the cases rapid dissolve in body fluid.

[][]Using the BCS, appropriate formulation study shall be developed such as Type II drugs designed as Permeable but insoluble, this class is not the actual right candidate for development of a new moiety.

[][]So, solubility shall be developed to acquire the right dissolution profile. Based on the solubility and permeability BCS has classified the four categories of the product as depicted below

BCS

Dosage form challenge

[][]Comparison has been drawn from old drug to new drug formulation, where older drugs compare to the current products are more prone to solubilities. Class II compound has been remarkably increased as 30% to 60% where class I compound has down to 40% to 20% where low solubility has the main cause to encounter the issue.

 A oral solid dosage form is the preferred option but all time this can’t possible the suspension or solution is continued to prove its existence  

[][]Generally a highly soluble active substance and rapidly dissolve dosage form provide better bioavailability and in this case biowaiver can be waived for bioequivalence studies base on its dissolution profile.

[][]If a active substance found low solubility but high permeability then the rate limiting steps of absorption may be consider as dissolution. Most of the cases dissolution profile control the more than one of excipients or special design matrix compounds. So Test condition may be consider as various time frame (10, 15, 20,30, 45 & 6 minutes).

[][]Drugs that are poor soluble in water then various time frame are considered and accepted timeframe is set for dissolution profile. Here USP Type 4 apparatus to be used to develop such type dissolution profile. Most of the time, monograph for combination product is not available at BP or USP the individual monograph shall be used to set the dissolution profile.

Selection of Dissolution Media

Selection of the dissolution media is the vital point to achieve the goal. pH of the media as the key role as all of the dosage form goes to GI[Gastro Intestinal] tract so pH shall be simulate with the GI Tract environment. pH shall be 1.2 to 6.8 which is the physiologic pH range of the body.

ZonepH
[A]Pre-prandial
Stomach
1.8(1~3)
Duodenum6.0(4~7)
Upper Jejunum 6.5(5.5~7)
Lower Jejunum 6.8(6~7.2)
Upper Ileum7.2(6.5~7.5)
Lower Ileum7.5(7~8)
Proximal Colon(5.5 ~6.5)
[B]Post-prandial
Stomach
4.0(3~6)
Duodenum5.0(4~7)
Upper Jejunum 5.5(5.5~7)
Lower Jejunum 6.5(6~7.2)
Upper Ileum7.2(6.5~7.5)
Lower Ileum7.5(7~8)
Proximal Colon(5.5 ~6.5)

Dissolution Statistics

Different cases obtaining after multipoint dissolution which is calculative as follows:
[][]If Test Product and Reference Product both shows dissolution rate more than 85% within first 15 minutes then no calculation is required, they are considered as similar. If it didn’t achieved then seek for next step.
[][]Seek for f2 value[ f2, similarity factor] if f2>50% then it consider similar then in vivo study is not required.
[][]Difference Factor [f1] is the percentage (%) difference between the two curve at the each time period and also measure the relative error between two curve.

How it works

To determine the difference and similarity factor(f2) following pont shall be noted:
[][]Use the Two different products for study, from each product collect 12 unit [12 unit from Test Product & 12 Unit from Reference Product].

[][]Three time point shall be considered[Exclude Point Zero], only one measurement after 85% shall be measured.
[][]Produced curve shall be similar, f2 values shall be close to 100. Most of the time f2 value more than 50 denote similarity of the two curves as well as equivalence of the two products.

 If Three/Four Time points come to the test then following points shall be considered. 

[][]The measurement for the Test Product and the Reference product shall be same. Dissolution Time point shall be same for the both product (10,15,20,30,45,60 minutes etc.). Products which tend to faster dissolution (85% dissolve within 30 minutes) then time frame shall be consider as 10, 15, 20, 30 minutes.
[][]Only One measurement shall be consider after completion of 85% dissolution of both sample and reference products.

System Requirements to Perform Comparative Dissolution

Dissolution Activities shall be continued on USP Type I Dissolution apparatus at 100 RPM or USP Type II Apparatus at 50 RPM using 900 ml of different dissolution media mentioned below.
[][]Media Use in Comparative Dissolution
[][]Acid Media: 0.1N HCL or Simulated Gastric Fluid USP without Enzyme
[][]Acetate Buffer pH 4.5
[][]Phosphate Buffer pH 6.8 or Simulated Intestinal Fluid without Enzyme
[][]If both the Test Product and Reference product shows more than 85% dissolution within first 15 minutes then no calculation required. If not meets the above requirements then calculate f2 Value.
[][]If found f2>50, then the profile considered as similar and in vivo study is not required. Minimum 12 unit of each shall be consider for comparative dissolution.

 

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Comparative Dissolution Study Protocol


Performance Qualification of WFI Phase 3

Performance Qualification Protocol, Pharma Operations, Protocol

Performance Qualification of WFI,  Purpose

Performance Qualification of WFI, To authenticate and document that the performance of the WFI Generation and Distribution System installed at the WFI & PS plant room (roof top) of Cephalosporin Block of XX Pharmaceuticals Limited is satisfactory in all critical features related to the operational requirements during Phase – 3 study.

Performance Qualification of WFI, Scope

This protocol will be applicable for performing Phase – 3 validation study to verify that the Water For Injection generation and distribution system installed at WFI & PS plant room (roof top) of Cephalosporin Block of XX Pharmaceuticals Limited consistently produce desired quality of Water For Injection over the study period of 01 year.

 

People also Read

Water For Injection Performance Qualification of Phase 2 Study

 

Responsibilities

[][]Preparation of the protocol
Validation (Engineering) Department.
[][]Executing the protocol
Validation team along with respective departmental person and engineers or other suitably qualified staff allocated from the site or contracted specialists as appropriate.
[][]Chemical test
Quality Control Department
[][]Microbiological Test
Microbiology Department
[][]Data documentation and preparation of the report
Validation (Engineering) department.
[][]Verifying the report
Concerned departmental person.
[][]Providing documentation on the equipment
Related departments i.e. Engineering, Quality Control, Microbiology, Validation.

System And Process Description

System Information

=>Manufacturer : Watertown
=>Capacity : 750 ltr/hr
=>Model : MS750/4T
=>Manufacturer no. : MS1132

The System under test

[][]The Water For Injection system is designed to generate and distribute the desired quantity & quality of Water For Injection to various user points.

Generation system of Water For Injection

[][]The WFI production process consists of purified water evaporation followed by pure steam separation and condensation through four multi-effect water still columns.

[][]Purified water from the storage tank is pressurized through a feed water pump and pre heated in the four pre heaters.

[][]Then, the purified water becomes pure steam in the four multi effect columns by exchanging heat with the plant steam.

[][]There are two condensers in the system. The first condenser is used to cool the pure steam by exchanging heat with the incoming feed water (PW).

[][]Finally, the WFI is produced in second condenser by exchanging heat with the chilled water which is then supplied to the WFI storage tank.

Distribution system of Water For Injection

[][]The WFI is stored in a WFI storage tank of 2000 ltr capacity and is distributed to the user points and circulated within a loop by a high pressure pump.

[][]There is a heat exchanger in the distribution section to sterilize the whole distribution system.

Tests To Be Performed And Sampling Plan

[][]A comprehensive validation study plan has been established where a weekly sampling plan has been developed for Phase-3 study of WFI system for 01 year concerning weekly testing of all main sampling points.

[][]The sampling will be taken one day a week on working days. The acceptance criterion of the tests are stated in the table.

Main Sampling Points

The sampling points of WFI are listed below:

Sl. No.Sample IDUser point LocationTestsMicrobial Count/
Chemical Tests
01WSP-1Final WFI after condenser – 2 (before WFI storage tank).Next TableWeekly
02WSP-2At supply of WFI Distribution LoopNext TableWeekly
03WSP-3At return of WFI Distribution LoopNext TableWeekly
04WUSP – 01WFI Distribution LoopNext TableWeekly
05WUSP – 02WFI Distribution LoopNext TableWeekly
06WUSP – 03WFI Distribution LoopNext TableWeekly
07WUSP – 04Cold User pointNext TableWeekly
Tests and Acceptance Criteria for Water for Injection
Sl. No.TestsFrequencyAcceptance CriteriaAlert LimitAction Limit
01Appearance Daily from each sampling point.Clear, colorless and odorless liquid.N/AN/A
02Conductivity Daily from each sampling point.Not more than 1.1 µS/cm at 20⁰C or
Not more than 1.3 µS/cm at 25⁰C
0.7 µS/cm0.9 µS/cm
03Total Organic CarbonDaily from each sampling point.Not more than 500 ppb106.4 ppb135.8 ppb
04Total Viable Microbial CountDaily from each sampling point.Not more than 10 CFU/100 mL5 CFU/100 mL8 CFU/100 mL
05E.coliDaily from each sampling point.Must be AbsentN/AN/A
06Staphylococcus aureusDaily from each sampling point.Must be AbsentN/AN/A
07Pseudomonas aeruginosaDaily from each sampling point.Must be AbsentN/AN/A
08Salmonella sppDaily from each sampling point.Must be AbsentN/AN/A
09Bacterial EndotoxinsDaily from each sampling point.Less than 0.25 EU /mLN/AN/A

[][]Performance Qualification shall be considered acceptable when all the conditions above have been met.
[][]Any deviation from the acceptance criteria of the specific check point shall be reported and decision should be taken for the rejection, replacement or rectification of the equipment/component/system.

Conclusion

[][]The results of the Phase – 3 study, as per the qualification protocol are recorded & analyzed.

[][]The observed parameters/tests and subsequent analytical results show that the Water For Injection Generation and Distribution System Complies/Does Not Comply as per the predetermined acceptance criteria.
[][]Hence, the Water For Injection Generation and Distribution is / is not qualifying the Phase – 3 study of Performance Qualification and the System can be / cannot be used for production purpose and continued to regular monitoring by Quality Control and Microbiology department.

 

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Performance Qualification Protocol of WFI Phase 3


Water For Injection Performance Qualification in Phase 2 Study

Performance Qualification Protocol, Pharma Operations, Protocol

Water For Injection Performance Qualification, Purpose

Water For Injection Performance Qualification, To validate and archive that the exhibition of the WFI Generation and Distribution System introduced at the WFI and PS plant room (rooftop top) of Cephalosporin Block of XX Pharmaceuticals Limited (XPL) is agreeable in all basic elements connected with the functional necessities during Phase – 2 Study.

Water For Injection Performance Qualification, Scope

This Protocol will be relevant for performing Phase – 2 study to check that the Water For Injection generation and conveyance framework introduced at WFI and PS plant room (rooftop top) of Cephalosporin Block of XX Pharmaceuticals Limited, reliably produce wanted nature of Water For Injection over the review time of 20 continuous working days.

 

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Water For Injection Performance Qualification Phase I Study

 

Responsibilities

[][]Preparation of the protocol
Validation (Engineering) Department.
[][]Executing the protocol
Validation team along with respective departmental person and engineers or other suitably qualified staff allocated from the site or contracted specialists as appropriate.
[][]Chemical test
Quality Control Department
[][]Microbiological Test
Microbiology Department
[][]Data documentation and preparation of the report
Validation (Engineering) department.
[][]Verifying the report
Concerned departmental person.
[][]Providing documentation on the equipment
Related departments i.e. Engineering, Quality Control, Microbiology, Validation.

System & Processing

System Information
Manufacturer : Watertown
Capacity : 750 ltr/hr
Model : MS750/4T
Manufacturer no. : MS1132

The System under test

The Water For Injection system is designed to generate and distribute the desired quantity & quality of Water For Injection to various user points.

Generation system of Water For Injection

[][]The WFI manufacturing process consists of purified water evaporation followed by pure steam separation & condensation through four multi-effect water still columns.

[][]Purified water from the storage tank is pressurized through feed water pump & pre heated in the four pre-heaters.

[][]Then, the purified water becomes pure steam in the four multi effect columns by exchanging heat with the plant steam.

[][]There are two condensers in the system. The first condenser is used to cool the pure steam by exchanging heat with the incoming feed water (PW).

[][]Finally, the WFI is produced in second condenser by exchanging heat with the chilled water which is then supplied to the WFI storage tank.

Distribution system of Water For Injection

The WFI is stored in a WFI storage tank of 2000 L capacity and is distributed to the user points and circulated within a loop by a high pressure pump. There is a heat exchanger in the distribution section to sterilize the whole distribution system.

Test to be perform & Sampling

[][]A comprehensive validation study plan has been established where a daily sampling plan has been developed for Phase-2 study of WFI system for 20 consecutive working days concerning daily testing of all main sampling points.The acceptance criterion of the tests are stated in the table of section.

Main Sampling Points

The sampling points of WFI are listed below:

Sl. No.Sample IDRoom NameTestsMicrobial Count/
Chemical Tests
01WSP-1WFI and Pure Steam plant roomBelow TableDaily
02WSP-2WFI and Pure Steam plant roomBelow TableDaily
03WSP-3WFI and Pure Steam plant roomBelow TableDaily
04WUSP – 01Vial Washing & SterilizationBelow TableDaily
05WUSP – 02Laundry & WashBelow TableDaily
06WUSP – 03Wash BayBelow TableDaily
07WUSP – 04Laundry & WashBelow TableDaily

[][]Performance Qualification shall be considered acceptable when all the conditions above have been met.
[][]Any deviation from the acceptance criteria of the specific check point shall be reported and decision should be taken for the rejection, replacement or rectification of the equipment/component/system.

Tests and Acceptance Criteria for Water for Injection (Based on Current USP 37)
Sl. No.TestsFrequencyAcceptance CriteriaAlert Limit
01Appearance Daily from each sampling point.Clear, colorless and odorless liquid.Not Available
02Conductivity Daily from each sampling point.Not more than 1.1 µS/cm at 20⁰C or
Not more than 1.3 µS/cm at 25⁰C
Not Available
03Total Organic CarbonDaily from each sampling point.Not more than 500 ppbNot Available
04Total Viable Microbial CountDaily from each sampling point.Not more than 10 CFU/100 mLNot Available
05E.coliDaily from each sampling point.Must be AbsentNot Available
06Staphylococcus aureusDaily from each sampling point.Must be AbsentNot Available
07Pseudomonas aeruginosaDaily from each sampling point.Must be AbsentNot Available
08Salmonella sppDaily from each sampling point.Must be AbsentNot Available
09Bacterial EndotoxinsDaily from each sampling point.Less than 0.25 EU /mLNot Available
Reference Documents
Sl. No.Title of the DocumentDocument No.
01WHO Good Manufacturing Practices: water for pharmaceutical use.WHO Technical Report Series, No. 929, 2005
02WHO Expert Committee on Specifications for Pharmaceutical Preparations.WHO Technical Report Series No. 970, 2012
03United States Pharmacopeia 37Not Available

Conclusion

[][]The results of the Phase – 2 study, as per the qualification protocol are recorded & analyzed. The observed parameters/tests and subsequent analytical results show that the Water For Injection Generation and Distribution System Complies/Does Not Comply as per the predetermined acceptance criteria.

[][]Hence, the Water For Injection Generation and Distribution is / is not qualifying the Phase – 2 study of Performance Qualification and the System can be / cannot be used for production purpose and continued to Phase – 3 study.

 

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Water For Injection Performance Qualification Phase 2 Study

 


WFI Performance Qualification, Phase-I Study

Performance Qualification Protocol, Pharma Operations, Protocol

WFI Performance Qualification, Purpose

WFI Performance Qualification, To authenticate and document that the performance of the WFI Generation and Distribution System installed at the WFI & PS plant room of Cephalosporin Block of XX Pharmaceuticals Limited (XPL) is satisfactory in all critical features related to the operational requirements during Phase – 1 (Investigational Phase) study.

WFI Performance Qualification, Scope

This protocol will be applicable for performing Phase -1 validation study to verify that the Water For Injection generation and distribution system installed at the utility area (roof top) of Cephalosporin Block of XX Pharmaceuticals Limited,  consistently produce desired quality of Water For Injection over the study period of 20 consecutive working days.

 

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Pure Steam System Performance Qualification

 

Responsibilities

[][]Preparation of the protocol
=>Validation (Engineering) Department.
[][]Executing the protocol
=>Validation team along with respective departmental person and engineers or other suitably qualified staff allocated from the site or contracted specialists as appropriate.
[][]Chemical Test
=>Quality Control Department
[][]Microbiological Test
=>Microbiology Department
[][]Data documentation and preparation of the report
=>Validation (Engineering) department.
[][]Verifying of the report
=>Concerned departmental person.
[][]Providing documentation on the equipment
=>Related departments i.e. Engineering, Quality Control, Microbiology, Validation.

System And Process Description

=>System Information

=>Manufacturer : Watertown
=>Capacity : 750 ltr/hr
=>Model : MS750/4T
=>Manufacturer no. : MS1132

The System under test

The Water For Injection system is designed to generate and distribute the desired quantity & quality of Water For Injection to various user points.

Generation system of Water For Injection

[][]The WFI production process consists of purified water evaporation followed by pure steam separation and condensation through four multi-effect water still columns.

[][]Purified water from the storage tank is pressurized through a feed water pump and pre heated in the four pre heaters.

[][]Then, the purified water becomes pure steam in the four multi effect columns by exchanging heat with the plant steam.

[][]There are two condensers in the system. The first condenser is used to cool the pure steam by exchanging heat with the incoming feed water (PW).

[][]Finally, the WFI is produced in second condenser by exchanging heat with the chilled water which is then supplied to the WFI storage tank.

Distribution system of Water For Injection

[][]The WFI is stored in a WFI storage tank of 2000 ltr capacity and is distributed to the user points and circulated within a loop by a high pressure pump.

[][]There is a heat exchanger in the distribution section to sterilize the whole distribution system.

Tests To Be Performed And Sampling Plan

[][]A complete validation study plan has been designed in accordance with the Validation Master Plan. In addition, a daily sampling plan has been also developed for Phase-1 study of WFI system for 20 consecutive working days concerning daily testing of all main sampling points .

[][]The acceptance criterion of each test is stated in the next table.
[][]Alert and action limits will be calculated using following formula after getting the test results and data:
=>Alert limit = Average value + 2σ
=>Action limit = Average value + 3σ

Main Sampling Points

The sampling points of WFI are listed below:

Sl. No.Sample IDRoom NumberUser point LocationTestsMicrobial Count & Chemical Tests
01WSP-1SRT001Final WFI after condenser – 2 (before WFI storage tank).Mention on next TableDaily
02WSP-2SRT001At supply of WFI Distribution LoopMention on next TableDaily
03WSP-3SRT001At return of WFI Distribution LoopMention on next TableDaily
04WUSP – 01SPR054WFI Distribution LoopMention on next TableDaily
05WUSP – 02SPR040WFI Distribution LoopMention on next TableDaily
06WUSP – 03SMB010WFI Distribution LoopMention on next TableDaily
07WUSP – 04SPR040Cold User pointMention on next TableDaily

[][]Performance Qualification shall be considered acceptable when all the conditions above have been met.
[][]Any deviation from the acceptance criteria of the specific check point shall be reported and decision should be taken for the rejection, replacement or rectification of the equipment/component/system.

Tests And Acceptance Criteria For Water For Injection

Sl. No.TestsFrequencyAcceptance CriteriaAlert Limit
1Appearance DailyClear, colorless and odorless liquid.N/A
2Conductivity DailyNot more than 1.1 µS/cm at 20⁰C or
Not more than 1.3 µS/cm at 25⁰C
N/A
3Total Organic CarbonDailyNot more than 500 ppbN/A
4Total Viable Microbial CountDailyNot more than 10 CFU/100 mLN/A
5E.coliDailyMust be AbsentN/A
6Staphylococcus aureusDailyMust be AbsentN/A
7Pseudomonas aeruginosaDailyMust be AbsentN/A
8Salmonella sppDailyMust be AbsentN/A
9Bacterial EndotoxinsDailyLess than 0.25 EU /mLN/A
Test Records

All the test reports of chemical and microbiological tests are attached with the report as attachment.

Reference Documents

Sl. No.Title of the DocumentDocument No.
01WHO Good Manufacturing Practices: water for pharmaceutical use.WHO Technical Report Series, No. 929, 2005
02WHO Expert Committee on Specifications for Pharmaceutical Preparations.WHO Technical Report Series No. 970, 2012
03United States Pharmacopeia N/A

 

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WFI Performance Qualification, Phase-I Study Protocol


Vial Washing Machine Performance Qualification

Performance Qualification Protocol, Pharma Operations, Protocol

Vial Washing Machine Performance Qualification, Purpose

Vial Washing Machine Performance Qualification, To authenticate and document that the performance of the Vial Washing Machine of Sterile Production area (Cephalosporin Block) of XX Pharmaceutical Limited (XPL) is satisfactory in all critical aspects related to the operational requirements during washing of vials. This protocol describes the performance qualification procedures of the Vial Washing Machine manufactured by Tofflon, China.

Vial Washing Machine Performance Qualification, Scope

This Performance Qualification (PQ) is to be performed against agreed acceptance criteria on 7.5 ml, 15 ml and 30 ml vials which will be washed by the Vial Washing Machine installed in the Sterile Production area of Cephalosporin Block of XX Pharmaceutical Limited.

 

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Responsibilities

[][]Preparation of the protocol

Validation (Engineering) Department with the assistance of Microbiology, Engineering and Maintenance department.
Executing the protocol

[][]Validation (Engineering) Department along with respective departmental person and engineers or other suitably qualified staff allocated from the site or contracted specialists as appropriate.
[][]Microbiological Challenge Test

Microbiology department
[][]Chemical Tests

Quality Control Department
[][]Data documentation and preparation of the report

Validation (Engineering) department.
[][]Verifying of the report

Concerned departmental person.
[][]Providing documentation on the equipment

Related departments i.e. Engineering, Production, Microbiology, Validation or other appropriate departments and manufacturer.

System And Process Description

[][]Equipment Information
=>Manufacturer : Tofflon, China
=>Capacity : 6000 – 9000 vials/hr.
=>Model : QCLX60
=>Serial no. : YF2014-078A

[][]The Equipment under test
The vials from the box are placed on the infeed conveyor belt and are showered by recycled WFI at first. Then, these are cleaned in the ultrasonic bath and transferred to the grippers. The infeed rotary screw transports the vials from the housing to the grippers. There are total twenty stations where 60 vials are washed using following sequence:
=>Internal blowing with compressed air.
=>Internal and external spraying with recycled WFI at ambient temperature.
=>Internal blowing with sterile compressed air.
=>Internal and external spraying with fresh WFI.
=>Internal blowing with compressed air.
=>Internal and external blowing with sterile compressed air.
=>The supply lines are equipped by filter with the following retention grade: compressed air 0.22 µm, recycled WFI 10 µm and 5 µm, and fresh WFI 0.22 µm.

Checking Parameters

The PQ of Vial Washing Machine will be carried out to evaluate the following conditions to confirm the sterilization conditions:
i) Riboflavin Test.
ii) Particulate Matter Test.
iii) Bacterial Endotoxin Test.
iv) Washing Efficiency Test.

Study Procedure:

[][]Riboflavin Test: Take the Vials and do the decartoning and check for any Physical deformity or damage. A 0.2 gm riboflavin sodium phosphate per liter of purified water solution is prepared.

[][]Take 60 vials, mark with the permanent marker and spray the interior and exterior of the vials with the solution so that every vial is properly moistened with the solution and keep for overnight.

[][]Next morning dry the vials in oven for 2 hrs at 150 °C. After that, rinse the vials with phosphate buffer solution of pH 7.0 and measure the absorption in a UV-VIS spectrophotometer using 1 cm cell at a wavelength 266 nm by setting the limit between 230 nm and 350 nm.

[][]Use phosphate buffer solution of pH 7.0 as blank. Record the spectrum. Place the marked 60 Vials with these and run the machine as per SOP and collect these vials after washing.

[][]Take these vials again; repeat the procedure in order to confirm the presence of any riboflavin on vials.
The test will be repeated at minimum and maximum speed of washing machine for each of three vials’ sizes 7.5ml, 15ml and 30ml.

[][]The results of above test will be attached with the report and will be accepted if met the acceptance criteria.

Acceptance Criteria:

Riboflavin content must be absent in all the spiked vials after washing.

Particulate Matter Test:

[][]10 gm of charcoal is dissolved in 1000 gm WFI to make 1% charcoal slurry.

[][]Approximately 0.1 ml of charcoal slurry is used to spike each of 60 vials by swirling the vial to coat the inner surface and evaporate the solution to dryness at room temperature.

[][]Spiked test vials with charcoal are marked in series with permanent marker on the outer surface.

[][]Take the particle count of the vials before washing. After that, load these vials on the tray and run the machine according to the SOP No.____________________.

[][]The test must be performed at minimum and maximum speed of washing machine for each of three vials’ sizes 7.5ml, 15ml and 30ml.
[][]The results of above test will be attached with the report and will be accepted if met the acceptance criteria.

Acceptance Criteria:

Vials should be free from foreign particle & fibers on visual inspection. 10µ particles should not be more than 25 and 25µ particles should not be more than 3.

Bacterial Endotoxin Test:

[][]Add 100 endotoxin units into 10 vials and allow them to dry at 45 – 50°C. Mark these spiked vials with permanent marker on outer surface.

[][]Separate 10 vials are used for each of above tests. About 3000 vials of selected size are loaded on the feed belt and vial washing machine is operated as per the standard operating procedure.

[][]Place the spiked vials marked with permanent marker in between the other vials while machine is running. Collect the marked vials after washing and store properly to avoid the other contamination from environment.

[][]These spiked vials are analyzed separately. It should be done three times for each vial size. The test must be performed at minimum and maximum speed of washing machine for each of three vials’ sizes 7.5ml, 15ml and 30ml.
[][]The results of above test will be attached with the report and will be accepted if met the acceptance criteria.

Acceptance Criteria:

Vials should comply endotoxin limit within 0.25 EU/vial.

[][]Following parameter also maintained as per protocol

=>Deviation And Failure Investigation Summary

=>Documentation Requirements

=>Report Summary

Conclusion

The performance qualification Complies / Does Not Comply with the acceptance criteria taken above and the results obtained are attached with the protocol.
The Vial Washing Machine of Sterile Production area of Cephalosporin Block is / is not qualifying the Performance Qualification test as per this Protocol. Therefore, the Vial Washing Machine can be / cannot be used for production operation.

 

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Vial washing Machine Performance Qualification Protocol


Laminar Air Flow Performance Qualification

Performance Qualification Protocol, Pharma Operations, Protocol

Laminar Air Flow Performance Qualification, Purpose

Laminar Air Flow Performance Qualification, To authenticate and document that the performance of the Laminar Air Flow unit of Sterile Production area of Cephalosporin Block of XX Pharmaceuticals Limited (XPL) meets the user’s requirements of XPL Pharmaceutical Limited.

Laminar Air Flow Performance Qualification, Scope

This Performance Qualification (PQ) is to be performed against agreed acceptance criteria on the Laminar Air Flow Unit, which has been installed above the turn table after Depyrogenation Tunnel in Room of Sterile Production floor of Cephalosporin Block.

 

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Laminar Air Flow Operational Qualification

 

Responsibilities

[][]Preparation of the protocol
Engineering Department with the assistance of Validation team.
[][]Executing the protocol
Validation (Engineering) Department along with respective departmental person and engineers or other suitably qualified staff allocated from the site or contracted specialists as appropriate.
[][]Microbiological Test
Microbiology department
[][]Data documentation and preparation of the report
Validation (Engineering) department.
[][]Verifying of the report
Concerned departmental person.
[][]Providing documentation on the equipment
Related departments i.e. Engineering, Production, Microbiology, Validation or other appropriate departments and manufacturer.

Performance testing

[][]Air borne particle count test
=>Purpose: the purpose of this test is to ensure that the air borne particles are under the acceptance limit.
=>Test method: carry out the particle count test according to respective sop. Perform the test at rest and in operation conditions for 3 consecutive working days at each condition. Record the results in appendix – 1.
=>Test instrument id:
=>Acceptance criteria: the particle count specifications under the laminar air flow unit should meet the specification of room class a.

People  Also Read

Laminar Air Flow Installation Qualification

Microbial Count test

[][]Purpose: To ensure that the microbial count meets the specification of clean room class A.
[][]Test Method: Perform the test at rest and in operation conditions for 3 consecutive working days at each condition. All results must be recorded on the appropriate forms of monitoring methodology and be compared with the alarm and specified action limits. The limits of sterile and non-sterile applications are specified below. Details are to be recorded in Appendix – 2.
[][]Test Instrument ID: N/A
[][]Acceptance Criteria: The microbial count must meet the clean room class – A specifications.

Sl. No.Room ClassAir Sample
(cfu/m3)
Settle Plates
(cfu/4 hours)
Contact Plate (cfu/plate)
01A<1<1<1
02B1055

Deviation And Failure Investigation Summary

Record in the column below any deviations or failures that occurred during the PQ exercise.

Deviation/ FailureDeviation/ FailureDescription and assessment of impact on validationInitialDate
1
2
3

Reference Documents

Sl. No.Title of the DocumentDocument No.
01Clean rooms and associated controlled environments part 1: classification of air cleanlinessISO 14644 – 1
02Clean rooms and associated controlled environments Part 3: Test methodsISO 14644 – 2
03Standard Operating Procedure For
Environmental Monitoring (Microbial & Particle Count)
In-house SOP

Conclusion

[][]The performance qualification complies / does not comply with the acceptance criteria taken above and the obtained results are attached with the protocol.
[][]The laminar air flow unit of sterile production area of cephalosporin block is / is not qualifying the performance qualification test as per this protocol.

[][]Hence, the system can be / cannot be used for normal operation.

 

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Laminar Air Flow Performance Qualification Protocol


Laminar Air Flow Operational Qualification

Operational Qualification, Pharma Operations, Protocol

Laminar Air Flow Operational Qualification, Purpose

Laminar Air Flow Operational Qualification, To authenticate and document that the Laminar Air Flow Unit of Sterile production area of Cephalosporin Block of XX Pharmaceuticals Limited (XPL) operates as designed and intended. The operational parameters should be consistent with the requirements for the manufacturing process.

Laminar Air Flow Operational Qualification, Scope

This Operational Qualification (OQ) is to be performed against agreed acceptance criteria on the Laminar Air Flow Unit installed above the turn table after Depyrogenation Tunnel in Room of Sterile Production floor of Cephalosporin Block. The scope will include the verification of previously calibrated instruments and the availability of operational, maintenance and cleaning procedures.

Responsibility

[][]Preparation of protocol
Engineering Department.
[][]Executing the protocol
Engineering department or other suitably qualified staff allocated from the site or contracted specialists as appropriate.
[][]Providing documentation of the equipment
Related departments i.e. Engineering Production, Validation or other appropriate departments and manufacturer.
[][]Data documentation and preparation of the report
Raw data documentation is the responsibility of those conducting the validation. Preparation of the report and incorporation of data will be the responsibility of the Engineering Department.

Background

Project Description & Related issues
[][]This Laminar Air Flow Unit has been installed in the year 20xx in the sterile production area of Cephalosporin Block for dispensing of raw materials.

Purchasing Information

[][]Manufacturer: GUSU
[][]Local Agent: LS Techno Trade
[][]Model Number: GMP Standard

System Description

[][]A Laminar Air Flow Unit is used to provide unidirectional air flow. Grade A is ensured under LAF using H14 HEPA filter.

[][]A blower is used to circulate the air. The air flow direction of this LAF is vertical.

[][]There is a differential pressure gauge to see the differential pressure across the filters which indicate the blockage of filters.

Verification of Sops

[][]The standard operating procedure for operation and cleaning procedure of Laminar Air Flow Unit must be at least in draft format before commencement of OQ. The necessary information are recorded in the following table:

Sl. No.SOP NameEffective DateAcceptable
(Yes/ No)
Initials with date
01Operation and Cleaning of Laminar Air Flow Unit.
02

Verification of Training

[][]Training should have been given regarding operation, maintenance and cleaning of Laminar Air Flow Unit to all operators and must be documented.

[][]The documentation status is to be recorded in the following tables.
[][]The training is to be recorded in the following tables.

Trainer NameTraining course/SOP NameTrainee NameInitialsDate

Operational testing

[][]Verification of start-up and normal sequence of operation
[][]Record results of checks in the following table:

Criterion No.Action to be takenAcceptance CriteriaCompliant
Yes/No
Initial/Date
01Switch ON the main power.The voltage will be shown on the display.
02Switch ON the blower by pressing the ON button.The blower has to be ON and air will start flowing vertically.
03Differential Pressure gauge for HEPA Filter is functioning properly.The differential pressure gauge should show pressure from zero to positive direction.

Smoke Test

[][]Purpose: The purpose of the smoke test is to justify the airflow direction under the HEPA Filter is unidirectional.
Test Method:
[][]The smoke test will be performed by ______________________ According to the SOP No. _____________________________.
[][]Test Equipment/Material: Dry Ice and water.
[][]Acceptance Criteria: Airflow direction is unidirectional and vertical. Attach a copy of the report of Smoke test.

Filter Integrity Test

[][]Purpose: Filter Integrity test is performed using Poly Alpha Olephin (PAO) to check any leakage of the filter.
[][]Test Method: The test is performed by ____________________ according to the SOP NO. ______________________________.
[][]Test Equipment: PAO generator, Optical Photometer.
[][]Acceptance Criteria: Any leakage greater than 0.01% of the upstream challenge aerosol concentration is considered unacceptable and wants repairs and resetting.
[][]Attach a copy of HEPA filter integrity test certificate in attachment.

Air Velocity Test

[][]Purpose: The purpose of this test is to ensure the air velocity for laminar flow.
Test Method
[][]Measure the air velocity under each HEPA filter of the equipment at the distance of 6” below the filter grill and record the velocity at 5 locations (Shown in following figure) and take the average reading with the anemometer.
[][]Measure the air velocity under each HEPA filter of the equipment at the operation level and record the velocity at 5 locations (Shown in following figure) and take the average reading with the anemometer.

Test Equipment: Calibrated anemometer.
Acceptance Criteria: Measured air velocity should be in the range of 0.36 m/sec ~ 0.54 m/sec.
Result:

No. 1 HEPA

No. 2 HEPA result shall be plotted.

Conclusion

[][]The Operational Qualification of Laminar Air Flow Unit of Cephalosporin Block Complies / Does Not Comply with the acceptance criteria taken above and the results obtained have been filled up in the respective table of each test.
[][]The Laminar Air Flow Unit of Cephalosporin Block is / is not qualifying the Operational Qualification test as per this Protocol. Hence, the system can be / cannot be used for Performance Qualification.

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Laminar Air Flow Operational Qualification


Laminar Air Flow Installation Qualification

Pharma Operations, Protocol

Laminar Air Flow Installation Qualification, Purpose

Laminar Air Flow Installation Qualification, To verify and document that the Laminar Air Flow Unit of Sterile Area of Cephalosporin Block is designed, built and installed according to XX Pharmaceuticals Limited’s demand and manufacturer specifications and that documentation is compiled to verify the integrity of the installation.

Laminar Air Flow Installation Qualification, Scope

This Installation Qualification (IQ) is to be performed against agreed acceptance criteria on the Laminar Air Flow Unit installed above the turn table after Depyrogenation Tunnel in Room of Sterile Production floor of Cephalosporin Block. The scope will include assessment of equipment design and installation, connection of utilities, presence and function of instruments.

 

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HVAC Operational Qualification

Responsibilities

[][]Preparation of protocol
=>Engineering Department.
[][]Executing the protocol
=>Engineering department or other suitably qualified staff allocated from the site or contracted specialists as appropriate.
[][]Providing documentation on the equipment
=>Related departments i.e. Engineering Production, Validation or other appropriate departments and manufacturer
[][]Data documentation and preparation of the report
=>Raw data documentation is the responsibility of those conducting the validation. Preparation of the report and incorporation of data will be the responsibility of the Engineering Department.

Background

[][]Project Description & Related issues
=>This Laminar Air Flow Unit has been installed in the year 20xx in the sterile production area of Cephalosporin Block for dispensing of raw materials.

Purchasing Information

Item/ Brand

=>Manufacturer: GUSU
=>Local Agent: Precisa Techno Trade
=>Model Number: Standard

System Description

A Laminar Air Flow Unit is used to provide unidirectional air flow. Grade A is ensured under LAF using H14 HEPA filter. A blower is used to circulate the air. The air flow direction of this LAF is vertical. There is a differential pressure gauge to see the differential pressure across the filters which indicate the blockage of filters.

Following Document Shall be noted:
[][]Verification of Installation
[][]Design Documentation
=>General Characteristics
=>Engineering Specifications
[][]Instruments verification
[][]Utility Verification
[][]Deviation and Failure Investigation Summary

Conclusion

[][]The Installation Qualification of Laminar Air Flow Unit of Cephalosporin Block Complies / Does Not Comply with the acceptance criteria taken above and the results obtained have been filled up in the respective table of each test.
[][]The Laminar Air Flow Unit of Cephalosporin Block is / is not qualifying the Installation Qualification test as per this Protocol. Hence, the system can be / cannot be used for Operational Qualification.

 

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Laminar Air Flow Installation Qualification


Air Compressor Performance Qualification

Performance Qualification Protocol, Pharma Operations, Protocol

Purpose

To determine that the oil free air compressor performs as per the given specifications, by running the system on its intended schedules and recording all relevant data under normal conditions & for worst-case situations where applicable.

Scope

This Performance Qualification (PQ) is to be performed against agreed acceptance criteria on the oil free air compressor systems, comprising of compressor, drying system, filtering system, piping, control system etc. installed in General Block of XX Pharmaceuticals Ltd. The scope will include measuring oil content, dew point test, particulate contamination and microbial count of compressed air system.

 

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Responsibilities

[][]Preparation of the protocol
=>Validation (Engineering) Department with the assistance of Microbiology, Quality Assurance and Engineering department.
[][]Executing the protocol
=>Validation team along with respective departmental person and engineers or other suitably qualified staffs allocated from the site or contracted specialists as appropriate.
[][]Oil and dew point test
=>Validation (Engineering) Department
[][]Microbiological Test
=>Microbiology Department
[][]Data documentation and preparation of the report
=>Validation (Engineering) department.
[][]Verifying of the report
=>Concerned departmental person.
[][]Providing documentation on the equipment
=>Related departments i.e. Engineering, Production, Microbiology, Validation or other appropriate departments and manufacturer.

System and process description

system information
=>Manufacturer : Atlas copco
=>Capacity : 10.4 m3/hr
=>Model : Zt-75
=>Serial no. : Apf166068

The System under test

[][]The Atlas Copco Air Compressor manufactured by Atlas Copco has a capacity of 10.4 m3/min. Air drawn through an air filter, is compressed in low-pressure compressor element and discharged to the intercooler.

[][]The cooled air is further compressed in high-pressure compressor element and discharged through silencer and after coolers. A check valve is provided downstream of the silencer.

[][]The compressed air leaves the compressor via the air outlet. The compressor delivers oil-free, pulsation-free air.
[][]This is an air cooled type compressor which is facilitated with air filter, moisture trap, high pressure and low pressure safety valve, desiccant type dryer system etc.
[][]After being compressed in compressor the oil free compressed air will be stored in a receiver tank. There are two desiccant type air dryers. Air is dried in the air dryers and then distributed through pipe line to the different facility.

Performance Tests

The tests for performance qualification of compressed air as follows:
#Oil content Test Method
[][]Ensure that the compressed air is supplied at a pressure between 2.8 – 3.2 bar.

[][]Connect the sampling point at the port of 10 bar of the pressure reducer of Drager Aerotest Simultan HP.

[][]After that, connect the measuring device with the pressure reducer and insert an oil impactor kit of Drager Aerotest Simultan HP into the oil testing port of the measuring device.

[][]Open the compressed air valve and collect the sample for 5 minutes. The time is counted by a calibrated timer.

[][]Finally, check the oil impactor kit if there is any spot on the screen. The following figures will be used to measure the quantity of the oil:

[][]Perform the test for 3 consecutive working days.
[][]Record the result in Appendix 1.

Acceptance Criteria

=>The compressed air should meet the specification of ISO 8573-1:2010 class 0. Hence, the compressed air must contain no oil.

Dew point test

Test Method
[][]Ensure that the compressed air is supplied at a pressure between 2.8 – 3.2 bar.

[][]Connect the sampling point at the port of 10 bar of the pressure reducer of Drager Aerotest Simultan HP.

[][]Break the both tips of a Water Content Test Kit. After that, connect the measuring device with the pressure reducer and insert a kit into the H2O testing port of the measuring device.

[][]Open the compressed air valve and collect the sample for 10 minutes.

[][]The time is counted by a calibrated timer. The color of the kit will be gradually changed from yellow to red.

[][]The reading is marked on the body of the kit. Get the reading up to which the color is changed.

[][]Calculate the dew point using the table provided in Appendix 06. Perform the test for 3 consecutive working days.
Record the result in Appendix 1.

#Acceptance Criteria
=>The compressed air should meet the specification of ISO 8573-1: 2010 class 2. Hence, the dew point of the compressed air must be equal to or less than – 400C.

Particulate contamination

Test Method

[][]Connect the sampling point with the High Pressure Diffuser and open the valve of compressed air to flush the line. After that, connect the other end of the High Pressure Diffuser with the air borne particle counter and commence particle counting for 0.5 micron and 5.0 micron particles.

[][]The sample collection time will depend on the room grade of the user point of compressed air.

[][]For example, if the user point is located in a Grade-D area, the sample will be collected for 1 minute. Please see the table of section for sample collection time for each grade.
[][]Perform the test for 3 consecutive working days.
[][]Record the results in the result sheet in Appendix 3.

#Acceptance Criteria

=>The specifications will differ according to the room classification, which are given below:

Maximum Permitted Number of Particles/m3

Room Class0.5mic.m5mic.m
A352020
B352029
C352000 2900
D352000029000

Microbial Count

Test Method

[][]The test will be performed according to the SOP No.: SOP/YY/XX where XX is the current revision of the SOP.
[][]Perform the test for 3 consecutive working days.
[][]Record the results in the result sheet in Appendix 4.

#Acceptance Criteria:

=>The specifications of this test according to the different room classifications are given below:

Room ClassAcceptance Limit
CFU/m3
Grade A<1
Grade B10
Grade C100
Grade D200

Sterility Test

Test Method
[][]This test will be performed only for ACSP – 03. The test will be performed according to the SOP No.: SOP, where XX is the current revision of the SOP.
[][]Perform the test for 3 consecutive working days. Record the results in the result sheet in Appendix 4.

#Acceptance Criteria:

=>The air at this point must be sterile.

Sampling Points and Test Frequency

[][]The list of sampling points which come into product contact is given below:

Sl. No.Sampling point nameRoom No.Room NameTestsFrequency
01Post StagingOil content, dew point, and particle count, microbial count 1 year
02Washing and Sterilization roomOil Content, Dew point and particle count, microbial count 1 year
03Vial Filling roomOil content, dew point, particle count and Sterility test1 year

Deviation And Failure Investigation Summary

=>In the column below, record any deviation or failure that occurred during the PQ exercise.

Reference Documents

=>ISO 8573-1:2010: Air Quality Classes.

Conclusion

[][]The Performance Qualification of Atlas Copco Air Compressor of General Block Complies / Does Not Comply with the acceptance criteria taken above and the results obtained are attached with the protocol.
[][]The Atlas Copco Air Compressor is / is not qualifying the Performance Qualification test as per this Protocol. Hence, the system can be / cannot be used for production operation.

 

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Air Compressor Performance Qualification Protocol


Air Compressor Operational Qualification

Protocol

Air Compressor Operational Qualification , Purpose

Air Compressor Operational Qualification , To verify and document that the oil free air compressor system operates as designed and intended. The operational parameters should be consistent with the requirements for the Manufacturing process. The OQ is aimed to verify that the installed equipment performs according to the manufacturer’s specifications.

Air Compressor Operational Qualification , Scope

This Operational Qualification (OQ) is to be performed against agreed acceptance criteria on the air compressor systems, comprising of compressor, drying system, filtering system, piping, control system etc. installed in the General Block of XX Pharmaceuticals Ltd. The scope will include assessment of equipment design and installation, connection to utilities, presence & function of instruments.
The scope will include the operational testing of the normal sequence of operation and verification of the target limits of operation.

People Also Read

Air Compressor Installation Qualification

 

Responsibility

[][]Preparation of protocol
=>Engineering Department.
[][]Executing the protocol
=>Engineering department or other suitably qualified staff allocated from the site or contracted specialists as appropriate.
[][]Providing documentation on the equipment
=>Related departments i.e. engineering Production, Validation or other appropriate departments and manufacturer.
[][]Data documentation and preparation of the report
=>Raw data documentation is the responsibility of those conducting the validation. Preparation of the report and incorporation of data will be the responsibility of the Engineering Department.

Background

Project Description & Related issues
[][]This air compressor system is installed to serve General and Cephalosporin Block. To meet the demand of quality of compressed air, this oil free air compressor has been installed.

Purchasing Information
ItemBrandModelOrigin
Air CompressorAtlas CopcoZT 75Belgium
DryerAtlas CopcoCD185+Belgium
Air receiverAtlas CopcoNAGermany
Piping and distributionFabricated N/ALocal

System Description

[][]The Atlas Copco Air Compressor and Air Dryer manufactured by Atlas Copco has a capacity of 10.4 m3/min. Air drawn through an air filter is compressed in low-pressure compressor element and discharged to the intercooler.

[][]The cooled air is further compressed in high-pressure compressor element and discharged through silencer and after coolers.

[][]A check valve is provided downstream of the silencer. The compressed air leaves the compressor via the air outlet. The compressor delivers oil-free, pulsation-free air.
This is an air cooled type compressor which is facilitated with air filter, moisture trap, high pressure and low pressure safety valve, desiccant type dryer system etc.

Following parameter shall be perform at the time of Operational Qualification

[][]Verification of completion of sops
[][]Verification of training
[][]Operational testing
[][]Instrument calibration
[][]Deviation and failure investigation summary
[][]Report summary

Conclusion

The Operational Qualification of Compressed Air System installed at General Block Complies / Does Not Comply with the acceptance criteria taken above and the results obtained are attached with the protocol.
The Compressed Air System is / is not qualifying the Operational Qualification test as per this Protocol. Hence, the system can be / cannot be used for Performance Qualification.

 

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Air Compressor Operational Qualification Protocol


Air Compressor Installation Qualification Protocol

Protocol

Air Compressor Installation Qualification, Purpose

Air Compressor Installation Qualification, To verify and document that the oil free air compressor systems are designed, built and installed according to the XX Pharmaceuticals Ltd. demand and manufacturer specifications and documentation is compiled to verify the integrity of the installation.
This should result in acceptable documented evidence that the oil free air compressor system have been correctly installed in compliance with specification. This new IQ protocol will focus both the General and Cephalosporin Block.

Air Compressor Installation Qualification, Scope

This Installation Qualification (IQ) is to be performed against agreed acceptance criteria on the air compressor systems, comprising of compressor, drying system, filtering system, piping, control system etc. installed in the General Manufacturing area at the XX Pharmaceuticals Ltd. The scope will include assessment of equipment design and installation, connection to utilities, presence & function of instruments.

 

People Also Read

HVAC Operational Qualification

 

Responsibilities

[][]Preparation of protocol
=>Engineering Department
[][]Executing the protocol
=>Engineering department or other suitably qualified staff allocated from the site or contracted specialists as appropriate.
[][]Providing documentation on the equipment
=>Related departments i.e. Engineering, Validation or other appropriate departments and manufacturer
[][]Data documentation and preparation of the report
=>Raw data documentation is the responsibility of those conducting the validation. Preparation of the report and incorporation of data will be the
=>responsibility of the Engineering Department.

Background

[][]Project Description & Related issues
[][]This air compressor system is installed to serve Cephalosporin and General Block. To meet the demand of quality compressed air this oil free air compressor will be installed.

Purchasing Information

ItemBrandModelOrigin
Air CompressorAtlas CopcoZT 75Belgium
DryerAtlas CopcoCD 185+Belgium
Air receiving tankAtlas CopcoN/AGermany
Piping and distributionFabricated N/ALocal

System Description

[][]The Atlas Copco Air Compressor and Air Dryer manufactured by Atlas Copco has a capacity of 10.4 m3/min. Air drawn through an air filter is compressed in low-pressure compressor element and discharged to the intercooler.

[][]The cooled air is further compressed in high-pressure compressor element and discharged through silencer and after coolers. A check valve is provided downstream of the silencer.

[][]The compressed air leaves the compressor via the air outlet. The compressor delivers oil-free, pulsation-free air.
[][]This is an air cooled type compressor which is facilitated with air filter, moisture trap, high pressure and low pressure safety valve, desiccant type dryer system etc.
[][]After being compressed in compressor the oil free compressed air will be stored in a receiver tank.

[][]Air will be dried in the desiccant type dryer and then distributed through pipe line to the different production facility.

Verification Of Installation

Drawings

[][]Physical installation of all the Compressed air related work has to be verified against reference drawings.

[][]The installations that will be found identical with the drawings will be marked by green color and those which will not match with the drawings will be marked by red/orange color.

Drawing DetailsDrawing TitleDrawing NumberDrawing Change Required
Yes/No
Initial with Date
Distribution of Compressed Air in Cephalosporin and General BlockDistribution of Compressed Air in Cephalosporin and General Block
Airflow SchematicsAir flow schematic Drawing for Atlas copco Air Compressor
Air Compressor Floor Plan drawingGeneral Building Roof Top
Electrical WorkElectrical diagram

Item Wise Verification

1.0 Air Compressor

2.0 Desiccant Dryer

3.0 Air Filter

4.0 Air Reservoir

5.0 General Installation Checking

6.0 Instrumentation

7.0 Utilities

All of the parameter has been depicted on assigned protocol.

Deviation And Failure Investigation Summary

In the column below, record any deviations or failures that occurred during the IQ exercise.

Report summary

The report summary of installation qualification of atlas copco air compressor of general block is as as described.

Conclusion

[][]The Installation Qualification of Atlas Copco Air Compressor installed at General Block Complies / Does Not Comply with the acceptance criteria taken above and the results obtained are attached with the protocol.
[][]The Atlas Copco Air Compressor of General Block is / is not qualifying the Installation Qualification test as per this Protocol. Hence, the system can be / cannot be used for Operational Qualification.

 

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Compressed Air Installation Qualification Protocol


HVAC Operational Qualification

Operational Qualification, Performance Qualification Protocol

HVAC Operational Qualification, Purpose

HVAC Operational Qualification, To authenticate and document that the HVAC system of Sterile Production area of Cephalosporin Block of XX Pharmaceuticals Limited operates as per requirements and all the parameters of HVAC system meet the acceptance criteria of XX and manufacturer specifications.

HVAC Operational Qualification, Scope

This Operational Qualification (OQ) is to be performed against agreed acceptance criteria on the HVAC systems, comprising of Air Handling Units, Distribution / Return Ductworks, Chiller, Chilled Water Piping, Pumps, Control System etc. installed in the Cephalosporin Block of XX to serve the Sterile Production area of Cephalosporin Block.

 

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Responsibilities

[][]Protocol Preparation
[][]Validation (Engineering) Department of XX
[][]Protocol Execution
[][]Validation Team of XPL or other suitably qualified third party.
[][]Providing documentation on the equipment
[][]Related departments i.e. Engineering, Production, Validation, Microbiology department of PPL or other third party.
[][]Data documentation and preparation of the report
[][]Validation (Engineering) Department of PPL.

Project Description & Related issues

[][]The rooms of Sterile Production area have been classified as EU Class C and Class B. The air is supplied to the rooms of Class C area by AHU 2C.CE through three stages filtration by pre filter (G4), intermediate filter (F7 and F9) and finally HEPA (H14) filters.
[][]Furthermore, AHU 3B.CE supplies air to the class B area through 3 stages filtration such as pre filter (G4), intermediate filter (F7) and terminal filter (U15).

Operational Testing

Air flow verification

Test Method:
[][]Measure the supply air flow rate by using a flow hood. Assemble the flow-hood by firmly covering the whole supply diffusers. Open the flap of flow hood and switch on to get the readings of air flow.
[][]Set the flow-hood firmly to prevent air leakage over each individual supply air diffusers, HEPA filter and record the reading of the air flow volume in the result sheet.
Record the result in Appendix 1.

Acceptance Criteria:

[][]The air flow should be balanced throughout the area in such a way that it will produce an air volume not less than 10.00% of the design specification at each terminal.
[][]In some cases, exact air volume may be accepted at values lower or higher than 10.00% of design in order to meet room pressure requirements. Where the value is lower than the design, the value must be explained and justified.

Room Differential Pressure

Test Method:

[][]Prior to performing the test, verify that the design airflow volume tests have been carried out. HVAC system of the entire facility must be in continuous operation while performing this test.

[][]To avoid unexpected changes in pressure and to establish a baseline, all doors in the facility must be closed and no traffic is to be allowed through the facility during the test.

[][]Record the differential pressure from the calibrated magnehelic pressure gauge in the result sheet twice a day at rest and in operation conditions for three consecutive working days at each condition.
[][]Record the result in Appendix – 2.

Acceptance Criteria:

The acceptance criteria of differential pressure for each room have been stated in Appendix – 2.

Air change rate

Test Method:

[][]Measure the internal dimensions of each room and calculate the room volume.

[][]Calculate the total air supply to each room by summing the air supply from the individually measured HEPA filters or diffusers in above.

[][]Then calculate the number of air changes per hour for each room using the following formula:

=>Air change rate = Total measured room supply (m3/h)/ Measured room volume (m3)

Record the results in the result sheet in Appendix 3.

Acceptance Criteria:

[][]With reference to the previous section of ISPE Baseline Guide: Sterile Manufacturing Facilities the Air Change rate in all Classified area must be minimum 20.

Temperature and relative humidity

Test Method:

[][]Verify completion of HVAC system testing, adjusting and balancing work prior to performing these tests.

[][]Place calibrated thermometer/sensor and humidity device/sensor at the Return Air Grill.

[][]Allow time for the sensors to stabilize sufficiently for accurate readings.
[][]Measure the temperature and relative humidity at each processing room, twice a day under ‘at rest and in operation’ conditions for three consecutive working days each. Record the results in Appendix 4 and 5.

Acceptance Criteria:

[][]Temperature: 22deg.C±2deg.C for SPR058, SPR058, SPR066, SPR079 and NMT 25deg.C for other rooms in B area.
[][]NMT 25deg.C for C area.
[][]Relative Humidity (RH): NMT 30% for SPR058, SPR058, SPR066, SPR079 and NMT 55% for other rooms in B area.
[][]There is no limit of RH (%) in Grade C area as there will be no handling of Raw materials.

Particle count test

Test Method:

[][]Measure the particle count according to the procedure described in SOP and the printed data are attached with the report.
[][]Using the particle analyzer, count particles greater than or equal to 0.5 micron and also 5 micron in diameter at 1 m height at predefined number of positions in each room.
[][]The test will be performed for both at rest and at operation conditions and for three consecutive working days at each condition.
[][]The report is given from the Microbiology department which will be attached with the report.

Microbial count test:

Test method:

[][]Air borne microbial test is to be done according to the procedure described in SOP and the data are attached with the report.
[][]The test will be performed at rest and in operation conditions for three consecutive working days at each condition.
[][]All the results must be recorded on the appropriate forms of monitoring methodology.
[][]The limits of sterile and non sterile applications are recorded below.
[][]The report will be provided from the Microbiology department which will be attached with the report.

Clean up time or Recovery Test

Test Method:

[][]The recovery test is performed by………………according to the SOP No. …………. The results are recorded in Appendix – 6. The test will be performed only for the rooms where HEPA filter is installed in the supply terminal.

Acceptance Criteria:

[][]Clean up time will NMT 20 minutes. The “clean up” or “recovery” test should demonstrate a change in particle concentration by a factor of 100 within the specified time (according to ISO 14644-3 clause B.12).

Filter Integrity Test

Test Method:

[][]The test will be performed by……………………………..according to the SOP No. …………………………………..The copy of the test report is attached with the report.

Acceptance Criteria:

[][]Any leakage greater than 0.01% for H14 respectively of the upstream challenge aerosol concentration is considered unacceptable. HEPA Filter test report to be recorded in the Attachment.

Smoke test

Test Method:

=>The test will be performed by _______________________ according to the SOP No. ________________.

Acceptance Criteria:

[][]All the processing rooms are at positive pressure with respect to the adjacent corridor.

[][]Furthermore, in case of any two adjacent rooms of different classified areas, the higher classified area will be at positive pressure.

[][]So, the smoke will flow from positive to negative areas.

Instrument Calibration

=>The necessary instruments to complete the OQ of HVAC system of Sterile Production area of Cephalosporin Block is listed below:

Sl. No.Instrument TypeID No.Calibration DateCalibration Due DateCertificate No.Initial & Date
01Thermo hygrometerCC-000-000-TMH-001
02Differential Pressure ProbeCC-000-000-PID-001 with B1
03Aerosol Photometer

Deviation And Failure Investigation Summary

=>Record in the column below any deviations or failures that occurred during the OQ exercise.

Report Summary

=>The report summary of Operational Qualification of HVAC system of Sterile Production area of Cephalosporin Block Is as found.

Conclusion

[][]All / Some testing parameters of the Operational Qualification of HVAC system of Sterile Production area of Cephalosporin Block Comply / Do Not Comply with the acceptance criteria and the results obtained are attached with the protocol.
[][]The HVAC system of Sterile Production area of Cephalosporin Block is / is not qualifying the Operational Qualification test as per this protocol after proper justification of the deviation (if found). Hence, the system can be / cannot be used for production operation.

 

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HVAC Operational Qualification Protocol


Pure Steam System Performance Qualification

Performance Qualification Protocol

Pure Steam Performance Qualification , Purpose

Pure Steam Performance Qualification , To determine that the Pure steam generator performs as per the given specifications, by running the system on its intended schedules and recording all relevant data under normal conditions & for worst-case situations where applicable.

Pure Steam Performance Qualification , Scope

This Performance Qualification (PQ) is to be performed against agreed acceptance criteria on the pure steam generator system Cephalosporin Block of XX Pharmaceuticals Ltd. The scope will include the measurement of Non-condensable gases, superheat value, dryness value and microbiological test of pure steam system.

People Also Read

Autoclave Performance Qualification Protocol

 

Responsibilities

[][]Preparation of the protocol
=>Validation (Engineering) Department with the assistance of Microbiology, Quality Assurance and Engineering department.

[][]Executing the protocol
=>Validation team along with respective departmental person and engineers or other suitably qualified staffs allocated from the site or contracted specialists as appropriate.

[][]Non-condensable gas, superheat value, dryness fraction
=>Validation (Engineering) Department

[][]Microbiological Test
=>Microbiology Department

[][]Data documentation and preparation of the report
=>Validation (Engineering) department.

[][]Verifying of the report
=>Concerned departmental person.

[][]Providing documentation on the equipment
=>Related departments i.e. Engineering, Production, Microbiology, Validation or other appropriate departments and manufacturer.

System And Process Description

=>System Information
=>Manufacturer : Watertown
=>Capacity : 200kg/hr
=>Model : MS750/4T
=>Serial No. : MS1132

Reference Instruments

=>Name : Steam quality test kit
=>Manufacturer : Dekon Solutions, UK
=>Model : SQ kit Option – A.

The System under test

[][]The pure steam is generated in the WFI plant located at the roof top utility area of Cephalosporin Block. Industrial steam enters into the first heat exchanger of WFI plant and exchanges heat with the purified water and is converted into pure steam. Therefore, pure steam is supplied at a pressure of around 2.5 bar – 4 bar to the autoclave room of sterile area of cephalosporin block.

Performance Tests

[][]The tests for performance qualification of pure steam as follows:

=>Non-condensable gas test
=>Test Method

[][]The measurement of non-condensable gases is made by cooling a steam sample, using water through an efficient condenser.
[][]Water can be supplied either directly from a pressurized supply or simply by siphoning from a tank at a flow rate of 200ml/minute, provided that a minimum head of 1.0 meter is maintained and at a temperature not exceeding 250C.
[][]When the sampled steam is condensed, any non-condensable gases that may be present are liberated and separated from the produced condensate into two sight glass columns.
[][]The gas and steam condensate volumes are measured by the ‘zero adjustable’ scale mounted behind the two sight glasses.
[][]Perform the test for 3 consecutive working days.
[][]Record the result in Appendix 1.

 Acceptance Criteria

[][]The results of the non-condensable gas test are deemed to be acceptable for sterilization purposes if the percentage of gas to condensate is less than 3.5%.
[][]Observations:
[][]Done by: Checked by:

Steam Superheat Value

Test Method
[][]The temperature of steam passing through an orifice in a pitot tube is measured.
[][]The temperature is measured by using a thermocouple which is located at the centre of the expansion tube placed over the pitot tube.
[][]The test is intended to demonstrate that the amount of moisture in the steam supply is sufficient to prevent the steam from being superheated as it enters the expanded space of a sterilizer chamber.
[][]Perform the test for 3 consecutive working days.
[][]Record the result in Appendix 2.

Acceptance Criteria

The temperature of the pure steam is considered to be acceptable if it is less than 250C above that of the local temperature of boiling water, which is altitude dependent.

Pure Steam Dryness Value

Test Method

[][]The purpose of the steam dryness value test is to ensure that an acceptable amount of moisture is present in the steam supply. If too little moisture were present, superheating of the steam may occur.

[][]Too little moisture may also prevent the optimum sterilization conditions occurring within the sterilizer load because, moisture is the critical factor breaking down the cell structure of sporing organisms.

[][]The method employed is the heat balance using a stainless steel vacuum flask. The principal being that the flask is primed with a known mass of water at a known temperature.

[][]Steam is then condensed in the flask thus raising the temperature of the water. When the final mass and temperature of the water are measured and placed to the excel worksheet, provided by the manufacturer of the Steam Quality Test Kit, the dryness value is calculated.
[][]Perform the test for 3 consecutive working days.
[][]Record the results in Appendix 03.

Acceptance Criteria

=>The Pure Steam Dryness Value must be within 0.9 – 0.95.

Chemical tests

Test Method

[][]Three tests will be performed as chemical tests such as Appearance test, conductivity as well as TOC. The pure steam will be collected in a depyrogenated flask and the chemical tests would be performed for the condensate of the pure steam. Wear hand gloves and goggles while collecting the sample.
[][]Perform the test for 3 consecutive working days.
[][]The results will be provided from the Quality Control department in the respective forms and will be attached with the report.

Acceptance Criteria:

=>The specifications of these tests according to QC/SPEC/RMEXXX/01:

TestsAcceptance Limit
AppearanceClear, colorless and odorless liquid.
ConductivityNot more than 1.1µS.cm-1 at 200C
Or
Not more than 1.3µS.cm-1 at 250C
TOCNot more than 0.5 mg/L

Microbiological tests

Test Method

[][]Microbiological tests will be performed by collecting the pure steam in a depyrogenated flask. Wear hand gloves and goggles while collecting the sample.
Perform the test for 3 consecutive working days.
[][]The results will be provided from the Microbiology department in the respective forms and will be attached with the report.

Acceptance Criteria:

The specifications of these tests according to QC/SPEC/RMXXX/01:

TestsAcceptance Limit
Total viable Microbial CountNot more than 10 CFU/100mL.
E.ColiMust be absent
Staphylococcus aureusMust be absent
Pseudomonas aeruginosaMust be absent
Salmonella sppMust be absent
Bacterial EndotoxinsLess than 0.25 EU/ml

Sampling Points and Test Frequency

The list of sampling points which come into product contact is given below:

Sl. No.Sampling point nameRoom No.BlockRoom NameTestsFrequency
01PS – 01SPR0XXCephalosporinAutoclaveNon-condensable gas, steam superheat value, steam dryness factor, chemical and microbiological tests.6 months.

Deviation And Failure Investigation Summary

[][]In the column below, record any deviation or failure that occurred during the PQ exercise.

Report Summary

The report summary of performance qualification of Pure Steam system shall be mention here.

Conclusion

The Performance Qualification of the Pure Steam system of Cephalosporin Block Complies / Does Not Comply with the acceptance criteria taken above and the results obtained are attached with the protocol.
The Pure Steam system is / is not qualifying the Performance Qualification test as per this Protocol. Hence, the system can be / cannot be used for production operation.

 

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Performance Qualification of Pure Steam Protocol


Vial Filling Machine Performance Qualification

Performance Qualification Protocol

Vial Filling Machine Performance Qualification, Purpose

[][] Vial Filling Machine Performance Qualification, The purpose of this protocol is to provide an outline for the Performance Qualification of Vial/Vial Filling Machine to:
=>Demonstrate that the system performs as intended by repeatedly running the system on its intended schedules under normal operating conditions and worst-case conditions, where appropriate.
=>To assess the machine capability to fill consistent volumes at various running speed.
=>To check the stoppering of vials.
=>To check the presence of any particulate matter visually.

Vial Filling Machine Performance Qualification, Scope

[][]The aim of this qualification is to perform the performance qualification of the following machine. It is documented evidence that the machine installed properly and functions correctly in accordance with the desired specification as well as manufacturer’s information. It also certifies that the machine operates reliably and within prescribed or specified operating limit. This protocol covers the following machine:

=>Equipment Name

=>Machine No.

=>Location

People Also Read

Cartridge Filling Machine Performance Qualification Protocol

 

Responsibility

[][]Protocol preparation as per the guideline of Validation Master Plan
=>Validation Dept.
[][]Check & review of the protocol
=>Validation & Technical Expert*
[][]Approval of protocol prior to execution
=>Head of Validation, QA, Engg., Plant
[][]M/C operation , testing and data processing
=>Validation team
[][]Microbiology challenge test
=>Microbiology
[][]Preparation of report
=>Validation Dept.
[][]Check & review of the report
=>Validation & Technical Expert*
[][]Approval of the qualification report
=>Head of Validation/QA/Engg./Plant
[][]Authorization of the report
=>Director, Technical Operations
[][]Protocol preparation as per the guideline of Validation Master Plan
=>Validation Dept.

System and process Description

The Vial filling and stoppering machine is used to fill and stopper the vials. The machine consists of following parts:

Line 1:
[][]This line is a compact filling line with capacity to fill around 6000 Vials/ hr. This machine can fill from 0.3 ml to 2.1 ml. In brief its function is as follows:
[][]The vials are fed upright from a depyrogenation tunnel connected to upstream on to an in feed rotary table.
[][]This table rotates continuously and guides the vials with various deflectors through two infeed lanes into the walking beam transport system.
[][]There are two sensors attached in each lane to detect fallen containers, which after detection goes to bin.
[][]These containers are stopped by two infeed gates.
[][]If there are enough containers in the in feed tracks the container feed sensors at the in feed are actuated and infeed gates open.
[][]The walking beam advances the containers intermittently to various work station where two containers are processed at each machine cycle as per following sequence:

 

Nitrogen flushing=>Filling=>Nitrogen flushing =>Stoppering=>Discharge=>stopper Checking =>Visual Inspection=>Confirmation

 

Machine consists of following parts:.
Infeed Rotary Table —

[][]The containers are placed upright on the infeed rotary table by the machine upstream- The containers are conveyed continuously until they are stopped by infeed gates.
[][]There is ultrasonic sensor on table which detects Quantity of containers on the table.
[][]If too many containers accumulate on table then sensor give message to tunnel to reduce the speed of tunnel automatically.
[][]When Quantity is reduced , automatically tunnel increase its speed.

Container feed tracks and monitoring –

[][]The containers from above table are feed into two tracks, where they pass an outlet in the rim of table where fallen containers roll out into a bin beneath the rotary table.
[][]A sensor is located in each feed track. If the container supply in one of the track is very much low , then infeed gates closes, so no further container enter the machine from this track.
[][]When the supply replenish the gates reopen.

Infeed gates

[][]The containers arriving in the infeed tracks are stopped by the infeed gates and are prevented from entering the walking beam.
[][]When the infeed gates are switched on at the operating panel, each gate opens to let containers into transport system provided that the respective container feed sensor detect sufficient containers in the track.

Container Registration sensor

[][]This detect the containers in walking beam and transform information to machine cycle to start the process.
[][]If no container is detected then work station is blocked automatically.

Walking beam transport System –

[][]This system transport the vials through the machine.
[][]They are conveyed upright on a base guide between walking beam and the counterguide.
[][]This walking beam consist of two parts : one part centers the vials and the other one transport them.

Liquid dosing unit –

[][]The product is filled by 2(two) rotary piston pump. The amount dispensed is virtually proportional to the pump stroke.

[][]As the pump piston rise. Product is drawn from the manifold to the pump via hoses.

[][]The piston then turns through 180°, so that the grooves are directed towards the filling needle.
[][]As the pistons are lowered, the product is discharged through dosing hoses and filling needle in to the vials.
[][]This dose can be adjusted by altering the pump stroke.

Gas-flushing Equipment –

[][]Two needles for pre flushing and two needle for post flushing are provided in this system.
[][]The gas flushing needles are lowered in containers with the filling needle movement and flush the container interior with 0.2µ filtered Nitrogen, thereby displacing the ambient air from the container.

Stopper insertion station –

[][]At this station the rubber stoppers are placed on the neck of containers and then pressed in.
[][]The vacuum required for the insertion station is provided by inbuilt vacuum pump.
[][]This station consists of Stopper feed, sorting bowl filling level monitor, Feed track monitoring, stopper check sensors, discharge wheel and tray loading unit.

Line-2:

[][]This line is a compact filling line with capacity to fill around 12000 ampoules/ hr. It has ampoule sealing machine also. This machine can fill from 0.3 ml to 2.1ml. In brief its function is as follows:
[][]The Ampoules are fed upright from a Depyrogenation tunnel connected to upstream on to a in feed belt.
[][]At the end of belt the ampoules are picked by the feed scroll, spaced by the recesses of the scroll and pushed into the individual transport recesses around the periphery of star wheel.
[][]The star wheel conveys the ampoules in a continuous movement and present to individual work stations.
[][]The rotation discs located at the work stations rotate the ampoules during all the work process to ensure smooth functioning of each step.
[][]All the work stations move forward synchronously with the containers during ampoule processing and swivel back to initial position after end of process.
[][]Four ampoules are processed at each machine cycle with following sequence:

Nitrogen flushing=> Filling =>Nitrogen flushing =>Heating of tips of Ampoules =>Sealing by Fusing =>Pulling of Ampoule tips=>Discharge

 

Machine consist of following parts:.

Infeed belt

[][]The containers are placed upright on the infeed belt by the machine upstream.
[][]If too many containers accumulate on belt then sensor give message to tunnel to reduce the speed of tunnel automatically.
[][]When Quantity is reduced, automatically tunnel increase its speed.
[][]If no container arrive from tunnel, then infeed scroll of AFV stops, preventing any further ampoules from entering the star wheel.

Container Registration sensor

[][]Before each transport recess on the star wheel reaches the first work station, a light sensor checks for the presence of Ampoule.
[][]If ampoule is detected, the pulse emitted by the photoelectric sensor is memorized in electronic control and this information is transferred for running all machine cycles.
[][]If no ampoule is detected then work stations are blocked automatically..

Liquid dosing unit

[][]The product is filled by 4(Four) rotary piston pump. The amount dispensed is virtually proportional to the pump stroke. As the pump piston rise.
[][]Product is drawn from the manifold to the pump via hoses.
[][]The piston then turns through 180°, so that the grooves are directed towards the filling needle.
[][]As the pistons are lowered, the product is discharged through dosing hoses and filling needles in the ampoules.
[][]This dose can be adjusted by altering the pump stroke.

Gas-flushing Equipment

[][]Four needles for pre flushing and Four needle for post flushing are provided in this system.
[][]The gas flushing needles are lowered in Ampoules with the filling needle movement and flush inside the Ampoule interior with 0.2µ filtered Nitrogen, thereby displacing the ambient air from the Ampoule.

Line 3 :

[][]This line is a compact filling line with capacity to fill around 6000 vials/ hr.
[][]It is also set for full stoppering as this line is only for liquid filling.
[][]This machine can fill from 0.3 ml to 2.1 ml. This machine is same as line 1.

Line 4:

[][]This line is a standalone filling line with capacity to fill around 6000 vials/ hr.
[][]It is also set for full stoppering as this line is for liquid filling.
[][]This machine can fill from 0.7 ml to 5.5 ml and 8 ml to 50 ml.
[][]In this machine the vials are sterilized in Dry Heat sterilizer in trays and are feed manually to machine.

Tests To Be Performed and Planned

Sl.NoTestPlan/Frequency
01Consistency in fill volume at various speedConsecutive 3 runs
02Proper StopperingConsecutive 3 runs
03Check of presence of any particulate matterConsecutive 3 runs

Test Details and Records

Consistency of Filled Volume

[][]The vial filling machine is started at a main drive motor speed of 100% and after 15 minutes 10 vials are collected to check the consistency of filled volume.
The same procedure is repeated for 90% and 80% main drive motor speed.
[][]Result is recorded in the result sheet form.

Record of consistency of filled volume

=>Media used for filling
=>Vial Size

ParticularsRun 1 Date:Run 2 Date:Run 3 Date:
No. of 3ml vials to fill at main drive motor speed of 100%
Average volume of 10 Vials at 15 Minutes after start
No. of 3ml vials to fill at main drive motor speed of 90%
Average volume of 10 Vials at 15 Minutes after start
No. of 3ml vials to fill at main drive motor speed of 80%
Average volume of 10 Vials at 15 Minutes after start

Acceptance Criteria:  The filled volume has to be within 10ml ± 0.5ml.

Check of Stoppering

[][]In each run 20 vials are collected to visually check the stoppering.

Result of checking stoppering
Run no.DateNo. of properly stroppered vialsNo. of not properly stroppered vialsPercentage of rejected vials

Acceptance Criteria:   The number of rejected vials has to be less than 1.0%.

Check of presence of any particulate matter

[][]In each run 20 vials are collected to check the presence of any visible particulate matter.

Result of checking presence of any particulate matter
Run no.DateNo. of total filled vialsNo. of rejected vialsPercentage of rejected vials

[][]Acceptance Criteria:   The number of rejected vials has to be less than 1.0%.

Report Summary

[][]The Performance Qualification study for Vial/Vial Filling machine was carried out for 3 consecutive date and following result summary was obtained.

No.TestsAcceptance limitsRun 1
Passed (Y/N)
Run 2
Passed (Y/N)
Run 3
Passed (Y/N)
01Consistency in fill volume at various speedNMT 0.5ml Variation from adjusted Limit
02Proper Stoppering99% Complies
03Check of presence of any particulate matter.99% Complies

The Result of this Performance Qualification study was recorded, summarized and analyzed. The observed parameters/tests and subsequent analytical results show that the vial filling machine perform as per predetermined acceptance criteria. Hence, the machine successfully qualifies the performance Qualification test.

Conclusion

The performance qualification complies with the acceptance criteria taken above and the results obtained are attached to the protocol.

Vial/Vial Filling Machine bearing Equipment ID No. ……….………….Is / Is Not qualifying the Performance Qualification test as per the guideline described in this Protocol No. ————- and Can Be / Cannot Be use for production.

 

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Vial Filling Machine Performance Qualification Protocol


Cartridge Filling Machine Performance Qualification

Performance Qualification Protocol

Cartridge Filling Machine Performance Qualification, Purpose

[][]Cartridge Filling Machine Performance Qualification, The purpose of this protocol is to provide an outline for the Performance Qualification of Vial/Cartridge Filling Machine to:
[][]Demonstrate that the system performs as intended by repeatedly running the system on its intended schedules under normal operating conditions and worst-case conditions, where appropriate.
[][]To assess the machine capability to fill consistent volumes at maximum and minimum running speed.
[][]To verify the gliding force of filled cartridges.
[][]To ensure proper stoppering.
[][]To check the air bubble size with respect to glass bead size.

Cartridge Filling Machine Performance Qualification, Scope

[][]The aim of this qualification is to perform the performance qualification of the following machine. It is documented evidence that the machine installed properly and functions correctly in accordance with the desired specification as well as manufacturer’s information.
[][]It also certifies that the machine operates reliably and within prescribed or specified operating limit. This protocol covers the following machine:

 

People Also Read

Vial Filling Machine Performance Qualification Protocol

 

Responsibility

[][]Validation Dept.
Protocol preparation as per the guideline of Validation Master Plan
[][]Validation & Technical Expert*
Check & review of the protocol
[][]Head of Validation, QA, Engg., Plant
Approval of protocol prior to execution
[][]Validation team
M/C operation , testing and data processing
[][]Microbiology
Microbiology challenge test
[][]Validation Dept.
Preparation of report
[][]Validation & Technical Expert*
Check & review of the report
[][]Head of Validation/QA/Engg./Plant
Approval of the qualification report
[][]Director, Technical Operations
Authorization of the report
[][]Validation Dept.
Protocol preparation as per the guideline of Validation Master Plan

System and process Description

[][]The Cartridge filling and stoppering machine is used to fill and stopper the Cartridges. The machine consists of following parts:
[][]This line is a compact filling line with capacity to fill around 2500 cartridges/ hr. The cartridges are fed upright from a depyrogenation tunnel connected to upstream on to an in feed rotary table.
[][]There is a vibrator by which this table is vibrated continuously and guides the cartridges with various deflectors through infeed lanes into the filling portion. There is a sensor to detect fallen containers.
[][] If there is any fallen cartridge, it shows alarms on the display and the machine is stopped. If there are enough containers in the in feed tracks the container feed sensors at the in feed are actuated and infeed gates open. After coming through the in feed rotary screw the glass beads are inserted into the cartridges.
[][]There are two rotary piston pumps for transferring the filling media from vessel to the two filling nozzles. First nozzle is for filling half of the required volume and second one is for remaining half.
[][] There is a nozzle for sucking the access media at the 2nd filling nozzle. The filling volume is virtually proportional to the stroke of the piston pumps.
After filling, the flip off seals are attached at the top of the cartridges.
[][]There is a container for flip off seals and these are transferred by using the vibration. A proximity sensor detects the presence of flip off seals.
[][]The whole process occurs under a Laminar Air Flow Unit which ensures a clean area of Class A (ISO Class 5). The flow diagram of filling machine is as follows:

Tests To Be Performed and Planned

SR./NO.TestPlan/Frequency
01Consistency in fill volume at various speedConsecutive 3 runs
02Gliding force measurement for filled cartridges.Consecutive 3 runs
03To check the bubble size with respect to size of Glass beads.Consecutive 3 runs
04To check proper stoppering.Consecutive 3 runs

Test Details and Records

Consistency of Filled Volume

[][]The cartridge filling machine is started at a main drive motor speed of 100% and after 15 minutes 10 cartridges are collected to check the consistency of filled volume.
[][]The same procedure is repeated for 90% and 80% main drive motor speed.
[][]Result is recorded in the result sheet form.

Record of consistency of filled volume

Cartridge SizeRun 1
Date:		Run 2
Date:		Run 3
Date:
No. of 3ml cartridges to fill at main drive motor speed of 100%
Average volume of 10 Cartridges at 15 Minutes after start
No. of 3ml cartridges to fill at main drive motor speed of 90%
Average volume of 10 Cartridges at 15 Minutes after start
No. of 3ml cartridges to fill at main drive motor speed of 80%
Average volume of 10 Cartridges at 15 Minutes after start

Acceptance Criteria: The filled volume has to be within 3ml ± 0.3ml.

Gliding Force for Filled Cartridges

[][]10 cartridges are marked and loaded with the cartridges of total batch.
[][]After filling and stoppering 10 filled cartridges are collected at 15 minutes after starting the machine at a speed of 100% of main motor.
[][]The procedure is repeated twice by varying the speed to 90% and 80% of the main motor.

Record of Gliding Force for Filled Cartridges

Run no.Gliding Force Measuring Machine SpecificationDateAverage Gliding Force
(Newton)
Met Acceptance Criteria (Y/N)
01
02
03

Acceptance Criteria: The gliding force has to be less than 20N.

Bubble Size

[][]In each run 20 cartridges are collected to visually check the presence of glass beads and the bubble size with respect to glass bead size.

[][]Result of checking bubble size

Run no.DateGlass bead present (Y/N)Bubble present (Y/N)Bubble size is smaller than glass bead size (Y/N)Percentage of rejected cartridges

Check of Stoppering

In each run 20 cartridges are collected to visually check the stoppering.

Result of checking stoppering

Run no.DateNo. of properly stroppered cartridgesNo. of not properly stroppered cartridgesPercentage of rejected cartridges

Acceptance Criteria: The number of rejected cartridges has to be less than 10%.

[][]List of Reference Involved in Validation Study

[][]Details Of Attachments To Validation Report

Report Summary

The Performance Qualification study for Vial/Cartridge Filling machine was carried out for 3 consecutive date and following result summary was obtained.

No.TestsAcceptance limitsRun 1
Passed (Y/N)
Run 2
Passed (Y/N)
Run 3
Passed (Y/N)
Consistency in fill volume at various speedNMT 0.3ml Variation from adjusted Limit
Gliding force for filled cartridgesGliding Force for filled cartridges has to be less than 20 Newton.
Bubble SizeBubble size has to be less than glass beads size.
Proper Stoppering99% Complies

[][]The Result of this Performance Qualification study was recorded, summarized and analyzed. The observed parameters/tests and subsequent analytical results show that the cartridge filling machine perform as per predetermined acceptance criteria. Hence, the machine successfully qualifies the performance Qualification test.

Conclusion

[][]The performance qualification complies with the acceptance criteria taken above and the results obtained are attached to the protocol.

[][]Vial/Cartridge Filling Machine bearing Equipment ID No. ……….………….Is / Is Not qualifying the Performance Qualification test as per the guideline described in this Protocol No. ————- and Can Be / Cannot Be use for production.

 

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Performance Qualification of Cartridge Filling Machine Protocol


Depyrogenation Tunnel Performance Qualification

Performance Qualification Protocol

Depyrogenation Tunnel Performance Qualification, Purpose

Depyrogenation Tunnel Performance Qualification, To authenticate and document that the performance of the Depyrogenation Tunnel of Sterile Production area (Cephalosporin Block) of XX Pharmaceutical Limited (PPL) is satisfactory in all critical aspects related to the operational requirements. This protocol describes the performance qualification procedures of the Depyrogenation Tunnel manufactured by Tofflon, China.

Depyrogenation Tunnel Performance Qualification, Scope

This Performance Qualification (PQ) is to be performed against agreed acceptance criteria on the vials of three sizes such as 7.5 ml, 15 ml and 30 ml, which will be sterilized by the Depyrogenation Tunnel installed in the Sterile Production area of Cephalosporin Block of XX Pharmaceutical Limited.

 

People Also Read

Autoclave Performance Qualification Protocol

 

Responsibilities

Preparation of the protocol

[][]Validation (Engineering) Department with the assistance of Microbiology, Engineering and Maintenance department.

Executing the protocol

[][]Validation (Engineering) Department along with respective departmental person and engineers or other suitably qualified staff allocated from the site or contracted specialists as appropriate.

Microbiological Challenge Test

[][]Microbiology department

Data documentation and preparation of the report

[][]Validation (Engineering) department.

Verifying of the report

[][]Concerned departmental person.

Providing documentation on the equipment

[][]Related departments i.e. Engineering, Production, Microbiology, Validation or other appropriate departments and manufacturer.

Equipment Information

=>Manufacturer : Tofflon, China
=>Capacity : 6000-9000 vials /hr
=>Model : SZA 620
=>Serial no. : YF2014-078B

The Equipment under test

[][]The Depyrogenation tunnel under validation study has the following segments:
=>Pre-heating zone
=>Sterilization zone
=>Cooling zone
[][]The whole production process combines in a line consecutively with a Vial washing machine, Depyrogenation tunnel, Vial Filling machine and Cap sealing machine.

[][]The washed Vials are conveyed into the Pre-heating Zone of the Depyrogenation tunnel automatically after washing in the vial washing machine.

[][]The Vials are flooded with sterile air in this zone. The temperature controlling preset values maintain the circulating air temperature at that preset value.

[][]The warm Vials are then transported into the Sterilizing Zone and are sterilized & depyrogenated by a low turbulence air flow (up to 300°C). The air is heated in an air circulation duct and then flows through the high temperature HEPA filters prior to reaching the vials.

[][]These filters ensure that the air quality corresponds to clean room class A (class 5 according to ISO 14644) in all operation modes, even in the heating and cooling phases. In the last work zone (cooling zone) of the tunnel, the sterilized Vials are cooled down by a vertical low turbulence air flow.

[][]The discharge from the tunnel opens into a clean room where the depyrogenated Vials are stored on a turn table and conveyed by belt transfer system to the infeed of filling machine.

Checking Parameters

[][]The PQ of Depyrogenation Tunnel will be carried out to evaluate the following conditions to confirm the sterilization conditions:
=>Heat Penetration (HP) studies.
=>Microbiological Challenge (MC) test using Endotoxin Challenge Vials.

The system/ equipment to be used as Standard for testing

[][]Performance of the Depyrogenation Tunnel will be judged based on thermal and biological studies which are mentioned below:
=>Equipment Name: Anville Data Logger, TQ Soft Version 6.1.2 with thermocouples.
=>Requirement for challenge test: -Endotoxin Challenge Vials.

Pre requirement For Validation:

[][]Calibration of thermocouples of the data logger/Validator before and after validation with proper identification.
[][]Valid calibration record of Data Logger/Validator.
[][]Data logger reading intervals set at 30 seconds (maximum).
[][]Successful calibration of the Temperature sensors of Depyrogenation Tunnel.
[][]Successful completion of IQ and OQ.
[][]Endotoxin Challenge Vials for ensuring 3 log reduction.

Study Procedure:

Heat Penetration (HP) Study:

[][]The equipment must be run three times at fully loaded condition for each size of vial where seven thermocouples are exposed to monitor the temperature within the loads.
[][]The number of measurement points will be dependent of the width of the tunnel. As the width of the tunnel is 590 mm, seven thermocouples will be placed at 98 mm distance from each other as shown in Appendix – 01.
[][]The conveyer belt of the tunnel will be run at about 98.4 mm/min and 90.2 mm/min for 7.5ml, 15ml and 30 ml vials respectively.
[][]Care must be taken to avoid contact between the thermocouples and the metal surface of the chamber. Evenly distribute the thermocouples as it is shown in the Appendix – 01.
[][]The Results of this test will be recorded in the Appendix-03 (Number of this appendix will be increased as per number of cycles) and will be accepted if met the acceptance criteria.

Microbiological Challenge (MC) test:

[][]This test will be performed while performing the HP study. Seven Endotoxin challenge Vials (ECV) are distributed along with the thermocouples at defined positions of conveyer belt of tunnel at fully loaded condition as per specified load pattern as specified in Appendix -1.
[][]After completion of the cycle ECVs will be tested by the microbiology department for required log reduction.
[][]The results of above test should be recorded in the designated form (Appendix-4).

Acceptance Criteria

For Heat Penetration (HP) study:

[][]During sterilization period; all thermocouple readings must be within set temperature (300deg.C)±15deg.C.
[][]During sterilization period; when all thermocouples are showing a minimum of 285deg.C, temperature difference among the thermocouples are not more than 15deg.C.
[][]For cooling zone performance study:
[][]After passing sterilization zone, minimum reading of all thermocouples are below 35deg.C.

For Microbiological Challenge Test:

[][]The ECVs not exposed to the Depyrogenation cycle (control) should show clot after incubation at time and temperature as per COA.
[][]The Endotoxin content of a challenge vial must be reduced at least 1000 fold (> 3 log reduction).

Deviation And Failure Investigation Summary

In the column below, record any deviations or failures that occurred during the PQ exercise.

Deviation/ Failure No.Description and Assessment of Impact on ValidationInitialDate
1
2
3

Reference Documents

[][]FDA Guidance for Industry ( for the Submission Documentation for Sterilization Process Validation in Applications for Human and Veterinary Drug Products).

Download Here

Depyrogenation Tunnel Performance Qualification Protocol


Autoclave Performance Qualification Protocol

Performance Qualification Protocol

Autoclave Performance Qualification Protocol, Purpose

Autoclave Performance Qualification Protocol, To authenticate and document that the performance of the Autoclave (Steam sterilizer) of Sterile Production area (Cephalosporin Block) of XX Pharmaceutical Limited (LPL) is satisfactory in all critical aspects related to the operational requirements during sterilization of porous, solid and liquid loads. This protocol describes the performance qualification procedures of the Autoclave manufactured by Zirbus, Germany.

Autoclave Performance Qualification Protocol, Scope

This Performance Qualification (PQ) is to be performed against agreed acceptance criteria on different types of loads which will be sterilized by the Autoclave (Steam Sterilizer) installed in the Sterile Production area of Cephalosporin Block of XX Pharmaceutical Limited.

[][]Preparation of the Protocol
Validation (Engineering) Department with the assistance of Microbiology, Engineering and Maintenance department.
[][]Executing the protocol
Validation (Engineering) Department along with respective departmental person and engineers or other suitably qualified staff allocated from the site or contracted specialists as appropriate.
[][]Microbiological Challenge Test
Microbiology department
[][]Data documentation and preparation of the report
Validation (Engineering) department.
[][]Verifying of the report
Concerned departmental person.
[][]Providing documentation on the equipment
Related departments i.e. Engineering, Production, Microbiology, Validation or other appropriate departments and manufacturer.

 

People Also Read

Depyrogenation Tunnel Performance Qualification Protocol

 

System and process Description

Equipment Information

=>Manufacturer : ZIRBUS, Germany
=>Capacity : 702 Ltr.
=>Model : HST 6×6×12
=>Serial no. : 3609

The Equipment under test

[][]The autoclave under validation study is a double door horizontal autoclave; chamber is made of SS 316L. The product is fed into the chamber via a loading port and drawn off after the sterilization cycle via the discharging port in a clean room of Grade B.
[][]A chamber leak test is performed to ensure that there is no leakage. It is very important to remove the air from the chamber. A water ring vacuum pump is used to remove the air from the chamber.
[][]For porous loads pre vacuum is important to remove the air pockets from the pores of the loads. To remove residual air vacuum pulse followed by steam pulse is used. After completion of vacuum and steam pulse the chamber is heated up with pure steam to the set sterilization temperature.
[][]There are two temperature sensors of which one is set inside the chamber and another is set in the drain port of the chamber. When the solid cycle is run, the drain temperature sensor controls the cycle. On the other hand, when the liquid cycle is run, the product temperature sensor controls the cycle

Checking Parameters

The PQ of autoclave will be carried out to evaluate the following conditions to confirm the sterilization conditions:
=>Chamber Leak Test (LT).
=>Bowie-Dick (BD) test.
=>Heat Penetration (HP) studies.
=>Microbiological Challenge (MC) test using Biological Indicators (BI).

The system/ equipment to be used as Standard for testing

Performance of the autoclave will be judged based on thermal and biological studies which are mentioned below:
=>Equipment Name: Anville Data Logger, Series 825 NATO.
=>Software: TQ Soft version 6.0

Requirement for challenge test:

=>Bowie-Dick test pack
=>Biological Indicator
[][]After completion of the cycles, all individual cycle records are summarized and compared with the autoclave printouts to verify the cycle consistency and performance.
[][]For Biological studies, Biological Indicators will be placed along with probes and will be studied for microbiological challenge test.

Pre requirement For Validation:

[][]Calibration of thermocouples of the data logger/Validator before and after validation with proper identification.
[][]Valid calibration record of Data Logger/Validator.
[][]Data logger reading intervals set at 30 seconds (maximum).
[][]Successful calibration of the Pressure and Temperature sensors of autoclave.
[][]Successful completion of IQ and OQ of Autoclave.
[][]Tubes of Geobacillus Stearothermophilus spores will be used as biological indicators. They should be labeled and placed at the front, middle and back of the autoclave chamber.

Study Procedure:

Chamber Leak (CL) Test:

[][]Thermocouples and reference pressure transducer are introduced into the chamber via the validation port. Then, the port and doors are sealed properly. There is a cycle, named as “Vacuum air test” cycle for leak test which is programmed in the PLC of the machine.
[][]During leak test, chamber pressure is reduced to a 70 mbar pressure and then this pressure is compensated and hold for 5 and 10 minutes respectively. The test is declared passed if the pressure rise is within 13 mbar within the holding time.
[][]If there is any leakage of steam for disintegration of gasket or any other reason, the autoclave might fail to achieve vacuum and leak test will be failed.
The results of above test will be recorded in the Appendix – 03 and will be accepted if met the acceptance criteria.

Bowie-Dick (BD) test:

[][]The Bowie-Dick (BD) test is done to detect air pockets and to evaluate that the vacuum retains as well as steam penetrates sufficiently for sterilization. This is because, air removal from the pores of the loads is essential for proper sterilization and to remove this air pre-vacuum pulse is important.
[][]For conducting this test, Bowie-Dick test paper kits will be exposed for 10 minutes at a temperature of 121.1OC inside the chamber. If the color of the centered sheet turns completely into black, it ensures proper vacuum of the chamber as well as proper steam penetration into the load and the test will pass.
[][]Any intermediate color change of centered sheets except black (e. g. grey, brown or blue) indicates the presence of residual air in the chamber.
[][]So, the test will fail. It may occur due to the failure of retaining required vacuum of the chamber and the insufficient steam penetration.
[][] In that case, increase the pre-vacuum pulse number or sterilization time which will ensure proper removal of air as well as the steam penetration respectively. This must be recorded in the report.
[][]The successful bowie-dick test’s pre-vacuum pulse numbers and sterilization time must be followed in the porous loads’ cycle.
The results of above test should be recorded in the Appendix – 04 and will be accepted if met the acceptance criteria.

Heat Penetration (HP) Study:

[][]The equipment must be run three times at fully loaded condition for each load pattern where twelve sensors are exposed to monitor the temperature within the loads as well as in the chamber.
[][]Care must be taken to avoid contact between the thermocouples and the metal surface of the chamber.
[][]Evenly distribute the thermocouples as it is shown in the Appendix – 2. In case of liquid load place the thermocouple no. 02, 03, 07 inside the container of the liquid.
[][]The Results of this test will be recorded in the Appendix-05 (Number of this appendix will be increased as per number of cycles) and will be accepted if met the acceptance criteria.

Microbiological Challenge (MC) test:

[][]This test will be performed with HP study. The temperature probes are distributed at different positions within the chamber and loads as per specified load pattern. Biological Indicators are placed beside the thermocouples as per BI placement diagram (Appendix – 01).
[][]It is to be noted that the Microbiological challenge test will be conducted for the heat penetration study cycles. Furthermore, the lethality value (F0) must be calculated by the TQ software and minimum lethality value must be recorded in Appendix 06.
[][]The results of above test should be recorded in the designated form (Appendix – 06). (Number of this Appendix will be increased as per number of cycles).

Acceptance Criteria

Chamber Leak test:

=>This test is deemed to be passed if the pressure rise of the chamber is within 13 mbar.

For Bowie-Dick test:

=>This test is passed if the color of the Bowie-Dick test kit turned uniformly to black having no intermediate color change throughout the entire pattern (e.g. gray, blue or violet) which ensures full vacuum and complete steam penetration.

For Heat Penetration (HP) study:

=>Throughout the sterilization period; all temperatures measured in the chamber has to be within a 4°C band from the set point i.e. 121°C (–1°C/+3°C).
During sterilization period; the difference in temperature between the coolest spot and the mean chamber temperature during sterilization hold period shall be within ±2°C.

For Biological Indicator Test:

=>Biological indicators must have an initial viable spore count of 106 or greater of the selected microorganism.
=>Biological Indicator must not show any growth after autoclaving and subsequent incubation.
=>Positive control biological indicators must show “growth” of Geobacillus Stearothermophilus.
=>The lethality (F0 value) must be equal or greater than 12 minutes.

Deviation And Failure Investigation Summary

In the column below, record any deviations or failures that occurred during the PQ exercise.

Deviation/ Failure No.Description and Assessment of Impact on ValidationInitialDate
1
2
3

Reference Documents

[][]SOP for validation of Moist Heat Sterilizer by Biological Indicator.
[][]USP general chapter <1222> Terminal Sterilized Pharmaceutical Products-Parametric release
[][]FDA Guidance for Industry ( for the Submission Documentation for Sterilization Process Validation in Applications for Human and Veterinary Drug Products); November 1994
[][]Practical Guide to Autoclave Validation by Raymond G. Lewis.

Download Protocol:

Autoclave Performance Qualification Protocol


Pest Control Procedure

Pest Control, SOPs

Pest Control Procedure, Purpose

Pest Control Procedure, To prevent/control the entrance of pest & rodents within the facilities.

Pest Control Procedure, Scope

This SOP is applicable to control the entrance of rodents and insects both in-door and outdoor of the Plant of XX Pharma Limited.

Definition & Abbreviation

[][]Pest: Insects or animals that destroy plants, food & materials.
[][]Pest Control: Destruction of pest by appling poisons, traps or controlling of insets harmful for food, medicine, plants or packaging materials.

Responsibility

[][]‘YY Pest Control Company ’ is responsible to carry out the pest control activities on previously defined contact basis as per agreed valid schedule.
[][]Production & Quality Assurance  personnel are responsible to monitor that all insecticides are used in proper valid concentration & in all areas/points as described in the approved layout.
[][]Head of Quality Assurance & Head of Production shall ensure the implementation of this SOP according to GMP Guidance to ensure the safety of personnel, materials & products.
[][]Head of Administration or his nominee is mainly responsible to confirm that all Pest Control activities has been carried out in accordance with the predefined schedule.

Materials & Equipment

[][]Actellic 50ec
[][]Hydramethylnon
[][]Icon 10wp
[][]Icon 2.5ec
[][]Permakill concentate (Fogging)
[][]Phenol (C6H50H)
[][]Silosan
[][]Tespi liquid (Fogging)

Precaution

[][]Confirm that all raw material, finished goods, intermediates or any type of process goods should not be present in area of fumigation, if present cover all the materials with polythene bag.
[][]Perform all pest control activities only on weekly holiday/any Govt. Holiday when the Plant production activities are completely closed.
[][]Do not spray any insecticide inside the factory. Use only in outside of the factory.
[][]Before spraying/fogging confirm that all doors and windows of the factory are properly closed.
[][]Do not smoke/drink /eat during handling of any type of pesticides, do not breathe mists or dust, avoid prolonged contact with the skin.
[][]Always read the Material Safety Data Sheet (MSDS) for safe use and handling precautions given on the label.
[][] In the very beginning of office hour, Remove feeding traps from all application points.
[][]Always use goggles & nose-mask while doing fumigation.
[][]AHU shall be  switched off before starting fumigation.

Procedure

[][]Pest control operation shall be performed by the selected approved contractor (External: XX PEST CONTROL).
[][]The contractor shall provide the chemicals & plates of glue/gum & trap/baiting for trapping rats and mice.
[][]Admin Department shall prepare schedule with contractor & notify the date to Quality Assurance & other concerned department at least one week before initiating the program.
[][]Concerned department shall take necessary steps for covering related materials which are suspected to expose during pest control activities.
[][]Permanent precaution shall be taken so that no rats,  cockroach or insects can enter factory.

Schedule For Pest Control

Area
(Pharma Building)
Service
(Pest Control By)
Frequency
CorridorSpray1 time per month
Utility AreaULV2 times per month
Outside BuildingRat2 times per month
Canteen DormitoryFogging (Outside)2 times per month
Extra AreaSnakes1 time per month

Materials use for pest control

Ustaad (Sray & ULV)

[][]Active ingredient: cypermethrin
[][]Target pests: Mosquito, ants, cockroach, housefly,  bugs & ticks
[][]Dose & use strategy: 50-100ml/10 liter water

Dursban 20ec (for sray & ULV)

[][]Active ingredient: chloropyrifos
[][]Target pests: Cockroach, ants,  housefly, mosquito, bugs & termites
[][]Dose & use strategy: 50-100ml/10 liter water

Actara (for sray & ULV)

[][]Active ingredient: thiamethoxam
[][]Target pests: all types of termites,  ants,  white flies
[][]Dose & use strategy: 2-8g/10 liter water

Icon 2.5 EC (indoor/outdoor space spray & fogging)

[][]Active ingredient: lambda-cyhalothrin
[][]Target pests: pest adult
[][]Dose & use strategy:
[][]Hand held thermal fogging kerosene: mix 20-70 ml of icon 2.5ec in 1 liter of diesel or kerosene & apply fog.
[][]Fogging: mix 70 ml of icon 2.5 ec in 1liter of diesel or kerosene & apply fog in 2 ha space.
[][]Space spraying (water solvent) : mix 50-100 ml of icon 2.5 ec in 10 liter of water & spray

Permakill( for fogging)

[][]Active ingredient: permethrin
[][]Target pests: mosquitoes, flies, cockroach flying insects
[][]Dose & use strategy: 50-70 ml/1 liter diesel or kerosene for fogging.

Tepsi liquid (for fogging)

[][]Active ingredient: permethrin
[][]Active ingredient: Tetramethrin, Permetrin,Tralletrin
[][]Target pests: ants, cockroach, housefly, mosquito, bugs & ticks
[][]Use strategy: 50-500ml/10 ltr water for spray
[][]4:1 with diesel for fogging
[][]Materials use for use rodent only

Lanirat

[][]Active ingredient : 50 mg bromadeolon per kg-3-[3-(4-bromo[1,1-byfinail]-4il)-3hydroxy-1-finailprofile]-4-hydroxy-2h-1benzofiran-2-one)
[][]Target: rodent

Altorarat

[][]Active ingredient : non poisonous glue
[][]Target : rodent

Materials use snakes control

[][]Trapping is effective to control snakes. However rodent control is performed regularly, snakes control will be reduced. Following steps will be followed for snakes control:
[][]Use Phenol
[][]Use black hole trap
[][]Use snakes tongue for capture snakes safety

Annexure

Appendix –I: log book for pest control
Appendix –II: log book for cleaning after pest control


Functions of Quality Assurance

Quality Assurance, SOPs

Functions of Quality Assurance, Purpose:

Functions of Quality Assurance, The purpose of this SOP ( Standard Operating Procedure) is to outline the functions, principle duties and responsibilities of personnel working in Quality Assurance Department.

Functions of Quality Assurance, Scope:

To provide the guidelines for the proper implementation of the Quality Assurance System at XX Pharmaceuticals Limited ( Both General and Cephalosporin Block).

Definitions / Abbreviation:

[][]Quality Control Department : The Department carrying out day to day activities for the control of procedure, tests & analysis of products/ raw materials/ packaging materials/ stability samples and other relevant analysis of samples at laboratory to assist the manufacturing functions.
[][]Quality Assurance Department: The department carrying out day to day activities for the control of procedure, analysis of documents, regulatory functions, to assist the plant functions for the manufacturing, distributions and other relevant functions.
[][]CAPA : Corrective Action and Preventive Action.

Responsibilities:

[][]The roles and responsibility is as follows:

Executive, Quality Assurance

[][]To follow the guidelines of Quality Assurance
[][]To report their findings to their seniors

Asst. Manager, Quality Assurance

[][]To ensure implementation of the SOP.

AGM, Quality Assurance

[][]Approval of the SOP.

Procedure:

[][]Quality Assurance Department shall function for assuring the quality of all the manufactured batches and every stage of manufacturing / processing of drug Products.
[][]This shall be achieved by performing the functions of monitoring as per the laid down QA systems for the following areas:
[][]Monitor of incoming starting and packaging materials.
[][]Manufacturing process and process checks.
[][]Process monitoring and process control.
[][]Production Record Review.
[][]Final release or rejection of every batch of Drug Products for distribution and sale.
[][]Monitor stability testing and evaluation of shelf-life of products.
[][]Complaints handling and product recalls.
[][]Handling of Change Control Systems.
[][]Out of specification investigation.
[][]Investigation of Deviations.
[][]Returned products ( salvage and disposal ).
[][]Internal Quality Audits.
[][]Co-ordinate monthly Quality Review Meeting and implement the effective CAPAs regarding quality improvement.
[][]Control of non-confirming products.
[][]Co-ordinate all validation and qualification activities.
[][]Reprocessing of non-confirming products.
[][]To achieve the objectives of Quality Assurance functions of XX Pharmaceuticals Limited is classified as follows :
[][]To plan and manage all the activities of Quality Assurance Department to assure the quality of all products manufactured by the Company.
[][]To co-ordinate with manufacturing department in controlling their process and products at every stage of manufacturing to meet the established specifications though testing, auditing and reporting.
[][]To co-ordinate for the development of new product formulation, development of specifications, analytical procedure in co-ordination with Quality Control Department and Product Development Department.

[][]To review the adequacy and relevance of specifications & analytical procedures in co-ordination with Quality Control Department and Product Development Department.
[][]To co-ordinate technical audits of the Quality Control Laboratory to determine the analytical quality systems are yielding the highest quality information and to ensure that the analytical instrumentation is functioning properly and calibration and servicing is as per schedule.
[][]To be responsible for the release functions of the QA Department which shall include :
[][]Maintenance of Quality Control records of manufacturing procedures for each manufactured batch.
[][]Records of release, quarantine or rejection of components and finished products, containers, closures and labels based on Quality Control test results.

[][]Routine “Good Manufacturing Practices Auditing” of manufacturing process, control and related areas.
[][]To suggest and organize training program for the development of technical and administration skills of all the employees to meet with cGMP regulations on continuous basis, coordinating with GM, Plant and Quality Head.
[][]To assist Change Control Committee/Technical Committee for overall reviews of non-conformances, failure investigations, analyzing the Quality trends, investigations of market complaints, batch failure investigations, deviations, verifications of change control procedures, updating the specifications, test procedures, manufacturing processes etc.
[][]To liaison with regulatory authorities for new products manufacturing license and renewals of the same and other regulatory requirement.

Annexure:

N/A


Contract Manufacturing by Third Party

Job Solution, Quality Assurance, SOPs

Contract Manufacturing, Purpose:

Contract Manufacturing, To establish a procedure that XX products are manufactured by the contractor using facilities and operations and to ensure that all batches of product manufactured at third party contract manufacturer that conforms to cGMP requirements undergo a formal evaluation of suitability for use prior to release to the market.

Contract Manufacturing, Scope:

The SOP is applicable for all products of XX Pharmaceuticals Limited manufactured & packed by a third party contract manufacturer.

Definitions / Abbreviation:

[][]QA – Quality Assurance
[][]QC – Quality Control
[][]QA – Quality Assurance
[][]BMR – Batch Manufacturing Record
[][]BPR – Batch Packaging Record
[][]ERP – Enterprise resource planning.
[][]cGMP – Current Good Manufacturing Practice
[][]COA – Certificate of Analysis

Responsibilities:

[][]The roles and responsibility is as follows:

Third party contractor

[][]To perform all the manufacturing related activities, analysis of the manufactured & packed product as per the contract/ toll manufacturing agreement

Executive, Production

[][]To check and review the production related activities.

Executive, Warehouse

[][]To supply and update the required raw and packaging materials as per forecast

Executive, QA

[][]To verify the overall manufacturing activities, collection of sample and related documents

General Manager, Plant

[][]Proper follow-up of overall activities

Manager, Quality Assurance

[][]Approval of all the toll manufacturing activities.

Procedure:

Selection of Third Party/ Contract Manufacturer

[][]Carry out GMP audit to assess the prospective contractor’s technical capability, capacity, cost effectiveness & the capability to maintain the required standards of cGMP & product quality.
[][]Document the business objectives and the justification for selecting a third party contractor.
[][]Review the manufacturing strategy which will be applied to the third party contractors.
[][]After developing a third party contract manufacturer, provide the product and their volume to the third party contractor for its technical assessment of manufacturing capability.
[][]Multiple strategies to be followed in selecting third party contractor.
[][]Consider the sources of materials which must meet the approved specification.
[][]Sign a contract manufacturing agreement with the selected contractor for manufacturing / packaging of products which will be followed accordingly.

[][]XX personnel will generate all the relevant documents as per contract manufacturer’s requirements for batch production.
[][]Production Executive will supply a production forecast of the required quantities of each product two months in advance so as to consider in third party’s

[][]production plan. XX shall have the right to revise the forecast in accordance with the market situation informing contractors one and half month in advance.
[][]Warehouse personnel of contract manufacturer will generate a month wise stock statement for raw and packaging materials to XX.
[][]Production Executive will generate the batch no. as per production forecast to Quality Assurance Executive along with requisition copy for BMR & BPR.

[][] QA Executive will issue the photocopy of BMR & BPR to Production Executive for manufacturing by third party. Master copy of all documents will be preserved at QA end.

[][]For testing procedure of raw and packaging materials will be followed as per contract manufacturing agreement. If any material (Raw/ Packaging) which will be tested by third party, will be forwarded by QC Executive from QUARANTINED stage along with forwarding letter to the contractor.
[][]After receiving the test report from third party, QC personnel will disposition the materials as PASSED/ REJECTED following the SOP.
[][]Production Executive along with warehouse Executive will supply all the materials to third party following the production forecast as per requirement within first week of running month. During supply of materials warehouse executive to be ensured the status label as per requirement by third party.
[][]Contract manufacturer will follow their production schedule and manufacturing operation will be started at the presence of Production and QA personnel of XX.

[][]XX personnel will verify all the written instruction in the BMR & BPR following the third party’s SOP as per cGMP requirement.
[][]All the in-process checks (IPC) will be conducted by contract manufacturer along with XX personnel.
[][]In case of any process validation activities will be conducted by XX personnel using the facility of third party.
[][]For testing of bulk intermediate and finished product, responsibility will be performed by XX and contract manufacturer as per contract manufacturing agreement.
[][]Sample for in-process check, chemical test and microbial test will be withdrawn as per agreement policy following the SOP of XX or contract manufacturer. [][]Finished product samples will be withdrawn as per same requirement.
[][]Retention sample will be kept at contract manufacturer’s end. If the retention sample is required for XX, then the sample will be forwarded to XX end by contract manufacturer following their own policy.
[][]Stability sample will be withdrawn from packaging line as per stability protocol and to be forwarded by contract manufacturer to XX end.

[][]If the stability test will be performed by contract manufacturer, samples will be kept in the manufacturer’s end as per protocol. In that cases test report will be forwarded to XX end accordingly. After receiving all the stability data, QA Executive will prepare the stability report.
[][]Third party contract manufacturer’s site will provide XX personnel with full batch documentation, copies of any unplanned event or deviation (including OOS), a copy of any investigation reports and COA reporting analytical test results against specification.
[][]QA and production personnel will review all the batch documents along with supportive records as per checklist for batch documentation after prior release from contract manufacturer.
[][]Original batch document or photocopy of the original will be provided by the contract manufacturer to XX end.

[][]Production personnel will issue the used quantity of raw and packaging materials in the ERP software with the help of IT personnel according to batch production record to update the material status.
[][]After reviewing the batch document, Production and QA representative will send the notification to the third party contract manufacturer about the batch disposition decision.
[][]Upon receiving the batch disposition decision from XX Pharmaceuticals Limited, the third party contract manufacturer will take step accordingly.
[][]XX shall take delivery of the finished products in XX’s own liabilities within fifteen days of intimation by contract manufacturer that the product is ready for dispatch.

[][]After completion of cost related process by both XX and contract manufacturer, central warehouse will receive the finished product and kept in the central warehouse of XX as per storage condition.

Annexure:

None


Finished Product Handling, Storage & Distribution

Quality Assurance, SOPs

Finished Product Handling, Purpose:

Finished Product Handling, The of these guidelines is to assist in ensuring the quality and identity of pharmaceutical products during all aspects of the distribution process such as storage, distribution, transportation, packaging, labeling, documentation and record-keeping practices.

Finished Product Handling, Scope:

This procedure is applicable for all finished products received and stored after receiving from Packaging department by Central Warehouse and different depots of XX Pharmaceuticals Ltd.

Definitions / Abbreviation:

[][]QA – Quality Assurance
[][]DIC – Depot In Charge
[][]ERP – Enterprise Resource Planning
[][]CWH – Central Ware House
[][]FIFO – First In First Out
[][]XX – Current version no. of the SOP

Responsibilities:

[][]The roles and responsibility is as follows:

Head of Distribution

[][]Head of Distribution shall responsible for overall the distribution activities.

Depot In Charge (DIC), Central Warehouse & Different Depots

[][]To verify, receive, storage and distribution the finished goods ensuring all the quality.

Head of Sales

[][]To monitor the distribution procedure as per market requirement.

Head of Marketing

[][]Prepare the market requirement for distribution and follow-up of overall activities.

General Manager, Plant

[][]Follow-up of overall activities.

Executive, Vat

[][]Follow the distribution activities as per Government legislation

Executive, QA

[][]Responsible for effective implementation and monitoring of procedure.
[][]Annual depot audit to verify the effectiveness of this procedure.

Manager, HR & Admin

[][]Shall responsible for monitor the effective distribution procedure

Manager, Quality Assurance

[][]To approve of all the distribution activities.

Procedure :

Precautions:

[][]The entire finished product should be handle carefully during distribution, storage, ensuring the quality and identity of the product.
[][]The entire finished product should be stored in product wise respective area maintaining product’s storage condition.
[][]During distribution FIFO should be controlled to avoid mix-up & errors.

Storage :

[][]Finished product will be received by central warehouse personnel from packaging department after getting the finished product release note from QA.
[][]Released finished product will be stored in the central warehouse at the product wise respective area as per storage condition.
[][]Warehouse personnel will monitor and record the temperature in “temperature monitoring record sheet ( Annexure – I)” for twice in a day.
[][]Storage areas should be designed or adapted to ensure appropriate and good storage conditions.
[][]In particular, they should be clean and dry and maintained within acceptable temperature limits. Products should be stored in the pallet which is suitably spaced to permit cleaning and inspection.
[][]Physical or other equivalent segregation should be provided for the storage of released, rejected, expired, recalled or returned products and suspected counterfeits.
[][]Broken or damaged items should be withdrawn from usable stock and stored separately up to final disposition.
[][]Storage areas should be provided with adequate lighting to enable all operations to be carried out accurately and safely.
[][]Periodic stock reconciliation should be performed by comparing the actual and recorded stocks. Stock discrepancies should be investigated by a multidisciplinary committee headed by HR & Admin.

Distribution

[][]All parties involved in the distribution of pharmaceutical products have a responsibility to ensure that the quality of pharmaceutical products and the integrity of the distribution chain are maintained throughout the distribution process from the site of the manufacturer to the entity responsible for dispensing or providing the product to the target consumer as per Government legislation.
[][]Head of Distribution send the depot wise market allocation to central ware house as per marketing/sales requirement.
[][]Central warehouse personal will prepare the released finished product as per market allocation for different depots along with necessary tertiary packaging.
[][]In-charge, CWH will prepare invoice/challan copy as well as ERP entry as per different depot requirement approved by head of Plant or his designee.
Executive, Vat will prepare the vat challan according to depot allocation ( through Musak-11) as per Government rule.
[][]After performing all the related activities, finished products will be transferred to different depot by company own transport or transport agent along with vat challan and invoice copy.
[][]DIC or designee will receive and check the finished pack according to invoice and to be stored following the procedure described on previous steps.

Market Dispatch :

[][]DIC will allocate the finished product as per market requirement for sale. The dispatch and transportation of products should be undertaken only after the receipt of a valid delivery order, which should be documented
[][]Dispatch record will be prepared by DIC and should include at least the following information:
[][]Date of dispatch;
=>Complete business name and address (no acronyms), type of entity responsible for the transportation, telephone number and names of contact persons;
=>Complete business name, address ( no acronyms), and status of the addressee (e.g. retail pharmacy, hospital or clinic);
=>A description of the products including, e.g. name, dosage form and strength ( if applicable);
=>Quantity of the products, e.g. number of containers and quantity per container ( if applicable);
=>Applicable transport and storage conditions;
=>A unique number to allow identification of the delivery order; and
=>Assigned batch number and expiry date ( where not possible at dispatch, this information should at least be kept at receipt to facilitate traceability).

Returned :

[][]If any products undergo as expired or packet damaged which is not fit for use then record the product and stored in a separate area of the depot/warehouse with proper labeling following annexure– II under custody of depot in-charge.
[][]DIC will make an invoice of those products and sent to central warehouse after entry in the ERP to adjust the stock. Returned products will be sent to CWH at every three months interval.
[][]Head of distribution will collect this invoice/challan from different depots and sent to central warehouse after getting prior approval from Head of Sales & Head of Marketing.

[][]After receiving the returned products from different depots, in-charge, CWH will report to QA department along with the approved invoice/challan copy. In-charge, CWH will segregate the returned products according to their nature in a separate area with proper labeling as per annexure-II.
[][]QA executive will take actions following the SOP ‘Disposition of Returned Finished Products.
[][]In case of market compliant or product recall, DIC will inform to Sales or Marketing Department following the respective SOPs Head of distribution will collect the market compliant sample (s) or recalled product(s), batch(s) within seven days of initiation.
[][]Head of QA will take actions for the market compliant and product recall procedure following SOP.
[][]Stock verification of different depots will make through a physical audit by the representatives of Audit & Accounts department once in a year.
[][]A quality audit will be conducted for all the depots headed by QA representative once in a year.

Annexure:

Annexure I – Temperature monitoring record sheet
Annexure II – Returned product label


Returned Finished Products Disposition

Quality Assurance, SOPs

Returned Finished Products Disposition, Purpose :

Returned Finished Products Disposition, The objective is to specify a system to handle the returned finished products for their appropriate and adequate review and disposition in line with the Quality Management System.

Returned Finished Products Disposition, Scope :

This procedure is applicable for disposition of returned finished products and expired ones at XX Pharmaceuticals Limited. (Both General & Cephalosporin Block).

Definitions / Abbreviation:

[][]QA : Quality Assurance
[][]DIC : Depot In Charge
[][]XX : Current Version of SOP

Responsibilities:

[][]The roles and responsibility is as follows:

Head of Distribution

[][]Head of distribution shall collect the finished products from different depots and forward to the central warehouse for final disposition as per procedure.

Depot In Charge (DIC), Central Warehouse

[][]To verify, receive and separately quarantine the returned goods.

Executive, QA

[][]Responsible for effective implementation and monitoring of procedure.

Senior Executive, Cost & Budget (Factory)

[][]To verify all the returned products and make report for stock adjustment memo.

Head of Plant Operation

[][]Follow-up of overall activities.

Head of Quality Assurance

[][]Approval of all the disposition activities.

Procedure:

[][]The returned finished products shall either be destroyed or repacked and made fit for use depending upon the reason for which they have been returned. In either case, the associated risks must be well understood and addressed.
[][]Hence the procedure for disposition of returned finished products is defined depending upon the reason for which products are returned.
[][]Head of Distribution will collect the finished product as per requirement from different depots and send to Central warehouse following the Invoice/ Challan.
[][]On receipt of the products, warehouse (Central) In Charge or designee shall verify the products as per Invoice / Challan. Then warehouse in-charge will label the products to identify the primary cause of return and segregate the returned products in the respective area.
[][]Quarantine the products in area as per classification and inform QA and Head of Plant Operation through Returned Finished Product Note, (Annexure – I).
[][]Reference number for Returned finished products shall be alphanumeric system containing 7 characters. Numbering breakdown is as follows : RG/YY/001
For example : RG/XX/001
=>The first two alphabets shall stand for Returned Goods
=>Next two numeric characters shall stand for year code XX shall denote year 20XX.
=>Next character is followed by three numerical shall stand for serial number, which shall start every year
from 001.

[][]All the expired products returned from the market shall be directed and received at the distribution Department and these shall be destroyed in presence of QA Executive following the SOP of Procedure for Disposal of Materials & Products.
[][]QA Executive shall prepare Authorization and Disposal From for Materials & Products and take authorization for disposal activities.
[][]Head of Quality Assurance or designee shall arrange to verify the reason for return/ recall of the returned products against the intimation.
[][]If the returned products (except expired products) which are fit for further use they shall be repacked through repackaging request form following the Reprocessing/reworking and Repackaging Procedure.
[][]Quality Assurance personal shall examine the products returned because of dirty labeling, packed damaged products can be repacked. To ensure the product quality, QA executive shall draw the sufficient sample for complete analysis (If necessary) and only if found satisfactory and certified accordingly, then the batch shall be allowed for repacking.
[][]For the repackaging activities minimum five unit packs are required for the returned product of same batch no. Less than five unit pack of a same batch shall be disposed following the disposal SOP.
[][]The returned products except expired products which can be repacked to be sent from central warehouse to the manufacturing site and shall be classified and stored separately depending upon the primary cause of return.
[][]Record for issue of packaging material, overprinting and packing shall be maintained on Additional Batch Packaging Record (Primary/Secondary) along with the Repackaging Request Form authorization by Head of Quality Assurance.
[][]If the returned products in the opinion of the Quality Assurance personnel are not considered fit for repackaging, the same shall be destroyed after approval from Head of Quality Assurance.
[][]This repacked part shall be released after compiling of the all related documents and shall be attached to the earlier batch record (BMR/BPR)
Products recalled voluntarily or recalled, as per the directives from Drug Control Authorities the recalled products shall be handled depending upon the reason for product recall; they may be require to be destroyed or repacked.

Annexure:

Annexure I – Returned Finished Product Note


Cleaning Validation Procedure

Job Solution, Quality Assurance, SOPs

Cleaning Validation, Purpose:

Cleaning Validation, To lay down a procedure for carrying out cleaning validation to establish validated cleaning procedure for manufacturing and primary packaging equipment and effectively maintain cleaning process in validated state. Cleaning must be demonstrated to be effective in order to provide assurance that unacceptable levels of contamination are not carried over into subsequent products. It defines the cleaning validation and verification requirements to ensure that all cleaning procedures which may impact product quality are formally validated or verified. Cleaning must be demonstrated to be effective in order to provide assurance that unacceptable levels of contamination are not carried over into subsequent products. It defines the cleaning validation and verification requirements to ensure that all cleaning procedures which may impact product quality are formally validated or verified.

Cleaning Validation, Scope:

This procedure is applicable for equipment’s used in product manufacturing and primary packaging of XX Pharmaceuticals Limited (Both General & Cephalosporin Block).

Definitions / Abbreviation:

[][]QA : Quality Assurance
[][]QC : Quality Control
[][]CIP : Clean-in-place
[][]OOS : Out of Specification
[][]MACO : Maximum Allowable Carryover

Responsibilities:

[][]The roles and responsibility is as follows:

Concerned Department

[][]To cooperate the validation team to make the cleaning validation job successful.

Quality Assurance

[][]Responsible for the developing and co-ordinate the entire cleaning validation activities as a team leader.

Quality Control

[][]Ensure that analytical method has been prepared and validated before conducting cleaning validation and coordinate all analytical & Microbiological test.
To coordinate all the sampling activities.

Head of Plant Operation

[][]Proper follow-up of overall activities.

Head of Quality Assurance

[][]Approval of all the validation activities.

Procedure:

[][]Prior to conducting a cleaning validation study on an Active Ingredient (of previous product) following activities need to be summarized. A Validation team shall be formed comprising of members from Production, Engineering, Quality Control, Validation / Quality Assurance.

Defining the key elements

[][]Define solubility, toxicity of active ingredient in cleaning validation protocol. If any of the active ingredients are deemed to be more potent or less soluble in water than the ingredients for which cleaning validation has already been completed, or deemed to be particularly difficult to clean from equipment, a new validation study will be carried out.
[][]Define the product-equipment matrix.
[][]Prepare the equipment matrix. Determine the total contact surface area of the equipment/ instruments which are to be used in the manufacturing of that product with the help of Engineering and Production Department.
[][]Determine the scope and establish acceptance criteria.
[][]Develop and validate sampling procedure and analytical method.
[][]Designing the cleaning validation protocol. All protocols shall be as per the Format given I Annexure- I.
[][]Execute the cleaning validation study and protocol.
[][]Summarize the data and compilation of the final report.
[][]Devising and monitoring program to establish that the cleaning process is continued to be in validated state.
[][]Establishing conditions for which re-validation would be required.

Describing the key elements

[][]The product – equipment matrix
[][]Prepare a Product–equipment matrix (Annexure-II) & Equipment matrix (Annexure-III) for the products, equipments used in the cleaning validation study.
[][]The matrixes will provide information about the manufacturing and packing line used for multiple products and possible product contact surface area.
[][]The matrix will indicate the worst case at a glance and justify the acceptance criteria for a cleaning validation.

Determining the scope

[][]The scope includes evaluation of residual contamination of active ingredient.
[][]Cleaning validation to be done based on matrix for including any new product in to the matrix for supplying product to local market. However, all products deemed to be supplied to highly regulated markets, the cleaning validation to be done for every product.
[][]Acceptance criteria for Residual active ingredients: The approach for setting limits can be (1) product specific cleaning validation for all products; (2) grouping into product families and choosing a worst case product; (3) grouping into groups of risk (e.g. cleaning difficulty, solubility, toxicity potency of API, facility volume of product); (4) setting limits on not allowing more than a certain fraction of carryover; (5) different safety factors for different dosage forms.
[][]For determining cleaning validation process, widely used criteria, i.e. 1/1000, will be consider for MACO calculation and to evaluate the cleaning effectiveness.
Establish the limit for Maximum Allowable Carryover (MACO) according to the following equation.

MACO = TDD Previous X MBS/ SF X TDD Next

 

Where,
=>MACO = Maximum Allowable Carryover: acceptable transferred amount from the investigated product ( “previous” )
=>TDD Previous = Standard therapeutic dose of the investigated product ( in the same dosage form as TDD next)
=>TDD Next = Standard therapeutic dose of the daily dose for the next product.
=>MBS = Minimum Batch Size for the next product(s) (where MACO can end up)
=>SF = Safety Factor ( normally 1000 is used in calculation based on TDD )
#(Ref. APIC : Active Pharmaceutical Ingredients Committee)

[][]However, the other criteria i.e. 10 ppm Criteria, API toxicity data will also be taken into consideration for evaluation of cleaning effectiveness. The cleaned equipment’s will also be checked visually to ensure the cleaning effectiveness.
[][]1/1000 Criteria: NMT 0.1% of the normal therapeutic dose of any product to appear in the maximum daily dose of the following product.
[][]10 ppm Criteria : NMT 10 ppm of any product to appear in another product;
[][]Based on toxicity : LD50 Value of API will be considered;
[][]Visual Inspection: No quantity of residue to be visible on the equipment after cleaning procedures is performed.
[][]API Solubility: The solubility of drug in washing solvent plays a great role in cleaning. The lesser the solubility greater will be the difficulty to remove the residue from surface.
[][]Thus least soluble molecule (based on the pharmacopoeia or other reliable reference) will be taken for the analysis since if least soluble molecule gives satisfactory result in cleaning validation and routine monitoring then we can rest assure for the other higher soluble drug.
[][]API Toxicity: An evaluation according to the toxicities should be carried out based on the material safety data sheet (MSDS).
[][]Other risk factors such as potency and facility volume of a particular product should also be taken into consideration during designing cleaning validation program.
[][]Develop and validate analytical method for cleaning validation sample analysis.

Swab sampling

[][]Generally method involves swabbing of 5 cm2 but larger area could be considered as per regulatory dossier or with proper justification and difficult to clean areas will be considered as per below Diagrammatic representation.
[][]Define the most difficult to clean areas in the piece of equipment (show delineate pictorially as far as possible).
[][]A polyester tipped swab (Texwipe, Alpha swab with long handle) shall be used. One side of swab shall be given horizontal 10 strokes and then reverse side of the swab shall be given vertical 10 strokes.
[][]The swab stick shall be dipped into the screw cap test tubes/ vials containing solvent (Approximately 10 ml). One test tube / vial will be taken for each swab sample.
[][]The test tube / vial will be labeled specifying the particular piece of equipment swabbed & the location (where appropriate).
[][]The soaked swab (in solvent) to be firmly squeezed along the side of the test tubes / vials and then sampling side to be swabbed. After taking samples from the equipment/utensils the swab to be returned to the respective screw cap test tube/vial.

[][]Each vial will be closed with swab inside & sent to QC for analysis of the swab sample.
[][]Study and establish the stability of sample solution storage condition & storage time, based on a protocol.
[][]Perform the recovery analysis on the swab with spiked SS surface/ similar to the equipment material of construction. Recovery of drug shall be not less than 85% after taking into account interference of swabbing material.
[][]Perform the recovery study of the API from the swab stick for record only.
[][]Mention the swab sampling point details in the cleaning validation protocol.

Rinse sampling

[][]For rinse sample collection graduated plastic mug/container, plastic squeezer, stainless steel container to be used, will be cleaned first with 70% IPA followed by sufficient purified water (Wipe with lint free cloth soaked in 70% IPA if required after visual inspection).
[][] After collection of each rinse the required quantity will be transferred to the conical flask for QC submission. To discard the leftover residue in the SS container/ plastic mug these utensils will be cleaned with sufficient purified water before next use.
[][]Same procedure will be followed for MDI unit except for cleaning purpose only absolute ethanol will be used instead of 70% IPA and purified water.
[][]Rinse sample can be evaluated at intervals during the cleaning and at the completion of the cleaning process. Collection of rinse samples should consider location, timing and volume.
[][]Rinse sample allow sampling of a large surface area and of inaccessible systems or ones that cannot be routinely disassembled. However consideration should be given to the fact that the residue or contaminant may be insoluble or may be physically occluded in the equipment.
[][]Study and establish the stability of sample storage conditions and storage time, based on a protocol.
[][]For those equipment or parts (e.g. turret, die and punch of compression machine, hopper) rinse sampling method is not feasible, only swab sampling method will be applied.
[][]At first swab sample will be collected as per plan and will be sent to QC. Then the swab taken area will be cleaned with purified water and finally with lint free cloth.
[][]At first the equipment will be cleaned as per the equipment cleaning SOP and the dismantled parts will be stored in the clean equipment store room after drying.
[][]After collecting rinse samples the cleaned equipment’s will be allowed for self drying before next use. Finally the rinse sample in a closed conical flask with proper labeling will be sent to QC for analysis.

[][]Perform the recovery analysis on the rinse with spiked SS surface/ similar to the equipment material of construction. Recovery of drug shall be not less than 85%.
[][]Microbiological considerations: weather or not CIP systems are used for cleaning of processing equipment, consider the microbiological aspects of equipment cleaning.
[][]The equipment/utensils are considered clean if the total microbial count is less then 25 CFU per 25 cm2/ per swab or 100 cfu/ml taken from equipment/utensils surface and there are no objectionable organisms present ( e.g. E.coli, Salmonella, Pseudomonas aeruginosa, Staphylococcus aureus).

[][]If any growth is observed, appropriate tests to identify the organisms are to be conducted. If the acceptance limit is exceeded, or an objectionable microorganism is identified, then then an OOS investigation must be initiated by the Microbiological Laboratory to identify the source of microbial contamination. Investigation should be done by the manufacturing department.

[][]Contaminated equipment must be re-cleaned and re-swabbed/re-rinsed and it be must meet acceptance limits prior to release for further manufacturing.
For all the types of equipment initial cleaning validation shall be performed on at least three consecutive batches or three runs.

Bracket Approach

[][]The design uses the extremes to cover in between range. That is the largest pieces of identical equipment could cover all of the in between sizes.
[][]The lowest and highest strength of the products.

Worst Case Approach

[][]The most difficult to clean equipment could cover all the easier to clean equipment also.

[][]Initially cover all the types of equipment for three runs.
[][]Type A cleaning done after 6 days (144 hours) from the first day of use of the equipment or area of solid dosage forms.
[][]The dirty holding period of manufacturing equipment should not be more than 5 days.
[][]In case of batch size change, either increase or reduction in the batch size, the matrix shall be re-evaluated.
[][]If a drug product is manufactured in different strengths, cleaning procedures shall be validated for the highest strength of that particular drug product. If the manufacturing line contains multiple products or a single product contains multiple active ingredients, the active ingredient which is least soluble/more in concentration and/or more toxic, hard to clean shall be taken into consideration for cleaning validation/verification.
[][]If there are multiples of particular equipment with same configuration, material of construction and cleaning procedure then cleaning validation of one piece of that particular equipment will be adequate.
[][]If there are different sizes of the same equipment with same cleaning procedure, cleaning validation for the largest size of that particular equipment is adequate.
[][]The worst case selection criteria will be a) Hard to clean product (Color and Flavor) b) Least soluble API c) Maximum toxicity of API d) Minimum therapeutic daily dose e) Facility volume of a particular product.

Execution of cleaning validation protocol/study

[][]Adequate training to the operators (Production, QC and Engineering) shall be given and documented to execute the protocol efficiency.
[][]Ensure that during validation study the results and activities represent regular daily operations.
[][]Ensure that the same piece of equipment is available for the execution of the cleaning by the operators.
[][]Ensure that operator’s variability is addressed during the process design to maximize the representation of results.

=>Cleaning Validation Protocol number shall be given as follow;
CVR/XXX/YY
Where
=>CVP stands for Cleaning Validation Protocol/stands for separator
=>XXX stands for the sequential number which starts from 001 for calendar year.
=>YY stands for the last two digit of the year.

Summarize the data and generate the report

[][]The final result of particular sampling site shall be ‘difficult to clean’ reported and incorporated in the calculations.
[][]Test results shall be complied by Validation/QA.
[][]Any change in procedure shall be approved by QA.
[][]Evaluation of product matrix shall be done periodically or during introduction of any new product into the existing facility.
[][]Objective & Scope: Describe the objective and scope of the cleaning validation / verification in cleaning validation /verification protocol.
[][]Cleaning Validation/Verification Protocol: provides the tabulated test results and the acceptance criteria for each piece of equipment and equipment train.
[][]Cleaning Validation/Verification process shall be concluded with a summarized report incorporated as a final report, which is written and approved.
[][]Tabulation of test results: provides the tabulated test results and mention the acceptance criteria for each piece of equipment and equipment train.
[][]Discussion and Conclusion: discuss the cleaning validation program under study and summarize the outcome of the cleaning validation program.
[][]Cleaning Validation Report number will be same as protocol no. given as follows.
=>CVR/XXX/YY
=>Where, CVR stands for Cleaning Validation Report.
=>Revalidation of cleaning procedure is required in case of following change
=>Equipment or equipment configuration changes.
=>Changes in cleaning procedure and change of formulation where active quality is increased (e.g. overage).
=>Change in acceptance criteria due to change in batch size or introduction of new product (the matrix shall be Re-evaluated by preparing a separate cleaning validation protocol).
=>Process change in manufacturing process (e.g. wet granulation to direct compression and vice versa).
=>The significance of change shall be evaluated collectively by Production, Engineering and QA.
=>Whenever any change control is made to a validated cleaning procedure, due to change in equipment, process, repair or any other valid reason, then the need evaluation shall be done jointly by the Head of Production, Head of Engineering and finally approved by Manager QA.
=> If the decision is made to revalidate, the same be implemented.

Annexure:

Annexure I-Cleaning Validation Protocol
Annexure II-Product Equipment Matrix
Annexure III-Equipment Matrix


Product Quality Review

Quality Assurance, SOPs

Product Quality Review, Purpose :

Product Quality Review, The objective of carrying out Product Quality Review (APR) is to establish that the product is manufactured as per approved procedures and the trends of results of critical quality attributes are well within acceptable limits.

PQR will also address the review of raw & primary packaging materials used, process validation & revalidation, analytical method validation, cleaning validation & revalidation, stability testing reports, yields, change controls, out of specification results, deviations, failure investigations, CAPAs, rework & reprocessing, market complaints report, trend analysis data, vendor addition/deletion, supplier performance review, retention sample review, batch documentation, drug authority (legal) notices, equipment/utility required, environmental monitoring, etc. done during the review period.

Scope :

[][]This procedure applies to all product manufactured XX Pharmaceuticals Limited (both General & Sterile Block) and is carried out for products manufactured for during calendar year e.g., January to December.

Definition/Abbreviation:

[][]SOP : Standard Operating Procedure
[][]CAPA : Corrective and Preventive Action
[][]PQR : Product Quality Review

Responsibilities:

[][]The roles and responsibility is as follows:

Executive, QA

[][]Responsible to carry out the periodic review of particular product and prepare a report.

Asst. Manager, QA

[][]Responsible to ensure that a formal review of Drug Product / API is undertaken and reported periodically and demonstrate control of the process and effectiveness of any corrective actions required.

Head of Concern Department

[][]To ensure implementation of suggested CAPA.

Head of Quality Assurance

[][]Approval the SOP

Procedure:

Selection of batches

[][]Select the all batches of a product manufactured in the review period.
[][]The batches which are reworked / reprocessed are used must be included in product quality review.
[][]Frequency
[][]Product quality reviews of Drug Products shall be conducted and documented annually.

Schedules for Review

[][]A suitable schedule has to be drawn up by assigning products to person so that review of all products is completed for the stipulated period. The compilation data should preferably to be completed within one month after receiving all data of last batch of evaluation period.
[][]Review of Batch Manufacturing and Packing Records
[][]Review the batch production records for the following particulars:
[][]Review the batch production and packing records of all the batches selected for PQR and record the details like batch numbers, batch production record number and final yields etc.
[][]Review any batch rejections and reprocessing or reworking done during the review period. In such cases highlight the reason, and record the corrective action taken.
[][]Review the process deviation reports are duly adequately investigated, completed and approved.
[][]Record yields of all isolated stages of the product and the yield ranges for all the batches reviewed. Highlight reasons for out of specification yields if any as well as extremes, which are well within limits.
[][]Compile the yield data and prepare the trend charts. Analyze the trend charts, identify and investigate any discernible trends, which are within acceptable upper and lower specifications. Attach the trend charts as in graphical presentation a part of PQR report.
[][]Review in-process control data for key process steps carried out during the manufacture and highlight critical deficiencies.

Review of Environmental Condition

[][]Record the observation for Assurance with environmental condition of manufacturing areas. Critical deviation, if any must be examined in detail to assure how the deviations were taken care of and record observations.

Review of Analytical Reports

[][]For all the batches under product quality review verify all the analytical reports for the following:
[][]Validity of analytical specifications and methods for the products, raw materials and primary packaging materials employed.
[][]Any out of specification analysis and re-testing carried out with explanations for the same.
[][]Review the analytical results for critical parameters like assay, dissolution, loss on drying/water content, related substances etc.
[][]Review any specification changes and also any new analytical instruments added for the testing of the product and raw/primary packaging materials involved in manufacturing the batches for PQR.
[][]Review the calibration /qualification status of instruments used in the analysis of the batches under review.
[][]Review the retention samples randomly for deterioration.
[][]Compile all the critical analytical data (e.g. assay, dissolution) in a graphical presentation as a part of PQR.

Review of Stability Study Program and Data

[][]Stability review data generated for the product during the review period must be verified and critical observations, if any, highlighted with corrective action recommended. On need basis, the review should be extended to previous years as well.

[][]Any recommendations for changes in shelf life must be examined. Record any changes to stability testing protocol and methods during the review period. Any stability failure during the period must be reviewed in detail.

Review of Market Complaints, Returns and Recalls

[][]Market complaints received during the 12 months period of review should be verified for appropriate closure. The corrective & preventive actions taken subsequent to the complaint investigations should be reviewed in detail. Any recall during the period also must be reviewed in detail.

Review of Regulatory Actions

[][]Any regulatory queries with respect to the product under review must be examined in detail. The corrective actions taken and company response to the queries must be examined.

Review of Validation Status

[][]Any validation or revalidation exercises carried out for the process or equipment related to the product under review must be reviewed and findings to be highlighted. Corrective & preventive actions (CAPA) taken, if any, must also be reviewed. Analytical method validation and cleaning validation/revalidation performed during review period must be recorded.

Review of Change Control Documents

[][]Review all the changes made to the system related to the product under review and report the impact on the regulatory and or customer requirements.
[][]Review of Non-conformity and CAPAs
[][]Review the non-conformities and corrective & preventive actions (CAPA), if any, during the internal quality audits.

Review of Critical Equipment & Utility performance

[][]Performance of the critical equipment & utilities used for manufacturing, packaging & testing of the product during the period to be reviewed.

Review of Raw & Primary Packaging Materials

[][]All the batches/ lots of raw materials (active & excipients) and primary packaging materials used for manufacturing & packing of product during the review period to be reviewed.

Review of Vendor Addition/Deletion and Supplier Performance Report

[][]Vendor addition/deletion and supplier performance reports of raw materials (active & excipients) and primary packaging materials to be reviewed.

Review of Retain Sample

[][]Retain samples (retention samples) of all the batches of the finished products to be reviewed every year by visual examination for any evidence of deterioration and observation shall be documented in respective retention sample register. A summary report to be prepared based on the visual inspection. The same report will go to the PQR.

Review of previous APR Report

[][]Observations/recommendations of the previous Product Quality Review report to be reviewed.

Review of Environmental Monitoring:

[][]Annual review of environmental monitoring summary report to be reviewed and a copy of the summary to be affixed as an annexure with the PQR. Any result exceeds the action limit and the actions against the exceed results to be recorded in the review report.

Report:

[][]An overall summary of the annual product review report shall be prepared by the person conducting the review.

[][]Any other observations or improvements or recommendations for improvements if any shall be given in the report.
[][]The report should include trend charts for all relevant data supporting the review.
[][]The report should include a summary and recommendations for actions to be initiated for any deficiencies.
[][]Document Numbering:
[][]Annual Product Review report shall be numbered as follows:
=>PQR/XX/YYY
=>Where ‘PQR’ represents for Product Quality Review.
=>‘XX’ represents the last two digits of the year (e.g. XX for 20XX).
=>“YYY’ represents for serial number of the PQR report.

Annexure: Product Quality Review

N/A


Environment, Health & Safety Procedure

Job Solution, Quality Assurance, SOPs

Environment, Health & Safety, Purpose :

Environment, Health & Safety, To establish a system for the environment, health and safety procedure. This covers the various steps that are required to be followed for EHS policy.

Environment, Health & Safety, Scope :

This procedure is applies for all the employees, visitors, suppliers, contractual third party employee and all the persons enter into the premises of XX Pharmaceuticals Limited (Both General and Cephalosporin Block).

Definitions / Abbreviation:

[][]QA : Quality Assurance
[][]QC : Quality Control
[][]PD : Product Development
[][]EHS : Environment, Health and Safety

Responsibilities:

[][]The roles and responsibility is as follows:

All Concerned Personnel

[][]To be responsible to follow the SOP

Emergency Response

[][]Team Member
[][]Key personnel to perform their duties as per procedure

Head of Plant Operation

[][]Responsible to ensure the overall procedure

Head of Quality Assurance

[][]Responsible to Assurance the overall procedure

Procedure:

[][]All the concerned personnel to be followed the updated systems for safety, health and environmental Hazards & risks associated with activities and products.
[][]All the personnel should be followed the improve conditions in order to prevent accidents, health hazards & pollutions.
[][]Everyone should be aware of minimization of waste generation, promote recycling and green Chemistry.
[][]Every personnel should be well known about energy consumption.
[][]Reduce harmful solids, liquids and gas generation.
[][]Safety awareness to be created to our suppliers and customers.
[][]The best extent possible to work with suppliers who themselves have sound safety, health and environmental policies.
[][]To set environmental, health and safety objectives and targets by all departments to improve EHS Performance.

Periodic Health Check-up

[][]After the employment of a new employee, health check-up is conducted by plant physician.
[][]Every employee, particularly production, QA, QC, PD and Warehouse department personnel will have to undergo health examination include health status and personal health history.
[][]Health examination covers general status, respiratory tract status, eyes status, skin cleanliness, cephalosporin sensitivity test.
[][]Personal health report covers the details history of his/her health status.
[][]Health report will be preserved by Executive, HR & Admin.
[][]General frequency of health check-up: At least twice a year.

Personal Hygiene

[][]Any person shows at any time to have an apparent illness or open leisions that may adversely affect the quality of products is not be allowed to handle starting materials, packaging materials, in-process materials or drug products until the condition is no longer judged to be a risk.
[][]All employees will report to their immediate supervisor about any conditions (relating to plant, equipment or personnel) that they consider may adverse effect the products. Health, safety and environment department manage record/documentation of each employee’s health status and maintain the record/documentation updating.
[][]Direct contact is avoided between the operator’s hand and starting materials, primary packaging materials and immediate or bulk product. All personnel are trained in the practices of personnel hygiene.

Emergency Responses

First Aid:

[][]All injuries, regardless of how small, must be reported and treated as soon as possible after an injury.
[][]First Aid facilities are located throughout the working areas.
[][]Supervisor will show his/her employee for the facility locations. If anyone becomes injured or ill any here due to an industrial or non-industrial problem and need immediate medical aid, he/she has to report the Emergency Responses Team and go to the nearest first aid facility the medical department or the security desk.
[][]If the immediate aid is not needed, notify his/her supervisor before proceeding to the nearest first aid facility.
[][]Whenever outside medical assistance is needed, designed first aid responder as per annexure-1 or plant head will call for this assistance.

Fire Emergency Procedure

[][]Every employee will be familiarize themselves during their induction training period with the location of the evacuation routes(Primary &Secondary),first aid station or kit, each fire alarm, each fire extinguisher, the nearest public telephone and the location of the stairway (as indicated on the emergency evacuation Diagrams).
[][]If any person discover fire anywhere in the building, immediately active the nearest fire alarm pull box and call the HR & Admin. State his/her name, location and type of fire.
[][]Only consider attempting to extinguish a fire if it is a very minor and every person should have been trained in the proper operation and use of portable fire extinguishers.
[][]Use procedure of fire extinguisher.
[][]Pull the pin of the extinguisher.
[][]Stand about six to eight feet from the fire where aim is the hose at the base of the fire.
[][]Squeeze the trigger.
[][]Mount, Locate and identify extinguishers so that they are readily accessible to employees.
[][]Only approved extinguisher shall be used. Maintain extinguisher in a fully charged and operable
[][]Condition and keep in their designated places at all times except during use.
[][]Soldered or riveted shell inverting type extinguisher shall be permanently removed from service.
[][]Extinguisher shall be visually inspected monthly, maintained annually and hydrostatically tested
[][]Periodically by Engineering personnel.

Fire protection and control

[][]All employees shall know the location and be properly trained in the operation of all firefighting equipment.
[][]Portable fire extinguishers shall be suitable to the conditions and hazards involved. They also will be provided and maintained in good operating condition.
[][]Each extinguisher will be serviced at least once a year and tagged and dated and dated to show this.
[][]An approved safety container shall be used for handling flammable liquids up to five gallons.
[][]The employee should immediately leave the area using the designated evacuation route through emergency exit path.
[][]When evacuating no one should use elevators, keep to the right, walk-not to run and remain calm but take immediate action.
[][]A preplanned procedure has been established to assist non-ambulatory individuals and have to obey the directions of building Emergency Response Officials.
[][]Small fires can spread rapidly and overwhelmed an area. To contain the fire close all doors behind exit the building. Before opening any door of a room or office that leads to the main hallway feel the door first to see if it is hot.
[][]Open the windows for fresh air and hang a sheet or other similar article, out the window to let the HR department to know him are still inside.
[][]If all exists from a floor are blocked or if any reason personnel must remain in a room/office during a fire or other emergency and advice of his location and situation. Wait for the fire department to assist him.
[][]After exiting the building get far away from the building, all staff members are to assemble in the emergency assembly point located east or west corner of the plant premises for accountability.
[][]Everyone should remain outside the building until the management staff informs him/her that it is safe to return to the building.
Plant head will count the total present employee as per total employee list provided by HR Executive to become sure that there is no one remains contact in the fire.

Emergency disaster procedure

[][]Everyone will be familiarizing with the location of the evacuation routes(Primary and secondary) the nearest public telephone and the location of the stairway (as indicated on the Emergency Evacuation Diagrams).
[][]Depending on the disaster the watch period should be used to prepare for an easy transition into the nearest designated emergency assembly point.
[][]Plant head will count the total present employee as per total employee list provided by HR Executive to become sure that there is no one remains contact in risk area for easy rescue.

Annexure:

Annexure-I: Emergency Response Team (General Block & Cephalosporin Block)


Disposal of Materials & Products Procedure

Quality Assurance, SOPs

Disposal of Materials, Purpose:

Disposal of Materials, To establish a system for the authorization and disposal of rejected/expired materials and products. This covers the various steps that are required to be followed for destruction of rejected/expired materials and products in a safe and legal way with proper authorization.

Disposal of Materials, Scope:

This SOP applies to quality related non-complies or undesirable materials in XX Pharmaceuticals Ltd. (Both General & Cephalosporin Block) from any one of the following interface steps.

Rejected Raw & Packaging Materials

[][]Expired Retention Samples
[][]Manufacturing waste and in process waste (Both raw & packaging materials)
[][]Rejected Intermediate/Bulk Products/Batch Tails/Finished Products
[][]Trial sample for product development
[][]Laboratory waste (Reagent, analysis sample etc.)

Definitions / Abbreviation:

[][]QA – Quality Assurance
[][]QC – Quality Control
[][]PD – Product Development
[][]BMR – Batch Manufacturing Record
[][]Waste – Materials if they no longer are fit for their originally intended purpose.
[][]Non-Waste – Materials that can be recovered and reused in a process.
[][]Hazardous Waste – Waste is considered to be hazardous if it exhibits any of a number of properties related to flammability, explosivity, water/air reactivity, corrosivity, oxidizing potential, acute or chronic toxicity, ecotoxicity or infection.
[][]Non- Hazardous Waste – Waste is considered to be non-hazardous if it DOES NOT exhibit any of the properties related to flammability, explosivity, water/air reactivity, corrosivity, oxidizing potential, acute or chronic toxicity, ecotoxicity or infection.

Responsibilities:

[][]The roles and responsibility is as follows:

Concerned Department

[][]To collect, disposition and proper storage & disposal of rejected materials/products according to this SOP.

Quality Assurance

[][]To review and get prior approval for initial disposition.

HR Executive

[][]To check and monitor regular disposition activities

Senior Executive, Cost & Budget (Factory)

[][]To verifying that all the disposed items and make report for stock adjustment memo.

Head of Plant Operation

[][]Proper follow-up of overall activities

Head of Quality Assurance

[][]Approval of all the disposal activities

Procedure:

Precautions / Special instructions

[][]Wear masks, gloves & safety goggles (eye protective glasses) and other necessary precautions during destruction works and disposal of wastage and expired materials/products.
[][]Avoid scattering after completion of work.
[][]Always keep the plastic bucket/dustbin covered with lids after work.
[][]Wash the container after completion of work.
[][]Do not dispose the waste tablets and capsules directly into drain.
[][]Do not store the in-process waste for disposal for next day.

Disposal procedure for manufacturing & In-process waste from production area

[][]Departmental executives/ operators will ensure that the waste materials are segregated at sources of generation as hazardous & non-hazardous.
[][]Departmental executives/ operators will ensure the waste materials are in their respective designated containers and their physical segregation from passed, approved, quarantined or any finished good materials. They will also separate solid & non-solid waste materials.
[][]In case of new product, Product Development will assess and identify the nature of materials as hazardous & non-hazardous at development stage. Product [][]Development will notify the relevant owners about the disposal procedure of wastes.
[][]The waste packaging materials (polythene bags/cartons/labels/drums/fiber board boxes etc.) will be removed daily from the sections and transferred to salvage yard according to nature of disposal process by service people.

[][]The manufacturing related solid waste materials (waste raw materials, products, IPC materials etc.) will be removed daily from the sections.
Each working area contains separate waste bin with proper labeling for different types of waste as per annexure-V.

[][]Put all the tablets checked during in process check (IPC) for hardness, thickness, friability and weight variation in waste bin placed in respective compression room, IPC room. The same procedure will be applicable for capsule, powder for suspension, rejected tablets, and capsule from blister area and bottles which are used for leak test.
[][]Collect the dust from Dispensing, Granulation, Compression, Encapsulation and Powder filling area in the waste bin placed in the respective area except hazardous waste.
[][]Take all the waste in the washing area. Production & QCOM Executive will be present during disposal and follow up the whole activities.
[][]Take approximately 10 – 15 liters of potable water into a bucket. Dissolve any types of waste mentioned above in this water in quantity sufficient.
[][]After dissolving, transfer the dissolved wastes into washing area and dispose them into drain with plenty of water to ensure proper cleanliness of the drain.
[][]Clean the bucket using Sodium bi carbonate & Sodium Lauryl Sulphate (detergent) powder solution.
[][]Dispose the dust or tablets or capsules collected in a vacuum cleaner in the same way as described above.
[][]The manufacturing waste should have to be disposed immediately the same day of waste produced.
[][]Disposal procedure for laboratory waste (Reagent, analysis sample etc.)
[][]For laboratory waste follow the SOP “Waste management in Quality Control Laboratory” Where XX denote current version.
[][]Disposal procedure for waste generated in the Product Development Laboratory
[][]For the waste generated in the PD laboratory follow the SOP “General waste disposal procedure for product development lab.”  Where XX denote current version.
[][]Disposal procedure for intermediate/bulk products/batch tails/finished products/hazardous waste from manufacturing area
[][]When a finished product/ intermediate products/ bulk product/ batch tails, hazardous waste is to be rejected, the concerned department Head shall raise “Disposal Form for Materials & Products” as per annexure-I for write-off in the part-A.
[][]The form is first to be signed by Concerned Department Head followed by concerned personnel of Factory Accounts & Budget, HR & Admin personnel, General Manager plant and approved by Head of Quality Assurance.
[][]After approval of the Disposal Form for Materials & Products, concerned department will attached the “To Be Disposed” label as per Annexure-III with the rejected materials and to be kept in a dedicated area of the respective production department before the schedule for disposal activities.

[][]The disposal activities to be carried out in the concerned department in the respective washing area.

[][]All the disposal activities will be conducted in a dedicated washing area with direct supervision of QA Executive

Tablets, Capsules & PFS : Non-Betalactam

[][]Wear appropriate Personal Protective Equipment/Clothes.
[][]Sort out the blister strips of tablets & capsules.
[][]Tear the blister strips and take out the tablets from the pouches.
[][]For PFS: Open the Alu. Cap & tear the label.
[][]Pour the powder of the bottles into a plastic bucket.
[][]Keep aside the deformed Alu. Cap, LDP stopper & spoon and send to salvage yard.
[][]Keep the Dry powder, tablets and capsules in a bucket; mix/dissolve the tablets/capsules with water and stirring.
[][]Neutralize the liquid (pH 6 – 9) by using acid/alkali. Dilute 10 – 20% of the liquid by fresh water and drain out with plenty of water or burg.

[][]Tear the printed packaging materials and transfer all the torn packing materials to the salvage yard.

Tablet, Capsules and PFS (Cephalosporin)

[][]Wear appropriate Personal Protective Equipment/Clothes.
[][]Make sufficient quantity of 0.4% (v/v) sodium hypo-chlorite solution.
[][]Sort out the products.
[][]Take out the strips from the cartons.
[][]Tear the blister strips and take out the capsules/tablets & keep in a bucket.
[][]Keep the torn blister strips into a polythene bag.
[][]For PFS: Open the Alu. Cap, LDP stopper & tear the label.
[][]Pour the powder of the bottles into a plastic bucket.
[][]Keep aside the deformed Alu. Cap & spoon and send to salvage yard.
=>Dissolve/mix the dry powder, tablets and capsules in a covered plastic bucket with previously made 0.4% (v/v) sodium hypochlorite solution and stir with a rod. Leave it overnight for at least 12 hrs.
=>Neutralize the liquid (pH 6 – 9) by using acid/alkali. Dilute 10 – 20% of the liquid by fresh water and drain out slowly the materials on the following working day.
=>Clean the drain with adequate water flushing.
=>Tear all packaging materials and transfer the torn packaging material for salvage yard.
[][]After disposal of the product/ materials, Part B of the Disposal Form for Materials & Products shall be signed by concerned person with designation who disposed the products and then jointly checked by Executive, QA and Executive, HR & Admin. and finally approved by Head of QA.
[][]All master copy of disposal records shall be maintained and kept by QA department and another copy will be sent to Concerned Department, HR & Admin Department and Cost & Budget (Factory) department.

Expired Retention Samples

[][]For expired retention sample the same procedure to be followed the procedure stated in 7.4 by raising the Authorization and Disposal Form for materials & products.

Waste Packaging Materials

[][]Collect all the in-processed waste produced from packaging area from the waste bin placed in the respective area.
[][]Tear the wastage label, carton, leaflet and put into a polythene bag by attaching “To Be Disposed” label as per Annexure-III.
[][]All wastage of cap, spoon, and dropper are to be deformed and then put into a polythene bag by attaching “To Be Disposed” label. All wastage of foils, films to be cut and put into polythene bag.
[][]All the wastage packaging materials are to be checked by Production and QA Executive daily. Then the daily waste materials sent to the dedicated salvage yard through warehouse with waste material transfer note (Annexure-IV) with proper notification to HR executive.
[][]After receiving of this waste transfer note by HR executive, this copy will be returned to respective department and to be preserved.
[][]All these packaging waste materials are kept in the salvage yard. These wastages are disposed by the third party as per company policy.
This procedure also applicable for the online rejected materials.
[][]In case of large number of online rejected materials the disposal procedure to be followed by prior approval from Head of QA following the Authorization and Disposal Form for Materials & Products.

Stock Adjustment Procedure

[][]After approval of Authorization and Disposal Form for Materials & Products for Rejected Intermediate / Bulk Products / Batch Tails / Finished Products and online rejected materials, stock adjust memo to be filled up by Cost & Budget (Factory) personnel as per Annexure-II.
[][]After approval from relevant personnel the main copy to be kept in the Cost & Budget department and another copy will be attached with the relevant Authorization and Disposal Form for Materials & Products.

[][]Finally the adjustment to be done on the ERP.

Annexure:

Annexure I- Authorization and Disposal Form for Materials & Products
Annexure II- Stock Adjustment Memo
Annexure III- Label for “To be disposed”
Annexure IV- Waste Material Transfer Note
Annexure V- Waste Collection & Disposal Procedure


Quality Review Meeting

Quality Assurance, SOPs

Quality Review Meeting, Purpose :

Quality Review Meeting, To define the Quality Review Meeting requirements to ensure that the review and escalation of quality and. Assurance risks, improvement opportunities and strategy settings are handled effectively.

Quality Review Meeting, Scope :

This SOP is applicable for holding Quality review meeting of XX Pharmaceuticals Limited.

Definitions / Abbreviation:

[][]CAPA : Corrective Action and Preventive Action
[][]IPC : In-Process Check
[][]QMS : Quality Management System
[][]OOS : Out of Specification
[][]PPR : Periodic Product Review

Responsibilities:

[][]The roles and responsibility is as follows:

Manager, Quality Assurance

[][]Facilitate the Quality Review Meeting.
[][]Prepare the yearly calendar for the meeting.
[][]Recommend the participant list.
[][]Prepare the meeting agenda.
[][]Communicate with the participants for the meeting.
[][]Prepare and issue the minutes.

Manager, Quality Control

[][]Update Environmental monitoring/ Laboratory system/ KPI/ Rejection.

Head of Engineering

[][]Update maintenance status of plant/machinery.

Head of Plant Operation

[][]Chair the Quality Review Meeting.

Head of Quality Assurance

[][]Approve the yearly calendar for the meeting.
[][]Approve the meeting agenda.
[][]Approve the participant list.

Procedure:

Overview of Quality Review Meeting:

[][]Quality Review Meeting is an essential part of the governance and improvement framework for Quality and Regulatory Assurance within XX Pharmaceuticals Limited.

Operation of the Site Quality Review Meeting:

Attendance

[][]It is essential to have adequate senior representation of quality, operational, and supporting roles at the QRM. The ownership of this Quality Review Meeting lies with Head of Quality Assurance. The meeting will be chaired by Head of Plant Operation or his designee.
[][]The Team members of Quality Review Meeting will be all technical person of the Plant. It is essential that the members shall be present in all the meetings. To conduct a meeting at least 70% participation of the members is mandatory. However, either one of i e Head of Plant or Head of Quality Assurance must be present in the meeting.

Frequency

[][]The QRM will be held on monthly basis. A yearly calendar will be followed, which will be issued at the beginning of the year. The responsibility lies with Head of Quality Assurance.

Meeting Process and Communication

[][]It is the responsibility of Head of Quality Assurance to notify the members of QRM a week before the meeting with agenda (Annexure I).
[][]The members will give their feedback on their part of actions at least three days before the
[][]meeting to the Head of Quality Assurance. This will facilitate the process of updating the previous meeting.

[][]The minutes will contain the following attributes:

For actions and decisions

=>Owner (a single name in preference to group actions)
=>Content
=>Context for full understanding/reason including related agenda item.
=>Current status of action
=>Target completion date

Record Maintenance

[][]Manager, Quality Assurance will maintain all records of the Quality Review Meeting as per SOP for Document Archiving, Retention, and Retrieval & Destruction. Following records will be maintained:
=>Minutes
=>Actions taken
=>Decisions taken
=>Communications

Brief Description of Agenda items

Review of CAPA status

=>Review actions for most significant CAPAs
=>CAPA update on Level of internal audits
[][]Changes to regulatory requirements
=>Quality Review Meeting will Review of any new regulatory requirement that is to be addressed.
[][]Quality Management System
=>Confirm that the review of current practices/standards gaps versus the QMS is rigorous.
=>Review actual QMS performance versus target.
=>Review significant changes within the QMS.

Risk Management – Governance and Improvement

[][]Risk Register: The Quality Risk Register must be reviewed to ensure
=>Risks are being identified.
=>Risks are being assessed.
=>Action plans are being progressed.

[][]Periodic Review of QRM Plan
=>Schedule adherence of QRM Plan
=>Endorse new Quality Plan and any change in Quality plan

[][]Quality KPI Review
=>Batches Not Right First Time (Process & Testing error)
=>Batches Not Right First Time (Documentation error)
[][]Change Controls
=>Review the overall status of Change Control Tracker and ensure there is no overdue.
=>Endorse the final closing of Change Control
=>Review all critical and major change controls.
=>Check that the closure is timely and the actions taken are effective

[][]Deviations, Out of Specifications, Rejects and Reworks
=>Quality Review Meeting will
=>Review deviations, OOS, rejects and reworks
=>Assure itself that reporting is full and complete and that closure is timely (Investigation will not open more than 30 days).
=>Review overall trends and set strategic improvement actions.
[][]Complaints – Vendor and Customer
=>QRM will Ensure that all vendor and customer complaints are reviewed.
=>Ensure that any ‘unofficial’ complaints or comments are reviewed
=>Review the root cause and proposed CAPA
=>Review overall trends and set strategic improvement actions.
=>Review Recalls and Product Incident Review. .
=>Understand and endorse resultant CAPAs.
[][]Periodic Product Review
=>Quality Review Meeting will review.
=>Schedule adherence for the year, and monitor timely completion.
=>Key findings (executive summary) of PPR.
=>Improvement recommendations (CAPA) in PPRs are actioned and tracked.
=>Adverse quality trends are reviewed and actioned.
=>Positive quality trends are reviewed to ensure sustainability (or transfer of a good practice).
=>Correlate change controls with product quality trends.

[][]Validation
=>Schedule adherence of VMP
=>Issue triggered from validation
[][]Stability Studies
=>Review stability test status.
=>Review any adverse stability data and assess impact on product quality and shelf life
=>Take corrective action to mitigate the risk.
[][]Environmental/Utility Issues
=>Review any adverse trend of environmental monitoring results and results of water testing and to assess impact on product quality.
=>Take corrective action to mitigate the risk.

[][]Training
=>Progress against plan (Schedule adherence)
=>Man-hours utilized Retention & Archiving of Documents
[][]Retention & Archiving of Documents
=>Progress against plan
[][]Preventive Maintenance
=>Schedule adherence
[][]IPC Trending
=>Review the monthly IPC observations for any GMP non Compliance
=>Review the IPC observation trend to minimize the IPC failure/ error.
[][]Review of last minutes
=>Comments on previous minutes from the participants.
=>Track progress of actions in the previous minutes of the meeting.
[][]Any other matters to discuss
=>Any other matters not discussed earlier but have an impact on product quality.
[][]After Action Review
=>At the end of the meeting members will review the meeting process, confirm whether it has met the purpose and identify the needs for its improvement for the next meeting.

Annexure:

Annexure-I: Agenda of Quality Review Meeting


Personnel Movement, Documents & Materials Transfer Between Cephalosporin & General Block

Quality Assurance, SOPs

Personnel Movement, Purpose:

Personnel Movement, To define the procedure to be applied for the movement of people & transfer of documents & materials between Cephalosporin & General block.

Personnel Movement, Scope:

This document lays down the guidelines for the movement of people & transfer of documents & materials between the Cephalosporin & General block of XX Pharmaceuticals Limited.

Definitions / Abbreviation:

[][]QC – Quality Control
[][]QA- Quality Assurance
[][]QA – Quality Assurance
[][]SOP – Standard Operating Procedure

Responsibilities:

[][]The roles and responsibility is as follows:

All Concerned Personnel

[][]To be responsible to follow the SOP

General Manager, Plant

[][]Proper follow-up of overall activities

Manager, Quality Assurance

[][]Responsible to ensure the Assurance to the procedure.

Procedure:

[][]Where the need arises to move or to transfer documents & materials between the Cephalosporin and General block, care should be taken to prevent contamination, to eliminate the potential sources of contamination. Following provisions have to be maintained in such cases:

Movement of people

[][]Entry of the people working in the Cephalosporin Block is restricted to the General Block during or after their working time. They can enter General Block only before entering the Cephalosporin Block as per requirement.
[][]People working in the General Block can enter into the Cephalosporin Block at any time as per requirement. But it should be maintained that they will not enter again into the General Block at that day.
[][]To transfer any documents / samples / tools / equipment from the General Block to the Cephalosporin Block, the assigned personnel will handover that to the person who work at the lobby area of Cephalosporin Block.
[][]The people working in the lobby area will then handover those to the persons inside the change room.

Transfer of Documents

[][]All the master documents related with Cephalosporin block will be preserved in the document archive room of Cephalosporin Block.
Issuing of BMR, BPR, Logbooks, Forms etc. which control is in the General Block will be done after receiving the requisition from the concerned department to Quality Assurance.
[][]But all the requisition will be performed electronically through mail.
[][]Some common SOPs are shared both by Cephalosporin & General Block. In such cases, all the master copies will be preserved in AGM, QA room of the General Block and controlled copies will be distributed in the Cephalosporin Block.
[][]All signatories will be taken within the Cephalosporin Block.
[][]No documents are allowed to be transferred from the Cephalosporin Block to the General Block. If any document is necessary to be sent to the General Block from Cephalosporin Block (e.g. atomic absorption spectrophotometer reading) it will be sent as an information copy through fax or scan or as a form of soft copy through LAN / Internet.
[][]Before the transfer of materials, the required amount of material is collected & to be placed on a pallet. The material is then transferred manually from General warehouse to the receiving bay of the Cephalosporin warehouse. From the receiving bay, the material is transferred to another pallet (dedicated for Cephalosporin block).
[][]For washed & dried glass bottle or crushed sucrose the same procedure stated in above will be followed.
[][]The pallets/ HDPE drums which were used for transferring materials from the General warehouse can be used only after proper cleaning. These pallets must not be used in the production floor; they will be used only in the warehouse.
[][]For analytical purpose, a set of reference / working standard which is required for analysis must be available in the Cephalosporin QC/ Microbiology laboratory.
[][]Product Development Activities: Any kind of process or product development work related with Cephalosporin product must be conducted within the Cephalosporin block.
[][]Engineering Activities: Any kind of maintenance, calibration activities will be done by the dedicated personnel and equipment’s. In case of single calibration instruments, after finishing the tasks at Cephalosporin Block, all the equipment’s will be transferred to Calibration lab. after proper cleaning and de-contamination.

Annexure:

Annexure I- Inter Departmental Materials Transfer Record
Annexure II- Status Label for Inter Departmental Transferred Materials


Document Control Procedure

Quality Assurance, SOPs

Document Control, Purpose:

Document Control, To describe the procedure for activities involved in the preparation, control, retrieval and archiving of quality related documents.

Document Control, Scope:

This procedure covers all the documents issued by Quality Assurance and it also includes documents related to regulatory, calibration, qualification and validation activities at XX Pharmaceuticals Limited (Both General & Sterile Block)

Definitions / Abbreviation:

[][]QA – Quality Assurance
[][]SOP – Standard Operating Procedure
[][]XX – Current Version of SOP

Responsibilities:

[][]The roles and responsibility is as follows:

Procedure:

[][]This procedure shall be applicable for all the new documents, which are prepared from the effective date of this document. The existing document shall be modified as per this procedure whenever due for periodic review or whenever they need to be revised on need basis.
[][]The layout of the Quality Related documents
[][]The layout of SOPs, calibration, validations, guidelines, QA policies, and qualification should be as per the respective templates.
[][]Formats: The format can be designed according to the data that is to be entered. The document number along with revision number, concerned document reference number shall be placed at the top of each page of the format.
[][]Validation protocols and Reports: The format and contents are described in the procedure for validation protocols and Reports.

[][]Quality related documents are essential documents, which establish the quality systems, and are required as per Good Manufacturing Practices (GMP).
Batch Manufacturing Record (BMR) & Batch Packaging Record (BPR): The format and contents are described in the procedure for Preparation, approval, distribution, control & revision of Batch processing records according to SOP.
[][]Specifications, Method of analysis & analytical work sheet: The format and contents are described in the procedure SOP.

Preparation, review and approval/ authorization of documents:

[][]All documents (new or existing) are to be drafted by appropriately qualified personnel of the concerned department and submit to the head of the department for checking. Before submission for checking, the responsible personnel shall initiate a draft copy.
[][]The department Head shall circulate the draft document to concern section Heads for checking. All the comments / inputs shall be written directly on the draft, signed and dated by the respective persons.
[][]After the draft document has been commented on by all the concerned Heads, a final checking /review is carried out by the QA department.
[][]If there are changes, a further document is prepared and circulated until the final draft is agreed.
[][]Concerned department then shall prepare the final copy and assign sequential number (in case of new documents). In case of existing documents, only the version number will be changed.

[][]The final document shall then be signed by the responsible staff. All the draft copies are to be destroyed subsequently.
[][]Concerned department Head shall send the approved master copy to QA for distribution or Issuance of controlled copies.
[][]QA shall issue the controlled copy of documents to concerned departments.

Standard Operating Procedures

[][]Follow the previous step
[][]Sufficient time is given between issue date and effective date to enable training of concerned people.
[][]Batch Manufacturing Records (BMRs) and Batch Packaging Records (BPRs)
[][]After finalization of Manufacturing Record and Batch Packaging Record shall be prepared by Product Development department.
[][]BMR & BPR shall be drafted by Product Development by using relevant template.
[][]Product Development shall send duly signed master copy of BMR & BPR to QA for distribution or Issuance of controlled copies.
[][]QA shall issue the controlled copy of documents to concerned departments.

Specifications, Method of Analysis

[][]Specification: A list of tests, references to analytical procedures and appropriate acceptance criteria that can be numerical limits, ranges or other criteria to which a material must conform to be considered acceptable for intended use.
[][]Test Procedure: Analytical procedures that are to be followed against any test described in method of analysis.
[][]Each material must have unique specifications and test procedures. The test procedure shall give the details of methods to be carried out against each test parameter defined in the specifications.
[][]QC shall prepare final copy of documents and assign sequential number to all specifications, method and analytical work sheet. These Documents shall be prepared, checked and approved by persons as defined in the responsibility.
[][]QC shall send the duly approved master copy to QA for distribution or issuance of controlled copies.
[][]QA shall issue the controlled copy of documents to concerned departments as per previous step.

Qualification and Validation Documents

[][]Concerned Department shall prepare the Qualification documents by using relevant templates.
[][]After finalization of BMR and BPR concerned QA personnel shall be prepared validation documents by using relevant template.
[][]Other qualification and validation documents shall be prepared, checked and approved by persons as defined in the responsibility.
[][]QA shall issue the controlled copy of documents to concerned departments as per previous step.

Distribution or Issuance of Controlled and Uncontrolled documents

[][]All the GMP documents related to the manufacturing plant will be issued by Quality Assurance. The Controlled copies of documents shall be made by Quality Assurance by photocopying the master copy and sealed as

CONTROLLED
Initial………Date..…

=>in blue ink with initial & date of QA Personnel.

[][]If an additional copy of document is required by any department for operational use then Quality Assurance dept. shall issue an additional copy only after written approval from Head of Quality. Such requests shall be obtained through the Request Form as per Annexure – I.
[][]The controlled copies of new documents shall be distributed to the concerned departments and sufficient time should be given before the effective date of the document to enable training of the concerned people.
[][]All formats shall be controlled by QA. The required number of working format shall be copied from control copy by respective department head or his nominee and reconciliation of copied format shall be done by respective department head or his nominee.

Revision of existing documents

[][]Documents such as SOPs, BMR, BPR etc which requires revision due to change control shall be revised by concerned department.
[][]Revised documents shall be given sequential revision No. and controlled by Quality Assurance.
[][]Documents undergoing change due to regulatory requirements / audit Assurance shall also be revised through proper change control by the concerned department.
[][]QA shall distribute the controlled copies of revised documents to concerned departments as per previous step.

Document Archive

[][]All the master documents will be archived at QA end at the document archiving room of both two blocks. At the archiving room, master documents will be kept after recording the archiving no. in the document archive register as per annexure-V.
[][]In the archive room, master document will be kept in a departmental manner as per allocated area for the individual department.
=>Document archive no. will be given as the following format-
=>GDA/XXXX/YYYY
=>Where, GDA represents as General Document Archive. For Sterile block it will be CDA that’s represents as Sterile Document Archive.

=>XXX represents as the Departmental Code as per following List-

[][]Quality Assurance/QA
[][]Quality Control/QC
[][]Engineering/ENG
[][]Production/PRD
[][]Product Development/PD
[][]Microbiology/MICRO

=>YYYY- represents as sequential number which starts from 001.

[][]Document archive room will be lock & key controlled system. Only authorized personnel of QA department will enter in this room for documents preservation. Any other will take authorization from Head of QA to enter this room for document checking or reviewing.
[][]Retrieval or Recall of Obsolete Controlled copies and Superseding of Obsolete Master documents
[][]When the document has been revised following a change request, the older version must be superseded.
[][]Obsolete versions of documents are retrieved and reconciled and entries are made in the specific obsolete register.
[][]All retrieved controlled copies of documents shall be destroyed immediately & recorded.
[][]The Master Copies of the superseded documents along with document change /approval request form shall be archived in the QA department stamped as in Red Ink maintaining the a register.

OBSOLETE
Initial………Date..…

=>in RED ink with initial & date of QA Personnel.

Document Retention

[][]The Retention period of quality related documents is mentioned in Annexure – II.
[][]All quality related documents should be stored securely and safely with controlled access, protected from damage and mutilation. The storage areas and access restriction to the retention of these documents are in the documents archiving room.
[][]The documents related to legal proceeding should be securely kept till the legal proceeding are over.
[][]All documents relevant to quality of the in-house manufactured products must be included in the documents archiving register having a archiving no.

[][]Quality Assurance shall maintain all the Master documents
[][]Responsible Quality Assurance executive shall maintain a log register for taking & re-archiving of documents from Documentation Archiving Room of QAD.
[][]A log register shall be maintained by responsible Quality Assurance executive to archive the Batch Production Records.

Destruction

[][]QA department shall destroy the documents after the retention period is over and maintain a record of the same.
[][]The destruction may be performed by shredding, cutting, tearing, to make the documents non-usable.
[][]A file note will be prepared. A list of documents with sufficient information like document number, effective date, review date etc. (or manufacturing date, expiry date, batch number or lot number of the materials or products etc.) will be attached as an annexure in the file note. Destruction approval will be given by GM, Plant and Manager, Quality Assurance.

Annexure:

Annexure-I: Request for Issuance of Additional Copy of Documents
Annexure-III: Retention Period of Quality Related Documents.
Annexure-III: Document Control Register
Annexure-IV: Log Register for Obsolete Documents
Annexure-V : Document Archive Register


Hold Time Study

Quality Assurance, SOPs

Hold Time Study, Purpose:

Hold Time Study, To establish a procedure for determination of in-process holding time limits.

Hold Time Study, Scope:

This procedure is applicable for all products to be manufactured at both General block and Sterile block of XX Pharmaceuticals Ltd.

Definitions / Abbreviation:

[][]RH – Relative Humidity
[][]NMT – Not more than
[][]QA – Quality Assurance
[][]SOP – Standard Operating Procedure

Responsibilities:

[][]The roles and responsibility is as follows:

Executive, Quality Assurance

[][]To ensure proper handling & storage of hold time sample following this SOP.

Executive, Quality Control

[][]To be responsible to provide analytical support

Manager, Quality Assurance

[][]Approval of the SOP.

Procedure:

[][]Hold time study for dispensed materials (Active materials), blended granules, bulk tablet, coated tablets, bulk capsules, blister strips, filled bottles to be done.

[][]The sampling & testing frequency will be 7 days and 15 days. In addition for blister and filled bottles-60 days study to be performed. Based on the holding time study the holding period will be fixed.
[][]During holding time study all products were considered withstand the controlled environmental condition (The environmental condition is; %RH: NMT 55.0% and Temperature NMT 25deg.C).
[][]If the holding period of dispensed active materials, blended granules, bulk tablets/capsules, filled bottle and blister strips is more than the time period specified in this SOP then further assessment/retesting to be conducted before further proceeding.
[][]However in case of recoverable residue consumption of capsule products the h. study will be conducted up to four months and based on the analytical data the holding period will be fixed.
[][]The numbering of hold time study report for individual products shall be assigned as per
=>HSR/PXXXXX/YY
=>Where, HSR means Hold time Study Report
=>PXXXXX means the product code
=>YY means the version number of the study report.
[][]Sampling, analytical testing shall be conducted according to annexure- I.
[][]Hold time test of dispensed active materials for a product of different strengths will be done once.
[][]Data shall be compiled and used for establishing in-process holding time limits for different stages of product manufacturer.
[][]The  H. study for equipment should be performed and both clean and unclean state of equipment also be considered. Based on the documented data the equipment holding time period will be established.
[][]After collecting all data the H. time study report will be generated for each product following the annexure-II.

Annexure:

Annexure-I: Sampling stage and testing frequency for hold time study
Annexure-III: Hold time study Report format


Retention Sample Handling

Quality Assurance, SOPs

Retention Sample, Purpose:

Retention Sample, To establish general guidelines for sampling, handling and storage of Retention sample of finished products for regulatory testing and for resolution of customer complaints.

Retention Sample, Scope:

This procedure is applicable for both General block and Sterile block at XX Pharmaceuticals Ltd.

Definitions / Abbreviation:

[][]BPR: Batch Packaging Record
[][]QA: Quality Assurance
[][]QA: Quality Assurance

Responsibilities:

[][]The roles and responsibility is as follows:

Executive, Quality Assurance