Validation Master Plan[VMP] encompass all type of validation activates of a site especially for the new firm, the firm must be validated before run any routine commercial production. The validation activities which consider the major area as Facility, Utility, Machine, Process etc.. Facility, utility, and machine must be validated before run the production operation.
Validation procedure and Validation Master plan is not the same and doesn’t implies the same thing. Validation protocol describe the specific procedure to perform the specific activities where as Validation Master Plan is the series of plan/schedule which describe the plan with a tentative define timeline. Any plan/schedule may be change which to be cover by raising deviation management with proper justification and action to be triggered followed by CAPA.
Validation Master Plan is beneficial for planning purpose and subsequently identifying the related resources to complete the assigned activates on due time. It covers the all type of major documentation like procedures, processes, product, facilities, utilities and equipment.
How a Validation Master Plan works?
Validation master plan is the core guidance of the firm which implies that how the validation activates of the firm will perform within a time frame. It details the activities of the all functional department like production, quality control, Engineering will operate their activities regarding validation events.
The plan demonstrate by the Validation master plan is set upon the agreement of the all functional department and any type of failure is properly justified which satisfy the regulatory body. The proper implementation of the VMP of the respective firm denote that they have the proper control over their quality system.
Functions of the Validation Master Plan
Management learning
Top management of the company is not concern about the requirement of the qualification and validation activities of the respective firm. Here VMP plays the major role and provide the essential information to the company top management. The content of the VMP describe the total quality requirement events of the validation process. It also denote that only the properly validated facility can provide the repeated/continuous quality product through daily activities.
Project nursing and management
By preparing the Gantt chart from the content of the VMP, the management can track the activities of the new facility and set a tentative deadline for the competition of the defined activities. Everyone will be proactive when set a tentative deadline with proper justification through a site quality review meeting. Assigned personnel must be monitored for the progression of the events by daily /weekly /fortnightly/ monthly then VMP will be fully effective and action will cover on due date.
Conducting the validation program
Validation master plan describe the all events in the validation process and the qualification of the processing equipment’s and utilities. As the VMP provide the timeline for the completion of the defined activates base on the criticality. All related resource must be on site to conduct the validation activities and recheck/double/ triple check may be conduct before starting validation activities, for any shortcoming notify the same and after solving the events proceed to validation activities.
Planning purposes
As the VMP detect the list of resources which is required to perform the validation activities in a time line then the list of document may affect by this activity-
Equipment
Facilities
Product
Processes
Procedures
Utilities
Criteria of a Validation Master Plan
VMP require specific preparedness and vigorous planning of different steps in the particular process. All type of activates need to perform in due time as per approved working plan avoiding any type of major/critical deviations. Beside this a VMP is generally written off as-
Multidisciplinary methodology:
This is not the one man job, its require multidepartment involvement, various type of SME [Subject Matter Expert] from various department are involve to perform the specific job. Expert such as chemical analysts, pharmacists, microbiologists, technologists, engineers, metrologists, and SME from QA departments must involve to this activities.
Time bound:
Any type of validation
Generally validation work is submitted to rigorous time schedules. These studies are always the last stage prior to taking new processes, facilities into routine operation.
Costing matters:
To run a successful validation activities to the site, huge resources and expert personnel are involve so that no deviation occur on the site. Lot of financial involvement require to perform the designated activities. A new machine/equipment may be involve to solve the emergency issue.
List of critical point of Standard VMP
All VMPs must include the following:
Title page with Authorization where appropriate signing with date will be present. Title page must be include title of the document, document number and version no. and Signature from the appropriate body including Head of site quality. List content to be present on a VMP-
Table of contents
Abbreviations and glossary
Validation plan
Purpose and approach to validation
Scope of validation
Roles and responsibilities
Outsourced services
Deviation management in validation
Change control in validation
Risk management principles in validation
Training
Validation matrix
References
Table of contents
The table content is the brief of the major substance/content present in the VMP. It contains all of the critical area of VMP. Page no. to be mentioned on the table of the content page along with the major content. It will denote where will find the major content of the VMP.
Abbreviations and glossary
Abbreviations and glossary provides necessary information’s to the reader regarding the various term or short/abbreviate form use in the VPM which may not familiar to the respective reader.
Validation plan
A VMP implies that what should be validated and when, where, how and why it should be executed. Critical process mention on the VMP must breakdown into several parts and criticality must identified to perform require validation.
Purpose and approach to validation
Purpose provides an overview of the every process also describe validation approach with supporting data. It must be sum up clearly so that the respective user can understand the actual process/procedure by tracking the document. Validation approach states the persistence of the VMP denoting critical process, equipment and system as described.
This methodology confirm that all validation events to be conducted in prospective manner following approved protocols. VMP speaks about the change control and qualification of equipment and systems and confirm the stipulated events has been done based on existing policies and procedures.
Scope of validation
Scope of the VMP describe all evets relating to the processes, systems, equipment, utilities, and procedures which may affect the quality of the product at the manufacturing site.
Specific equipment, utilities, systems, and procedure be mentioned properly and validation execution to be done based on the documented risk assessment. Define clearly which area will be under validation and where not under the scope. Procedure to be describe in such a way so that anyone possess the same understanding to coverage VMP.
Roles and responsibilities
This area specially denote the dedicated responsibility for the designated department. Generally validation department/team is responsible for preparing all type of validation protocols, validation reports, List of SOP’s deviation reporting, and change control procedure and achieving, storage of validation related all documents.
Generally, Engineering, Production, QC, Microbiology and QA personnel prepare the validation documents as when required based on define timeframe subsequently. Quality Assurance department is responsible to review the all protocol, reports, SOP’s etc. then approve the same.
Outsourced services
Any type of out sources activities regarding qualification and validation must be mention the validation master plan and record/supporting documents/agreements must be keep the same. Certified vendor to be involve to the validation activities, before engage the validation/qualification activities vendor competency certificate to be check.
Deviation management in validation
Any deviation regarding validation to be address and record must be keep for further clarification, if machine involve then call the supplier to resolve the problem. All of critical deviation must be investigate and corrective action to be taken. All validation report to be approve before starting the operation.
Change control in validation
VMP must implies all change management which have the potential impact on the validated process/system must be notify and it should be handle with the existing change management procedure.
Risk management principles in validation
Quality Risk Management Procedure to be define on the Validation Master Plan as to perform the validation activities, quality risk may be the major to be notify same and record must be done and impact to be analyze properly through FMEA[Failure mode and effects analysis] method.
Training
The defined personnel who will perform the validation activates must be trained properly and to be ensure that they have the proper knowledge and skill to perform the right job at the right time.
All validations
This include the following area-
Analytical method
Cleaning
Computer validation
Equipment
Premises
Processes
Qualification
Revalidation
Utilities
The description of the major area must be include VMP such as Manufacturing, Material Management, Facilities, and Central Plant. Attachment with VMP must define the GMP compliance area and non-GMP compliance areas. Describe the cleaning validation strategy and manufacturing process steps, use process flow diagram to describe the specific product manufacturing activities with major equipment involvement on the diagram. Performance qualification of the major equipment to be done showing that it repeats its intended use subsequently.
Validation matrix
Performing an effective validation matrix by prioritizing the critical validation at first then the next one. In this way the VMP activities may be more fruitful. List the all critical validation then perform the task as per justified time frame.
References
List of references to be add at the end of the VMP documentation. Proper guideline reference is mandatory to prove your documented evidence.
Writing the VMP
To write the effective VMP, a team may be form due to a single/individual/specific person didn’t contain the all idea/knowledge regarding different activates. A QA person may not be expert about Engineering activates and a QC person may not be expert about production activities, so a team from different functional department may be effective way to gather comprehensive knowledge from different perspectives then write down the right VMP.
Involving the multidepartment people from different parts confirm that all equipment, utilities, processes, and systems has been properly addressed on the VMP. T write an effective VMP, every team member must be proactive to address the every point of view seems critical to his side.
What “WHO” says about Preparation of VMP?
“A manufacturer should have a validation master plan that reflects the key elements of validation. It should be concise and clear and at least contain reference to/have a short description”.
List of Major content of VMP as per WHO GMP guideline-
Analytical method validation
Change control
Cleaning validation
Computerized system validation
Deviation management
Equipment & instrument qualification
Outsourced services
Personnel qualification
Premises qualification
Process validation
Validation matrix
Validation policy
References
Risk management principles
Roles and responsibilities
Scope of qualification & validation
Training
Conclusion
A well described VMP is the true asset of the firm as well as the critical document to avoid the regulatory noncompliance. An incomplete VMP always brought more 483 with subsequent warning letters from FDA. A standard VMP must be more precise, to the point and actual to the system, process, and procedure.
Every sentence of the VMP must be “may”, “may be”, “should be” etc. free, sentence must be in active form in present tense. A well decorated VMP implies the organization positive image as well as quality products avoiding non-compliance, deviation etc.
HEPA filter, High-Efficiency Particulate Air/ High-Efficiency Particulate Arrestance Filter / High-Efficiency Particulate Absorbing Filter is known as HEPA filter denote higher degree of efficiency. The efficiency level denote the grade of the HEPA filters. There are several grades of HEPA filters available as per their area of application.
A standard HEPA filter must remove the particles from the air at least 99.5%[EU standard] or 99.97%[ASME,US.DOE] having particle diameter equal to 0.3 μm and subsequently increase efficiency with particle diameter greater than or equal to0.3 μm.
All type of standards HEPA filter generally retain particle and microorganism like dust, pollen, dirt, moisture, virus (0.02-0.3 μm), bacteria (0.2-2.0 μm), Bacillus subtilis, submicron liquid aerosol (0.02-0.5 μm), Penicillium citrinum, Aspergillus niger, Clostridia, Staphylococcus epidermidis, Bacilli, Bacteroidia, photocatalytic oxidation (PCO) etc.
HEPA filters use in wide area since its commercialization at 1950 where need to control contamination-
Aerospace industry
Cosmetic industry
Materials dispensing area
Electronics
Food Industry
Hard disk drives mfg. industry
Hospitals
Medical devices
Microbiological Lab
Nuclear Plant
Pharmaceuticals
Sterile products mfg. facility
Semiconductor industry
Vaccine and blood products mfg. area
Vehicle industry
Type of HEPA filters
Generally HEPA filters can be classified as [A], [B], [C], [D], [E] and [F]. Types testes are demonstrates on the following table.
How it works?
All type of HEPA filters are generally composed of mat where fibers are randomly arrange, these fibers are actually set of poly propylene or fiberglass varies diameter between 0.5 and 2.0 micrometers. Frequently use tangled bundles of fine fibers to prepare these filters. Air passes through the convoluted pathway crated by the tangled bundles of fine fibers.
Actually this fibers act like sieve which retain the big particles which subject to try pass through it. Most time the smaller particles can’t hold its motion when they are passed with air, in result the small particle crush with the fibers. As per Brownian motion, the small particle possess the little materiality to move randomly with air as these particles are suffered to bombard action.
As the small particles crush with the fibers, here the key factors are mainly filter thickness, fiber diameter and velocity of the air. The air space between the HEPA filter subject to greater than or equal to 0.3 μm provide high level of efficiency. In sieves or membrane filters, particles which are less than the pore or openings can pass through but in HEPA filters the particles are attached to the fibers. There are several mechanisms has been identified which play the major role trap the particle to the pore.
Diffusion
All the particles under 0.3 μm retained by the HEPA filter in diffusion method. This the main theme of the Brownian motion where smaller particle below or equal to 0.1 μm in diameter are hindered and trapped in the filter. This mechanism is not prominent is low velocity of air.
Interception
Particles which are subject to flow in a line come with same radius/diameter of a fiber and adhere to it, this is very prominent to mid-size particle and which are retain by this process.
Impaction
Particles with higher diameter subject to unable to pass the fibers and directly retain on them, the effect increase subsequently with the air velocity.
Particle having size at or below 0.1 μm diameter, diffusion method is predominant and particle above0.4 μm predominant to impaction and interception. The MPPS [Most Penetrating Particle Size] is 0.21 μm, here the impaction and interception are remarkably inadequate. And this this point consider the weakest point of HEPA filter. The classification of the HEPA filters remarkably depend on the particle retention capacity at or below or equal to 0.3 μm particle size.
What is Gas filtration?
All types of HEPA filters are designed to retain particles but HEPA filters are unable to retain odor and gases molecules. HEPA filters can’t filter the odor or gases molecules. Alternative have been developed by British Armed Forces[BAF]. To filter the chemical vapors, organic compounds, volatile compounds, pet, cigarette, or flatulence odors, activated carbon filter or other filters are used.
HEGA [High Efficiency Gas Adsorption] filters plays the major role here, composed of Carbon cloth filters which is more efficient than granular activated carbon form. This filters [HEGA] designed by BAF to face chemical warfare.
Effective Usage of HEPA filter with Pre-filter
In a common air handing unit, a pre-filter[Carbon activated] use with the HEPA bag filter to extend the usage life/shelf life of more expensive HEPA filter. At the first stage of the filtering the pre-filter, removes the almost all type of dust, hair, particle from the air. Particles which can’t remove by pre-filters or escape from it then the fine particles remove by the HEPA filters in AHUs[air handling units].
Specifications of HEPA Filter
HEPA filters are defined by the US, DOE[United States Department of Energy] in almost all American industry which removes at least 99.97% of particulate at 0.3 μm in diameter. At the standard volumetric air flow, the minimal resistance of the air flow or pressure drop is around 0.044 psi[300 pascals].
In EU, filters are classified based on MPPS [Most Penetrating Particle Size] as HEPA, EPA, and ULPA where the average efficiency defined as “Overall” and the specific point efficiency defined as “Local”.
Marketing View Regarding HEPA Filter
Now a days some of the company highlighted the term “True HEPA” supposed to give assurance to the end user/customer to confirm that their filter is the original HEPA filter. This term “True HEPA” has no significant scientific value or no legal meaning. Some of the company marketed as designed as”99% HEPA”,”HEPA-style””HEPA-like,” “HEPA-type,” etc. which didn’t comply the HEPA standard[99.97% efficiency] and this type of material may not have the original test certificate of may not undergo any type test like filter integrity test.
Safetyconsideration of HEPA Filter
Mid-size particles ranges between 0.15 µm and 0.2 µm is considered hardest to filter through HEPA. The mechanism of working of HEPA filter is totally different from Ionic filters and Ozone filters which work through negative ions and ozone gas respectively. So HEPA plays a great role in pulmonary side-effects like asthma and allergies which are much lower with HEPA filters.
Where the HEPA filters subject to use in commercial grade, it is better practice to change the HEPA filter in every six month to hold its efficiency at desired level of work but if it use in residential purpose then it may be change in every two to three years. In the period of time, the efficiency of HEPA filters decrease day by day and failing to change the same in due to create hazard to the machine or system and particulate contamination spread day by day.
Applications of HEPA filters
Biomedical
HEPA filters generally remove the air borne particle, bacteria, virus and various type of organism resulting infections. High energy ultraviolet light units or panels with anti-microbial coating integrated HEPA filters are specially use to serve medical purpose to kill the live bacteria and virus which trapped by the filter media. Airborne disease transmission successfully protect by the special design HEPA filter which efficiency declared as 99.995%.
Heating, ventilation, and air conditioning[HVAC]
HVAC [Heating, ventilation, and air] technology uses HEPA filters to remove airborne particulate, dust, microorganism etc. in indoors and vehicle, greatly use in sensitive pharmaceutical product manufacturing where subject to clean room class. To ensure better environment and better health, HVAC play a major role various organization who are concern this activities.
COVID-19
HEPA filters plays a great role to get entrapped SARS‑CoV‑2 Airborne droplets which size approximately 0.125 µm even if they are present on the floor. Various type of HEPA incorporated mask are available at the current market which is the best solution to prevent the pandemic situation for personal use.
Motor vehicles
HEPA filters is using in the latest car, “Tesla Mode X” using HEPA filters since 2016 and now their update “Model S” also using the additional HEPA filter.
Vacuum cleaners
HEPA filters are also use in many well designed vacuum cleaners as a part of their filtration systems. This option of the vacuum cleaners plays beneficial role for the patients having asthma and allergy problem due to HEPA filters traps fine particles reduce to size 0.1 µm which is mainly responsible to induce asthma and allergy. Before using the Vacuum cleaner integrated with HEPA filters, check the filter efficiency [at least 99.97%] unless authorized. HEPA like, True HEPA, HEPA are not the actual term to declared standard HEPA efficiency.
A powerful motor is essential to provide adequate cleaning power due to the high density of the HEPA filters. A vacuum cleaners containing washable HEPA filters subject to more expensive. A standard high quality HEPA filter generally trapped the particles having 0.3 µm in diameter where a natural human hair is 50 to 150 microns in diameter. So a HEPA filter traps the particle which are reduce to several hundred times smaller than the standard width of Human hair.
Sometimes, is remarkably noticeable that some of the manufactured declared HEPA 4/HEPA 3/HEPA 2 etc. without proper explanation behind them. This is actually declares their MERV [Minimum Efficiency Reporting Value] rating. This the ability of the air cleaner filter to remove the particle, dust, and microorganism etc. which passes with air through the filter. The MERV scale distributed between 1 and 16 which declare the efficiency of the filters remove particle between 10 to 0.3 µm in size.
Vehicles
Airlines
All types of modern airlines uses HEPA filters to reduce contamination in the air. As most of the air in air plane cabin is recirculated, so this is crucial to filter the air using high grade of HEPA filters to avoid cross contamination.
Maximum quantities of standard pressurized aircraft brought air from the outside and circulate it the cabin exhausted it through the outflow valves in the rear side of the respective aircraft. Almost 60% of air comes from outside of the plane and 40% cabin air passes through the HEPA filters in well-designed aircraft.
What are drawback of HEPA filters?
Every filtration technology has the shortcomings that no filter can pass the 100% contamination free air. The efficiency is almost 99.9997% not 100% same for HEPA filters. Besides this the HEPA filter has the following two types of drawback which can dissatisfy to you to buy a HEPA filter/HEPA filter integrated equipment’s-
Insignificant Pollutants Can Escape Filter:
HEPA filters are effectively act on the particle size at equal to or above 0.3 µm, there various type of microorganism which particles are reduce <0.1µm can easily pass the HEPA filters. So using HEPA filters you can trap/remove all type of organism, this myth is actually invalid. The smaller particulate cause the serious health hazard for the patient/personnel who are previously suffering from asthma or allergic problem. Alternative technology should be used to face this tiny size particles.
Various type of Mold & Bacteria Growth on Filter:
When bacteria and mold gather on the air system on the HEPA filter, this accumulate organism have the potential chance to grow in geometric order. As the number of the microorganism tend to grow outside the filter then the health hazard outside the controlled environment growth day by day. To solve this issue, a UV light integrated HEPA filter to be use to kill the mold and bacteria at your indoor environment.
So what is the best alternative of HEPA filters?
The best alternative of HEPA filters are ULPA [Ultra-low Penetration Air] filters. HEPA filters remove particles size equal to or above 0.3 µm having efficiency of 99.97% where ULPA filters remove particles size equal to or above 0.12 µm having efficiency of 99.999%.
Can HEPA filters be Wash or Reuse?
All type of HEPA filters can’t wash. Some of the HEPA filter can be wash and some are not. If your HEPA filter labelled with“Washable” then you can wash the HEPA filter but a non-washable HEPA filter may be wash by appropriate way.
To rinse a HEPA filter decrease its efficiency and proper study didn’t found that how much efficiency loss upon rinsing the HEPA filters. Moreover, this has been proved that upon rinsing the HEPA filter, its efficiency loss due to losing/damaging of fiber occur in this time.
During cleaning of HEPA filter, if individual face lack of awareness, fall in serious health hazard upon accidentally taking some of pollutants from HEPA filter. After cleaning, drying activity must complete for a long time. Check the same before use as the wet filter is the great source of mold.
HEPA filters can be reuse if you can clean it properly. Use a vacuum cleaner to clean the filter rather than rinse it. Even non washable filter can be clean this way, proper measures to be taken before cleaning the HEPA filter. Avoid direct touching it. If you rinse your filter, the dry the filter properly by placing it outdoor. Before placing, shake the it to remove the water properly. Set it at outdoor in such way that it get air from all direction and faster the drying process.
After washing the filter may withheld its efficiency maximum 99.7% and you can was your filter every six months or once in a year but it is the best practice to replace the same. Some of the filter labelled with “Permanent” then you can’t wash it, just replace it.
Poly Alpha Olefin (PAO) is used in in HEPA filter integrity during validation of HVAC system in different pharmaceuticals. This is the best alternative of DOP which was previously used for the same purpose as PAO is subject to use. DOP was using long time for HEPA filter integrity test during HVAC qualification.
International Agency for Research on Cancer (IARC) has classified DEHP/DOP as carcinogenic 2B substance According to evidence from rodent studies which has also been identified carcinogen (cause cancer) for the human. For this reason scientist was trying to replace DOP for similar materials for a long time.
In 2021, JICA[Japan Air Cleaning Association] introduce a guideline to substitute the DOP[Dioctyl phthalate] with PAO[Poly Alpha Olefin]. PAO provides the same performance as provided by DOP additionally doesn’t provide any harmful/carcinogenic effect to human.
Food and Drug Administration[FDA] stated that the alternative aerosols are also suitable but it shouldn’t promote the microbial growth in the respective area. Generated aerosol ranges from PAO[Poly Alpha Olefin] is 0.1 to 1.0μm.
The aerosol generator, generate the PAO aerosol and subsequently passed through the HEPA[High-Efficiency Particulate Absorbing/High-Efficiency Particulate Arrestance/ High Efficiency Particulate Air having six types A, B, C, D, E & F] filter and then with the help of a Photometer the integrity is checked as 99.97% particle contains size 0.3 μm shouldn’t pass to the HEPA filter.
Chemically, PAO is the polymer of alpha-olefin which is the class of Olefins those contains double bond between first and second carbon of the polymer chains. Poly Alpha Olefin is the mixture of dimers, trimers and tetramers of 1-octane, 1-decane and 1-dodecane in chemically.
Poly alpha olefin is a polymer of alpha-olefin. Alpha-olefin is a class of olefins those have a double bond between first and second carbons of the polymer chains. PAO contains better lubrication properties and having greater viscosity compare to mineral oils. Poly-alpha-olefins have good lubrication properties and greater viscosity than mineral oils.
Poly alpha olefins are also used as a coolant in radiators and synthetic lubricants. Generally, the declared shelf life of PAO is 10 Years but when subject to open the container, the shelf life down to only one year. This is the best practice to protect PAO from direct exposure of sunlight and protect from UV light.
Why DOP[Dioctyl phthalate] banned?
Due to carcinogenic effect for human using of DOP [Dioctyl phthalate] was banned in pharmaceutical company, additionally DOP has the following significant effect which is also the major cause to ban the DOP.
Endocrine disruption
Causes endocrine disruption in male, act as androgen antagonist subsequently effect on reproductive system. Exhibits insignificant levels of reproductive function in adolescent males in Prenatal phthalate exposure. Chromatin DNA integrity and Sperm motility expressively reduce in PVC pellet plant where presence of higher airborne concentrations of DOP. Subsequent study has been proved that the significant exposure of DOP reduce the Chromatin DNA integrity and Sperm motility in men.
Development
Several studies have been shown that significant exposure of DOP has been change the sexual function and development in rats and mice. During pregnancy, excessive exposure of DOP disrupt development and placental growth in mice which cause premature birth, low birthweight, and fetal loss. Advanced levels of anxiety during puberty and hypertrophy of the adrenal glands may arise if excessive DOP exposure occur in neonatal mice through lactation.
Obesity
Intestinal lipases convert DOP to MEHP upon DOP ingestion then MEHP absorbed. MEHP is considered for the obesogenic effect. DOP is the possible disruptor for the thyroid function which have already verified by human studies and rodent studies. Subsequent exposure of DOP is significantly relevant with plasma thyroxine levels and patient with hypothyroidism inclined to to weight gain.
Cardiotoxicity
A minor dose of DOP predominately effect the activity of mice. The duration of the exposure of and clinical dose of DOP has the significant effect of the behavior of cardiac cell at culture. Cell face the slow propagation speeds with fractured wave fronts.
Mix up can be defined as taking something which is not subject to take; taking one thing to another. Taking wrong item unintentionally which can be easily identified such as taking Aceclofenac tablet in place of Metronidazole tablet having different size and shape. Mix up is a mix of diverse item but essentially contaminated. For example one blister strip of batch [A] tablet found with another batch [B] tablet.
Mix up is
Assume wrong item to right thing
Failure to take right action on due time
Mixture of various item/elements
Selection of wrong item
Selection similar product/material/item
Unintentionally taking one thing to another
Wrong selection of desired material
Wrong action taken due to lack of attention
Probable cause of Mix up
Breakdown of processing equipment.
Collation/procure similar packaging/printed material from same vendor.
Conducting packaging operation in other than main packaging belt.
Discontinuous packaging/partial packaging of single batch.
Engaging untrained/partial trained personnel.
Engaging single operator to multiple packaging line.
Failure to follow written procedure for line clearance.
Inappropriate labelling.
Improper segregation of products/item during manufacturing operation.
Improper labelling during dispensing.
Inadequate controls.
Manual operation other than automated system
Multiple product packaging operation in insufficient packaging area.
No barcode/QR code/Identification code
Process validation not properly conducted
Previous batch item such as label, carton, accessories etc. not removed properly
Rejection material handling
Reprocess
Rework
Return of IPC checks item to the wrong/ similar packaging belt.
Repackaging and packaging of similar product/item.
Similar Size, shape, color of multiple products.
Similar design of primary packaging/secondary material.
Similar product line clearance in same time.
Same instruments/apparatus use for multiple item/products/material.
System failure
Wrong labelling
Contamination
Contamination can be defined as the presence of undesirable element, impurity or constituent which infects, corrupts, spoils, makes substandard or makes unhealthy a factory, normal environment, physical body, material, process steps, bulk, liquid, granules, solid etc.
As per US FDA, contamination can be defined as-
Type of Contamination
Non-Viable
Liquid or solid particulate contamination range from 001 and 1000 microns such as smoke, dust, fogs, fumes, and mists.
Viable
Particulate contamination that supports, or consists of one or more live microorganisms such as Viruses, Bacteria, and spores.
Sources of Contamination
Atmosphere
Clothing
Equipment
Fluid
HVAC System
Manufacturing Debris
Premises
People
Processing Operations
Surface
Utilities and Services
Various source of contamination has been illustrated on the respective table-
Contamination of products can be caused by:
Contaminated dress/attire
Contaminated equipment/apparatus/instruments
Contaminated or damaged HVAC system
Contaminated Premises/sites/areas
Individuals, e.g., carrying harmful bacteria
Processing Operations negligibly
Utilities/Services/facilities
Cross Contamination
Cross Contamination can be defined as unintentional transfer of chemical contaminants, microorganism from one person, food, and object to another person, food.
Risk of cross contamination
The involving risk of cross contamination depends on the type/class of contaminant and which product or item will be affected.
The most hazardous contaminant are;
Allergens
Biological item/product/living organisms
Hormones
Sensitizing materials
Toxic materials/Item
Sensitive product for contamination
Administer booster doses
Injections
Prolong period of time
Product Applied to open wounds
Cytotoxic agents
Consequences to Company
Company image crisis
Financial losses
Loss of Company reputation / Adverse Publicity
License cancellation
Market share down
Product Recall
Show cause notice
Shutdown of premises
Vigorous audit by regulatory authorities
Withdrawal of product
Warning letter
Employee Consequences
Financial losses
Jail / Penalty
Reputation loss
Personal Image crisis
Suspension order
Show cause notice
Termination of services
Minimizing the risk of cross contamination
Minimizing the risk of cross contamination from mix up
Allocation and utility connect expertise that are exclusive to the process
Bar coding, QR coding, and RFID of materials and equipment’s
Distinct dispensing areas
Enormous Electronic confirmation of material
Enormous manual check
Isolated raw material staging area with proper labelling
Using of Color coding
Using of Locked and key Stainless steel cages to store APIs with chain of safekeeping
Using of PAT [Process analytical technology, i.e. NIR]
Minimizing the risk of cross contamination from residue carryover
Cleaning validation
Distinct product contact parts
Equipment design for CIP and SIP
Single use product contact parts
Process Analytical Technology [PAT]/online monitoring
Setting of cleaning limit
Set base limits on statistical analysis, science, and risk assessment
Minimizing the risk of cross contamination from Mechanical Transfer
Airlocks system
Cleaning mobile equipment’s/machine in processing room/area
Encompass at the source
Gowning procedures
HSG [High Shear Granulator], Milling and Drying in same suite
Limiting the transfer of compounds between same suits
Room Airflow
Separate work areas to a single product
Sprinkling showers
Wipe down protocols for mobile equipment’s
Minimizing the risk of cross contamination from Air borne transfer
Cross-contamination, Before taking steps regarding Prevention of Cross-Contamination during processing, this is very important to know basic about contamination and Cross-Contamination and what is the basic difference between contamination and Cross-Contamination.
Cross-contamination can be defined as unintentional transfer of chemical contaminants (including allergens), microorganisms, or any other foreign substances from person, food, or object to another person, object or food product.
This problem is generally occurs at raw food to RTE[ready-to-eat] products, also occurs between allergen free and allegen products.
Cross-contamination products can cause severe food poisoning as harmful bacteria transfer from RTE products which doesn’t subject to any type processing or treatment on not taken any steps to eliminate harmful bacteria from those foods[RTE]. The best example of cross contamination is transfer of bacteria from raw food to cooked food.
Pharmaceutical products are the highest risk of Cross Contamination. Presence of small amount of antibiotics or trace amount of potent drugs cause severe damage to the patients. Carryover of one products residue to another products is consider the highest risk to the patient.
In the recent year, as per UK MHRA[United Kingdom Medicines & Healthcare Products Regulatory Agency], product contamination is the second to third cause to recall products from the market.
Understanding Cross-Contamination
There are several ways to where cross-contamination can occur:
Equipment to food
Food to food
People to food
Equipment to Food
Contamination can be transfer from pantry equipment & utensils to food staff. This type of contamination can be transfer from improper cleaned equipment or utensils to food items and which is not properly sanitized before each use. Here is some example-
Using of improper cleaned items such as utensils, slicers, knives, grinder, and juicer to prepare food.
Using of cutting and chopping board and use the same knives to cut different food items, such as cutting raw beef and then prepare vegetable salad or RTE food items.
Storing RTE [ready-to-eat] food items in an improperly sanitized container, which was previously used for raw food item such as raw beef.
Food to Food
Food can contaminate by bacteria from comes from other foods. This type of cross-contamination seriously dangerous when raw type foods contact with cooked/finished food/RTE Food. Here is some example for of food-to-food cross-contamination-
Storing raw chicken in the upper shelf of the refrigerator but cooked chicken store lower shelf of the refrigerator where cooked chicken dripping from raw chicken.
Raw meat placed on a on a grill touching another meat that is being cooked.
People to Food
Personnel can be great source of cross-contamination to food items for their inappropriate behavior or lack of training to do the task properly. Here is some points to notify the situation-
Handling of food items just using after the toilet without properly personal clean up.
Touching Raw Chicken and prepare vegetable salad without properly clean up between the tasks.
Handling of apron with wipe hand and subsequently serve foods to individual.
Using of towel to clean the kitchen and further use the towel after dry hand.
How to prevent cross-contamination
Production & Related Area
All type of line clearance should be perform as per approved SOP and related checklist mentioned on BMR/BPR
Avoid similar type of product clearance in same time in side-by-side line.
All the system must be properly validated [Equipment/Machine/Facility/System/Process etc.]
Before starting of any type of product processing, processing product, list of materials, printing materials, primary packaging materials must be contamination free.
Check any type or related starting materials, product residues, products, documents, records, process flow and related documents of the previous products during starting of the new line.
Closed system to be introduce for critical products, if possible close system to be introduce for all type of products handling.
Campaign production may be the best procedure to achieve satisfactory contamination/cross-contamination free products by following appropriate validated cleaning procedure.
During processing, products and direct products contacts part should not be handled with bare hand, use latex free gloves to handle the same with properly spray cleaned with IPA [70% IPA]
During production/processing all type of maintenance work must be prohibited and production/processing to be stop during maintenance activities.
If any area subject to maintenance activities, to restart of the operation, the area must be properly cleaned and maintenance clearance to be ensure from respective department.
Packaging must be properly segregate from processing/filling area, a physical barrier must be introduce to prevent contamination and related operation must be controlled.
Product subject to in process control in production area to be confirm that it should not provide the risk for the product and remaining IPC products must be discard and not to add the processed products.
Production accessories/stationary/liquid item/ink of image printer/other solvent etc. must be kept in labelled container as per their content present in the defined container.
Single line processing to be introduce, never start multiple line/product in the same line
Solution container subject to filling should be properly cleaned before using for filling operation especially for aseptic products such as eye drops, which cannot be terminally sterilized due to container criteria [Plastic container].
Try to reduce bioburden especially for injectable products and remove outer additional/unnecessary/additional wrapping during delivery at the point of use.
Clothing& Hygiene
Appropriate clothing and gowning system to be ensure as per classified area.
Clothing should be different for every shit/working hour/every time before entering the processing/filling area.
Cleaning agents to be use in proper quantity and agents must be contamination free
Clothing and its quality should be appropriate for the process and the grade of the working area.
Daily environment monitoring by particle counter machine, air sampling, settle plate count to be carried out as when appropriate.
During handling of hazardous material/container/liquid/gas, appropriate PPE[Personnel Protective Equipment] should be ensure.
Footwear to be clean properly and each pair of clean shoe to be confirm before entering to the processing/filling area.
Lint free non-shedding cloth to be ensure.
Minimize the exposure of body surface as less as possible.
Repeated wear of same gown in same days must be avoid in processing/filling area.
Separate/dedicate PPE to be ensure for beta-lactam and non-beta lactam, other antibiotics, hormone, generic medicine, cytotoxic etc. products.
Slippery sandal/shoe/loose shoe etc. to be avoid and appropriate shoe to be use such as lint free clothing shoe to be ensure especially in sterile processing/filling area.
Wash the cloth each time before entry of the process room.
Washing system to be separate as per designated area.
Utilities and Service
Appropriate water to be use in pharmaceutical preparations for its targeted use.
Any type of failure regarding water quality test must be notify and action to be taken and production must stop.
Chemical and microbial limits and requirements must be made.
Validation of the water system to be ensure before using water in pharmaceutical preparations especially First and Second phase must be validate and third phase must be ongoing and report should be made.
Water quality must be check before its use.
SteamQuality
PQ[Performance qualification] of steam to be ensure.
Pure steam and industrial steam to be use as when and where appropriate.
Steam must be additive free.
Steam must be contamination free and microbial quality must be passed.
Compressed air/Transportation/Cleaning and related activities
Air quality to be ensure by passing through appropriate filter.
Any sign of spillage/broken/contamination during transport, full quantity must me discard.
All type of processed or partially processed, in-process materials, raw materials, partially packed, finished packed should be properly labelled with Product Name, Batch no., Quantity, Packed by, Packing date, Manufacturing date, Expiry date etc.
Cleaning solvent/materials use for cleaning, lubrication, pest control should not direct contact to the product and suitable grade of cleaning agent to be ensure.
During production, high degree of cleaning and sanitation to be ensure before entering into the processing/production area.
Measures must be taken to prevent cross-contamination and its effectiveness to be ensure.
Processing/manufacturing area for hormones, penicillin, cephalosporin, generic products, vaccine, antibiotics must be dedicate/segregate to prevent cross-contamination.
Transport of Beta lactam and non-Beta lactam antibiotics should not be perform in disclose condition, container must be tightly bind with the appropriate material/stripe. Finished product may be transport with tight pack condition simultaneously.
To be clean/clean label should be properly attached on any containers subject to use or unused with product/material name/batch no.
Granulation, Generally, all of the particles are distributed in irregular manner, when particles create bond between them then granules are formed. To create bond between the particles is not automatic process, mechanical forces are applied to the particles or various types of binding agents are used to create granules. Granulation is simply a particle collecting process where particles are particles create bond between them by compression or with the help of binding agent.
List of binding agent used in pharmaceutical company in granulation process of different material-Various types of binders use in pharmaceutical industry such as-
Natural Binders
Alginic Acid
Acacia
Cellulose
Gelatin
Pregelatinized Starch
Starch Paste
Tragacanth
Synthetic/Semisynthetic Polymer
Ethyl Cellulose
Hydroxy Propyl Methyl Cellulose (HPMC)
Hydroxy Propyl Cellulose
Methyl Cellulose
Microcrystalline Cellulose
Polyvinyl Pyrrolidone (PVP)
Polyvinylcaprolactam
Polyethylene Glycol (PEG)
Polyvinyl Alcohols
Polymethacrylates
Sodium Carboxy Methyl Cellulose
Top Binder Manufacturer
BASF Company
Colorcon
Dow Chemicals
FMC Corporation
Natural Starch and Chemical Company
Penwest Pharmaceutical
Quest International Group
Wolff-Cellulosics
Most of the granules size distribute from 0.2 to 4.0mm and this size may be change based on their mode of use. Granulation process refers to the activity where particles are adhere to form larger and this repeated procedure create multiple particle entities called granules. Granules are formed from series of primary particle, after completion of the process the identity of the primary particle is no longer available.
Objective of Granulation:
1. To produce quality product is the top most priority of the granulation process.
2. To avoid segregation of the ingredients in the powder mix.
-Different size of particle presents in particle mix, segregation mainly occur for the different size of particle with irregular ratio in power mix. Normally two types of particle present in a mix. Normally smaller and coarser particle tend to settle down in the bottom of the container and comparatively large particle store on the top of the container. If granulation process conducted standard way then no particle settle down on the container.
If segregation of the powder mix occur then, tablet compression leads to irregular pattern. Physical criteria didn’t match as per set parameter then directly affect the product quality. To avoid this problem, granulation process to be conduct by using suitable binding agent from appropriate source. Correct proportion of particle mix prevent settle down of the granules.
3. To increase the flow properties of the powder mix.
-Powder contains small size particle, irregular shape or surface characteristics denote poor flow property as the cohesive forces are not dominant here. Cohesive forces to be increase to get better flow property of powder. If cohesive forces is not dominant, particles are generally settle down to the bottom of the container.
4. To produce even mixtures.
5. To control powder density.
6. To produce dust free preparation.
7. To remove poor content uniformity.
8. To increase the compaction characteristics of the Mix.
9. To seizure and fuse small quantities of active material.
Mechanism of Granulation: How granules are formed
In pharmaceutical industry, granulation is the key step to prepare any type of tablets, pellets, powder for suspension and related powder products. So this is very important to know how to develop gangues from powder. How granules quantity may be develop and how we can overcome associate problem during granulation.
This is very important to form bond between powder particles as they adhere between them form particle-particle bond. The bond formation to be adequately strong so that they can overcome the breakdown tendency during subsequent handling.
Type of bonding mechanism: Five Types
Solid bridges
Mobile liquid films
Immobile liquid films
Mechanical interlocking
Attractive forces between solid particles
Methods of Granulation
Wet Granulation
Dry Granulation
1. Adhesion and cohesion forces in immobile films
In the presence of sufficient liquid in powder mix to form thin and immobile layer then inter-particulate distance will be reparably decrease and subsequently contact area between the particles will be increase.
Due to more surface availability bond strength between the particles will be increase, as per Van Der Waals force of Attraction, the forces are proportion to the particle diameter and inversely proportional to the separation distance.
During Dry Granulation, the pressure will increase the contact surface between the layers and subsequently decrease inter-particulate distance in the result; this will contribute the granule strength.
In the presence of highly viscus solution of adhesive, the thin, immobile layer form which will strengthen the bond between the particles compare to mobile films.
2.Interfacial forces in mobile liquid films
In the time of wet granulation, sufficient liquid is added to the powder and this liquid distributed around and between the particles. Sufficient liquid help to exceed the immobile layer to convert into the mobile film. Several types of water distribution systems which has been demonstrate here-
Pendular Phase:
During this phase, lens shaped rings of liquid hold particles where as this phase generally occur low moisture condition in the powder mix. Surface tension forces in the liquid-air interface and the hydrostatic suction pressure in the liquid bridge cause adhesion.
Funicular Phase:
This is the intermediate stage between the pendular and capillary phase when air start to displace between the particles then the particles arrange funicular phase. After completion of the intermediate phase- Funicular Phase then capillary phase visible where air completely displace/remove between the particles.
Capillary Phase:
As all the air remove between the particles, the Capillary Phase arrive and the entire particle held by the help of capillary suction in liquid-air interface at the granule surface. Tensile strength increases almost three times in moist granule in capillary and pendular phase.
The total moisture content plays a vital role in the phase of the power bed where total moisture content is the key factor, if separation of the particle can be decrease capillary phase may be reached easily which is the most desirable phase in granulation.
Droplet Phase:
This is the most undesirable phase in granulation. This phase is important in granulation at spray drying of suspension.
Mechanism
During the wetting and mechanical handling of particulates, the Agglomeration, granulation and pelletizing processes is greatly involved. If we increase the wetting and mixing, then open and porous agglomerate structure changes into more close and grain like granule structure. The control of moisture is the main factor in particle engineering, energy input require achieving desired structure of the granules.
Generally wet bridges considered as temporary structure as the moist granule will be dried in the certain period of time. This phase is measured prerequisite for the creation of solid bridges which is created by adhesive present the liquid.
3. Formation of Solid Bridge after Evaporation:
Solid bridges:
First, solid bridges formed by the help of adhesives present in the liquid or dissolving materials present in the granulating liquid. This can be formed in several ways-
Partial melting
Hardening binders
Crystallization of dissolved substances
Partial melting
Most of the low melting substances present in granulation process melt down by applying of pressure in the dry granulating process. Particles are readily bind with one after another and crystallization develop as the applying of pressure.
Hardening binders
By the help of adhesive which add to the granulating solvent, the liquid form liquid bridges, and upon drying the adhesive harden the phase and form solid bridges and bind the particles together. Common uses binders like PVP[ Polyvinylpyrrolidone], CMC[Carboxymethylcellulose], starch etc. plays the vital role.
Crystallization of dissolved substances
The powdered ingredients use in the solvent use in wet granulation may partially dissolve the powdered ingredients. At time of drying of granules, crystallization of powder material occur and act as hardening binder.
Drying rate of the granules are greatly hampered by the size of the crystals create in the bridges, larger the particle size will require more drying time and vice-versa.
4. Attractive forces between solid particles
There are two types of attractive forced which can operate between particle in pharmaceutical system beside the liquids and solid bridges formed by binding agents, demonstrate here-
•Van der Waals forces
•Electrostatic forces
This to me mention here that the Electrostatic forces don’t contribute to the final strength of the granules moreover this is important in the powder cohesion and initial formation of agglomerates e.g. during mixing. This force may be increase during when grain sizes decrease.
Van der Waals forces having four orders of magnitude which consider the greater compare to electrostatic and add great strength to the granules. When the distance between adjacent surfaces decreases then the magnitude of these forces increase. Dry graduation process is achieved by applying the forces to the particles.
5. Mechanical Interlocking:
mechanical interlocking phases that the adhesion occurs when adhesive properly penetrates into the holes, crevices and pores, and other loopholes of the adhered surface of a substrate and which locks mechanically of the substrate and must have the right rheological properties which will help to penetrate pores and other opening in due time.
Adhesion
Besides adsorption, there are Four other mechanisms of adhesion has been projected. The first mechanism is mechanical interlocking, which occur when adhesive drifts into the pores in the adhered surface. The second mechanism is interdiffusion, result when liquid adhesives are subject to dissolve and diffuse in the adhered materials. Adsorption and surface reaction projected to third reaction.
Mechanisms of Granule Formation:
a)Nucleation
Particle with particle[Particle-particle] contact and adhesion for liquid bridges is the key factor in the Granulation process. Particles are joined together to form pendular phase. Application of agitation, desifies the pendular forms and form the capillary phase and this form act as nuclei for granule growth and the next phase.
b) Transition
Nuclei can grow in two ways e.g. Single particle can be added to the respective nuclei with the help of pendular bridges, another possible ways, where two or more nuclei combine and form big nuclei. After completion of the phase, upon application of agitation to the bed the combined nuclei reshape and this phase can defined as a condition where large number of small granule present in greater range of distribution.
c) Ball Growth
Whenagitation continued, granule coalescence continue produce unusable, over-massed system where this phase greatly depend on the liquid quantity and material properties.
Coalescence
In this stage, two or more granule join and form large granule.
Breakage
Granules subject to break into fragments and this fragments adhere/join with other granule form a layer to the persisting/living granule.
Layering
Addition of the new powder mix with the existing granules, the powder mix adhere with the existing granules and form a layer over the existing granule and increase the granule size.
Abrasion Transfer
If agitation applied to the granules bed, then agitated granule leave abraded materials, which further add to the other granules and accelerate the granules growth.
Factors Affecting Granulation Methods
Liquid Requirement
In high shear mixers, the liquid requirement margin is narrow to granule growth and produce over wetted mas. For the intensive wet mass and densification of the granule less liquid requirement assume compare to low share mixers. Impeller rotation speed is another factor for liquid requirements and resulting evaporation of the solvent specially water in the binder solution. In high-shear mixers, intense agitation results temperature rise and subsequently loss of solvent for evaporation.
Theory of granule formation in general
At the early stage of studies near at 1950’s, it was stated that the granules growth by coalescence and limiting moisture content and further mechanical agitation modifies granule shape.
The modern science has divided the process in four major class for granulation process such as-
Powder wetting and nucleation
Granule coalescence or growth
Granule consolidation
Granule attrition or breakage
Granulation is a complex combination of these subsequent processes.
Pharmaceutical Granulation Technology
The word “granulated” derived from Latin Word ‘‘granulatum,’’ denote “grained”. Granulated materials come from two way, by “size enlargement” of primary particles and “size reduction” of dry compacted materials. Now a day’s granulation technology has been widely applicate at mining, agrochemical and coal industry.
In these industries, agglomeration techniques mainly used to reduce dust and this technique provide easy handling and boost the material’s decisive effectiveness.
In the year of 1843, W. rockedon invent the tablet press and subsequent modification and patent was done by J. A. McFerran[1874], T. J. Young (1874), and J. Dunton (1876) in USA which tremendously hit the granulation technology in pharmaceutical technology. The granulation technology was further reshuffle at 1970 when high speed tablet and capsule filling machine with PLC was invented.
The regulatory bindings such as content uniformity/blend uniformity facilitate to produce desired granule characteristics for pharmaceutical company. On the other hand, continuous uniform materials/granule flow must be ensure for high-speed compression and capsule filling machines. Granulation is the best example of particle design. The attributes of the granules controlled by formulation and the process respectively.
Granulation method can be divided into two major group as Wet granulation where liquid use to bind primary particles and Dry Granulation where no liquid is used.
The reasons for granulating a pharmaceutical compound are demonstrated as follows:
To decrease dust.
To densify the materials.
To increase the appearance of the product.
To simplify metering or volumetric dispensing.
To improve the flow rates and rate of uniformity.
To escalation the uniformity of drug dissemination in the product.
Processing steps of drug substance can be easily achieved avoiding granulation steps. By using a direct compressible excipients like MCC[Microcrystalline Cellulose] which was introduce in 1970s in a blender then compress tablets or filled hard gelatin capsule. This is very efficient method for cost effective method, faster process time and simple process steps.
In this technique, low dose of drug substance show reverse criteria, uniformity of drug substance is not possible/ accurate result may not found. The sample need to collect from the blender and time require performing the test to get satisfactory result. A newly introduce PAT[Process Analytical Technology], online measurement of ingredients made possible. FDA also release latest guideline about PAT.
Beside content uniformity, there are numerous cause to avoid direct compression technique for wide range of products where drugs substance need to densified to reduce size and physical criteria such as disintegration, hardness, friability need to meet.
Another approach like traditional spray-drying process become popular in day to day to produce drum to hopper granulation avoiding conventional granulation process. This is very suitable for OTC drug which generally produce large amounts.
In pharmaceutical company, some of the products/drug substances are moisture sensitive which can’t subject to direct compression, then roller compaction is the best method to compress this product.
Before introduce of high shear-mixer, low-shear mixer was the first priority, shear-mixer generally use in in wet granulation their efficient, reproducible and modern process control capability. High-shear mixers enhanced with new technologies as one-pot processing and subsequent drying using gas stripping/vacuum or microwave.
The most versatile featured Fluid-bed processors has been using in the pharmaceutical industry over the last 35 years though initially it was introduce with single dryer, now enhanced with multiprocessor to coat particles, pelletize, granulate and drying. Now combination of high-shear mixer for granulate and fluid bed as dryer is the most popular method in granulation technology.
Theory of Granulation
Wet granulation technology is especially considered in size enlargement where small particles are compacted; agglomerated or else brought together to form larger particle comparatively permanent structure though the original particle can be distinguished. Size-enlargement and Granulation technology has the wide range of application in various industries like pharmaceutical, fertilizer and detergent production factory.
ALCOA Plus [ALCO+] is the most powerful and sharp compare to previously introduced ALCO has the great importance regarding data integrity in pharmaceuticals company. Data security is the provocative questions is the pharmaceutical and related healthcare sector. Adulteration of data leads to serious health hazard to the end user.
All of the regulatory authority of healthcare related sector has taken their active place against data Adulteration. Data must be accurate, No an Adulterate data is accepted at any situation. Everybody desire the right data at any time any place. Data violation define the serious non-compliance of GMP.
ALCOA is abbreviate form, which indicate Attributable, Legible, Contemporaneous, Original and Accurate. In the period ALCOA, extend to ALCOA Plus[ALCOA+] by addition of Complete, Consistent, Enduring and Available.
In previous time all of the GMP compliance company use ALCOA, now they use ALCOA Plus concept to capture its place the most dependable tool for data security. Most of the GMP oriented company taken the tool for data security and data quality. ALCOA Plus ensure the data security and Integrity. All of the major GMP authority choose ALCOA Plus and implemented their respective directive. ALCOA determine the all-out of data quality. UK MHRA, FRA, TGA, WHO purely involved in data security, quality and data integrity.
The ALCOA and ALCOA Plus concept has been illustrated for better understanding of data related matters.
1. Attributable
Attributable define that the data must be easily traceable, so that anyone can identify that a specific person has collect the data in define time and noted down correctly. To correct any type of error regarding data recording, correction to be made in such way that anyone can read the error data and the corrected data easily. Reason must be noted down with specific signature and date.
Any document subject to data recording must be contains specific field where anyone can note down his/her name then signature and date option. Specific must contains sufficient space so that anyone can record data easily. If any alteration required, put a straight line over the error data then write down the actual data with signature and reason. If space is not available the put an asterisk mask then put another asterisk in a place where sufficient space for signature and reason recording.
2. Legible
Most of document in pharmaceutical company subject to data recording in specific field of a specific document. Entered data must be readable. Data which can be easily readable defined as legible data. Unclear data create confusion to reader and result of a specific test or critical point create unwanted error. The personnel who are responsible to entered data must be trained on GDP [Good Documentation Practice].
Permanent ink or indelible ink to be use to record the data, ball point pen to be use instead of fountain pen. Different color ink to be use to identify the recorded data easily i.e. if the printed document is black color then blue color ink pen can be use to record the data. Similar color ink pen with printed document create delay to identify the specific data.
The input data must be clear and easy to traceable who is responsible to input the data. Data should be entered in such way that no visibility of data subject to misunderstanding to the reader. Anyone who is going to deal with the recorded data must be comfortable with it.
3. Contemporaneous
All the data subject to recoded in document must be recorded on time indicate contemporary data. All data must be entry on the specific field of the document, just after completion of the work with signature and date, if any error occur during data recording then GDP to be follow to correct the issue.
If any correction identified after recording of data in the later date then actual data to be entered data and time with signature on that date. No advance or later data entry is not indicate cGMP culture at your firm. On time data recording is the pre-requisite of the compliance.
A person on the specific date may be absent or leave or fall any unwanted situation, if he fail to entry the data cause serious non-compliance so in time data entry to be ensure. If require, a training session may be conduct to emphasize the importance of contemporary data. Contemporary data culture on the document define that your firm is up to date and ready to face any compliance audit both local and global.
4. Original
To protect the data integrity, the original record must be preserved in such way that it can be preserved till it expiry. Batch document and some documents to be kept additional one year from its product expiry but validation document lasts company life so all type of document preservation may not same. A policy to be develop to preserve the documents and record.
Some document need to duplicate in multiple copy, in this case the creator must ensure the authenticity of the multiple copy with the help of site quality head other that QA documents. A controlled copy seal may be introduce for this issue.
5. Accurate
All data subject to record in the document must be error free. Data can’t be change at any cost. Alteration of data is strictly prohibited. Print out any data create its accuracy, hand written or manually input data, subject to change or alteration. If any facility declare to print out option then manually input data is totally invalid. You must follow the machine print out. To maintain the data quality is the big compliance issue.
Alteration of any digit in manually define the serious discrepancy data quality. It is undesirable to may any digit to next digit or similar digit. Data rounding may be accepted as per USP method but it is not mandatory to follow.
6. Complete
If it’s declare that the data is complete, then it means no alteration, deletion, only original data has been taken from its actual documented time. Incomplete data create haphazard situation to identify the original. Incomplete data recording leads the false result. Data to be record at actual from its predefined time as mention on the document.
If any document declare that you have to record data in 45 minutes interval then you have to record the data at 45 minutes interval not 50 or 60 minutes interval. If you note/record data other than 45 minutes create incomplete/false data. This data is purely incomplete.
7. Consistent
Data must be consistent, chronologically arranged in appropriate time frame. Data should be record in in such way that any audit can rely on it. GDP practice is the best way to record the data. Series of data that is chronologically organized define the data is more consistent and reliable. A reliable data can face any type of GMP audit due to it provides best data integrity.
Most of the pharma company face serious non-compliance at regulatory audit for data integrity. If your firm confirm data integrity then you can create best GMP culture at your firm. To maintain data integrity is the prior conditions of the cGMP.
8. Enduring
All type of material is not suitable for data recording, specific paper to be introduce for specific data recording. Data to be record in such material that it can be traceable after a period of time. Generally long lasting material use for data recording. You should take care about readability of data after a specific period of time based on its impotence.
Usually better quality paper use to record validation related document as its last till company life. Regular uses document like batch production record may be record in general usage paper as its last maximum 3 to 5 years including shelf life plus one year.
Document subject to destruction, proper recording to be marinated as it can be easily teachable. Approval must be taken before proceeded any type of destruction related activities.
9. Available
Data should be kept in a specific place where you can easily find it or it is available as when required. It should be keep in a secure place and access must be limited. List of personnel must be define to access the specific area. Data plays an important role when any organization want to take any decision based on previous history. By this time you have to make it available on that time so you have to keep it in right place. All type of future reference backed by data history so you must pay attention to secure your data.
Technical person, a person having STEM degree or person possess degree in lab-based science, technology, mathematics and engineering.
People who are attained STEM degree contain common set of traits. These traits make him ideal scientist, technologist, mathematician and engineer.
What do you mean by STEM?
STEM, this term often found in university advertisement, campaign, website, leaflet etc. but most of the people is not sure what does it mean. Here is the solution-
The term STEM define Science, Technology, Engineering and Mathematics and relevant subjects that are all under these basic subject.
Due to these subjects are not straight forward so series of subjects are undergo these subjects. Different terms are used in place of STEM as STREAM and METALS but the term STEM is more widely used.
Though these subjects are widely distributed but huge volume of vacancy found the respective field. From its beginning of STEM, various types of institutions are try to attract the students/people. STEM courses are the top most priority of the most of the counties to remove the shortfall.
STEM subjects the best option for the people who are searching for a longtime to be a resident to the other country/ immigration to expected country. This also beneficial for all type of students who want to study in higher level in different countries.
What are STEM subjects?
The STEM subjects [Science, Technology, Engineering and Mathematics] is not standalone, various type of subjects are closely related/derived from STEM so they are also STEM subjects. Here is the list of some STEM subjects-
Aerospace engineering
Astronomy
Biology
Biochemistry
Chemistry
Chemical engineering
Civil engineering
Computer science
Electrical engineering
Mechanical engineering
Mathematics
Physics
Psychology
Statistics
This list is far more extensive, the list will be more distributed based the basic criteria. This list my helpful for someone who are really searching for STEM subject and he will get som idea about the pattern of the STEM subjects.
The career prospects of some the subjects is more exclusive such Astronomy leads to the straight forward career patch than others subjects which tends to multiple career facility. Most of the STEM related subjects tends to more valuable sector such as Finance, Accounts, Aerospace, Cinema, Special Effects, Design and communications, Sportswear, consistency, Farming, Telecoms, Energy, Pharmaceuticals, Healthcare, Medical device etc.
What is the current situation in the practical field?
The history says, most of the STEM degree holders are male compare to Female. Introducing women in technical field is not satisfactory, the completion is less to female. More than Eight times male are more involve than female in STEM subjects related activities.
About 12% women are graduated in STEM degree; only 3% engage in practical field others are tend to alternative sector or stop to practice. The gender balance is dominant tend to pay gap in STEM field. More than 30% pay gab observed in in Australia at 2013. A remarkable initiative to be taken in this field to fill up the gender gap in STEM related subject.
How to become a Technical person?
1. Take post-secondary science classes
To enter into the professional STEM subject program, two years of college education is required. Most of the STEM subject’s candidate take 4 years of post-secondary education and achieved bachelor’s degree before applying any Doctoral program. As a STEM subject student you have to meet the requirements of the respective organization to get admitted for Doctoral Program.
2. Pass the Admissions Test
To enter into any doctoral program you have to pass the specific test. The specific exam includes various types of questions such as writing, critical reading, quantitative reading, critical reading, different type of process based on your STEM subject including one writing prompt. Exam occur all around the year, at least six times a year.
3. Earn a Degree of STEM subject
After passing the required test, you can apply for for Doctoral program of STEM subject, it may take 2 to 4 years based on subjects. If you want to gain practical knowledge, choose a program with 1 year internship.
4. Cultivate essential skills
To be successful in your next professional life then think deeply about your subject oriented skills, initially basic computer skill is required to run various type of thesis program and assignment oriented job.
5. Attend In plant Training
If you want to work in a factory related job/any job, you can apply for in plant training. Various types of organization offer this type of facility. If you select a program with 1 year internship, please escape this step.
6. Apply for license to practice in your state
You may face to license process based on your state require requirement. To start your career as profession STEM subject oriented job, license is mandatory in most of the state. Here you may face a single or multiple exam to prove your competency of the respective subject.
7. Pre assessment for interview
An interview process may arrange where SME[Subject Matter Expert]/ Assessors may present to conduct an interview. Number of SME/Assessors may vary state to state.
8. Attend interview
A representative will call you to attend an interview session based on your application with specific time and place.
9. Complete required training
If you want to work independently then you have to complete several training program based on your subject. Most of the SYTEM subject holder choose one or two years training program and on the job training program to facilitate his professional activities.
10. Responsible Technical person
After passing the exam and complete the required training program you can work independently or you can join a suitable position in any organization where you can create a value for yourself.
Qualified Person (QP), is mainly responsible to confirming/assuring the quality of certain batch of pharmaceuticals products. So this is very important that a Qualified Person (QP) must be in depth understanding of the pharmaceutical manufacturing, quality control and overall activities of the marketed products.
Qualified Person (QP), is the responsible person to certify a certain batch of pharmaceutical product prior to use for trail purpose or to send in the distribution channel for marketing.
This is not mandatory to understanding the manufacturing practice/process/procedure accurately but he must be understand the critical factors which may affect the critical quality parameters, safety and distribution/supply chain of the marketed products.
Qualified Person working area:
Most of the Qualified Person[QP] working in different pharmaceutical companies in various role mainly in product releasing activities but they also involve in national health sector, in such type of departments which hold different manufacturer authorisation to create various medicinal products mainly use in investigational purpose.
How do I become a Qualified Person?
1.0 Find a sponsor
A sponsor to be find out regarding individual guidance, training, prepare for final assessment, sponsor reporting about your eligibility to act as a Qualified Person[QP]. The sponsor also verify your application form signature required in various section of the application form.
Eligibility of Sponsor:
The sponsor must be the member one of the three professional body [The Royal Pharmaceutical Society, the Royal Society of Biology and Royal Society of Chemistry] and he must a QP [Qualified Person]. If your sponsor fail to meet criteria, then the sponsors form must be countersigned by the QP [Qualified Person] who will responsible to acting this issue about your engagement.
The sponsor must be involve in practicing QP who is known to you and he professionally known you in qualified period experience[1 year for Pharmacist and 2 Years for other professionals]. If you didn’t manage it, then you can use a Quality Assurance Line manager provided the report and countersigned by a QP.
Your sponsor is projected to:
Confirm that you have the sufficient knowledge of the subject that covered by the study guide. Certify the adequate experience.
A sponsor is actually a mentor for you. He will help you regarding your preparedness of the assessment, he will guide you to attain your success. He will confirm you that you possess the sufficient knowledge for final assessment. He will trained you in every step for apply the final assessment. Your Sponsor will provide you the necessary study guide and confirm that you possess the essential knowledge, skill, experience and personal attribute to act as QP[Qualified Person] at actual.
Role of an active sponsor
Role of the sponsor is the key to success of the applicant. This is very important for the applicant to find out an active sponsor because a sponsor is always involve the applicant training and application process. A sponsorship is always appreciated if role and responsibilities perform on great care. Regular interaction with the applicant is very important and this activity will be consider as mentor.
The sponsor Form and the application form is the first step of assessment process due to these two forms provide the documented evidence regarding employee background. The well documented application provide the positive impression to the Assessors.
The sponsor must have the experience and knowledge about pharmaceutical manufacturing, Quality Assurance and GMP[Good Manufacturing Practice]. Well conversant and up to date of the legal framework of EU and UK. Better understanding and relationship with professional bodies of MHRA & VMD [Medicine and Healthcare products Regulatory Agency & Veterinary Medicines Directorate].
The code of practice, role and responsibility of QP to be known including Study Guide and practical experience requirements. It is top most priority to be well familiar with the pharmaceutical business especially in Research and Development, production, Quality, Marketing and distribution.
An active Sponsor must possess good inter-personal skills and well communicator, having good contacts outside the company will add extra benefit. A better Sponsor will work as mentor who will provide the guidance to the aspiring applicant including positive direction.
Regular interaction is the key factor of the success, sponsor may communicate with applicant via various type of communication method [FB Messenger, WhatsApp,SMS,Emailing etc.] if unable to direct contact. Sponsor should monitor the daily activities of the applicant and prepare a progress report.
Sponsor’s report
Before submitting the application a sponsor form must be submit with the application. An application will not accept/review without sponsor report. A sponsor report must be different from applicant, sponsor report may not represent the same as applicant form.
A honest review is always create positive impression to the applicant. A sponsor report well be well described about the candidate. Every single details will be mention here. Applicant strong side as well as weak side, strength, personal attribute, development field need to mention very clearly.
The report is a key part of the sponsor’s input and it is not sufficient for you to simply provide a declaration of belief that an applicant complies with the requirements. It should be a critical and honest evaluation of the applicant’s technical and professional knowledge. It should also include information on the applicant’s personal attributes, including his or her strengths and weaknesses or areas for development.
A sponsor may indicate the following criteria of the Applicant but not limited to-
Attitude
Communications skill
Extracurricular activities
Flexibility
Hobbies
Open Mindedness
Organizational behavior
Peer coworker relationships
Planning and organizing skill
Professional integrity and ethics
Problem solving capacity
Verbal skill
Reliability
Working under pressure
This very important to notify the every single points on the report. Application primary assessment may be late based on the points and further clarification may be asked. Sponsor need to confirm that the applicant has gained the proper knowledge and experience in the Manufacturer’s Authorization and Manufacturer’s Authorization number with issue date to be mention with the application. A sponsor must declare the direct the working experience with the applicant. Different report will claim for multiple establishment.
2. Gain relevant experience
To be a QP[Qualified Person], a person shall be possess a certificate, diploma, or other evidence which can prove his formal qualification evidence which achieved after completion of University course, covering a duration at least Four Years of theoretical and practical studies one of the listed scientific discipline:
Chemistry
Medicine
Pharmacy
Pharmaceutical chemistry
Pharmaceutical technology
Pharmaceutical biology
Veterinary medicine
The minimum duration of the university course may be three and half year, where the course followed the theoretical and practical training duration minimum one year and training period will be six month in a pharmacy open to public collaborated by examination at university level will be preferred.
When two university course declared equivalent and one course extend to Four years but other course extend to three years then the three years course will be treat as diploma, the course shall include the listed basic subjects at least:
Analytical chemistry
Experimental physics
General and inorganic chemistry
General and applied biochemistry (medical)
Microbiology
Organic chemistry
Pharmaceutical chemistry
Pharmacognosy
Physiology
Pharmacology
Pharmaceutical technology
Toxicology
The QP[Qualified Person] experienced in practical required two years in authorized manufactures and experienced may be reduced to One Year where the university course extending to Five years.
Overall, at least Two years expected is required in one or multiple facility which produce medicinal products but if you are pharmacist, you need only one year.
3. Apply through your professional body
The eligibility of QP, he must be the Pharmaceutical Scientist or Associate or Fellow or member of RPS[ Royal Pharmaceutical Society] who has qualified on the basis of formal course of study lasting not less than three years in fulltime or equivalent.
Minimum One year of practical experience is required for pharmacist, if anyone want to apply for QP eligibility but not registered a as pharmacist recommended to contact with QP officer for advice prior to apply.
If your Sponsor is satisfied that you are ready to apply then submit the application form with required fee [£700, may be change anytime], sponsors report and countersigned copy of your own certificates.
4. Wait for your initial assessment
If you application fulfill the requirement then QP officer will confirm you that your application has been received. Your application will be assessed be the designated assessor if the result goet to positive then you will be invited for interview session.
5.0 Attend your interview
Your interview will be held on London physically if situation is normal. Sometime virtual interview may held based on situation, QP officer will confirm you about this issue. If you passed the interview then you will be listed as QP person at your professional body.
Role and responsibility of QP
All of the pharmaceutical manufacturing authority and regulatory body ensure that the end user [Patients] are safe and the medicinal products meets its predetermined specification for sale or supply and confirm the basic requirements for safety, quality and efficacy.
In a pharmaceutical company a QP plays a vital role certifying the batch confirms the predetermined specifications and its can be released for sale or supply or trial.
QP is responsible to confirm that each manufactured batch has been checked in compliance with the laws in specific certifying authority.
QP role and responsibility irrespective where the product will be sale/distributed/used.
QP to be understand the demand of specific Authorization and confirm that PQS[Pharmaceutical Quality System] in place and satisfactory for the purpose.
QP must understand the relevant steps of pharmaceutical manufacturing steps before certifying the specific batch.
Must be full understanding of EU GMP guideline.
QP must have decline to certify the specific products which process and procedure is unknown to him.
Career prospects of QP
The Career is widely distributed for the QP in various types of pharmaceutical industry as well as other designated industries who are involving in manufacturing of healthcare related products undergo to regulatory bindings. In pharmaceutical industry a QP can work in production, marketing, quality control, product development, quality assurance, project management etc. areas.
Resources to become QP and formal application process
All the manufactures who are engage to produce Foods, Drugs, Medicine, cosmetics and other healthcare related products want to follow the all basic rule of the GMP/cGMP. This is to be stated here that the compliance of the GMP is very much easy to follow if the facility design perform right way from the start.
To run a smoot operation, this is very important to follow the principles of GMP as well as First Golden Rule of GMP ”Get The Facility Design Right From The Start”.
“If facility didn’t design right way from the first then you may fall in great problem and may be reconsider the whole facility design”
Facility Design
There will be a healthy harmonization between the sequence of facility design where the main target of the facility design is to reduce the mix-up, cross contamination as well as smooth production process. You can’t allow blister packing room near raw dispensing area. The area must be design as such a way that change of non-compliance can be reduce.
A well planned facility design may reduce the overhead of production and least change of product failure. This also prevent back flow and increase productivity to the respective firm. The aim of the best facility design is to –
Lest traffic movement at the production area.
Align the material in specific room/area.
Reduce contamination/mix-up of the products.
Minimize the wrong interpretation.
The target of the good production design is to continue the linear production area so that man and material flow will be unidirectional no backflow the same. The Zigzag and irregular design of the facility tends to misinterpretation of the production design and design failure exhibit predominantly. To apply/introduce/change the existing facility design must be review the SME [Subject Matter Expert].
Environment
This is very important to control the water, lighting, ventilation, temperature, humidity, air etc. so that the respective variable can’t effect the product quality, safety, and efficacy. So the facility must be design must be precisely and risk of non-compliance can be reduce.
A suitable facility must be confirm-
Temperature, Humidity, Pressure, light is appropriate to the standard practice.
The surface of the wall must be free from all types of crack/dam/swelling/dust/rust etc.
Wall must be design in such a way so that it can be clean easily.
All type of drainage must contain 1% slope so that the backflow can be prevent easily.
Equipment
The equipment to be locate, design, install, operate, in such a way so that the intend use can be confirmed to its standard. A standard equipment should be-
Well designed, properly installed, easily operable and easily cleanable.
Easily usable
Properly labeled
Not reactive with the product
Rust free
Calibrated at specific interval
Ten golden rules of GMP
2.0 GMP Golden Rule-2
Validate processes
After design the full facility and equipment of a farm, this the mandatory rule that you must ensure the machine and the facility are operate to its standard but how do you prove this state? Now the term Validation come here first.
Documented evidence is mandatory to prove that the process and equipment doing its own function they supposed to do. To achieve a quality product the consistent function of the machine is essential and this activities can be achieved by effective validation of the process and equipment.
Validation
The validation is the documented evidence which provide the high degree of confidence that specific process will consistently produce a specific product meeting its previously approved specification and related quality parameter.
The validation is the GMP requirements which prove that a specific process, equipment and facility operates right way from the first time to every time without any significant change. The new facility, equipment, process need to validate prior its regular use. Any significant/substantial change in the existing validated system need to validate the system/process/equipment etc.
Validation usually involves:
An equipment/machine generally undergo the several process to complete its validation status. IQ[Installation Qualification] confirms that a specific machine/equipment has been installed correctly to its predefined specifications mentioned its approved IQ protocol.
OQ [Operational Qualification] confirms that the equipment has been successfully installed and operate to its specification mention its approved OQ protocol.
PQ [Performance Qualification], confirms that a specific machine/equipment can produce a product to its predefined specification mention on its approved protocol.
The above all protocol mention the specific process steps, one the work completed successfully a report must be generate to prove the specific activity.
Change control
After completion of the validation programme of the system/equipment/machine/process the maintaining the validation status is important. Once the change is made in any part of the validated facility subject to change control process. A formal change control process must follow to control the whole system. A substantial/ significant change subject to revalidation the system and record must be keep the same.
If a process/part of process/part of the equipment subject to change which may affect the quality of the product need to record keeping through change control process so that the respective firm may overcome regulatory bindings.
Ten golden rules of GMP
3.0 GMP Golden Rule-3
“Write good procedures and follow them”
It can’t be imagine a good company without proper written procedure. An unwanted situation may arise to repeat the specific job from memory. Most of the manufacturer of the firm rely on the experienced operator rather than new one.
This is very logical than an experienced person is always expected to perform the right job but it is not possible to memorize the right job every time may be forget to perform the any specific critical steps resulting failure of the product.
This is the best practice to write down the whole process at actual which perform on the machine/specific stage.
A firm must be document specific not operator specific.
In a foods, drugs, cosmetics industry this is very important that the specific procedure must be clear, concise and logical and must be in place so that anyone can trace and realize it when required and this is the important part of the GMP.
You may consider the SME [Subject Matter Expert]/Third Party Audit Team/Experienced Existing Professional to develop your documentation. When an independent team/party/organization audit your firm they will develop your documented activities and find out your loop hole of the specific process/ procedure/stage and then you will get the huge opportunity to develop it.
List of documents require for standard Firm:
A typical Firm [Foods, Drugs, Medical Device, cosmetic industry] contains the following document but not limited to-
Standard Operating Procedure: Describe the details written procedure/instructions/process to complete the specific task where relevant.
Product/Materials Specification: This the core of the product/Materials which have to confirm/meets to evaluate its quality attribute.
Records Keeping: This state provides history/executed option of the certain products/materials that the products/Materials are following its predefined approved criteria and repeated the criteria each time when produced.
How to write good procedures:
First of all, before writing a good procedure you have to read the all relevant document then start write the main procedure. Use small breakdown of the large paragraph and use Flow Diagram, Chart, Table, Keyword, etc. for precise and easy understanding.
Generally, people don’t have the much time to read the whole procedure from the start to end; want to eye through the whole procedure on the keyword.
A critical/Big process/ procedure can be divided several small things as-
Bold Text
Bullet Points
Charts
Follow Diagram
Heading
Highlighted Text
Image
Instructions
Table
This type of activities reduce the man hour as well as easy understanding the documented evidence. Write down the language in very easy process, where required mother language rather than English use the same for better result. Don’t include extra paragraph for a little information. Write down the whole process in imperative sentence. An ambiguous word mislead the information; so use easy word that is more familiar to everyone.
Use as many simple sentence as possible so that anyone can read it easily. You can follow ALCOA[Attributable, Legible, Contemporaneous, Original and Accurate] and ALCOA+[ Attributable, Legible, Contemporaneous, Original and Accurate with Complete, Consistent, Enduring and Available] method to create a better legible document.
After creating an initial document, printout the same and handover this copy to the relevant personnel and collect the feedback from the personnel and request them to notify which part of the document is confusing and hard to understand the main content of the document.
Mark this section and review the document and apply the correction to the document then you will able to create desirable document for the relevant personnel. This is the method to make a simple standard document but not limited to, you can apply various methods to generate a better documents.
A crated documents need to review it’s periodically to keep it up to date. Most of the company review their document at a Two/Three year’s period. You can review the document yearly or anytime when the relevant topics change based on the available/reliable approved information. Without strong reference/approved information, changing a document create hassle to the existing system.
Follow the written procedures
This is the best practice to have the better written procedure at the place in controlled manner and everyone is following it. A document may be descriptive to the specific process/procedure where alternative/shortcut process/procedure may save the time or you can do it efficiently. Don’t do that.
Do the thing what is written on the document, if require any change, notify the respective authority/your supervisor/Head of Site Quality Person about the issue. Change the document through change control process and until change the document you have to follow the document due to your proposal may not accept if critical change require to apply the proposed change.
You can’t apply your proposed change without approval, due to-
Your process/proposal may not be cost effective in the long run.
Each validated steps/procedure/process has its importance which change may affect the product quality/efficacy/safety.
Ten golden rules of GMP
GMP Golden Rule-4
“Identify who does what”
Every employee must have the clear, precise, specific responsibilities to the respective department. He must know what he supposed to do or what not his responsibility. The specific responsibility will reduce the man hour and better working environment. Every department of the firm must have job description of their employee. A typical job description will contain the specific point such as-
Job Title
Duties and Responsibility
Experience
Total Service length
Service length of the existing firm
Core Responsibility
Additional Responsibility
Administrative Activities
Special Responsibility
The responsibility must be stand alone. No overlapping isn’t acceptable. Doing similar job by multiple employee cause serious misunderstanding and job undone. Better to display the everyone responsibility on the firm notice board at specific department will show that who does what. The cross functional department will easily contact with the responsible personnel if job description available on intranet/sharing folder/common FTP sharing within the firm.
The responsibility may be overlap in the following cases but not limited to-
Calibration Activities
Cleaning Activities
Validation Activities
IPC in multiple section
Production activities
Analytical Activities
Before assigning a specific task for a specific employee, he must be train first and a mock test will be perform before final certification of the employee. An employee must confirm that he is capable for the specific job.
Especially critical activities like Validation of the specific product/process/facility, a series of work to be done precisely without any significant non-compliance, then a person must be assign who is capable to perform the series of task with great responsibility.
Ten golden rules of GMP
GMP Golden Rule-5
“Keep good records”
A good records determine that your system is under control and you are compliance with the GMP which also demonstrate your visibility in terms of quality matters. A good records exhibit that you have followed the all steps and activities describe in the batch production history from dispensing to finished products. This is the part and parcel of the GMP to keep the good records of your production activities.
How to keep Good record?
Make a culture to keep the good record in daily activities. Never try to memorize the activities. Keep your record up to date on the right time at right place.
Don’t perform any type of activities which you are not responsible for or you don’t have proper training to do the same. If you think that the work has been completed without proper documentation then you are in wrong concept. If you are unable to record the activity then it didn’t happen!!
Try to develop less signature option at your document, unnecessary signature creature signature fatigue to the employee.
Record all types of activities carried out during production.
Never try to memorize the activities, record it on time.
Record all type of activities if deviation occur, then inform the Site quality department and take the decision for the same.
Record all type of record in legible ink. Signing any type of record reveal that you are accepting the described activates.
Notify all type of mistakes drawing a single line and write the actual, give the date with sign and mention the reason for the correction.
Documents Record Keeping
Generally you should keep the record of all documented activities. Some important records are-
Analyst Personal Analytical Logbook
Batch Production Records
Cleaning/Equipment Logbook
Cleaning/Equipment Logbook
Environmental Monitoring Records
Material/Product storage condition records
Training Records of Employee
Keep the validation/calibration records life time of the company. Keep batch/production record for expiry date of the product with additional one year. After expiration, keep record for destruction of the document and you can take critical data from the expired documents on validated spreadsheet for further reference. You can keep your document as per your own define period.
Ten golden rules of GMP
GMP Golden Rule-6
“Train and develop staff”
If a firm is properly equipped with the right tools then consider the skilled employee to operate the machine. Document the activities through proper training before starting any type of commercial activates in a validated facility.
Every personnel of the firm must be trained before assigning any type of job. Confirm that the respective personnel have the desired skilled and capability to perform the right job at right time in right place. If you able to do the same then you can develop the GMP culture at your firm.
Training
First of all you have to train the all personnel related to production activities, Laboratory Activities, Quality Assurance activities or whose activities directly affect the quality of the product. Some basic training need to include their training curricula. A training need assessment to be arrange before engaging someone at specific duty.
Some training is common for all employee such as basic GMP training, personal safety and hygiene, Fire Fighting, emergency evacuation plan etc. to be include to the personal training profile.
If any situation occurs, where you have to allow someone to enter the specific area like production then you have to give him some instructions what to do or what not to do, additionally assign a experienced person with him for close monitoring purpose.
Train the employee as relevant as per job description, unnecessary training cause haphazard situation. Identify the group of employee for common training curricula will save your valuable time. Arrange the training as when required.
After completion of the training program certify the employee for specific task and record the same. Initially you may follow up the new employee with the close supervision of a senior experienced skilled person. If everything goes well then give him signing authority to the respective document.
Verified job capability
An employee must prove his job competence during everyday activities producing quality products/documents. After proper training of the respective employee, he must be prove himself that he is very much capable to do the same from the first time to every time in right way.
If he fail to do the specific job then arrange retraining for the same topic then involve the same. If any employee fail to do the same job in several times after retraining then change his job description to the next available job responsibilities.
You can assess the employee through annual appraisal plan, taking record for good/poor activities and discuss the employee with his week point and try to develop it. You can discuss a series of topic with the respective employee-
You must keep the record of all training record of the specific employee including retraining record, evaluation of the specific training at his training record file in a traceable place. A training coordinator to be available to monitor the training activity of the firm.
A person from every department will be responsible to communicate with the training coordinator regarding departmental training activities. Training coordinator will arrange the all type of training of the respective firm.
Ten golden rules of GMP
GMP Golden Rule-7
“Practice good hygiene”
Product contamination will be at higher level if proper hygiene and sanitation program is not maintained. Cleanliness is the key factor in the pharmaceutical industry due to some products like Injections/Infusions are directly administer to the blood stream, if products are contaminated/compromise with pyrogen then any one can face moderate to serious health hazard.
A Standard Operating Procedure [SOP] to be develop regarding hygiene and sanitation. The procedure to be maintained from the first time to every time before starting any type of production activities. A better hygiene practice can develop better GMP culture at your firm. Every employee must confirm to the sanitation and hygiene procedure.
Good to practices in everyday manufacturing-
Maintain personal hygiene everyday by wash your hand, wearing protective gloves, head cover, beard musk, protective musk, hand sanitizer [70%IPA] especially when you are in production area as when required.
Notify your senior/supervisor/authority/Department in-charge/Manager if you are ill/having open wound and probably you are not allowed to manufacturing are till you feel well.
Less/Minimum personnel to be allowed at direct manufacturing/filling area and less product contact to be your first priority.
All type of Eating/Drinking must be prohibited at any type of production/packaging area.
Cleaning and sanitation instructions to be hang on different area of factory premises to increase awareness regarding this issue to the existing employee.
Visitor/Outsider/Auditor Entry to be prohibited to the direct production/manufacturing area.
Notify any type of non-compliance to your Superior/In-charge.
Before starting any batch, remove all type of waste, dust, excess materials except relevant materials.
If possible arrange a personal hygiene and sanitation training program in each month. A schedule may be prepared for different department if it not possible to cover all employee in single time frame. Schedule to be organize in such way that every employee get training at least once in month. If this procedure can develop then you can hope that your firm is conforms to its GMP compliance.
Ten golden rules of GMP
GMP Golden Rule-8
“Maintain facilities and equipment”
Maintenance schedule must be established to facilitate the activities of the daily work. A regular maintenance activities reduce the sudden machine failure during production. Maintenance activities also reduce the product contamination.
A maintenance schedule to be followed effectively and supporting machine parts, oil, coolants, Lubricants, grease, Mobil etc. must be available to continue the activities. Maintenance schedule must be available in place and authorized personnel to be assigned to perform the specific job.
Maintenance Logbook:
A maintenance record must be keep in a specific form and store the same at the custody of maintenance department and must be traceable as when required. Maintenance trend to be done in monthly/yearly basis to identify the machine breakdown frequency and corrective action.
You may use maintenance Logbook for better documentation activities. A maintenance logbook generally contains-
Activities performed
Clean date
Calibration date
Equipment use date
Last maintenance date
Ten golden rules of GMP
GMP Golden Rule-9
“Design quality into the whole product lifecycle”
Personnel engage in Foods, Drugs, Cosmetics, Medical Device Manufacturing company to aware about the safety parameters of the end user[Patient]. Final stage of the products are tested by the Quality Control Personnel to identify/confirms its predetermine specifications only so quality to be ensure all the stage of manufacturing prior marketing in whole product lifecycle.
An inferior quality products tends to degrade in market in a short period of time loss its potency from marginal level fail to confirm its intended use. Patients didn’t receive the desired effect, unable to get early recovery cause unwanted health hazard. The patients start to believe that the product is not fit for him as its fail to satisfy his basic need.
The manufacturing step of the product need to effectively control so that a product can achieve its desired quality parameter through its life cycle.
Checking and Testing of Incoming Materials:
Check all the incoming materials during receiving and sort out the damaged container at specific area to prevent mix-up. Attached “Quarantine Label” to the good one and store it Quarantine area and inform Quality Control Department for Sampling and next activities after completion of Warehousing Activities.
Collect Approval from Quality Control department then use it for manufacturing activities. If the sampled products fail then segregate it and store it Reject Area for further decision[Destroy/Return]
A checklist may be develop to check the basic parameters of the incoming material will prevent the missing/discrepancy of the materials. Purchase order number, material description, quantity, accepted, conditionally accepted, or rejected materials etc. parameters may be add the Checklist for Inspection of Incoming materials.
Manufacturing Process Control
A series of procedure to be perform at the manufacturing of a specific products. Process and procedure must be clearly defined on the Batch Manufacturing Record and the personnel engage in manufacturing activities must be trained properly. A GDP[Good Documentation Practice] to be develop to practice on time record keeping.
Approved master record to be develop and available in a secure place. A batch record must be represent the master record and update document to be issued prior its intended use. All data must be input on specific area of the batch document. All actions must be record including all QMS[Quality Management System] related activities. Specially cleaning activities during/prior batch manufacturing must be record.
Batch Packaging and Labelling Activities
Labeling is the vital part where maximum chance to mix-up of the products. Printed Label to be store securely especially in cut label/single label. Printed label to be store as per batch number/lot number to assure traceability.
Before starting a new batch, all the materials in previous batch must be remove from the packaging line. Follow the Line clearance procedure describe in Batch Manufacturing Record. Record the all activities during product change over and time interval to be define for In Process Control action.
Ten golden rules of GMP
GMP Golden Rule-10
“Perform regular audits”
Internal Audit/Self Inspections to be performed before a face any type of regulatory audit. External regulatory bodies Like UKMHRA [Medicines and Healthcare products Regulatory Agency], FDA [Food and Drug Administration], and TGA [Therapeutic Goods Association] will conduct audit. A self inspection checklist to be prepare and self inspections/Internal Audit to be perform at least once in a year, multiple times in a year may be the best practice.
Self-Audit Checklist
Written Procedures/Specification
Is approved procedure clearly defined the step by step instruction?
Do the procedure follow by the employee?
Is the procedure is up to date?
Is everyone is strictly adhere on the approved written procedure?
Skill
Is everyone is properly educated, trained, experienced in relation to their job?
Is everybody is performing their job right way?
Documentation and Recording
Is document is properly recorded on time?
Is everyone is using legible ink as required to fill the document?
Is all document/critical steps are checked/double checked?
Sanitation and Cleanliness
Is personal good hygiene is in practice?
Is gowning system is properly defined on production/Laboratory?
Is clean equipment’s/machine is stored properly?
Is regular health checkup is in practice?
Maintenance of the Workplace
Is scheduled preventive maintenance perform on time?
Is environment is controlled to minimize product contamination, mix-up, error etc.?
Is equipment logbook is properly maintained?
Quality Control
Is everyone is clear regarding quality control and quality assurance activities?
Is right batch number is declaring from QC department.
IS sampling is properly done & sampling SOP is up to date?
Is all machine calibration up to date?
Quality Assurance Are we concern about quality of our product? If satisfactory result didn’t get then take initiative to implement the same. All audit must be take positively, this the process where we can find our quality related observations and we can update the same.
This is all about the Ten golden rules of GMP which is mandatory to follow for successful operation of an ideal pharmaceuticals. The Ten golden rules of GMP define the ten different areas of a Pharmaceuticals company so this is very crucial to follow Ten golden rules of GMP to develop GMP culture of your firm.
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