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Risk Assessment Procedure

Quality Assurance, Quality Management, Quality Risk Management, SOPs

Risk Assessment , Purpose :

Risk Assessment , The objective of carrying out the Risk Assessment is to ensure the potential threats to the product quality/ supply are properly assessed and appropriate control measures are in place.

Risk Assessment , Scope :

This procedure applies for the risk assessment of facilities, utility services, equipment & machinery, warehousing, manufacturing, packaging, testing and transfer of quality products from at XX Pharmaceuticals Limited (Both General and Sterile Block).

Definitions / Abbreviation:

[][]Risk assessment: Risk assessment consists of the identification of product quality risk and evaluation of risks. Quality risk assessments begin with a well-defined problem description or risk question. When the risk in question is well defined, an appropriate risk management tool and the types of information needed to address the risk question will be more readily identifiable.

Responsibilities:

[][]The roles and responsibility is as follows

All concerned department heads

[][]To perform the risk assessment associated in his area in a cross-functional team, including one QA personnel as a mandatory member.

Manager, Quality Assurance

[][]To ensure that proper risk assessment is done if there any potential risk(s) involved in the product quality/ supply.

Head of Quality Assurance

[][]Approval of the SOP.
[][]Implementation of risk assessment procedure

Procedure:

=>Risk assessment: Risk assessment consists of the identification of product quality risk and evaluation of risks. Quality risk assessments begin with a well-defined problem description or risk question. When the risk in question is well defined, an appropriate risk management tool and the types of information needed to address the risk question will be more readily identifiable. As an aid to clearly defining the risk(s) for risk assessment purposes, three fundamental questions are often helpful:
[][]What might go wrong?
=>Output for Question 1: Problem/ Failure descriptions- Cause – Failure mode – Effects
[][]What is the likelihood (probability) it will go wrong?
[][]What are the consequences (severity)?
=>Output for Question 2 & 3: Risk Class, Job/Action Priority, Failure rates, Risk priority number (RPN).

[][]Risk identification: Risk identification is a systematic use of information to identify product quality risk or problem description. Information can include historical data, theoretical analysis, informed opinions, and the concerns of stakeholders.

[][]Risk analysis: Risk analysis is the estimation of the risk associated with the product quality. It is the qualitative or quantitative process of linking the likelihood of occurrence and severity of harms. In some risk management tools, the ability to detect the harm (detectability) also factors in the estimation of risk.

[][]Risk evaluation: Risk evaluation compares the identified and analyzed risk against given risk criteria. Risk evaluations consider the strength of evidence for all three of the fundamental questions.

[][]The output of a risk assessment is either a quantitative estimate of risk or a qualitative description of a range of risk. When risk is expressed quantitatively, a numerical probability is used.

[][]Alternatively, risk can be expressed using qualitative descriptors, such as “high”, “medium”, or “low” (Risk class one, Risk class two or Risk class three) , which should be defined in as much detail as possible.

[][]Sometimes a “risk score” is used to further define descriptors in risk ranking. In quantitative risk assessments, a risk estimate provides the likelihood of a specific consequence, given a set of risk-generating circumstances.

[][]Thus, quantitative risk estimation is useful for one particular consequence at a time.

[][]To access and manage risk the following recognized tools will be applied:
=>Risk ranking and filtering will be applied for qualitative (High, Medium or low) risk analysis.
=>Failure Mode Effect Analysis (FMEA) will be used for quantitative estimate of risk. (Score of RPN).
=>Fish Bone Diagram/ Cause & Effect Diagram Analysis

Procedure for Risk ranking and filtering:

[][]Identify the key stages for the part of the supply chain for which the company has responsibility from material supply through to use of product by patients & customers.
[][]Identify potential threats that could impact the product quality or security at each key stage.
[][]Estimate the consequences both in terms of threats and opportunities may be high, medium or low.

[][]Evaluate the exiting control measures for their effectiveness at controlling the threats.
[][]Determine the risk to product quality associated with each threat.
[][]Establish a plan for the introduction of improved controls (additional control measures) where existing threats are not adequately addressed.
[][]Implement the additional control measures and monitor their effectiveness.
[][]To identify the threats the following points should be considered:
=>Patient : Hazard/ risk to the patient safety, patient compliance.
=>Personnel : Attributes, training, education, competence, communication
=>Equipment : Type, design, condition, capacity, location, installation, operation, maintenance & calibration.
=>Facility : Layout, utilities, maintenance, dedication & hygiene.
=>Methods & Procedures : Checking, content, alterations, distribution, utilization, condition, change control, storage, trends, handling planned & abnormal events.
=>Materials : Identity, status, control, quantity, handling, specification, security arrangements, counterfeiting controls & material condition.
=>Environment : Physical effects of climatic & storage conditions (temperature, time, humidity, rain, air pressure, light, vibration etc.), pest infestation, contamination, and damage due to fire or natural disaster like flood, tornado, earthquake etc.

[][]When threats have been identified and commented upon, the table in Annexure – I should be completed.
[][]A judgment should be made on the severity of the consequences & the probability/ likelihood of the adverse events occurring taking into consideration any current control measures that are in place. Each of this can be “low”, “medium”, or “high”.
[][]Considering the severity and probability/likelihood of the events risk will be expressed Risk class one, Risk class two or Risk class three (or, High risk”, “medium risk”, or “low risk).
[][]Risk filtering will be done considering the Risk class (i.e. Risk class one, Risk class two or Risk class three) and detection of the events. Jobs/ actions will be prioritized as High priority, Medium priority or Low priority.
[][]All the jobs/actions for the changed situation shall be identified with in-depth analysis making sure all the impacted areas and the actions with the documentation requirements are assessed and completion date against all the identified actions are set.
[][]Below are two matrixes for clear understanding.

Procedure for Failure Mode Effect Analysis (FMEA):

[][]Risk in an FMEA evaluation has three components: Severity, Probability and detection/ detectability. The first step in any risk assessment is to define the component of FMEA
[][]Definition of the components of the FMEA are:
[][]Severity: if a failure were to occur, what effect would that failure have on the product quality and on the patient (if any)?
[][]Probability of occurrence: how likely is it for a particular failure to occur?
[][]Detectability (ability to detect): what mechanisms are in place (if any) to detect a failure if it were occur?
[][]Each of the above components requires clear descriptions and a corresponding scale to rank or score the projected impact (i.e. a scale for Severity; a scale for Probability; and a scale for ability to Detect). In addition, a composite score would then need to be calculated (e.g. severity multiplied by Probability multiplied by ability to detect)
[][]Non sequential number (e.g. 1,3,5,7, 9) will be used for probability and detection as the use of non-consecutive numbers allow more distinction between rating (table 2 & table 3) and to put more emphasis on the severity criteria a non-linear scoring scale will be utilized (e.g. 1, 4, 9,16, 25) . Please see table 1 for details.

[][]Table 1: Severity criteria for FMEA

Severity

Value	Description	Criteria
1	Irrelevant	No impact to product quality and process robustness
4	Slight	No impact to product quality
9	Important	Noticeable impact to product quality, but can be recovered by reprocessing
16	Critical	Definite impact to product quality that may require rework
25	Disastrous	Batch failure, not recoverable by rework

Note: Criteria in the above table will be changed based on the subject under assessment

[][]Table 2: Probability criteria for FMEA

Probability

Value	Description	Criteria
1	An unlikely probability of occurrence	Failure has never been seen in any relevant lab experiments, or scale-up batches yet but it is theoretically possible.
3	A remote probability of occurrence	Failure only seen once or twice in relevant lab experiments, never in scale-up batches.
5	An occasional probability of occurrence	Failure potential has been noted in several relevant lab experiments, or at scale-up. If procedures are followed the failure potential is minimal.
7	A moderate probability of occurrence	Failure potential has been noted in several relevant lab experiments, or at scale-up, in-process control maybe required to avoid failure.
9	A high probability of occurrence	Failure potential has been noted in several relevant lab experiment, or at scale-up, an active non-standard feedback control loop may be required.

Note: Criteria in the above table will be changed based on the subject under assessment

[][]Table 3: Detectability criteria for FMEA

Detection

Value	Description	Criteria
1	High degree of detectability	A: Validated automatic detection system that is a direct measure of failure. B: Two or more manual operated validated detection systems, direct or indirect. (e.g. Control range and IPC)
3	Good detectability	A: Single manually operated validated detection system that is a direct measure of failure. (e.g. IPC of failure, validated PAT)
5	Likely to detect	A: Single manually operated validated detection system that is not a direct measure of failure. (e.g. PAT measurements or IPC's not directly linked to failure)
7	Fair detectability	A: Non validated (manual or automated) detection. (e.g. visual level check, visual inspection of vessels).
9	Low or no detectability	No ability to detect the failure

Note: Criteria in the above table will be changed based on the subject under assessment

Risk Scoring Matrix

[][]The composite risk score for each unit operation step is the product of its three individual component ratings: severity, probability, and detection. This composite risk is called a risk priority number (RPN).
RPN = S x P x D (S= Severity; P= Probability & D= Detection)
[][]The RPN number is not absolute and should be considered in context with other factors that influence the product risk outside the scope of this evaluation. The RPN provides a relative priority for taking action – the bigger the RPN, the more important to address the corresponding failure being assessed.

[][]The table in Annexure – III will be used for FMEA. For each formulation component or manufacturing processing step under evaluation, the function of the component or processing step, potential failure mode and effect of the failure mode should be recorded.

[][]A severity score is then assigned. The root cause of the failure is described and a score is assigned to the probability of occurrence of the failure. Controls that are currently in place to detect the failure are listed and a detection score is then assigned.

[][]The RPN number is calculated. The action(s) that need to be taken to reduce or mitigate the risk are listed and individuals or departments responsible for implementing the actions are identified with target dates for completion.

[][]All the actions for the changed situation shall be identified with in-depth analysis making sure all the impacted areas and the actions with the documentation requirements are assessed and completion date against all the identified actions are set.

Fish Bone Diagram/ Cause & Effect Diagram Analysis

[][]The root cause analysis tool used for major or critical deviation, OOS, market complaint to identify quality defect prevention and potential factors causing an overall effect. Each cause or reason for imperfection is a source of variation. Causes are usually grouped into major categories to identify these sources of variation.

Defining “Effect”

[][]The first step in using the fishbone diagram as a problem solving tool is to clearly define your effect, or outcome that you don’t like. This could be a quality issues, not meeting metrics or troubleshooting the introduction of a new process or product line. This becomes the “head” of the diagram. Use butchers paper or a whiteboard to sketch out the fishbones template.

[][]Defining an effect takes a little practice. Make sure it is brief and succinct. Use facts and numbers where possible. Spend a few minutes reflecting on your effect with the team; does everyone agree that the statement defines the problem as fully as possible?
Brainstorming the “Causes”
[][]With your team, we want to add the bones to this diagram, brainstorming all of the possible influencing factors. Each idea needs to be put into a category or branch.
[][]The following probable categories to be assessed the probable causes through brainstorming is also known as 6M as per annexure-IV
=>Man
=>Machine
=>Method
=>Measurement
=>Material
=>Mother Nature

[][]Man/People/Personnel: Everyone involved with the process across the value stream, including support functions Processes / Methods: This defines how the process is performed and the all requirements needed for doing it, including quality procedures, work orders / travelers / work instructions, drawings.
[][]Machines / Equipment: All machines and equipment, needed to accomplish the job, including tools.
[][]Materials: Raw & Packaging materials, purchased parts and sub-assemblies that feed into the end product.
[][]Measurements: defines how have we determined that the outcome is wrong.

[][]Mother Nature: The standard one which turns to wrong or deviation of the standard outcome
[][]As the team suggests possible causes, determine which heading that idea belongs under, jotting it down clearly. Also add another branch, covering “why” that cause would influence the effect we are investigating. Continue until the team runs out of ideas.

[][]If is there any branches of the diagram that are missing, develop into that area further, asking questions; “Is it possible that the environment has affected our problem” too hot, too cold, too wet?
Document Numbering
[][]The unique document numbering for Risk Assessment shall consist of 9 (nine) alpha-neumerical characters, broken down as follows –
=>e.g. RA/XXX/YY
Where,
=>RA is the Risk Assessment
=>/ is separator
[][]XXX is the sequential number starting from 001, 002 & so on for a calendar year which will be further start from 001 for the next year.
=>YY is the last two digits of the year
=>For example; RA/001/YY
=>Here RA means Risk Assessment
=>001 is the sequential number
=>YY represents for the year 20YY
[][]QA shall issue the Risk Assessment document number and maintain the log register (Annexure – II).

Annexure:

Annexure-I: Risk Assessment Table and Action Plan
Annexure-II: Log Register for Risk Assessment
Annexure-III: Risk Assessment Table and Action Plan
Annexure-IV: Fish Bone Diagram Chart

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Rework and Repackaging Procedure

Quality Assurance, SOPs

Rework, Purpose :

Rework, To establish general guidelines for reprocessing, reworking of a full batch or part of a batch of product of an unacceptable quality from defined stage of production so that its quality may be rendered acceptable by one or more additional operation and to set forth method for repackaging of product with proper approval & proper documentation

Rework, Scope :

This procedure is applicable for concern department at XX Pharmaceuticals Limited (Both General and Sterile Block).

Definitions / Abbreviation:

[][]Reprocessing: Reprocessing means the reworking of all or part of a batch of product of an unacceptable quality from a refined stage of production so that its quality may be rendered acceptable by one or more additional operation.
[][]Reworking: Reworking is taking an out of spec. of product and running it through a non–standard process to bring it back in to spec.
[][]Repackaging: Repackaging requires that the final bulk product/ final product be repacked into a specific size or configuration for a special customer order.
[][]SAF: Sample Advice Form
[][]QA: Quality Assurance

Responsibilities:

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

Production

[][]To ensure that Reprocessing/Reworking and Repackaging is done following this SOP.

Concern Department Head

[][]Responsible to perform the job accordingly

Quality Assurance

[][]To monitor and implementation of the procedure

General Manager, Plant

[][]To ensure that the implementation of the procedure as per SOP.

Manager, Quality Assurance

[][]Approval of the SOP.
[][]To ensure that the implementation of the procedure as per SOP.

Procedure:

[][]Acceptable Reasons for Reprocessing
[][]Granules or Powder: Granules or Powder shall be reprocessed / reworked to correct uniformity of mixing, uniformity of fill wt. and potency to achieve required quality of granules.
[][]Plain and core tablets: Plain and core tablets shall be reprocessed to correct poor appearance, thickness, weight, hardness to improve content uniformity, disintegration or dissolution rate.
[][]Coated tablets: Coated tablets may be reprocessed to correct poor appearance, disintegration or dissolution.
[][]Capsules: Capsules may be reprocessed to correct weight variation, potency, dissolution rate etc.

Reprocessing/Reworking procedure:

Initiation & Approval of Reprocess/Rework Request form:
[][]If any reprocessing or reworking seems necessary, concerned Department shall raise Reprocess/Rework Request Form (Annexure-I) upon agreement of Product Development Department and Quality Assurance Department.

[][]Each Reprocess/Rework Request Form shall contain a full explanation of the reason for reprocessing and the proposed reprocessing steps.
[][]An investigation shall be carried out by QA with the help of PD and concerned department (if required) to identify the reason and process for reprocessing.
[][]After that the concerned Department Head, Head of PD and General Manager, Plant shall give their comments.
[][]The Reprocessing work shall start only after getting approval of the proposed reprocessing steps from Head of Quality Assurance.
[][]After completion of reprocess, concerned department shall advice Quality Control for analysis through SAF.
[][]When the test result is received from QC, QA shall then give decision about release of the product.
[][]The appropriately filled Reprocess/Rework Request Form (Annexure-I) along with other necessary documents shall become the part of the batch document.
[][]Assignment of Batch No., Manufacturing Date, Expiration Date and Reference No. for Reprocessing/Reworking batch.
[][]In case of reprocessing a part of a batch or full batch, the Batch No. of part shall be the original Batch No.
[][]In case of reprocessing of a product from different batches tails, the batch no. shall be the first batch of among those batches which are to be reprocessed and “R” shall be suffixed for identification of reprocessed batch.

[][]Manufacturing Date of different batches tails that composed/reformed a batch should be within two months.
[][]Reference No. for Reprocessing/Reworking shall be as
RW-001/07/XX
where-
=>RW represents Reprocess/Rework
=>001 represents monthly sequential number
07 represents Month of July. It will be changed in next month
=>XX represents year of 20XX. It will be changed in next year.

Repackaging Procedure (Primary & Secondary):

[][]When any repackaging of product seems necessary, concerned department shall raise proposal through Repackaging Request Form (Annexure-II)
[][]When any finished product (local/export) returned from central store and are required to convert into physician/local/export pack, it shall be processed through Repackaging Request Form (Annexure-II)
[][]An investigation shall be carried out by QA with the help of PD and concerned department (if required) to identify the reason for repackaging and product quality of the part of the batch which shall be repackaged. Necessary analytical work shall be done for repackaging part of the batch by QC (if required).
[][]Concerned Department shall forward sample through SAF (Sample Advice Form ) to QC for analytical work of repackaging part of the batch.
[][]After completion of analytical work, QC shall forward the analytical test result to concerned department.
[][]Concerned Department Head shall forward Repackaging Request Form to PD and subsequently to General Manager, Plant for their comments.
[][]After that, the Concerned Department forwards the Repackaging Request Form along with test result (SAF) to Head of QA for approval.
[][]Reference No. for Repackaging shall be as
RP-001/07/YY where-
=>RP represents Repackaging
=>001 represents monthly sequential number
=>07 represents Month of July. It will be changed in next month
=> YY represents year of 20YY. It will be changed in next year.
=>Finally Repackaging Request Form and related QC test results shall be the part of the batch document.

Annexure:

Annexure-I: Reprocess/Rework Request Form
Annexure-II: Repackaging Request Form

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Artwork Management Procedure

Quality Assurance, SOPs

Artwork Management , Purpose:

Artwork Management , To lay down the general guideline about preparation, approval and preservation of artwork, printed specimen and approved color and design standard of printed packaging materials that are required to develop packaging materials for products.

Artwork Management , Scope:

This SOP is applicable for art work development of new as well as existing products of both General and Sterile Block in XX pharmaceuticals limited.

Definition/Abbreviation:

[][]PD : Product Development
[][]PMD : Product Management Department
[][]QC : Quality Control
[][]QA : Quality Assurance
[][]SCM : Supply Chain Management
[][]XX : Current Version

Responsibilities:

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

Marketing Department

[][]Preparation and checking of text for the packing materials.
[][]Raise a change control in case of any change in the existing art work.
[][]Prepare the final art work for regulatory submission.
[][]Design of all art work as per dimension and text.

Product Development Department

[][]Checking the draft art work for dimension and texts.
[][]Checking dummy carton and machine proof sample and shade card.

Quality Control

[][]Generation of packing specification according to approved artwork and shade card.

Quality Assurance

[][]Checking the text of draft, dummy and machine proof sample.
[][]Preparation and timely review of the SOP.

Head of Marketing

[][]Check and review of all Art works.

Head of Plant Operation

[][]Review of all art work.

Head of Quality Assurance

[][]Approval of all art works as per XX specification.
[][]Approval of the SOP.

Procedure:

[][]After receiving product proposal report from PMD, PD will generate Artwork Technical specification according to Annexure–I and send to PMD. PD will also preserve a copy in the product master file.
[][]PMD will generate the artwork as per Artwork Technical specification (Annexure-I) and send two copies artwork to Quality Assurance. PMD will also generate material code in ERP.
[][]Each artwork will contain the respective material code and version no. with signature of PMD personnel.
[][]Quality Assurance will check the artwork and will take comment from PD regarding label claim, pack size, primary packaging information, and width of foil etc. for any new product and new width of foil or new dimension of carton for existing products. For any correction Quality Assurance will forward the artwork copy to PMD department for further action.

[][]After all reviewing, Quality Assurance & PD will sign the artwork and then forward to Head of Plant Operation for checking.
In the meantime, size and shape (dimension) of the Packaging materials will be confirmed by machine trial or by operation with dummy samples. After receiving dummy samples from PMD, PD and Production will work jointly to finalize the size and shape.
[][]PD will provide samples of required size strips/blisters to PMD for preparation of dummy carton when requested.

[][]Head of Plant Operation will review the artwork and send to Head of Quality Assurance for final approval.
[][]Quality Assurance will send one copy of approved artwork to PMD and preserve another copy at QA.

[][]For new product, PMD will raise commercial requisition after getting three month stability declaration from PD. After commercial requisition Supply Chain will find out the source for preparation of shade card.

Selection of Color:

[][]PMD will suggest the color of Printed components by considering the following:
[][]Preferably color shall be dissimilar in different strengths of same product.
[][]Color shall be stable and not fade on storage or during any operation of the material.
[][]Suggested color shall be forwarded to PD and Quality Assurance for comment.
[][]In case of any major anomaly in color selection, final decision shall be taken jointly by PMD and PD.

Approved Color and Design Standard of Printed Packaging material:

[][]PMD will then send 5 standards of packaging materials to Quality Assurance. Quality Assurance will check the text of printed components against approved artwork and give comments. These standards are for:
=>PMD Copy
=>Quality Control Copy
=>Quality Assurance Copy
=>Supply Chain Copy
=>Supplier Copy
[][]Quality Assurance will send one copy of approved shade card along with artwork to QC for preparation of specification.
[][]After approval of specification, QA will send controlled copy of specification along with shade card to QC, PMD, Supply Chain and the Supplier.
[][]For supplier approval / alternate source development, Supply Chain will send source approval document to QC through PMD. Source approval documents are:
=>Duly filled Vendor Questionnaire
=>Vendor Approval Form
=>Certificate of Analysis/ Conformation
=>Supplied list of material

Change Control:

[][]Any change in the printed components like foil/ carton/ leaflet/ label shall be processed following SOP.
[][]Any change in pack size or brand name of the product shall require approval of local Drugs Authority/Regulatory Authority.
[][]When any change in packaging components, PMD and Supply Chain should ensure that following documents will be collected from the supplier through Obsolete Form of Artwork/ Supplier (Annexure-II). Documents are:
=>Previous version of Artwork
=>Previous version of Shade card
=>Previous version of Plate positive
=>When any supplier will be rejected from approved vendor list, Supply Chain will be proceed through Obsolete Form of Artwork/ Supplier (Annexure-II).

Annexure:

Annexure – I: Artwork Technical Specification
Annexure – II: Obsolete Form of Artwork/ Supplier

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Line Clearance Procedure

Job Solution, Quality Assurance, SOPs

Line Clearance Procedure, Purpose :

Line Clearance Procedure, To ensure that the area and equipment to be used for the dispensing, manufacturing and packing of products are free from remnants of previous product/batch.

Line Clearance Procedure, Scope :

This procedure is applicable for clearance of dispensing, manufacturing, packing area & equipments at XX Pharmaceuticals Limited (Both General and Sterile Block).

Definitions / Abbreviation:

[][]N/A

Responsibilities:

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

Quality Assurance Personnel

[][]Responsible to perform the activities as per SOP.

Concerned department

[][]To maintain procedure as described in SOP

Manager, Quality Assurance

[][]Approval of the SOP.
[][]To ensure that the implementation of the procedure as per SOP.

Procedure:

Dispensing:

[][]Before start of dispensing of raw material/coating material Production Executive shall check the following and keep record in BMR.
[][]Area cleanliness, absence of irrelevant/ foreign material
[][]Equipment cleanliness
[][]Removal of material of previous batch/product from dispensing area
[][]Balance calibration records, daily accuracy check/ function check of balance
[][]Entry in Log book
[][]Status label of material/ component
[][]Cleanliness of container of material to be dispensed.
[][]Quality Assurance Executive shall monitor and then provide counter check/ signature to ensure that line clearance checking has been performed properly by dispensing people and all above stated parameters are satisfactory.

Manufacturing:

[][]For Granulation/ Compression/ Blending of Powder or Pellets/Coating
[][]Before start of any manufacturing operation concerned Production Executive shall check the following parameters and keep the records in BMR.
[][]Area cleanliness, absence of irrelevant/ foreign material
[][]Equipment/ machinery cleanliness
[][]Removal of material of previous batch/product from granulation/ compression/ blending/ coating area.
[][]Balance calibration records, daily accuracy check/ function check of balance
[][]Room Temperature and % Relative Humidity of the granulation/ compression/ blending/ coating area (if applicable)
[][]Entry in Log book
[][]Room display/ Product display

For Powder for Suspension/ Encapsulation:

[][]Before start of any manufacturing operation concerned Production Executive shall check the following parameters and keep the records in BMR.
[][]Area cleanliness, absence of irrelevant/ foreign material
[][]Equipment/ machinery cleanliness
[][]Removal of material of previous batch/product from area
[][]Balance calibration records, daily accuracy check/ function check of balance
[][]Room Temperature and % Relative Humidity of the manufacturing area (if applicable)
[][]Entry in Log book
[][]Room display/ Product display

Packaging:

[][]Before start of any packaging operation concerned Production Executive shall check the following parameters and keep the records in BPR.
[][]Printing Line Clearance
[][]Name of the previous product (to be recorded)
[][]Batch No. of previous product (to be recorded)
[][]Area cleanliness, absence of irrelevant/ foreign material
[][]Entry in Log book
[][]Room display/ Product display

Packaging Area Equipment Clearance:

[][]Area cleanliness, absence of irrelevant/ foreign material
[][]Equipment/ machinery cleanliness
[][]Removal of material of previous batch/product in packaging line
[][]Room Temperature and % Relative Humidity of the packaging area (if applicable)
[][]Entry in Log book
[][]Room display/ Product display

Annexure:

N/A

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Batch Release Procedure

Quality Assurance, SOPs

Batch Release, Purpose:

Batch Release, This procedure defines the correct procedures for the release and distribution of finished products to ensure Assurance with the requirements of GMP and includes details of the responsibility of the Authorized Persons.

Batch Release, Scope:

This SOP is applied to storage, release and distribution of finished products and it’s supporting activities at XX Pharmaceuticals Limited (Both General & Sterile).

Definitions / Abbreviation:

[][]QA : Quality Assurance
[][]SOP : Standard Operating Procedure
[][]FIFO : First In First Out
[][]COA : Certificate of Analysis

Responsibilities:

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

Production Executive

[][]Check the quantity of the product before transfer into the ware house.
[][]Transfer the finished goods to warehouse.
[][]Issue Transfer Note accordingly

Warehouse Executive

[][]Receive finished goods from the production floor after proper checking.
[][]Keep the finished product into the ware house accordingly.
[][]Transfer the finished goods to central warehouse after getting release note from QA.

Quality Assurance Executive

[][]Check the quantity of the product before transfer into the ware house.
[][]Compilation of Batch Production Record.
[][]Follow the overall batch release procedure.
[][]Quality Control Executive/ Microbiologist
[][]To provide analytical support for various samples drawn for batch release.
[][]Prepare Certificate of Analysis (COA).

Head Of Quality Assurance

[][]Give approval to release the finished goods into the market.
[][]To ensure Assurance of the SOP.
[][]Approval the SOP.

Annexure:

Annexure-I: Checklist for Batch Documentation
Annexure-II: Finished Product Release Note
Annexure-III: Final Inspection Sheet

Procedure:

[][]After completion of packaging operation, finished packed shipper cartons will be stored at the Quarantine area of packaging hall. Production Executive will raise the Finished Goods Transfer Note to Quality Assurance Department for final inspection mentioning product name, batch number, quantity, master carton number.

[][]The finished product will be transferred to warehouse after physical checking by Quality Assurance Executive according to final inspection sheet (Annexure- III).
[][]Warehouse Executive will check the product name, batch number, quantity, pack size, and label of finished product(s) against the transfer note during receiving.
[][]If all information (Product name, batch number, quantity, pack size, label) of finished product transfer note is matched with transferred quantity, then Warehouse Executive will receive & store the product in QUARANTINE AREA (for finished product) of warehouse maintaining storage condition as per attached product label on the shipping carton.
[][]After completion of full batch packaging, Production Executive will submit the Batch Packaging Record to Quality Assurance Department mentioning the transferred quantity in the BPR for release of the product.
[][]Quality Assurance personnel will review all the documents / parameters according to checklist . If all parameters are found complies, then he/she will compile the full batch production record (BMR, BPR) along with all related documents.
[][]After compilation of the batch documents, QA Executive will entry in the ERP of release note verification and Head of QA will approve the release in the software.
[][]Quality Assurance will attach the Approved Label in every pallet containing released product. (One labels per pallet).
[][]During reviewing the documents according to the check list, following matters need to be considered.
[][]Batch Manufacturing Record (BMR)
[][]Evaluate all the in-process result are within limit, cleaned/partially cleaned label are available, dispensing weights are accurate & dispensing slip along with print out is available, all manufacturing part has been done as per instruction, all the responsible persons have signed in respective operation stages in BMR.
[][]If any deviation/change control was raised, reference number is recorded in the respective place of BMR.
[][]Review the reconciliation steps are correctly calculated and loss result is justified.
[][]Review the line clearance in each steps of manufacturing and Packaging stages are signed by responsible person.
[][]Review the related Deviation/Change Control is closed and the reference number of this documents are recorded in the respective area of the BMR.
[][]Review the completed BMR is approved by Quality Assurance and Production after completion of operation.
[][]Review the associated documents such as all relevant labels, IPC record, particle count record (If any) is correct and signed. Review all the results are within limit or not. If any results are found out of limit, then related Out of Specification (OOS) is attached with the document.
[][]Review the completed BMR is approved by Head of Production or his/her designate and Head of Quality Assurance or his/her designate after completion of operation.

Certificate of Analysis (COA)

[][]Review the Certificate of Analysis (Chemical and Microbial) is signed and approve by responsible person. Review all the results are within the specification. Review all the print out of QC analysis result attached with COA.

Batch Packaging Record /BPR (Primary and Secondary)

[][]Review all the packaging materials are correctly dispensed and authentication information for packaging start up is correct.
[][]Review the in process checks are routinely performed.
[][]Review the reconciliation steps are correctly calculated and Yield & loss result is justified.
[][]Review the line clearance in each step (i.e. primary packing, secondary packing), inspection and labeling are signed by responsible person.
[][]Review the related Deviation/Change Control is closed check the presence of the Deviation/Change Control reference number into the respective place of BPR.
[][]Review the completed BPR is approved by Head of Production or his/her designate and Head of Quality Assurance or his/her designate after completion of operation.

Review the quantity of the packs and presence of all signatures accordingly.

[][]Head of QA/Designee shall verify the Batch Production Record as per checklist (Annexure-I) for correct entries, reconciliation of quantity, yield, change control, deviation, out of specification (OSS), (if any), in-process checking records analytical test results etc. After reviewing if all the parameters found satisfactory then the Manager, /designee shall release the product for dispatch.
[][]For dispatch of finished product, Quality Assurance personnel will issue the Finished Product Release Note (Annexure-II) for getting approval from Head of Quality Assurance. Finish Product Release Note is a self carbonated pre-printed copy as per the original approved copy of Annexure-II
[][]Which contains three different colors Then one carbonated (Yellow colored) copy of the finished product release note will send to central warehouse for distribution. The original blue colored copy will be attached with the batch document.
[][]In case of release of any optimization or validation batch before completion of process validation report, & risk analysis report must be conducted before release. All the documents are approved accordingly by Head of Quality Assurance or his/her designate.
[][]Full batch will be released at a time after completion of the total packaging operation of the batch.
[][]After QA release, Warehouse Executive will store the released product orderly in separated passed area maintaining storage condition. FIFO must be maintained by warehouse executive during dispatch of the released product for distribution.
[][]Quality Assurance Executive will compile all the batch records and kept in the respective Batch Production Record archive area after keeping record in the document archiving log book.
[][]Batch history which must be kept for one year after expiry of the batch.
[][]Fraction batch quantity can only be released with same batch number (while the batch is fractioned as Commercial, Trial Aid or Export) after approval of Head of Quality Assurance.

Batch Release Procedure Read More »

Room Numbering System

Quality Assurance, SOPs

Room Numbering , Purpose:

Room Numbering , To provide guidelines for numbering system to all rooms of General Block and Sterile Block in XX Pharmaceuticals Limited.

Room Numbering , Scope:

This procedure is applicable for assigning sequential identification number to all rooms located on each floor of the production, PD/QC/Microbiology area and other area related to Plant operations such as warehouse, plant room, utility area etc are also included in room numbering system.

Definition / Abbreviation:

[][]None

Responsibilities:

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

Executive / Sr. Executive, Engineering

[][]He / she shall be responsible for assigning the sequential identification number to all rooms.

Quality Assurance personnel

[][]He/she shall be responsible for effective implementation and monitoring of procedure.

Quality Assurance Head or Designee

[][]To ensure implementation of SOP.

Procedure:

[][]Numbering for Room
[][]Each room shall be assigned a unique identification number.
[][]Engineering department shall assign floor wise alpha numeric sequential identification Number to all rooms in a logical order on lay out and record the numbering details in Annexure –I.
[][]Do not repeat the same number to another room.
[][]The room numbering shall be a floor wise sequential number having 6 characters as shown below.
=>e.g. GPRXXX
where
=>(G) is the code for General Block
=>(PR) is the working area code for production
=>(XXX) is the first sequential number of room start from 001 to 999
=>Next room shall be numbered GPR002 ……….& so on.

[][]The Building code for each building is given below.

Building name/ Code

=>General Block/G
=>Sterile Block/C
[][]The Working area code for each area is given below.

Area/ Code

=>Production/PR
=>Packaging/PK
=>Warehouse/ WH
=>Product Development/ PD
=>Quality Control/QC
=>Microbiology/MB
=>Mezzanine /ME
=>Roof Top/RT
=>Engineering/EN

Annexure:

Annexure – I: List of rooms

Room Numbering System Read More »

In Process Check (IPC) Procedure

GMP, Quality Assurance, SOPs

In Process Check, Purpose :

In Process Check, To set up a general guideline for in-process checking that will be followed during the course of manufacturing. This SOP also includes handling of IPC parameters failure during production.

In Process Check, Scope :

This procedure is applicable to all Production activities such as Manufacturing, Packing and warehouse department at XX Pharmaceuticals Limited (Both General and Sterile Block).

Definitions / Abbreviation:

[][]SOP: Standard Operating Procedure
[][]QA: Quality Assurance

Responsibilities:

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

Executive, Quality Assurance

[][]To ensure that this procedure is followed.
[][]To maintain the records properly as per SOP.

Manager, Quality Assurance

[][]To ensure that this procedure is kept up to date.
[][]To arrange training on the SOP to all concerned personnel.
[][]To ensure implementation of the SOP after training.

Manager, Quality Assurance

[][]Approval of the SOP.

Procedure: In Process Check

General Instruction:

[][]Check the general environment in the department
[][]Ensure proper gowning by the personnel in concerned work area.
[][]Check for the daily calibration of balance.
[][]Check the calibration status label of machines.
[][]Ensure that the line clearance is obtained before starting the next step.
[][]Ensure the destruction of all In-process, rejects, excess overprinted packing material after packing.
[][]Ensure that the every stage of process, appropriate status label is affixed on equipment /machines and containers.
[][]Non Assurance shall be reported immediately to concerned department Head.
[][]Ensure the completion of documentation at the end of each processing stage.

Warehouse Raw Material: In Process Check

=>Ensure line clearance before commencement of dispensing activity.
=>Ensure all the material having properly labeled.
=>Ensure that only “Quarantine” material is stored in quarantine area.
=>Ensure the transfer of Approved material in “Approved Area”.
=>Ensure that storage conditions of raw material are met.

Ensure the following points on Approved Quality Control labels.

=>Analytical Report Number.
=>Re-test date.
=>Ensure that the loose containers are properly closed after dispensing.
=>Ensure that the material is issued on FIFO basis.
=>Ensure that the environmental conditions are maintained in the respective areas.
=>Ensure that the details on dispensed material, material issues slip/dispensing slip are matching with Material Issuance form.

Warehouse Packaging Material:

[][]Ensure proper segregation of materials.
[][]Ensure proper disposal of the rejected items.
[][]Ensure that the material is issued on First In First Out (FIFO) basis.

Warehouse Finished (Drug) Product:

[][]Ensure that the products are dispatched only after QA release.
[][]Ensure the proper storage of goods.
[][]Ensure that “Quarantine” drug product are stored in quarantine area of Warehouse drug product

Parameter for In-process checking during Dispensing:

[][]Area cleanliness, absence of irrelevant/ foreign material.
[][]Equipment cleanliness.
[][]Cleaning record.
[][]Removal of material of previous batch/product from dispensing area.
[][]Balance calibration records, daily accuracy check/ function check of balance.
[][]Status label checking of raw materials prior to weigh.
[][]Weight checking of materials.
[][]Room temperature and Relative Humidity of Dispensing area.

Parameter for In-process checking during Manufacturing:

[][]Generally following parameters shall be checked during manufacturing of tablet/ capsule/ dry powder
[][]Area cleanliness, absence of irrelevant/ foreign material.
[][]Equipment/ machinery cleanliness.
[][]Cleaning record.
[][]Removal of material of previous batch/product from granulation/ compression/ blending/ encapsulation/filling area.
[][]Balance calibration records, daily accuracy check/ function check of balance.
[][]Room temperature and Relative Humidity of the granulation/ compression area (if applicable).
[][]Room display/ product display.

For Tablets:

[][]In Granulation Stage:
[][]Moisture
[][]Temperature (if applicable)
[][]Relative Humidity (if applicable)

In Compression Stage: In Process Check

[][]Appearance (Shape, Surface texture, Physical flaws, Consistency, Identification marking etc.)
[][]Average weight
[][]Uniformity of weight
[][]Relative Standard Deviation
[][]Hardness
[][]Thickness
[][]Diameter
[][]Friability
[][]Room temperature
[][]Relative Humidity (if applicable)
[][]Disintegration time
[][]Machine speed
[][]Organoleptic test (if applicable)

In Coating Stage:

[][]Appearance (Physical flaws)
[][]Average weight
[][]Disintegration time
[][]Weight gain/ coating loss

For Capsules:

[][]In Encapsulation Stage:

[][]Appearance (Color, Size, Identification marking)
[][]Average fill weight
[][]Uniformity of weight
[][]Disintegration time
[][]Relative Humidity of encapsulation room/ area
[][]Temperature of encapsulation room/ area
[][]Locking of capsule

For Powder for Suspension or Syrup:

[][]In Blending Stage:
[][]Relative Humidity of blending/ manufacturing area.
[][]Temperature of blending/ manufacturing area.

In Filling Stage:

[][]Appearance
[][]Relative Humidity of filling room/ area
[][]Temperature of filling room/ area

[][]For Kidney Dialysis Fluid
=>In Manufacturing Stage:
=>Relative Humidity of manufacturing area
=>Temperature of manufacturing area.
[][]In Filling Stage:
=>Uniformity of filling weight
=>pH of solution
=>Conductivity of solution

Checking procedure for IPC during manufacturing:

[][]Room Temperature and Relative Humidity:
[][]Room Temperature and Relative Humidity shall be checked by using Digital Hygrometer and the result shall be recorded in the Batch Manufacturing Record (BMR) in mentioned stage. Room Temperature and Relative Humidity shall be checked as per frequency specified in BMR/BPR.

Moisture:

[][]Moisture shall be checked by using Mettler Toledo balance following corresponding SOP and the result shall be recorded in the Batch Manufacturing Record (BMR) in mentioned stage.

Appearance:

[][]Parameters (as applicable for dosage form type) as mentioned below shall be checked during start-up and in every fifteen (15) minutes interval. About 500 coated tablets from each part shall be checked after completion of coating. Physical flaws of coated tablets shall be recorded in Coated Tablet Visual Inspection Record Sheet.
[][]Color/ Clarity
[][]Shape of tablet
[][]Identification marking
[][]Physical flows in case of capsule

Physical Flaws/ Acceptable Quality Level

[][]Uncoated Tablet
=>Critical Defects (Cracking, Capping/Lamination)/ 0.025%
=>Major Defects (Erosion, Picking/ Sticking)/ 0.25%
=>Minor Defects (Roughness, Illegible logo, Peeling)/ 1.5%
[][]Coated Tablet
=>Critical Defects (Cracking) / 0.025%
=>Major Defects (Blocking, Color Variation, Erosion, Picking/ Sticking) / 0.25%
=>Minor Defects (Twinning, Roughness, Peeling, Core Erosion, Loss of Logo Definition, Logo Bridging ) / 1.5%

The acceptable quality level of physical flaws of coated/ uncoated tablet are as follows:

[][]Weight:

Tablet:

[][]Weight of 05 composite samples, each of which consists of 10/20 tablets shall be checked during start-up and in every fifteen (15) minutes and the result shall comply with the specification as mentioned below:
=>If theoretical tablet weight is ≤80 mg then composite weight shall be in between ±4.0% of theoretical tablet weight.
=>If theoretical tablet weight is >80 mg or <250 mg then composite weight shall be in between ±3.0% of theoretical tablet weight.
=>If the theoretical tablet weight is >250 mg then composite weight shall be in between ±2.5% of theoretical tablet weight.

Capsule:

[][]Composite Fill weight of 10/20 capsules shall be checked during start-up and in every fifteen (15) minutes and the result shall comply with the specification as mentioned below:
=>If fill weight is ≤300 mg then composite fill weight shall be in between ±5.0% of fill weight.
=>If fill weight is >300 mg then composite fill weight shall be in between ±3.0% of fill weight.

Dry powder:

[][]Empty bottle/ plastic container shall be weighted and then tare button of Mettler Toledo balance shall be recorded.
=>After filling with dry powder the filled bottle/ plastic container shall be weighted again to determine the fill weight.
=>Fill weight shall be checked from each filling nozzle. In case of single filling nozzle at least five fill weight shall be checked.
=>The fill weight shall be within the range as specified in BMR. Fill weight shall be checked during start-up and in every thirty (30) minutes interval.

Uniformity of weight: In Process Check

Uniformity weight for tablet and capsule shall be checked during start-up and in every two (2) hours interval.

Tablet:

[][]A number of tablets shall be weighted individually as per the number of punch (if no. of punch is less than 20, then uniformity of weight shall be checked with minimum 20 tablets) of the compression machine. The printed record of statistical data shall be taken and the result of average tablet weight, range of individual weight and % RSD shall be recorded in BMR. The result shall comply with the specification as mentioned below:
[][]Observed average weight shall be within the range calculated with ±2.5 of theoretical tablet weight.
[][]Relative Standard Deviation (RSD) shall be NMT 6.0%.
=>Observed individual tablet weight shall comply with the specification as mentioned below:
=>If tablet weight is ≤80 mg then NMT two tablets shall be outside ±10.0% and none shall be outside ±20.0% range of theoretical tablet weight.
=>If tablet weight is >80 mg or <250 mg then NMT two tablets shall be outside ±7.5% and none shall be outside ±15.0% range of theoretical tablet weight.
=>If tablet weight is ≥250 mg then NMT two tablets shall be outside ±5.0% and none shall be outside ±10.0% range of theoretical tablet weight.

Capsule:

[][]The uniformity of capsule’s fill weight shall be checked by weighing 20 capsules individually. Then the printed record of statistical data shall be taken and the result of average capsule weight shall be recorded in BMR. The result shall comply with the specification as mentioned below:
[][]Observed average capsule fill weight shall be within the range calculated with ±3.0 of theoretical capsule fill weight.
[][]Specification of Relative Standard Deviation (RSD) shall be NMT 6.0%.
Observed individual capsule fill weight shall comply with the specification as described below:
=>If capsule fill weight is ≥300 mg then NMT two shall be outside ±7.5% and none shall be outside ±15.0% range of theoretical capsule fill weight.
=>If capsule fill weight is <300 mg then NMT two shall be outside ±10.0% and none shall be outside ±20.0% range of theoretical capsule fill weight.

Hardness, Thickness and Diameter:

Tablet:

=>Hardness, thickness and diameter of randomly taken 10 tablets shall be checked by ERWEKA TBH 125 machine and a print of found data with statistical evaluation shall be taken and the result shall be recorded in BMR. Hardness, thickness and diameter shall comply with the limit as specified in BMR. Hardness and =>thickness shall be checked during start-up in every one hour interval and diameter shall be checked during start-up.

Disintegration Time: In Process Check

[][]Randomly selected 6 tablets/ capsule shall be placed in 6 different glass tubes of Electrolab ED2 disintegration tester with/without disc (as applicable). The time by which each tablet/ capsule is disintegrated into smaller particles or granules expressed in minutes shall be recorded in BMR. DT of tablet/capsule shall be checked during start-up and every five hours if the batch runs for more than five hours. General guideline for DT of different forms of tablet/ capsule is as follows:
=>Uncoated/ core tablet : NMT. 15 minutes
=>Film coated tablet : NMT. 30 minutes
=>Effervescent tablet : NMT. 5 minutes
=>Hard capsule : NMT. 30 minutes
=>Soft capsule : NMT. 30 minutes
=>Gastro-resistant capsule : 1-2 or 3 hours in acid medium and NMT. 1 hour in buffer medium.

Friability:

[][]Randomly 20 tablets/ 6.5 gm of tablets (for average weight ≤650 mg) or 10 tablets (for average weight >650 mg) shall be selected for friability test. Initially weight of tablets (W1) shall be taken and then be placed in the Friabilator.
[][]The Friabilator shall be run for four minutes at 25 rpm and then tablets of this machine shall be reweighted (W2).Friability of tablets shall be calculated with following formula:

% Friability =W1–W2/ W1×100

[][]A Maximum weight loss NMT 1.0% is considered acceptable for most of the products. Friability of effervescent tablets and chewable tablets may have different specifications.
[][]In case of hygroscopic tablets, an appropriate humidity-controlled environment is required for friability.
[][]Friability shall be checked during start-up and in every two (2) hours interval and be recorded in BMR.

Reconstituted volume for dry powder:

[][]Glassware required for doing the test is 50 ml or 100 ml graduated cylinder.
[][]Water (quantity) shall be taken as specified for the product with a graduated cylinder.
[][]Water shall be poured to the filled bottle and syrup/ suspension shall be made as specified in Leaflet/ Inner carton of the product.
[][]Any observed anomaly (e.g. color, odor, consistency etc.) and the volume with the same cylinder shall be checked.

Parameter for In-Process Checking during packaging:

[][]In case of export besides the following some additional parameters (where applicable) shall be checked like registration no. on foil/label/carton, Text of foil (English/ Bengali), Security overprint on blister/strip etc.

Area:

[][]Room cleanliness
[][]Machine cleanliness
[][]Temperature (0C) [if applicable] [][]% Relative Humidity (if applicable)

Bulk Product:

[][]Product name and strength
[][]Appearance of bulk
[][]Strip/ Blister packing:
[][]General appearance of bulk
[][]Cutting/ perforation
[][]Pocket formation, empty or ruptured pocket
[][]Broken tablets in pocket
[][]Print and color of foils
[][]Color and cleanliness of film (if applicable)
[][]Printing/embossing of Batch No., Mfg. Date and Expiry Date on blister/strip (as applicable)
[][]Improper or inadequate knurling
[][]Sealing (Leak Test)
[][]Camera challenge test (If available on blister machine)

Glass Bottle/ Plastic Container Filling & Packing (Tablets & Capsule):

[][]Appearance of bulk
[][]Quantity per bottle/ container
[][]Cap sealing/ Leak test (as applicable)
[][]Relative Humidity (RH) and Temperature in filling area
[][]Product name with strength on label
[][]Coding Batch no./ Mfg Date/ Exp. Date/ MRP on label (as applicable)
[][]Print and color of label
[][]Security overprint (if applicable)

Inner Cartoning:

[][]Product name and strength
[][]Coding Batch no./ Mfg. Date/ Exp. Date/ MRP (overprinting)
[][]Presence of Leaflet/ Dropper/ Spoon/ Cup/ Cylinder (if applicable)
[][]Adaptability
[][]No. of strip/ blister per pack
[][]Placing of Holographic sticker (if applicable)

Shipping Carton:

[][]Product name and strength
[][]Coding Batch no./ Mfg. Date/ Exp. Date (as applicable)
[][]No. of inner cartons
[][]Serial no.
[][]Size no. and adaptability
[][]Date of cartoning
[][]Signature of the person closing the shipping carton

Checking procedure for IPC during Packaging:

Room Temperature and Relative Humidity:

Room temperature and relative humidity shall be checked as stated above

Leak Test:

[][]At least one sample of conventional strip/ blister/ bottle/ plastic container from each delivery/ cutting channel of the machine shall be picked up from packaging line except sealing machine of one delivery/ cutting channel where two samples shall be collected and checked for integrity following corresponding SOP.
Frequency of Leak test shall be as per following table:

Sample/ Frequency

=>Blister/ Start-up and every hour
=>Empty sealed glass bottles/Start-up and in every hour

[][]If color solution enters into any of the pocket of the strip(s)/blister, into bottle(s)/ plastic container(s) it indicates the leakage.
[][]Calculate the percentage of leakage and record in Leak Test Record Sheet.

Tablet/ Capsule Counting Procedure:

[][]Tablet/ capsule counting procedure shall be performed during start-up and in every 30 minutes.

Annexure: In Process Check

Annexure-I: Coated Tablet Visual Inspection Record Sheet
Annexure-I: Leak Test Record Sheet

In Process Check (IPC) Procedure Read More »

Recall Procedure

Product Complaints, Product Defects, Product Recalls, Quality Assurance, SOPs

Recall, Purpose :

Recall, To ensure recall of products that are known or suspected to be defective or hazardous in accordance with a pre-determined plan promptly and effectively from the market

Recall, Scope :

This procedure is applicable for all products manufactured and distributed from XX Pharmaceuticals Limited (Both General and Sterile Block).

Definitions / Abbreviation:

[][]Recall: A process for withdrawing or removing a pharmaceutical product from the pharmaceutical distribution chain because of defects in the product, complaints of serious adverse reactions to the product and/ or concerns that the product is or may be counterfeit. The recall might be initiated by the manufacturer, wholesale dealer, license holder, or Department of Health.
[][]Market Withdrawal: Market Withdrawal means a firm’s removal or correction of a distributed product which involves a minor violation that would not be subjected to legal action by the Drugs Administration or which involves no violation, e.g., normal stock rotation practices, routine equipment adjustments and repairs etc.
[][]PMD: Product Management Department
[][]QA: Quality Assurance

Responsibilities:

The roles and responsibility is as follows:

Head of PMD

[][]Responsible for determining the intensity of recall to be taken by consultation with Head of QA and taking necessary action.
[][]When product is distributed in domestic/ overseas market, Head of PMD or his authorized nominee shall inform Head of QA for the action to be taken for recall.
[][]Coordinate the recall after obtaining approval from Managing Director.

Manager, Quality Assurance

[][]Approval of the SOP.
[][]To ensure that the implementation of the procedure as per SOP.

Classification of Recall:

[][]Recalls are classified according to the following system
Class I recalls: Occur when products are potentially life-threatening or could cause a serious risk to health.

Examples of Class I Defects

[][]Wrong Product (label and contents are different products)
[][]Correct product but wrong strength, with serious medical consequences
[][]Microbial contamination of sterile injection or ophthalmic product
[][]Chemical contamination with serious medical consequences
[][]Mix up of some products (‘rogues’) with more than one container involved.
[][]Wrong active ingredient in a multi-component product with serious medical consequences

Class II recalls: Occur when product defects could cause illness or mistreatment, but are not Class I.

Examples of Class II Defects

[][]Mislabeling e.g. wrong or missing text or figures
[][]Missing or incorrect information- leaflets or inserts
[][]Microbial contamination of non-injectable, non-ophthalmic sterile product with medical consequences
[][]Chemical/ physical contamination (significant impurities, cross contamination, particulates)
[][]Mix up of products in containers (“rogues”)
[][]Non-Assurance with specification (e.g. assay, stability, fill/ weight or dissolution)
[][]Insecure closure with serious medical consequences (e.g. cytotoxics, child resistant containers, potent products)
Class III recalls: occur when product defects may not pose a significant hazard to health, but withdraw may be initiated for other reasons.

Examples of Class III Defects

[][]Faulty packaging e.g. wrong or missing batch number or expiry date
[][]Faulty closure
[][]Contamination- microbial spoilage, dirt or detritus, particulate matter
[][]Recall system shall be followed in case of Instructions from Regulatory authorities or Voluntary recall by XX authority.

Reason:

=>Reports of adverse reaction.
=>Non-conforming result of on-going stability study.
=>Formulation problem/ Mix-up/ contamination.
=>Labeling errors.
=>Any other reasons.
[][]Head of Quality Assurance shall advise to carry out proper investigation for confirmation of reported defects either jointly or independently by QC, PD, Production & Quality Assurance. PMD personnel can also participate in investigation.
[][]After confirmation and justification of reported defects, Head of Quality Assurance shall discuss with Head of Production and Head of PMD.
[][]Once it is agreed to recall the product(s), Head of Quality Assurance shall seek permission for it from Managing Director (Annexure-III). A Recall Reference no. shall be given on this form as follows:

PR/XX/001
=>Where, ‘PR’ represents Product Recall.
=>‘XX’ represents the last two digits of the year 20XX
=>‘001’ represents for serial number

Recall Panel:

=>Managing Director (MD)
=>Head of Quality Assurance
=>Head of Production
=>Head of PMD
=>Head of Sales
=>Head of Distribution
=>Head of Quality Assurance shall furnish the batch details for recall notification in Annexure-IV. This shall be then forwarded to Head of PMD and Head of sales.

Recall notification shall include:

=>Products name including brand name, its strength and pack size and other details like,
=>Product License (D.A number) if applicable.
=>Batch or Lot number, Batch size, Mfg. date, Exp. date.
=>Nature of defect and reason.
=>Action to be taken (urgent within time frame/ immediate quarantining of stock /return stock) with labeling instruments & specific precautions.
=>Date of withdrawal.

[][]The Head of PMD through Distribution shall send a product recall circular, immediately upon receiving the product recall decision, to all concerned persons requesting them to return all stock of the batch under question to the depots and informing them that a credit note for the stocks returned shall be issued to them at the earliest.
[][]All product recall requests shall be given top priority unless otherwise indicated by recall coordinator.
[][]The Head of PMD along with Distribution shall immediately arrange to freeze all stocks of the batch lying with distributors, agents and customers. He shall also instruct the entire sales force to freeze further sales of batch at every distribution, sales point (stockiest, chemists, doctors, hospitals etc). This shall also include goods under transit.

[][]In case of recall as per directives of competent or Regulatory Authorities, the information shall be forwarded to them (To include Regulatory Authorities of other Countries to which the batch has been distributed). The decision of disposal of recalled batch shall be as per their directives and the destruction or disposal shall be done under notification and the Drugs Inspector’s supervision.
[][]Quality Assurance Department will record the receipt, origin & quantity of any recalled product received & holds the recalled product in a secure place to avoid mix up with other materials.
[][]The progress should be reviewed at regular, frequent intervals to monitor its effectiveness and ultimately to decide that the recall is completed.
[][]Completion will normally be reached when:
=>All the acknowledgement forms issued are returned.
=>The material listed in the acknowledgement forms has been returned.
=>There have been no further returns or further adverse reports concerning the product for a period of 2 weeks.
[][]After thorough investigation, Head of Quality Assurance will issue instructions for safe disposal of the recalled stock in due course and a disposal record will be maintained. An investigation into the root cause analysis of any product defect which led to a recall must be carried out and CAPAs to be prepared to prevent if happing again.
[][]Details of recalls shall be added to the batch dossier for all the batches concerned.
[][]Detailed records of all product returned as part of a recall must be kept.
[][]In case of recall when initiated by company (Voluntarily) this shall be informed to the Regulatory Authority.
[][]In case of voluntary recall, product when received back from market to our depots shall be identified and stored separately in a secured area while awaiting a decision on its disposal. The product shall be written off and destroyed as per the standard procedure.

Documentation:

[][]The decisions, activities and actions including progress of recall shall be documented and duly authorized.
[][]On completion of recall procedure, summary report shall be prepared which shall include the following (Annexure V).
[][]Reason for recall of a product (with Batch No. and other details about the product).
[][]Effectiveness of recall.
[][]Corrective action to prevent reason for recall.
[][]Appropriate training to concern as applicable.

[][]This summary report shall be prepared by Head of Quality Assurance and be circulated to all concerned departments (PD, Production, Accounts, Sales, PMD) and Managing Director.
[][]Distribution records should be readily made available to the person(s) responsible for recall and contain sufficient information of wholesalers, retailers, stockiest and customers/agents for prompt and effective it. (Examples: Addresses, Telephone numbers, inside or outside office working hours, batch number and its quantity with them for both domestic and exported products).

Recall Simulation:

[][]The recall procedure shall be regularly reviewed to ensure that it is up-to-date and shall be simulated ‘in house’ to ensure its effectiveness and familiarity to all key personnel.

[][]The required time limit for simulation exercise (from initiation of simulation to completion) will be not more than 15 days.

Annexure:

Annexure-I: Product Recall Flowchart
Annexure-II: Product Recall Log Book
Annexure-III: Product Recall Form
Annexure-IV: Recall Notification Form
Annexure-V: Summary Report of Recall

Recall Procedure Read More »

Floor Inspection by QA Inspector

Quality Assurance, Quality Management, SOPs

Floor Inspection, Purpose :

Floor Inspection, The purpose of this SOP is to describe the roles, responsibilities and activities of production and QC floor inspection and IPCs check by QA personnel and to ensure Assurance with cGMP requirements.

Floor Inspection, Scope :

This procedure is applicable for cGMP observations of production and QC floor at XX Pharmaceuticals Limited (Both General and Sterile Block).

Definitions / Abbreviation:

[][]IPC : In Process Check
[][]QA : Quality Assurance
[][]QC : Quality Control
[][]OOS : Out Of Specification
[][]DT : Disintegration Time

Responsibilities:

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

Quality Assurance Personnel

[][]Responsible for inspection of Production and QC floor to find out any cGMP observations.

Manager, Quality Assurance

[][]To ensure implementation of the procedure

Head of Quality Assurance

[][]Approval of SOP

Procedure:

[][]To assure Assurance with specification throughout a production process, Production Department will conduct the IPC checks following the In-process checks procedure.
[][]IPC inspectors of QA will verify the IPC data independently.
[][]The IPC specification will be mentioned in the relevant product specification and BMR & BPR.
[][]All OOS results will be investigated as per OOS results procedure.
[][]IPC inspector will verify the IPC data based on the frequency described in Annexure–I.
[][]During manufacturing of a batch, production personnel will check the IPC parameters.
[][]If a IPC data goes outside specification, production IPC checking personnel and QA IPC inspector will inform to production Executive for corrective measures.
[][]If QA IPC inspector observes that there is frequent failure of the IPC results then QA IPC inspector will notify the issue to Departmental Manager and Manager, Quality Assurance.

All IPCs will be performed by trained and certified QCOM and Production personnel. Inspection of

=>Adherence to Line clearance
=>Environmental conditions
=>Log books
=>General house keeping
=>Labelling status
=>Sampling
=>Reconciliation
=>Calibration status
=>Deviation
=>Pest controls
=>Cleaning & Contamination
=>Change Control
=>Document management
=>Adherence to maintenance schedule

Inspect GMP compliance in

=>Storage of Raw/Packaging materials/Finished packs
=>Manufacturing/packaging/cleaning operations
=>Dispensing of materials
=>Compliance with SOPs
=>Daily balance monitoring records
QA inspectors will visit the production floor daily. The inspection applies to all operations, specially The following:
=>If any unusual observation comes to the notice of area QA inspector, he will immediately communicate to the Departmental Executive. This report will be recorded in Daily IPC report format (Annexure-II).
=>This inspection report will be forwarded to Manager, Quality Assurance for further action.
=>QA inspectors will collect retention samples of finished packs from the running Secondary packaging line belts & record sampling date and quantity sampled in BPR with sign & date as per Sampling SOP.

In-Process Controls Check:

[][]QA Inspectors will independently conduct all In-process checks in addition to that done by production personnel as Procedure for In-Process Checks.
[][]QA inspectors will conduct the following IPC checks as per frequency described in Annexure–I and as a minimum at least once from every batch of product. This should be done at the start of every batch:

[][]Product: Tablets/Capsule

=>Manufacturing Stage: Encapsulation/ Compression/Coating
=>IPC Checks: Appearance, Average weight, Uniformity of weight, Hardness, Thickness, DT, RH & Temperature
=>Manufacturing Stage: Blister Packing
=>IPC Checks: Leak test, Overprinting, Cutting, RH, Temperature, Product name, Strength, Product code, Mfg & Expiry date, Price and Status label etc.

[][]Product: Powder for Suspension

=>Manufacturing Stage: Manufacturing, Filling & Packing
=>IPC Checks: Appearance, Uniformity of weight, Leak Test, RH, Temperature, Product code, Mfg & Expiry date, Overprinting, Price and Status label etc.

[][]Product: Sterile (Capsules/ Tablets)

=>Manufacturing Stage: Encapsulation/ Compression/Coating
=>IPC Checks: Appearance, Average weight, Uniformity of weight, Hardness, Thickness, DT, RH & Temperature.
=>Manufacturing Stage: Blister Packing
=>IPC Checks: Leak Test, Overprinting, Cutting, RH, Temperature, Product code, Mfg & Expiry date, Price and Status label etc.

[][]Product: Sterile (Powder for Suspension )

=>Manufacturing Stage: Manufacturing, Filling & Packing
=>IPC Checks: Appearance, Uniformity of weight, Leak Test, RH, Temperature, Product code, Mfg. & Expiry date, Overprinting, Price and Status Label etc.

[][]Product: Dialysis Fluid

=>Manufacturing Stage: Manufacturing, Filling & Packing
=>IPC Checks: A Appearance, pH, Weight, Induction Sealing, Cap Sealing, Leak Test, Temperature, Pressure

[][]QA inspectors will verify the IPC results as per specification.
[][]If any batch is completed before inspection of QA IPC inspector, then again QA IPC inspectors will verify the some critical parameters.
[][]In-process test failures must be brought to the attention of the Departmental Executive/ Manager & also Manager, Quality Assurance and appropriate action shall be taken and recorded.
[][]Any problem identified at production floor during printing or in-process checking during packaging, Problem observer immediately inform it, to his/her supervisor and if required Online Problem Notification Form (Annexure-III) to be raised by production through QA.
[][]Reference No. for Online Problem Notification will be as
PN-001/02/XX
Where-
=>PN represents Problem Notification
=>001 represents sequential number
=>02 represent Month of February
=>XX represents year of 20XX

[][]If any receiving quantity of packaging material requires replacement to run production smoothly, it shall be raised by production with Material Replacement Form (Annexure-IV) to warehouse through QA with justified reason for replacement.
[][]Reference No. for Material Replacement will be as
MR-001/02/XX
Where-
=>MR represents Material Replacement
=>001 represents sequential number
=>02 represent Month of February
=>XX represents year of 20XX
[][]The copy of raised Online Problem Notification Form should be sent to Manager, Supply Chain & Management with recommendation of Head of Quality Assurance if required.

QC Floor Inspection:

[][]QA IPC Inspector will also visit the Quality Control laboratory once daily for GLP in place and in use check.

Annexure:

Annexure-I: In-Process Checks
Annexure-II: Daily IPC Finding and Observation Report Sheet
Annexure-III: Online Problem Notification Form
Annexure-IV: Material Replacement Form

Floor Inspection by QA Inspector Read More »

Market Complaint Handling

Product Complaints, Product Defects, Quality Assurance, SOPs

Market Complaint , Purpose :

Market Complaint , To provide a system for timely response to a product complaint and to make relevant investigation and recommendation with proper documentation.

Market Complaint , Scope :

This procedure is applicable to all types of market complaints received from the market, related to quality, packing and shortage of the products manufactured at XX Pharmaceuticals Limited (Both General and Sterile Block).

Definitions / Abbreviation:

[][]Market Complaint: A written or verbal report originating from customer, retailers, physicians, field supervisor, regional sales coordinator, medical representative, hospitals, regulatory agency and our employees which relates to the inadequacy of the quality, i.e. non Assurance with standards or customer requirements and includes any packaging and labeling requirements, any query regarding specifications, analytical procedure, incomplete text and non conformance with customer requirements should be treated as complaint.
[][]Customer: The person or institution making the complaint.
[][]PMD: Product Management Department.

Responsibilities:

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

Executive/ Manager, PMD

[][]Send the complaints with appropriate details & samples to Manager, Quality Assurance.

Quality Assurance Manager/ designee

[][]Responsible for registering, carrying out the investigation and taking necessary corrective actions, providing necessary technical response to PMD in consultation with General Manager, Plant and Manager, Quality Assurance, generation of the complaint report and closure of the complaint.

Manager, Quality Control

[][]Responsible for carrying out the analysis of samples as per requirement.

Manager, Quality Assurance

[][]Approval of the SOP.
[][]To ensure that the implementation of the procedure as per SOP.

Procedure:

Classification of Complaints:

[][]Market complaints to be classified as minor, major and critical.
[][]Minor: Complaints related to physical appearance of packaging of the product.
[][]Major: Complaints related to physical appearance of the products (e.g. broken tablets, fading, spots etc), packaging quantity (e.g. empty blister, empty bottles, empty content etc), label missing, batch printing missing etc.
[][]Critical: Chemical property complaints related to any chemical test failure of a product, e.g. low purity, change in the impurity level and degradation and shall also include the complaints arising due to stability failure. In the event that a batch is considered to be actually or potentially harmful to user, thereby requiring a recall, following relevant SOP.

Raising of Product Complaint:

[][]Any market complaint received or to be raised by PMD / Sales team shall be filled up in the market complaint form (Annexure-III) along with complaint details (Attach original complaint document to this Annexure if applicable). If the details of the complain are not available in the document then the details of the chemist shop or recipient from where the complaint has been received will be recorded in the market complaint form.
[][]Customer complaints which are received by PMD or complaint raised by PMD will be forwarded to Manager, Quality Assurance with appropriate details in the market complaint form (Annexure- III).
[][]Head of Quality Assurance shall send the complaints along with complaint sample, if received, to Manager, Quality Assurance.
Manager, Quality Assurance shall arrange the investigation and generate a comprehensive report on the market complaints investigation form (Annexure–I).

Investigation of complaints:

[][]Manager, Quality Assurance shall record the complaint in a market compliant logbook (Annexure–II). This detail should include a complaint number, name of the product, batch No., Mfg. date, Expiry date, nature of the complaint, name & address of complainant and date of receipt at the investigating site.
[][]Quality Assurance shall assign a distinct control number to every complaint as follows:
MC/XX/001
Where,
MC – Market Complaint.
‘XX’ represents the last two digits of the year 20XX
‘001’ represents for serial number of the market compliant on continuous basis starting from
001 for the calendar year.
[][]If complaint sample is received along with the market complaint, the investigator shall record the quantity of sample received in the market complaint investigation form (Annexure–I).
[][]If no complaint sample is received along with the complaint, the investigator shall record the relevant details disclosed in the complaint form.
[][]Quality Assurance Manager shall carry out the detailed investigation of the market complaint under the supervision of Head of Quality Assurance to find out the root cause of the complaint and to generate corrective & preventive actions. In his/her absence, Head of Quality Assurance shall nominate any other person to carryout activities in this regard.
[][]Investigator shall carefully inspect and record the physical appearance of the sample, seal etc. and compare the details of the references available in documents of the same batch number. Chemical analysis shall be done on the sample at this point of time.
[][]The investigator in consultation with Head of Quality Assurance shall arrange to carry out chemical and / or microbiological analysis of the reference sample (along with the complaint sample, if available). The investigator must also scrutinize the analytical report of the product under reference.
[][]The investigator shall then discuss the results of the analysis with General Manager, Plant for the investigation at production end.
[][]General Manager, Plant along with the respective departmental manager shall investigate the complaint in details.
[][]The investigation should include scrutiny of batch production records for any manufacturing and/or packing problems encountered during the production of the batch.
[][]Any equipment breakdowns recorded during production of the batch and any material quality problems faced during manufacturing and packing of the batch also must be studied.
[][]In case of following nature of the market complaints, AGM, Quality Assurance in consultation with Managing Director may decide to recall the product / batch as per Recall procedure.
[][]Product mix up and label mix up
[][]Failure to meet regulatory specification (i.e. Assay, impurity)
[][]Adverse drug reaction due to product defect.
[][]Contamination due to foreign matter. (e.g. Glass pieces, metal pieces, black particles, particulate matter, microbial growth etc.)

[][]The closure of complaints along with redressal should be completed within 1(one) month period after the receipt of the complaints. Any delays shall be justified.

Product Complaint Redressal:

[][]Head of Strategic Marketing and Communication after consultation with Managing Director shall appraise the customer on the corrective actions taken and on the redressal actions, wherever necessary and a copy of such shall be forwarded to Head of Quality Assurance for his/her reference.
[][]Management Reviews of Complaints:
[][]The product complaint report, the trends, effectiveness of the corrective actions etc. shall be summarized and reviewed in management review meeting.

Annexure:

Annexure-I: Market Complaint Investigation Form
Annexure-II: Market Complaint Log Book
Annexure-III: Market Complaint Form
Annexure-IV: Flow Diagram For Handling of Market Complaints

Market Complaint Handling Read More »