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Janki Singh

APQR – Annual Product Quality Review in Pharma

Standard Operating Procedure for Annual Product Quality Review (APQR), also known as Product Quality Review (PQR) and Annual Product Review (APR) preparation.

Procedure for Annual Product Quality Review (APQR)

1.0   Objective:

    • To lay down the procedure for carrying out the Annual Product Quality Review (APQR).
    • The purpose of this SOP is to describe the procedure for Product Quality Review (APQR) to verify the consistency of the existing process, the appropriateness of current specification for both starting materials and finished product, and to identify the product and process improvements.

2.0   Scope :

    • This SOP is applicable for the Annual Product Quality data collection and Review (APQR).

3.0   Responsibility :

    • Officer QA / nominee:            
    • Preparation of report for annual product quality review (APQR).
    • Collection and compiling the data for continuous monitoring.
    • To prepare the interim Product Quality Review (APQR) report.

    • Head QA:

    • Approval of the Product Quality Review (APQR) report
    • Suggest CAPA / recommendation in Product Quality Review (APQR)
    • Ensure continuous monitoring of data.

    • Head Production:

    • Organize production-related data for compilation.
    • Review Product Quality Review (APQR) for production-related data and information.

    • Head QC:

    • To provide QC related data for compilation in Product Quality Review (APQR).
    • To review Product Quality Review (APQR) for QC related data and information.

    • Head Engineering:

    • To review Product Quality Review (APQR) for engineering related data and breakdown work.
    • To address findings related to machine breakdown and equipment functions in a timely and effective manner.

4.0   Procedure for Preparation and Review of Product Quality Report (APQR):

    • Product quality review (APQR) shall be carried out for each product manufactured in the year.
    • Products manufactured in the previous twelve (12) months shall be taken for Product Quality Review (APQR) on a staggered basis covering all the batches manufactured.
    • All products can be divided into three groups i.e. Group A (Tablets) – January to December, Group B (Oral Liquids) – April to March, and Group C (Capsules) – June to May and list them as per Annexure-I.
    • Priority in scheduling can be given on a risk-based approach (i.e. Market complaint, Product Recall, Stability, or any other product issue) if required.
    • Product quality review (APQR) shall be completed within 90 days; for example Product Quality Review (APQR) for products manufactured during the period of January – December 2018 shall be completed by March 2019.
    • The Product Quality Review (APQR) calendar shall be prepared by the quality assurance officer and approved by the Head QA before execution.
    • Product Quality Review (APQR) shall be prepared product-wise and shall include all batch size different API vendor, different code in single Product Quality Review (APQR),
    • If the same product is transferred/converted to other similar products, Product Quality Review (APQR) shall be prepared as one and all market details like pack style, Finish Pharmaceutical product testing (any additionally) shall be captured.

    • Different strength/Batch Size of a drug product :

    • The different strength of a drug product which contains the same source of material, same manufacturing process, and identical equipment can be clubbed/grouped together in a single Product Quality Review (APQR) provided having the same qualitative and quantitative composition (dose-weight proportion formula) and same specification parameter.
    • If a product has different batch size/different equipment then separate tabulation and trending of process parameter shall be done and the same shall be reviewed as a part of the same product Product Quality Review (APQR).
    • Grouping of products if any shall scientifically justified and each batch data shall be reviewed as per details mention in data review.

    • Example of grouping as follows but not limited to:

Appropriate Grouping Inappropriate Grouping
  • Different strength of drug having the same source of material and having the same qualitative and quantitative composition
  • The same formulation having a different pack size or brand name.
  • Same product manufactured in the different areas having the same.
  • The product having the same API but having a different Excipient,
  • Different strength with different process parameters and quality attributes
    • For common granule/Blend (mother) batch of all lots from which multiple strengths batches are compressed filled if required individual strength-wise Product Quality Review (APQR) can be prepared and reference of Common blend/Batch PQR can be given in each strength.
    • Product Quality Review (APQR) shall be prepared as per defined schedule for each product at least once in a year,

    • In case no batch is manufactured during the review period then Product Quality Review (APQR) shall be prepared with a review of all available documentary data like-

      • Complaint review,
      • Stability data,
      • Observation of control/retain sample,
      • Variation approval,
      • Product recall, etc.
    • All data shall be compiled in a Microsoft Excel spreadsheet if required and the same shall be cross-checked by alternate QA personnel.
    • For the trending and statistical analysis like (Cpk calculation, Control charts, etc.) at least 10 batches shall be considered.
    • If there were no batches in the previous year then statistical analysis calculation shall be done only after available of at least 10 batches data, if required.
    • If the number of batches is less (less than three) within the review period Product Quality Review (APQR) can be compiled for two years with both year data with proper justification, if required.
    • The product quality review report shall be provided to Marketing Authorization within 3 months from the end of the last review period.

    • Numbering System of Product Quality Review Report (APQR):

    • Product Quality Review (APQR) number shall be assigned to the product listed in Annexure-I.
    • APQR shall be numbered as APR/Y/ZZ/XXX where:
    • ‘APQR’ denotes “Annual Product Quality Review”.
    • ‘Y’ stands for dosage form code i.e. ‘T’ for tablets, ‘C’ for capsules, and ‘L’ for oral liquids.
    • ‘ZZ’ are numerical denotes the calendar year, for example, 20 for 2020 and so on.
    • ‘XXX’ are numerical denotes the serial number starts from 001

    • The review shall include the following aspects:

    • Product information shall contain the details as mention in Annexure-II. (but not limited to)
      • Generic name,
      • Shelf life,
      • Product code,
      • MFR,
      • Specification,
      • Testing procedure numbers,
    • The data shall be collected and recorded appropriately the data shall include the following parameters with the provided example but not limited to:
Sr. No. Parameters Examples of data to be reviewed/referred 
01.

Starting materials:

A review of starting materials including packaging materials used in the product, especially those from new sources.
  • Identify all starting and primary packaging materials received in the year and used in product manufacture from approved sources.
  • Name of the suppliers/manufacturers of the materials, address detail of broker/distributor/agent & Review the detail like change in route and mode of transport and transit condition.
  • Vendor’s Certificate of Analysis (CoA)
  • Trending of critical material attributed (in case of API) and significant deviations, if any.
  • Details of rejections of Materials
  • Changes to the production process or specifications by the vendor, if any
02.

In-­process controls and quality control testing:

A review of critical in-­process controls and finished product results.
  • Review  in-process test results and QC test results in the manufacturing and packaging process from both chemistry and microbiology aspects:
  • Trending may take into consideration as applicable :
    • Physical variations – e.g. weight/dimension, friability, hardness, disintegration time, fill volume/overage, uniformity of content
    • Chemical variations – e.g. assay, related substances, pH, residual solvents, Yield reconciliation.
03.

Manufactured batches

(intermediates, bulk, finished, products):
  • Details of all batches manufactured in the review period, details of converted batches. Details of different pack styles rejected batches if any
04.

Deviations and CAPA:

A review of all significant deviations
  • List the following relating to significant deviations and non­conformances:
  • Completed investigations, root cause, and CAPA is taken and effectiveness of previous CAPA if any
05.

Process or testing changes:

A review of all changes carried out to the processes, or analytical Methods and others related to the product
  • Summary of the changes, if any, made to the process e.g. change of mixing time, blending time, drying time, changes in the coating process, changes in compression speed /time, changes in filling speed, etc.
  • Changes Summary made to the analytical methods, e.g. change of solvents, buffers, reagents, pH, change in the composition of the mobile phase, change in HPLC method parameters i.e. flow rate, temperature, wavelength, run time, and change of HPLC column, etc.
  • Summary of the changes made to equipment like change in manufacturing equipment in the process, change in any major change part, etc.
  • Summary of the changes made to facilities like change in manufacturing cubicle, manufacturing area, and change in air supply, etc.
06.

Stability program:

A review of the results of the stability monitoring program and any adverse trends.
  • List the number of batches of product in the review included instability studies during the review period
  • Review the results Accelerated, long term and on­going stability of the marketed product
  • Include product information such as manufacturing date, reference to the associated method, shelf life, etc.
  • Review any out ­of ­specification (OOS) results
  • The summary sheet of the updated stability study including all batches that are still in date shall be attached with the PQR report.
07.

Returned product:

A review of all returns and the investigations performed at the time.
  • Batch number(s)
  • Reason for return and classification of reason Associated investigation actions are taken and batches affected, if any
08.

Complaints and/or adverse events:

A review of all quality ­related complaints

 
  • Batch number(s)
  • Reason for complaint and classification for trending
  • The associated investigation, root cause, affected batches, and current status
09.

Recalls:

A review of all recalls and the investigations

 
  • Batches recalled
  • Reason for recall and classification, Regulator(s) notified and required regional responses
  • Associated investigation and CAPA and Current status
10. Review of past PQR responses
  • Review the recommendation, if any of the previous PQR CAPAs and change implementation status.
11. Post­marketing commitments & new Marketing Authorizations and variations (if any).
  • Country of commitment, Product Name, and presentation, Description of the commitment, Status of the commitment.
  • A review of marketing authorization variation submitted/granted/refused, including those for third parties (export).
12.

Equipment qualification:

The qualification status of relevant equipment and utilities, e.g. HVAC, water, compressed gases, etc.
  • List and review for critical equipment/instruments and utilities used in the manufacturing of products associated with the product in review:
  • Qualification/re­qualification status and the next qualification due date of equipment used in the production processes
  • Reference to relevant qualification reports
13.

Contractual agreements:

A review of any contractual arrangements to ensure that they are up to date.
  • Review contracts for services associated with the product (if any)  in review and report:
  • Name and address of the contract acceptor availability and details of the written contract type of service provided e.g. testing or maintenance and calibration services confirmation that the services provided are aligned with the marketing authorization
14.

Review of validation:

Process, cleaning Analytical, hold time, etc.
  • Process Validation summary, cleaning Validation summary, analytical method validation summary shall be reviewed in the year to evaluate the changes regarding the change/modification in process validation status and parameter (if applicable),
  • Cleaning validation status, and analytical method validation status. If there will be any change in the validation status and implementation there cross-reference (Report No.) shall be mentioned in the product quality review.
15.

Risk assessment:

Product-related risk
  • Summary of Quality risk management carried out on the product; facility system, etc. this year shall be included in the review to evaluate the implementation status of recommended corrective and preventive action (if applicable to concerned product).
16. Control/ retain sample periodic review
  • Review of ongoing periodic observation report of control samples for its physical defects during annual product quality (which might lead to product recall) shall be included in the review.
17. OOS/OOT/Incident
  • All products related to OOS/OOT shall be reviewed with respect to the investigation, Root cause, affected batches/products, and CAPA.
  • Review of all batches that failed to meet established specification (OOS) and their investigation.
  • Product-related incidents review a quality impact.

    • Review of Data for Annual Product Quality Review (APQR):

    • A review of trend data for microbiological and chemical testing of purified water and findings shall be addressed.
    • Review of trend data for environmental monitoring and findings shall be addressed.
    • A review of the adequacy of any other previous product process or equipment corrective action.
    • For new marketing authorization and variation of marketing authorization, a review of post-marketing commitments.
    • The export department shall provide a summary of regulatory changes or requirements for the review period that affected the product.
    • All the regulatory updates shall be reviewed for the product manufactured in the year.

    • The critical manufacturing process parameters in tablets like-

      • Granulation time,
      • Ampere load,
      • Drying, LOD,
      • Lubrication details and stage-wise yield shall be reviewed and recorded in the Product Quality Review (APQR).
    • The critical manufacturing process parameters in Capsule like mixing time of the materials, Machine speed, etc. shall be reviewed and recorded in Product Quality Review (APQR).
    • The critical manufacturing process parameters in Oral liquid, pH shall be reviewed and recorded in Product Quality Review (APQR).

    • Review of critical in-process controls and finished product results

    • A review of critical in-process controls and finished product results shall be compiled product-wise and batch-wise.
    • Any out of trend (OOT) results obtained also shall be discussed in the report.
    • In the case of tablet parameters such as average weight, content uniformity, thickness, hardness, disintegration, dissolution, LOD/water, assay, yield, related substances microbial analysis trend (if applicable) shall be reviewed.
    • If the capsules parameters such as average fill weight, disintegration, dissolution, LOD/water, assay, yield, related substances, and microbial analysis trend (if applicable) shall be reviewed.
    • In the case of Oral liquid parameters such as fill volume, pH, weight per ml, assay, yield, related substances, and microbial analysis trend (if applicable) shall be reviewed.
    • Data for trending and review shall be collected from relevant documents like BMR/BPR, COA and logbooks.
    • Production, QC, Engineering shall provide relevant data to QA for Product Quality Review (APQR) preparation.
    • Officer QA / nominee shall collect and compile the data/information required and prepare the Product Quality Review (APQR) as per the template given in Annexure-II.
    • Statistical tools like-
      • Calculation of minimum-maximum value,
      • Average,
      • Standard Deviation,
      • Upper and lower control limit,
      • Process capability indices and preparation of trend charts can be used for the evaluation of the product.

    • Process capability:

    • A process capability study is used to determine whether a process is stable and capable.
    • Process capability indices are used to measure how well the data fits into the specification limits and state of control of the respective process.
    • The process capability index shall be calculated for the critical quality attributes as per release specification, as applicable.
    • Methodology for Process capability evaluation and upper and lower control limit :

    • The formula for UCL and LCL

    • UCL: Average+3SD
    • LCL: Average-3SD

    • The formula for two-sided specification:

    • Cp = (Allowable Range) / 6 X SD i.e. (UQL-LQL) / 6 X SD

    • Formula for one-sided specification:

    • CpK (min), Lower = Estimated Mean – LQL / 3 X SD
    • CpK (max), Upper = Estimated Mean – UQL / 3 X SD
    • Where,
    • Cp: evaluate variation of the process
    • Cpk: evaluate the centering of the process (minimum of CpK (min) and CpK (max))
    • SD: Denotes standard deviation.
    • UQL: Denotes Upper Quality level
    • LQL: Denotes Lower Quality level

    • Acceptance criteria for Cpk:

    • Cpk < 1.0, then process is not capable.
    • Cpk = 1.0-1.33, Process is barely capable.
    • Cpk ≥ 1.33 Process is capable.
    • In the case of Cpk < 1, check the probability or investigate the causal factor.
    • Parameters that can alter the quality of the product or have a direct impact on other parameters, if required recommend changing the limit by means of revalidation of product.
    • Whenever required each set of data of the product can also be presented in the form of statistical /graphical presentation in a fashion to easily exhibit results, deviations, and trends.
    • Product quality review shall be clubbed/grouped for a similar product (formulation, scientifically justified, primary packing same, and brand name or market is different.
    • If any abnormal trend of data observed during the compilation and review, it shall be commented on in the report, if required the investigation shall be done as per action plan Annexure-III.
    • Each section listed above shall be summarized and section-wise recommendation (if any) shall be given by Head QA / designee.

    • On the basis of summary & recommendation, a conclusion shall be drawn.

    • The Product Quality Review (APQR) report shall be sent to the below-mentioned personnel for review and comments.
      • Head – Production
      • QC – Head
      • Head – Engineering
      • Head – QA
    • Finally, the Product Quality Review (APQR) shall be reviewed and approved by Head QA.

    • Regulatory changes in the Pharmacopoeia /drug act:

    • Summary of any changes in Pharmacopoeial changes or any change in drug act shall be included in the review.
    • The completed Product Quality Review (APQR) report for the contract manufacturing products shall be reviewed with respect to the terms of the technical agreement between the contract giver and contract acceptor.
    • If the product quality review leads to the revalidation of the product/process the same shall be considered for revalidation with prior approval of Head-QA or /and MAH / Customer (if applicable).
    • Product Quality Review (APQR) shall be submitted to the contract giver and the contract giver’s name shall be recorded in relevant Product Quality Review (APQR) wherever applicable.
    • The comments and or queries of contract giver and other reviewers, if any shall be addressed and the same shall be enclosed with the Product Quality Review (APQR) report.
    • Head QA shall review all the comments/recommendations from the reviewers and the decision to implement or not to implement shall be given.
    • For those recommendations which are approved by Head QA, actions shall be implemented initiated within 30 working days of approval of Product Quality Review (APQR).

    • Continuous monitoring of data:

    • Officer QA / nominee shall collect and compile the data for products manufactured in routine for continuous monitoring.
    • Officer QA / nominee shall inform Head QA if he finds any discrepancy in results or significant trends in results while entering the data. Head QA shall evaluate the data and takes appropriate action.
    • The investigation shall be done if required based on the above online trend conclusion.
    • Continuous monitoring and compiled data and graphs shall be used for the preparation of the Product Quality Review (APQR) report.
    • Product Quality Review (APQR) shall be an integral part of the product life cycle as continuous process verification through a statistical evaluation of different Critical Quality Attributes (as applicable).
    • If there was any OOT observed investigation shall be performed and accordingly action plan shall be initiated. Annexure-III shall be filled for this OOT.

5.0   Reference (S) – Annual Product Quality Review (APQR) :

    • Volume 4:   EU Guidelines to Good Manufacturing Practice Medicinal Products for
      Human and Veterinary Use, Chapter 1 Pharmaceutical Quality System.
    • Revised Schedule M, Guidance for Industry
    • ICH Q7

6.0   Glossary:

SOP : Standard Operating Procedure
QA : Quality Assurance
BMR : Batch Manufacturing Record
BPR : Batch Packaging Record
OOS : Out of Specification
APQR : Annual Product Quality Review
PQR : Product Quality Review
LOD : Loss on Drying
OOS : Out of Specification
OOT : Out of trend
HVAC : Heating, ventilation and air conditioning
COA : Certificate of Analysis
RSD : Relative Standard Deviation
MAH : Marketing Authorization Holder
FPP : Finish Pharmaceutical Product

7.0   Annexure (S) – Annual Product Quality Review (APQR) :

Annexure I: Format for “Annual Product Quality Review Calendar (APQR)”.

Sr. No.

 Product Name PQR Number Total Batches Manufactured Target Date of Completion Status Updated By

Remarks
Group A (Tablets) – January to December
1
Group B (Oral Liquids) – April to March
1
Group C (Capsules) – June to May
1

Annexure-II: Format for “Annual Product Quality Review (APQR)”.

S. No. Title Page No.
1. Report Approval Sheet
2. Objective
3. Scope
4. Responsibility
5. Product Information
6. Review of supply chain integrity of API / Primary packing material.
7. Review of Starting Material
7.1. Source of packing Materials and its Specification Number
8. Review of Packaging Material
8.1 Source of packing Materials and its Specification Number are given below:
9. Review of Raw Material Rejections, Batch rejections, and their investigations
10. Review of Packing Material Rejections, rejections, and their investigations:
11. Review of critical manufacturing process parameters
12. Review of critical In-process controls:
13. Review of Finished Products:
14. Review of all batches that failed to  meet established specification
15. Review of OOS/OOT Quality impacting Incident
16. Review of Significant Deviations or Non-Conformance
17. Review of changes product-related  in-process specification or Analytical Methods
18. Review of the Stability Monitoring program
19. Review of Microbiological and chemical testing of purified water & Review of Environmental monitoring data
20. Review of Validation batches data
21. Review of Quality-Related Complaint / Recall / Any Investigation Conducted
21.1 Market Complaints
21.2 Batch Recalls
21.3 Returned/Salvaged Goods
22. Review of adequacy of any other previous product, process, and equipment corrective actions
23. Review of Marketing Authorization Variation
24. Review of New Marketing Authorization variations
25. Review of Qualification Status of relevant Equipment / Utility
26. Review of Technical Agreements
27. Control Sample
28. Review of Corrective action and preventive action
29. Review of regulatory updates
30. Review of Commitments described in previous PQR
31. Summary
32. Conclusion
33. Recommendations
34. Abbreviations

Click here for Format …..Annual Product Quality Review (APQR) – Format

Annexure III: Review of the Action plan for APQR Report”

Review of the Action plan for APQR Report
Product Name
Product Code PQR No.
Recommendation/observation
CAPA (if Any)
Action Plan
TCD
Head/Designee (Initiator) QA-Head/Designee
Review of Action Plan
Closed on Closed By:(QA)

 

Categories: Checklist Maintenance Microbiology Production Quality Quality Assurance Quality Control SOP's Stores
Tags: Acceptance criteria for CpkCpCpK (min)critical manufacturing process parametersformula for two-sided specificationformula for UCL and LCLProcess capabilityProduct Quality ReportRegulatory changes in APQR
Janki Singh: Mrs. Janki Singh is the professional pharmaceuticals Blogger. She has already posted more than #1000 articles on varrious topics at different blogging plateforms. Contact : guideline.sop@gmail.com

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