The GMPs necessitate annual evaluation of quality standards of a drug product to determine the need for adjustments in drug product specifications, manufacturing andcontrol procedures. Subpart J of 21 CFR 211.180 mandates establishing a written procedure for the Annual Product Review process, while, and recommends review of arepresentative number of approved as well as rejected batches.

The guidelines stress the importance of analyzing investigations/deviations conducted and product complaints received, while the APR report must explore, in-depth,causes of recalls and returns, if any. Overall, FDAs mandate is to look thoroughly and systematically for areas of improvement and to align processes to consistentlymanufacture quality products.

For these same general reasons, Canadian GMPs were updated in 2009 to include an explicit section for Annual Product Quality Review (C.02.011). Health Canadasregulations require manufacturers to analyze previous reviews, examine finished product testing results and critical in-process controls, and review: failed batches,deviations, CAPA effectiveness, changes, stability studies, returns, complaints, recalls, critical equipment qualifications, and quality agreements. CAPAs from annualproduct reviews need to be communicated to senior management and completed in a timely and effective manner, with effectiveness verified via self-inspections.

And in the EU, Product Quality Review requires a review of starting materials including packaging materials used, a review of marketing authorization variationssubmitted/granted/refused, and a review of post-marketing commitments. The Qualified Person is responsible for the accuracy and timely completion of the review.Finally, the PIC/S GMP guide is in line with the above requirements.

Despite the similarity of these expectations, there are a few unique expectations, as shown in Table 1.

Table 1. APR Requirements Unique to Regulatory Authorities

FDA Health Canada EU

Management review/notification

Review of returned or salvaged drug products

Review of regulatory GMP observations

Nonprescription Category IV drugs not exempted

Review of starting materials including packaging materials

Review of Marketing Authorization variations

Assessment of whether revalidation should be undertake

Structure of an APR ReportThe structure of a review report can vary based on different products and a firms specific documentation requirements. Yet, manufacturers should follow a standardtemplate to ensure that all required aspects are evaluated.

But an APR is also an evolving document. It can be of few sections with minimal requirements to an elaborate document with addenda containing information or datarelevant to the product (e.g., retain sample review). Each numbered sub-section (batch document review, change review, deviation review, etc.) is typically followed by asummary. A graphical or tabular representation will help in dissecting data and detecting adverse trends wherever applicable.

A sample list of contents is contained in Figure 1, while Figure 2 shows a typical list of data tables.

Figure 1

1. Scope

2. Manufactured Batches, Batch Record, Yield Review

3. Change Control Review

4. Label and Artwork Change Review

5. Analytical Data Review

6. Stability Data Review

7. Validation and Qualification Review

8. Non-Conformances and LI Review

9. Rejected Batches Review

10. Re-Packaged Batches Review

11. Compliant Review

12. Field Alert and Recall Review

13. Retain Sample Review

14. GMP Agreement

15. Review of Previous APR

16. Conclusions and Recommendations

17. References

18. Approval

Figure 2. Common Tables and Charts

Annual Product Reviews: How to Conduct an Effective Annual Product Quality ReviewMore than just a regulatory requirement, an APR helps the manufacturer to understand processes and make further improvements.

BY AJAY PAZHAYATTIL, DIRECTOR, QUALITY AND REGULATORY AFFAIRS, JARVIS STREET PHARMA INC.

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Summary of Lot Enumeration for Bulk Batches

Summary of Lot Enumeration for Finished Product

Summary of Batch Yield

Summary of Analytical Results

Summary of In-Process ResultsEncapsulation

Reserve Sample Annual Inspection

Summary of Changes

Description of Deviations and Non-Conformances

Batches introduced to the Stability Program During Review Period

On-going Stability Batches introduced Prior to Review Period

The scope of the review needs to explain the purpose and the product skus covered. Information from the batch processing and packaging records can follow. Thisincludes review of in-process, process SPC charts, yields, analytical results, and so on, as applicable.

Changes and CorrectionsChange review can be broken down to raw material changes, packaging component changes, master document changes and specification changes. Thenon-conformances/deviations section needs to review non-conformances but also corrective actions and their effectiveness. Any ineffective or overdue CAPA needs to bediscussed in the summary.

The crux of the APR document is the Conclusions and Corrective Actions/Recommendations section. This section should include summaries of each of the prior sections,and the appropriate corrective/preventive measures necessary for each observation made. Any trend observed needs to be addressed, not just those that are out ofspecification or borderline. Figures 3, 4, and 5 are representative charts.

Streamlining Data Sources and APR AdministrationStreamlining the entire process requires an APR schedule, based upon key regulatory submission dates. (For contract manufactured products, its critical to prioritize andnegotiate feasible reporting dates.) Compiling APR raw data is always a team effort, but the Compliance/QA department should take the lead and be ultimatelyresponsible for the program and its administration. An APR committee would typically include a representative from QA, QC, Validation, Operations, Stability,Engineering, and Materials Management. A draft report is completed upon critical analysis of the raw data, then discussed in APR committee meetings to determine

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effective CAPAs.

Another challenge for the APR administrator is data retrieval for review purposes. Firms with qualified data acquisition systems can use their database, whereaspaper-based manufacturers may have to review individual batch documents for processing parameters, in-process testing, finished testing, yields, and so on. In eithercase, the raw data used for analyses must be accurate in order to complete an effective assessment. If process drifts are observed during review, additional informationmay need to be collected to substantiate the findings.Data must be available to the APR administrator for his/her in a timely fashion. They all must then be verified by a second person if performed manually. If spreadsheetsare used, they must be qualified in advance.

FootnotePerforming an APR is a requirement for the regulated market. But more than this, the review helps the manufacturer to understand processes better and to gatheradditional information for further improvements. It greatly helps in determining if a product still meets the needs of patients, if it needs a formulation change, packagingmodification, a revised specification, or a more robust process. An APR conclusion is stepping stone towards the future development of the product and hence should beaccurate and backed by adequate data.

FDAs Process Validation guidelines call for continued process verification. Thus, an APR program can serve as an ongoing system (Stage 3: continued processverification) to collect and analyze product and process data that relate to product quality. The APR needs to be part of the risk management/mitigation plan developed,per ICH Q9 recommendations.

The information gathered and trends spotted can aid new product development as well, and so it is essential to distribute the report to all relevant and interested parties.The effort can also be reviewed and shared with Lean process improvement teams, while the CAPAs developed out of an APR are critical in avoiding potential risks to aproduct in the future.

References1. 21 CFR PART 211, Subpart J, Sec. 211.180.http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=211.1802. Health Canada Good Manufacturing Practices (GMP) Guidelines- 2009 Edition (GUI-0001): Section C.02.011http://www.hc-sc.gc.ca/dhp-mps/compli-conform/gmp-bpf/docs/gui-0001-eng.php3. EU Guidelines to Good Manufacturing Practice: Chapter 1. Quality Management:http://ec.europa.eu/health/documents/eudralex/vol-4/index_en.htm4. FDA Process Validation: General Principles and Practiceshttp://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070336.pdf5. ICH Q9:http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q9/Step4/Q9_Guideline.pdf6. ICH Q10:http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q10/Step4/Q10_Guideline.pdf

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