The GMPs necessitate annual evaluation of quality standards of a drug product to determine the need for adjustments in drug product specifications, manufacturing and control procedures. Subpart J of 21 CFR 211.180 mandates establishing a written procedure for the Annual Product Review process, while, and recommends review of a representative 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, FDA’s mandate is to look thoroughly and systematically for areas of improvement and to align processes to consistently manufacture quality products.
For these same general reasons, Canadian GMP’s were updated in 2009 to include an explicit section for Annual Product Quality Review (C.02.011). Health Canada’s regulations 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. CAPA’s from annual product 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 variations submitted/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
Structure of an APR Report
The structure of a review report can vary based on different products and a firm’s specific documentation requirements. Yet, manufacturers should follow a standard template 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 data relevant to the product (e.g., retain sample review). Each numbered sub-section (batch document review, change review, deviation review, etc.) is typically followed by a summary. 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.
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
|Figure 2. Common Tables and Charts|
|• 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 Results—Encapsulation
• 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 sku’s covered. Information from the batch processing and packaging records can follow. This includes review of in-process, process SPC charts, yields, analytical results, and so on, as applicable.
Changes and Corrections
Change review can be broken down to raw material changes, packaging component changes, master document changes and specification changes. The non-conformances/deviations section needs to review non-conformances but also corrective actions and their effectiveness. Any ineffective or overdue CAPA needs to be discussed 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 of specification or borderline. Figures 3, 4, and 5 are representative charts.