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Annual Product Reviews: How to Conduct an Effective

Annual Product Quality Review
More 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.

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, FDAs 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 GMPs were updated in 2009 to include an explicit
section for Annual Product Quality Review (C.02.011). Health Canadas 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.
CAPAs 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
FDA

Health Canada

EU

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Review of starting materials

Management

including packaging

review/notification

materials

Review of returned or

Nonprescription Category

Review of Marketing

salvaged drug products

IV drugs not exempted

Authorization variations

Review of regulatory GMP

Assessment of whether

observations

revalidation should be
undertake

Structure of an APR Report

The structure of a review report can vary based on different products and a firms 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.
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

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18. Approval
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 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. 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.

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Streamlining Data Sources and APR Administration

Streamlining the entire process requires an APR schedule, based upon key regulatory submission
dates. (For contract manufactured products, its critical to prioritize and negotiate feasible
reporting dates.) Compiling APR raw data is always a team effort, but the Compliance/QA

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department should take the lead and be ultimately responsible 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 effective CAPAs.
Another challenge for the APR administrator is data retrieval for review purposes. Firms with
qualified data acquisition systems can use their database, whereas paper-based manufacturers
may have to review individual batch documents for processing parameters, in-process testing,
finished testing, yields, and so on. In either case, the raw data used for analyses must be accurate
in order to complete an effective assessment. If process drifts are observed during review,
additional information may 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 spreadsheets are used, they must be
qualified in advance.
Footnote
Performing an APR is a requirement for the regulated market. But more than this, the review helps
the manufacturer to understand processes better and to gather additional information for further
improvements. It greatly helps in determining if a product still meets the needs of patients, if it
needs a formulation change, packaging modification, a revised specification, or a more robust
process. An APR conclusion is stepping stone towards the future development of the product and
hence should be accurate 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 process verification) 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 a product in the future.
References
1. 21 CFR PART 211, Subpart J, Sec. 211.180.
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=211.180
2. Health Canada Good Manufacturing Practices (GMP) Guidelines
- 2009 Edition (GUI-0001): Section C.02.011
http://www.hc-sc.gc.ca/dhp-mps/compli-conform/gmp-bpf/docs/gui-0001-eng.php
3. EU Guidelines to Good Manufacturing Practice: Chapter 1. Quality Management:
http://ec.europa.eu/health/documents/eudralex/vol-4/index_en.htm
4. FDA Process Validation: General Principles and Practices

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http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation
/Guidances/UCM070336.pdf
5. ICH Q9:
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q9/Step4
/Q9_Guideline.pdf
6. ICH Q10:
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q10/Step4
/Q10_Guideline.pdf

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