• Purpose of the APQR
• Purpose of the APR
• Regulatory expectations

Annual Product Quality Review vs. Annual Product Review

• US FDA 21 CFR 211, 21 CFR314
• ICH Annual Review Content
• Product Quality Review (EU GMP Guide)
• Annual Product Quality Review, AQPR (Canadian GMP)

• US requirements
• Canadian requirements
• EU requirements
• Techniques for preparation
• Investigations
• Responsibilities

Contents of an Annual Product Quality Review

• Critical in-process controls, finished product testing results and specifications.
• Review of all batches that failed to meet established specification(s) and their investigation.
• All significant deviations or non-conformances,
• All changes carried out to the processes, analytical methods, raw materials, packaging materials, or critical suppliers.
• The results of the continuing stability program and any adverse trends.
• All quality-related returns, complaints and recalls and the investigations performed at the time.
• The adequacy of any other previous product process or equipment corrective actions.
• The qualification status of relevant equipment and systems (e.g., HVAC, water, compressed gases, etc.).

Annual reports are required for NDA or ANDA within 60 days of the anniversary date of U.S. approval of the application. The report is expected to contain a brief summary of significant new information during the year, distribution data, labeling and related changes, CMC changes not requiring a supplemental application under 314.70(b) and (c), nonclinical laboratory studies of new toxicological findings, and clinical data including published clinical trials, summaries of completed unpublished clinical trials, analysis of available safety and efficacy data in the pediatric population, and status reports of postmarketing study commitments, status of other postmarketing studies, and a log of outstanding regulatory business. Although annual reports are not mandatory for licensed biological products, the regulations require annual reports for products marketed under a BLA for (i) certain changes made to the application (21 CFR 601.12(d)) summaries on submissions related to pediatric studies (21 CFR 601.28), status reports on postmarket study requirements and commitments related to clinical safety, clinical efficacy, clinical pharmacology, or nonclinical toxicology (21 CFR 601.70).

There have been some new reporting requirements under FDAAA. Section 505(o)(3)(E)(ii) of the FDCA requires an applicant to report periodically on the status of any study or clinical trial required under this section. This section also requires an applicant to periodically report to FDA on the status of any study or clinical trial otherwise undertaken to investigate a safety issue. FDA will consider the submission of an annual report under section 506B and 21 CFR 314.81(b)(2)(vii) to satisfy the periodic reporting requirement under section 505(o)(3)(E)(ii) provided that the report includes the elements listed in section 505(o) and 21 CFR 314.81(b)(2)(vii). To comply with section 505(o), an annual report must also include a report on the status of any study or clinical trial otherwise undertaken to investigate a safety issue. Failure to submit an annual report for studies or clinical trials required under section 505(o) on the date required will be considered a violation of FDCA section 505(o)(3)(E)(ii) and could result in enforcement action. Separate annual reports are not required for supplemental applications. An annual status report can address more than one commitment for a particular NDA, BLA, or ANDA.

CMC changes not requiring a supplemental application under 314.70(b) and (c) are to be filed under annual reports which are to be submitted within 60 days from the anniversary date of approval of an application. Typically, the CMC section of the annual report contains a description of test method changes, specification changes, excipient changes, manufacturing batch record changes, and packaging batch record changes permissible under annual report changes and stability updates. Lately, FDA has encouraged the submission of comparability protocols (CPs) along with the original NDA for foreseeable CMC changes. CPs are then reviewed as part of the NDA approval process and if accepted, they can be executed during postapproval phases and corresponding changes may be implemented with lesser filing requirement such as annual reporting. However, the filing strategy should be worked out with the FDA.

The detailed content and format of a standard CTD submission of Annual Report will be presented and discussed.

Developing Standard Operating Procedures (SOPs)

What should be included

APQR Preparation

• Systems for preparation of the A QPR
• Format and methods of APR documentation

• APR distribution – who reviews
• Follow-up
• US FDA Quality System Guidance
• Canadian Requirements
• ICH Q10 – The Pharmaceutical Quality System
• Management responsibilities

Often annual product review (APR) completion is thought of as one of those “add-on” responsibilities and gets pushed to the bottom of the priorities. Inasmuch as the annual product reviews are required under cGMPs, they also offer many benefits to the firms. Among many things, they provide an opportunity to assess the need for changes in product specifications, changes in manufacturing or control procedures, need for validation or revalidation, etc. However, many pharmaceutical firms, though complying with GMP requirements for APRs, fail to gain the intended benefits. These firms fail to realize that an annual, thorough review of all data associated with a product can be a vital element in a solid quality system. Thus, the benefits of a good APR are much greater than mere regulatory compliance.

Requirements for APRs are found in 21 CFR 211.180(e) and include:

• Written procedure
• Review of every batch (or representative) to determine the need for changes in specifications or manufacturing or control procedures
• Review of complaints
• Review of recalls
• Review of returned or salvaged products
• Review of investigations

The current expectations for APRs have grown to include other data sufficient to allow a determination for the need for changes in drug product specifications or manufacturing or control procedures. Some of these typical components of APRs will be discussed. In addition, many FDA investigators expect that APRs be reviewed and approved by members of senior management. This requirement, though not specifically spelled out in GMPs, is in line with the intended purpose of APRs to provide an opportunity to assess the state-of-control of the product and process.

The key to derive useful knowledge out of APRs is to present the data in a knowledge-rich manner so that the trends, profiles, similarities and differences etc, can be easily deciphered and linked to justify the “state of control.” With the advent of quality-by-design (QbD) approaches to drug development and with the widespread references to ICH Q8, ICH Q9, and ICH Q10, many firms are increasingly applying QbD principles and proposing design spaces for many processes and controls. Therefore, it becomes even more critical to analyze the manufacturing trends and place them in perspective to the QbD information to demonstrate whether the processes and controls are operating within the predefined design spaces or not. This kind of assessment is possible with a well-documented and knowledge-rich APR documentation, which is well established in a firm’s quality systems and supported by their management.

Although APRs can be organized in a variety of ways, some of the commonly used formats and typical contents of an APR will be provided and discussed. Additionally, some of the 483 citations for inadequate APRs will be shared and relevant case studies will be presented. The significance and relevance of APR documentation in the QbD-based drug development will be highlighted.

The Food and Drug Administration (FDA) convened a public meeting on February 7, 2007 to solicit comments on issues that FDA should consider when developing revisions to its regulations regarding chemistry, manufacturing, and controls (CMC) supplements and other changes to approved marketing applications for human drugs. Since then, FDA has evaluated how it could revise its regulations to allow for consideration of risk-based approaches based on manufacturing process understanding, including prior knowledge of similar products, and overall quality systems to provide an enhanced risk-based approach to the CMC regulatory process, which would reduce the number of supplements. In the interim, FDA also published guidance documents entitled “Changes to an approved NDA or ANDA-April 2004” and “Comparability Protocols- CMC Information- February 2003.” Lately, FDA has encouraged the submission of comparability protocols (CPs) along with the original NDA for foreseeable CMC changes. CPs are then reviewed as part of the NDA approval process and if accepted, they can be executed during postapproval phases and corresponding changes may be implemented with lesser filing requirement such as annual reporting. However, the filing strategy should be worked out with the FDA.

While the above guidance documents are developed based on 314.70 requirements for post-marketing CMC changes, the FDA is likely to revise this regulation to provide for a science and risk-based approach to managing post-approval CMC changes. Even though the three SUPAC guidance documents (IR, MR, and SS) published during the 1990s are available as source documents to refer to for effecting CMC changes, they are likely to be rendered obsolete by the above developments. As if to complicate further, the BACPAC I guidance for CMC changes to intermediates in drug substance synthesis was withdrawn on June 1, 2006 and this has led to many regulatory uncertainties at both FDA and the regulated industry and has essentially necessitated a risk-based approach to look at the post-approval changes. Additional impetus has been provided by the Quality-by-design (QbD) approaches to drug development, strongly championed by the FDA. Many NDAs were submitted and approved under the CMC pilot program at the FDA based on the QbD approaches where design spaces were proposed and approved. FDA has stated that any CMC changes that are within the approved design space are not considered regulatory changes needing prior approval and hence such changes could be managed within a firm’s quality systems. With the advent of ICH Q8R, ICH q9, and ICH Q10, pharmaceutical manufacturers are capitalizing on their rich knowledge base and process understanding to justify for reduced regulatory reporting for foreseeable CMC changes.

This talk will present the emerging postapproval CMC regulatory landscape at the FDA and will provide several recommendations on how pharmaceutical companies can take advantage of the FDA initiatives and ICH guidelines to better manage their post-approval CMC changes. Some redacted case studies will be presented to illustrate the points.

Implementing Best Practices for Writing Annual Reports

Performing Statistical Analysis of APQR Data