Conducting Effective Annual Product Reviews
Wednesday, November 09, 2005 - Journal of GXP Compliance, Volume 6 Number 2 January 2002
by Eldon Henson, Director, Quality Services, Novartis Consumer Health
Have you ever asked or faced any of the following questions regarding Annual Product Reviews (APRs): • • • • • • Why are APRs required? We are behind on our schedule – how can we get caught up? Who really is responsible for APRs? Why is completing APR information always the last priority? Can we shorten APRs to make them quicker and easier to complete? Does anything beneficial really result from APRs?
Believe me, most firms have faced these and other questions regarding APRs. It seems that APR completion is one of those “add-on” responsibilities that get placed on the bottom of the pile. Many pharmaceutical firms, though complying with GMP requirements for APRs, fail to gain the benefits intended by the authors of 21 CFR 211. 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. The benefits of a good APR are much greater than mere regulatory compliance. So, what are the GMP requirements for APRs and what are their benefits? This article will review the regulatory requirements, benefits and purposes, and typical contents of an APR. In addition, a discussion of the interpretation of APR results will be presented along with follow-up actions that can result from an APR. Some possible approaches for completing APRs will be offered. Finally, a review of FDA investigator expectations for APRs will be presented. Hopefully, this information will help you answer some of the nagging questions and issues that plague many industry professionals regarding APRs, and help you make the APR process as beneficial as originally intended.
GMP Requirements for Annual Product Reviews
Though some requirements of 21 CFR 211 can be termed ambiguous, the section detailing requirements for APRs is rather clear. So, unlike some aspects of “current” GMPs, the development and use of APRs in the pharmaceutical industry should be well established and be a minimal compliance issue. However, FDA investigators still regularly cite deficiencies in APRs, and recent Warning Letters have included references to poor or inadequate APRs. 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 Review Review Review
of of of of
complaints recalls returned or salvaged products 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.
Benefits of Good Annual Product Reviews
Several analogies to the APR can be found in everyday life: • Many couples or individuals utilize the annual preparation of income tax returns as an opportunity to assess the year in review. For example, did income and expenses meet expectations? Do unusual trends exist in expenses that require an adjustment in spending or budgeting? Are income and expenses in proper balance? The annual performance appraisal is dreaded by many. This process usually includes a review of performance against expectations, highlighting good results, and developing action plans to address concerns. Most companies conduct an extensive analysis of performance at the end of each year. A review of financial performance, safety, environmental issues, regulatory compliance, and overall results is usually published in the Annual Report. Any challenges for the upcoming year are highlighted and plans for improvement listed.
These examples demonstrate the overall purpose of APRs – to provide a look back on product performance to determine if changes are needed. There are seven key benefits or purposes for effective APRs:
Assess needed changes in product specifications
During a review of all product data from an extended period of time, the need to alter product specifications can be evident. For example, if the APR finds that many lots of a certain compressed tablet do not meet specifications for moisture, it could indicate that a specification change is warranted. Certainly, any specification change must be reviewed against product quality requirements and regulatory filing requirements. In addition, if this increased moisture represents a deviation from historical results or validation batch results, an investigation should occur to determine if the process, materials, or procedures have changed. However, if you find that increasing the moisture limit from one percent to two percent does not jeopardize product quality (scientifically verified with data), a specification change may be justified.
Assess needed changes in manufacturing or control procedures
Similarly, reviewing batch data for an extended period may indicate the need for changes other than product specifications. For example, if you find that several process deviations occurred during the year because an operator incorrectly set the formulation cooling temperature, a change in procedure to require a double verification or a change in instrument controls may be warranted. Ideally, these actions would have been identified and implemented during the investigation of temperature deviations. However, the APR may indicate a trend in results that can precipitate preventative action even when