Conducting Effective Annual Product Reviews From: Journal of GXP Compliance, Volume 6 Number 2 January 2002

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1 Conducting Effective Annual Product Reviews From: 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 (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

2 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: 1. 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. 2. 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 no deviations have been observed. 3. Determine if validation or revalidation is needed One of the most important benefits of APRs is to indicate the need for revalidation. If data indicate that the process or product is either no longer capable of consistently achieving required results, or if unexpected trends in

3 data are evident, the need for revalidation may be indicated. For example, if your APR reveals that seven of 34 batches of a water soluble powder product were rejected due to low potency, revalidation may be warranted. Again, an effective system for investigating failures should have resulted in this same recommendation earlier than the seventh failure. However, by taking a higher view of data during the APR, you are likely to reach a more sound conclusion regarding the need for revalidation than when investigations occur one batch at a time. 4. Identify product improvement or cost reduction opportunities Another important benefit of APRs is the possibility for product improvements or cost reductions. For example, you have a liquid product that has historically involved testing samples from the beginning, middle, and end for potency. Your APR indicates that variability from these samples is negligible and that results are uniformly consistent. A reduction in testing from individual beginning, middle, and end samples to a single composite sample may be justified. Certainly, proper regulatory approvals are required. However, you may realize cost reduction opportunities via APRs and the data already compiled may serve as justification for the changes. 5. Confirm change control systems Change control is the process of a required review of all changes to assure that the change will have no detrimental impact on the proper operation or validation of the equipment or process. However, during a single year, it is possible that dozens of small changes can occur, each predicted to have no impact on the product or process. However, the cumulative effect of dozens of small changes could be equivalent to a major change. The use of the APR to provide a birds-eye view of the product and processes involved might allow the detection of a cumulative negative effect. 6. Provide a preparation tool for FDA inspections Most FDA inspections begin with a request from the investigator for summary data from one or more products. If these data were not already assembled, such as in the APR, it could take several days to collect and summarize the information. Even then, you likely would have little time for a thorough evaluation of the data. The APR can serve as a means to organize data, anticipate any concerns, and initiate any needed corrective action to avoid FDA inspection concerns. 7. Communicate product and process status to management GMP regulations and recent FDA enforcement actions make it clear that management has the ultimate responsibility for assuring that products are safe, pure, and effective. As an example, 21 CFR (e) lists the requirements for APRs. The next paragraph discusses the requirement to notify the responsible officials of the firm regarding investigations, recalls, and inspectional reports from FDA. The APR can serve as an excellent communication tool that summarizes for management the current status of each product and any concerns or issues that require correction.

4 Typical Contents of an Annual Product Review APRs can be organized in a variety of ways. Some firms assemble comprehensive and detailed APRs that can comprise several hundred pages each. Others collect only minimal data and include extensive summaries of data. Each approach can meet GMP requirements provided the specified minimum information is included. Figure 1 illustrates three categories of APR content: that specifically listed in 21 CFR (e), that typically expected by FDA investigators, and that included by some companies as a matter of choice. The typical contents of an APR are listed below with a brief description of the important aspects of each. Time Period Covered It is important to specifically identify the time period covered for the APR. Typically, the APR will include all batches manufactured or dispositioned (released or rejected) during a specific period, usually one year. Some firms choose to use a strict calendar year for reviews, while others stagger the dates to prevent an excess burden during any period of the year. Product Description It is also important to include a detailed description of the product under review. For example, you should state the product, packaging configurations, and reference the control numbers in use to specifically identify the formulation in use. Any identifying references to production lines or equipment should be included if needed to differentiate products.

5 Summary of Review A summary statement early in the APR will serve to provide an overview of any key observations made. For example, you might use this section to state that a large number of deviations were observed that might indicate a shift in the process. This section might also be used to note any unexpected results. Recommendations and/or Corrective Actions It is usually prudent to mention early in the APR a listing of recommendations or corrective actions resulting from the review. This will aid the reader to focus on these key aspects of the review. In addition, some readers (i.e., management) may only read the first page or two of the APR, so it is important to highlight issues and concerns early. Finished Product Results Finished product results must be presented. Though the GMP regulation allows the use of a representative number of batches, most firms choose to review all batches produced. Presentation of data can be in any form desired. However, all key analytical and physical parameters must be included in summaries presented. In-Process Results In-process results could be even more important than finished product results. A close review of these data may provide clues regarding the integrity and consistency of the process. The APR should include both in-process analytical/physical results and critical processing parameters. For example, it may be more important to track the average time of drying to achieve required moisture levels than the actual final moisture. Time may be more indicative of the process control than final moisture. Deviations/Investigations/Rework The APR must include all product or process deviations, investigations conducted for deviations or nonconforming situations, and any rework conducted. Some firms summarize all corrective actions derived from these events, and include a status of the actions. The key to this section is to highlight concerns that did arise and provide evidence that actions are underway to correct the problems. Stability Results A key indicator of the control and consistency of any process is the stability data collected to support a product. A good APR should list any stability trends, deviations, or shifts apparent since the last review. These data can also be a good indicator of hidden process or product concerns. Complaint Results A summary of all product complaints is a required component of the APR. Any trends or problematic batches should receive additional review. Returned Goods

6 A summary of all product returned for quality concerns should also be included in the APR. This can provide valuable information not normally evident to the quality unit regarding product concerns or problems. Recalls If any product recalls occurred, they should be listed in the APR. The reasons for the recalls and corrective actions taken should be summarized. Conclusions Any conclusions regarding the product should be listed in this section. Some examples of typical conclusions include: no revalidation required, no product or process concerns noted, etc. Any recommendations for changes should be included in the recommendations section, along with responsibilities, and a timeline for corrective actions. Approvals Finally, the APR must include appropriate approvals. Usually, representatives from Production, Quality Control (QC), and Quality Assurance (QA) will approve the APR. However, it may be desirable for others (such as Validation, or Regulatory) to have the authority to approve the APR, depending upon its content or recommendations. The organization of the company may also dictate the approval process. In any event, a member of the quality unit must review and approve the APR. Interpretation of APR Results Data presented for APRs can be presented in a variety of ways. As discussed above, all data from batches produced during the review period must be included in the review. The GMP regulation does allow for statistical or representative sampling, but the effort to use sampling results, yet include all rejected data, investigations, etc. make the logistics of sampling difficult. Most firms include data from all batches produced. Data can essentially be presented in tabular form or in graphical form (i.e., charts or graphs). Both have advantages and most firms include a combination of both in APRs. With graphs, any trends or deviant results can be spotted quickly. However, it is not easy to compare individual specific results and perform further mathematical comparisons. In addition, some data (i.e., pass/fail results) cannot be graphically shown. In addition to graphs or tables, it is also helpful to summarize data. For example, the calculation and exhibition of the mean, standard deviation, and relative standard deviation is useful for most analytical data. These results usually readily illustrate if problems with the process are evident. The use of most refined statistical analyses can also be useful for comparing various populations of results or batches from one production period with another. The use of many readily available statistical software programs can also assist in the preparation of data. Many such programs are available and are relatively inexpensive. These tools can help in evaluating data for trends that might indicate a shift in the process. In general, the conclusion to the data review for an APR should result in one of the following:

7 Process in control this conclusion indicates no abnormalities within sets of data and confirms that the process continues to function as validated Actions recommended this conclusion indicates that some recommended actions should be considered, but the process is essentially functioning as designed and validated the process continues to operate in a state-ofcontrol Corrective actions required this conclusion indicates the need for immediate actions or corrections some consideration should be given, under this circumstance, to cease production and evaluate the impact of the problem on marketed product the process is not operating in a state-ofcontrol Approaches for Completing APRs As many different approaches for completing APRs exist as companies manufacturing pharmaceutical products. No single approach is the answer to all questions and concerns. In the author s experience, the best approach for completing APRs efficiently, on-time, and with effectiveness involves the following: APR Owner or Responsible Person No APR system can be truly effective when no single individual takes ownership of the process. Certainly, a team of individuals must participate and share APR responsibility. However, an owner is needed to assure that team members participate, contribute, and complete assignments on time. This individual need not serve in this role full-time, but as needed to assure that the process is successful. APR Administrator The APR administrator is the individual that will maintain the APR schedule, and assemble the sections of the APR into the final document. This individual may or may not also serve as APR owner. In addition, either of these individuals may actually author the final summary, and assure that final approvals occur. APR Team The APR team must include representatives of all departments that contribute data or review to the final APR. Typically, this would include members from QC, QA, Production, Stability, Distribution, Engineering, and other groups. The APR owner usually will coordinate activities of the team, and assure that each member is aware of assignments, and has resources required to accomplish tasks. SOP on the APR Process A comprehensive Standard Operating Procedure (SOP) must guide the entire APR process. This SOP must specify who will do what, how the APR will be formatted and constructed, the review and approval process, archiving, actions to be taken when issues arise, APR contents, and APR close-out. (Please see page 13 for the APR SOP.) APR Schedule It is imperative to establish an APR schedule or work plan. This schedule should list what APRs must be completed, their timetable, and when each major section of the APR must be submitted to the administrator. This schedule should be available to all team members to provide prioritization for on-time completion. APR Team Process or Meetings The APR process can best be assured if the team meets on a regular schedule. This can help assure that targets are achieved, and that slippage in assignments and

8 completion does not occur. Management Commitment Perhaps the single most important element in a successful APR process is management commitment. Without a commitment to support the process with resources and a sincere buy-in of the benefits of APRs, the program is likely to suffer. When FDA cites firms for APR deficiencies, the responsibility is always assigned to the management of the firm. Including each of these elements in your APR process may not guarantee success, but the omission of these elements ensures continual problems. FDA Inspections: Expectations for Annual Product Reviews The following can sum up current FDA expectations for APR programs: Develop a comprehensive SOP the SOP should be comprehensive and specific. Follow the SOP failure to follow the SOP will almost always result in concerns from investigators. Include all required and expected elements in the APR. Refer to Figure 1. Identify and implement corrective or improvement actions the routine assignment of corrective or improvement actions signals that you take the process seriously, and as originally intended by the authors of the GMP regulations. Follow-up on actions a system to assure that actions occurred and were effective is essential. Assure that the quality unit reviews and approves the APR most firms require QA approval on APRs. Involve management in the process the higher the level of involvement and interest in the process, the more APRs can be used as a tool for process control and product improvement. If these elements all exist in your firm, you should fare well during most FDA inspections regarding APRs. Conclusion So, do you treat APRs as a necessary GMP requirement, or as a key component of a solid quality system? Hopefully, you can now see that an effective APR can do both: provide compliance to GMP regulations, and provide an effective means for evaluating and implementing improvements to your products. The following aspects of an APR can be critical: Reference tool Data collected and assembled in the APR can assist in problem resolution activities, assist the Research and Development (R&D) organization in understanding how a proposed process may function in a commercial scale operation, or merely serve as a point of reference for future investigations. Quality improvement tool The effective use of a comprehensive APR can often lead to opportunities to either improve a process or lead to cost reductions.

9 Management tool It can provide annual feedback on your products and processes and define how well they operate. When used to supplement other components of a comprehensive quality system, APRs can help assure that your pharmaceutical products are safe, pure, and effective and our processes operate in the state-of-control required by GMP regulations. About the Author Eldon Henson is a member of the Editorial Advisory Board for the Institute of Validation Technology s (IVT s) Journal of Validation Technology. He currently serves as Director, Quality Services for Novartis Consumer Health in Lincoln, Nebraska, where he has overall responsibilities for quality assurance, quality control, and compliance activities for OTC, Rx, and a variety of other pharmaceutical products. Henson has B.A. and M.A. degrees in Microbiology from Southern Illinois University Carbondale, and over 20 years of FDA-regulated industry experience with Boehringer Ingelheim, Sigma-Aldrich, Abbott Laboratories, and Ralston Purina prior to joining Novartis in Henson has authored a variety of GMP-related publications, including IVT s Auditing Handbook, Quality Improvement Handbook, and articles on laboratory GMPs, validation, FDA inspections, training, documentation, auditing, and quality systems. In addition, he has written a number of training modules for Eduneering, a web-based provider of GMP and HSE training materials. Henson can be reached at , by fax at , or by at eldon.henson@ch.novartis.com.

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