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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 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.

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