Product Annual/Quality Review: US–EU Comparative Analysis and Interpretations - Pharmaceutical Technology

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Product Annual/Quality Review: US–EU Comparative Analysis and Interpretations
There are significant differences between the United States and European Union requirements for the annual review of records related to the manufacturing and control for pharmaceutical products and active pharmaceutical ingredients.

Pharmaceutical Technology
Volume 3, Issue 32

Objectives of the PAR/PQR program

Table II: Frequency and procedure for review.
The three required FDA objectives for performing the PAR are to determine the need to make changes in the manufacturing process, the manufacturing controls (e.g., in-process testing and monitoring), and product specifications. Only one of these three required objectives (i.e., to determine the need to make changes to product specifications) is specified in the EU PQR, and none of these FDA objectives is mentioned in the Q7A PQR. The EU PQR has additional required objectives that are not mentioned in either the FDA PAR or in the Q7A PQR. These include the identification of product and process improvements, highlighting trends, and determining the appropriateness of starting material specifications.

The required and expected GMP objectives are very important to ensure the development of an efficient and compliant PAR/PQR program. The written procedure for the PAR/PQR should specifically refer to the objectives to determine and justify the areas selected for review and the extent of the review. Any area or item that is not relevant to fulfilling the objectives should be excluded from the PAR/PQR.

As an example, the authors have seen FDA 483s criticizing the failure to trend raw-material test results as part of the PAR for a product. To determine whether this is a valid FDA 483 observation or whether raw-material trending should be included, the following should be considered. If the trending of a raw material (e.g., an active ingredient) identifies an adverse trend (e.g., more than 25% of all lots received in the past 12 months were rejected and sent back to the supplier), would this adverse trend cause the company that performed the PAR to change its manufacturing process for the drug product, the manufacturing controls for the drug product, or the final release specifications for the drug product? When the answers are "no" to all three parts of this question, raw-material trending should not be included as part of the PAR because any result from this trending would not be relevant to the objectives of the PAR and would not generate any follow-up action for implementing changes. To avoid confusion, this example is not to suggest that raw-material trending is not needed, but that it should be performed as part of another program (e.g., vendor qualification program) instead of the PAR program. It should be noted that the EU PQR requires the evaluation of the appropriateness of the raw-material specifications.

Two critical objectives that are specified in the EU PQR and Q7A PQR but not included in the FDA PAR are the verification of the consistency of the existing manufacturing process and the determination of the need for the revalidation of the manufacturing process. The procedures for performing a typical PAR/PQR involve the review, analysis, and trending of historical data (i.e., data generated in the past 12 months), which fit the definition of retrospective process validation as defined in FDA's validation guideline and the EU GMP Guide Annex 15 on qualification and validation (5, 6). A PAR/PQR is, therefore, actually an annual retrospective revalidation of the manufacturing process. When performed properly with the incorporation of the required elements of a retrospective process validation, and in the absence of significant process changes, a PAR/PQR may negate or substitute the need for the periodic prospective revalidation (i.e., intensive sampling and testing) of the manufacturing process. This is supported by the following statement in Section 12.6 of Q7A: "Where no significant changes have been made to the system or process, and a quality review confirms that the system or process is consistently producing material meeting its specifications, there is normally no need for revalidation." A similar statement appears in item 44 of the EU GMP Guide Annex 15. To take advantage of the PAR/PQR as the annual retrospective revalidation of the manufacturing process, the company's master validation plan for process validation should reference the PAR/PQR program as the determining factor for the need of a prospective revalidation of the manufacturing process, in the absence of significant changes.

The following are excerpts from FDA's validation guideline and the EU GMP Guide Annex 15 related to retrospective process validation.


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