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

PAR/PQR items and areas for review

Table IV: Responsibility, documentation, review and approvals, and follow-up.
The FDA PAR specifies six items that are required to be reviewed, the EU PQR specifies 19 items, and the Q7A PQR specifies 11. Four of the six FDA requirements are common to both the EU PQR and Q7A PQR, which are complaints, product recalls, returned products, and investigations. There are eight items that are required by the EU PQR but not specifically stated in either the Q7A PQR or the FDA PAR. These include the review of export-only products, starting materials and packaging materials, MA variations, postmarketing commitments, equipment qualification status, currency of technical agreements, effectiveness of preventive actions to significant nonconformities, and adequacy of previous product process or equipment corrective actions. Additional EU PQR review requirements that are not specifically stated in the FDA PAR are the review for all batches that failed specifications, critical deviations and nonconformities, product stability results, critical in-process controls and test results, changes to analytical methods, and the effectives of corrective actions.

Selection of product batches for review. FDA revised its GMP in January 1995 to eliminate the requirement for the review of all batches produced in the previous 12 months and to allow the review of a representative number of batches. The preamble to the revised GMP regulations states, however, that the review of all batches would be appropriate when the review of a representative number of batches identifies an adverse trend. The EU and Q7A PQRs do not state that all batches must be reviewed, other than rejected batches, but these two documents also do not specifically allow for the review of representative batches. FDA defined representative batches in the preamble of the GMP revision as batches that exhibited varying manufacturing experiences such as batches that were released, rejected or recalled, batches that were the subject of FDA field alert reporting filings, batches with manufacturing discrepancies, and any batches with outcomes that might indicate the need for change (8). FDA later refined the definition for representative to include each batch that was rejected for a different reason, or a different category of rejection (10).

Marketing authorization, postmarketing commitments, and technical agreements. The review requirements in the EU PQR for MA variations, currency of technical agreements, and the postmarketing commitments do not reflect the typical industry practice for PAR/PQR, and there were industry comments that some of these review requirements appeared to be outside the scope of a PQR. The review requirements for MA and postmarketing commitments reflect the long-standing EU emphasis on license compliance and the heightened global emphasis on drug safety, respectively. The MA or, specifically, the marketing authorization application (MAA) is the product license in the EU comparable to the new drug application (NDA) in the US. During an inspection, it is typical for an EU inspector to question the firm's management about their knowledge and assurance of commitments made in the MA. The site master file (SMF) is another submission document that is often discussed during an inspection, though the SMF is not mentioned in the revised PQR section of the GMP guide. In terms of the review of postmarketing commitments, this is an essential activity, but it is not immediately obvious as to why it is required in the EU PQR. The stated objective of the PQR is "...verifying the consistency of the existing process, the appropriateness of current specifications for both starting materials and finished product to highlight any trends and to identify product and process improvements"(3).


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