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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.
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).
John Y. Lee is executive director at Pharmaceutical Compliance Associates, and a former FDA investigator at New Jersey District, 523 No. Bay Avenue, No. Massapequa, NY 11758, tel: 516.752.0998, fax: 516.752.8931, e-mail: jyleepca@aol.com.
Articles by John Y. Lee
John G. Grazal
John G. Grazal is senior director of the Global Compliance Management Group at AstraZeneca (Wilmington, DE).
Articles by John G. Grazal
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