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.
Mar 02, 2008
Volume 3, Issue 32

Table I: Review objectives.
The US Food and Drug Administration proposed a requirement for preparing a written summary for each product in its February 13, 1976 rewriting of the good manufacturing practices (GMPs) for drug products. The purpose for this proposed GMP requirement was to provide reliable procedures for a drug manufacturer to review the quality standards for each drug product. In response to numerous comments from industry objecting to the preparation of written summaries, FDA revised the proposal to allow each company to establish its own procedures for the evaluation of product quality standards, by reviewing the records required by the GMPs on an annual basis. This requirement was published in the September 1978 final current good manufacturing practices (CGMP) regulations for drug products (21 CFR 211.180(e)) and became effective on March 28, 1979 (1). Since its publication, 21 CFR 211.180(e) has been commonly referred to—by FDA and the pharmaceutical industry—as the "product annual review" (PAR) or the "annual product review" (APR).

In August 2001, FDA adopted and published the guidance for industry Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients. This guidance was developed within the Expert Working Group of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). This guidance was incorporated as Part II of the European Community Guide to GMP (EU GMP Guide) in October 2005. Sections 2.5 and 12.6 of this guidance specify and refer to the performance of a product quality review (PQR) for active ingredients (2).

The European Medicines Agency (EMEA) is the group responsible for coordinating the scientific evaluation of the safety, efficacy, and quality of medicinal products undergoing official review via the centralized or mutual recognition procedures. EMEA also proposes changes in pharmaceutical legislation for approval by the European Commission. The EU GMP Guide is the document that provides the details supporting the principles of GMPs within the EU. In 2004, EMEA made available for public comment a draft revision of the EU GMP Guide proposing, for the first time, a requirement for a PQR. The European Federation of Pharmaceutical Industry Associations (EFPIA), the Parenteral Drug Association (PDA), and other organizations and individual pharmaceutical companies provided comments to this draft revision. The European Commission officially announced the finalized revision to the EU GMP Guide in November 2005 with an effective date of January 2006. Chapter 1 of the GMP Guide now contains a requirement to perform a PQR (3). The European authorities stated that the industry generally should have the requested information available but acknowledged that it would take some time to "develop and establish a system and associated procedures to implement this new requirement"(4). PQRs for 2006 were to cover at least a six-month period with full annual reports required from 2007 onward.

Comparison of regulations and guidance

Tables I–V provide a summary comparing the GMP requirements and guidance for the PAR/PQR among the US GMP (211.180(e)), the EU GMP (section 1.5), and the ICH Q7A (section 2.5). The authors used three terms for this comparison. "Required" means that the review action or item is specifically written in the regulations or guidance. "Expected, not specified" means that the review action or item is expected by the respective authorities but not written in the regulations or guidance. This review "expectation" is based on written guidance contained in other documents from the respective authorities, recurring citations in FDA 483s (the form used by investigators to record observations of noncompliance with CGMPs) and FDA warning letters, or an industry standard that has been recognized by authorities. "Not specified" means that the review action or item is not a current expectation from the respective authorities.