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Russell E. Madsen is the former senior vice-president of science and technology at PDA, and is a current member of Pharmaceutical Technology's editorial advisory board.
James E. Akers is the president of Akers Kennedy & Associates, PO Box 22562, Kansas City, MO 64113, firstname.lastname@example.org.
James P. Agalloco is the president of Agalloco & Associates, P.O. Box 899, Belle Mead, NJ 08502, tel. 908.874.7558, email@example.com. He is also a member of Pharmaceutical Technology’s editorial advisory board.
The revised Annex 1 on sterile manufacturing includes incorrect and ambiguous statements that must be fixed before implementation.
The December 2017 revision of EudraLex, Volume 4, EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use, Annex 1, Manufacture of Sterile Medicinal Products (1), when finalized, will be legally binding. Non-compliance could result in regulatory action, refusal, or revocation of marketing authorizations and civil and criminal penalties. Given the revised Annex 1’s legal standing, it is vital that the document delineates appropriate regulatory expectations and accepts contemporary manufacturing and control procedures and practices.
The European Medicines Agency (EMA) has put forward Annex 1 for comment, but the document is so badly written that understanding it, much less commenting on it, is far more difficult than it should be. As it stands, this version of Annex 1 will inevitably generate thousands of comments that will be difficult for EMA to reconcile within the framework of the current document. Preliminary review of the document indicates that it is poorly worded, ambiguous, and technically incorrect in many areas. The following comments represent a fraction of those identified during our review. They are categorized by general areas of concern.
There are many instances where inconsistent use of terms or wording results in ambiguity and the inability to determine or demonstrate compliance, such as listed in the following:
The use and application of airlocks, barrier systems, isolation technology, and environmental and personnel monitoring systems are incorrectly described or applied, such as:
The following technical errors dot the pages of the document:
There is a misdirected focus toward factors that do not increase patient safety or relate to the safety, identity, strength, quality, or purity of a drug product beyond the official or other established requirement:
The document presents a view of sterile product manufacture inconsistent with that developed elsewhere, as codified in regulations, international standards, and pharmaceutical compendia, such as:
EMA should withdraw this draft of Annex 1. It should be significantly revised to include more contemporary and global content on sterile product manufacture and control and reissued for comment once its many faults have been corrected.
The cited examples represent only a fraction of the more than 130 issues we identified in the document and we plan to submit a comprehensive response to EMA by the comment deadline of March 20, 2018 in the event that the draft is not withdrawn.
1. European Commission, EudraLex, Volume 4, EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use, Annex 1, Manufacture of Sterile Medicinal Products, December 2017.
2. USP, <1211> Sterilization and Sterility Assurance of Compendial Articles, USP 40-NF 35 (USP, 2017).
3. USP, <1228> Depyrogenation, USP 40-NF 35 (USP, 2017).
4. USP <1229> Sterilization of Compendial Articles, USP 40-NF 35 (USP, 2017).
Russell Madsen is president of the The Williamsburg Group, LLC, James Agalloco is president of Agalloco and Associates, and Jim Akers is president of Akers Kennedy & Associates.