PDA Letter Article

You Had Micro Questions, FDA Had Big Answers

by Marilyn L. Foster, PDA

The 2021 PDA Pharmaceutical Microbiology Conference, held 4-6 Oct, concluded with an “Ask the Regulators” panel which answered questions that had been submitted by attendees during the Conference.

Co-moderator John W. Metcalfe, PhD, Division of Microbiology Assessment/Office of Pharmaceutical Manufacturing Assessment, CDER, opened this interactive session by noting that it may be the first PDA Microbiology “Ask the Regulators” panel composed entirely of female panelists, which he thought was fitting as the first product quality microbiologist who came to FDA CDER was Vivian Greenman. Yeissa M. Chabrier-Rosello, PhD, Division of Microbiology Assessment /Office of Pharmaceutical Manufacturing Assessment, CDER, co-moderated the session. Metcalfe asked the panelists, who represented various offices of CDER and CVM, to introduce themselves and give some background about their roles in the Agency.

  • Candace Y. Gomez-Broughton, PhD, Division of Biotechnology Manufacturing, Office of Pharmaceutical Manufacturing Assessment, CDER
  • Brooke K. Higgins, MS, Global Compliance Branch 3, Office of Manufacturing Quality, CDER
  • Marla K. Stevens-Riley, PhD, Division of Microbiology Assessment, Office of Pharmaceutical Manufacturing Assessment, CDER
  • Renée S. Blosser, MS, Division of Manufacturing Technologies, Office of New Animal Drug Evaluation, Center for Veterinary Medicine (CVM)

The panelists fielded a wide range of questions, providing as much information as they could and being as “transparent as possible” while sharing FDA’s thinking at the time of the meeting. The panel answered the questions in the order of those voted the most important by the audience, though several questions were excluded that required either a very detailed answer or were beyond the expertise of the panel. Several questions prompted extensive discussion.

EU GMP Annex I

The revision of the European Union’s GMP Annex I, as always, was a popular topic. Responding to questions, the panel talked about rapid methods for environmental monitoring, documented control strategies and container closure integrity testing. The panel stressed that FDA evaluates each application and facility CGMP compliance individually and considers all the aspects involved in each product’s safe manufacture, including justifying the types of methods used for environmental monitoring.

The Agency has always worked closely with the EU to maintain alignment with Annex I guidelines and its provisions, though some terminology might differ. For instance, the new Annex 1 includes a requirement for a “documented contamination control strategy” that is similarly addressed in U.S. regulations (21 CFR 211.113), which require “appropriate written procedures, designed to prevent microbiological contamination….” Both expect companies to put controls in place to minimize the risk of contamination.

The question arose if the 100% container closure integrity testing required in Annex I for blow-fill-seal products might be extended to other presentations of parenterals. The Panel pointed out that the FDA also requires 100% CCIT for BFS products in its 2004 aseptic processing guidance but, of course, no one can predict if that would be extended to other parenterals in the future.


When asked about the future of Recombinant Factor C (rFc) methods being included in USP as a method of choice, the panel reminded the audience that the FDA currently sees rFc as an alternative method which can be, and has been, approved when the data supports its use. If it is included as an accepted test in the USP, it would still require supporting suitability data. (The panel encouraged listeners to see comments posted in the USP Pharmacopeial Forum for more information.) If rFc methods are to be used, whether for controlled or naturally occurring endotoxins, the applicant would need to justify its use and validate it appropriately.

A discussion about endotoxin limits ensued in response to a very specific question about reducing the limits in drug applications. The most important factor, the panel agreed, is evaluating how the drug will be introduced into the patient, how much the patient will receive per hour, if a diluent is involved, if the patient is an adult or a child and the state of the patient’s health. Calculations can be very complicated, they said, and should be assessed carefully on a case-by-case basis.

Metcalfe closed the session by thanking the panelists for their time and contributions. He appreciated their sharing some insight into how the various FDA offices work together to collaborate in obtaining information and making decisions. The open flow of discussions that took place during this Q&A session provided an excellent example of that teamwork.