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Experts Susan J. Schniepp, distinguished fellow for Regulatory Compliance Associates, and Steven J. Lynn, executive vice-president, Pharmaceuticals for Regulatory Compliance Associates, provide answers to frequently asked regulatory questions about advanced therapy medicinal products.
Q: Do I have to follow traditional pharma rules when I investigate deviations for my emerging therapy?
A: There is really no process difference when performing deviation investigations for traditional pharmaceutical products versus biotech products versus advanced therapy medicinal products (ATMPs). The purpose of performing an investigation into a deviation is to determine why the deviation happened and what its impact was on the product quality. To determine the impact of the deviation on the product quality, it is important to determine the root cause of the deviation.
The process used in the industry to determine root cause is, of course, the investigation procedure. This procedure, regardless of the type of product you are manufacturing, should require the investigator to review various systems and determine whether they were the cause of the deviation under investigation.
It is important to remember when performing an investigation to keep the following few general rules in mind:
The language in EudraLex Volume 4 for ATMPs (1) supports this concept by stating, “As long as the specifications for the finished product are met, a QP [Qualified Person] may confirm compliance/certify a batch where an unexpected deviation related to the manufacturing process and/or the analytical control methods has occurred provided that: (i) there is an in-depth assessment of the impact of the deviation which supports a conclusion that the occurrence does not have a negative effect on quality, safety or efficacy of the product, and (ii) the need for inclusion of the affected batch/batches in the on-going stability programme has been evaluated, where appropriate.”
Q: I need to get my product to the patient before the traditional test for sterility is concluded. This requires me to release product at risk. Is there any way to avoid this?
A: The global regulatory authorities are aware that the ATMP manufacturers face this and similar situations, and rather than have you release your product at risk, they have offered guidance that not only recognizes this situation but offers solutions to alleviate it.
The European Union states, “[a]pplication of the sterility test to the finished product (Ph. Eur. [European Pharmacopoeia] 2.6.1) may not always be possible due to the scarcity of materials available, or it may not be possible to wait for the final result before the product is released due to short shelf-life or medical need. In these cases, the strategy regarding sterility assurance has to be adapted” (1).
In a 2020 Guidance for Industry, FDA recognizes that traditional analytical methodology may not be suitable for this product category stating, “Analytical procedures different than those outlined in the USP [United States Pharmacopeia], FDA guidance, or Code of Federal Regulations (CFR) may be acceptable under IND [investigational new drug] if sponsors provide adequate information on test specificity, sensitivity, and robustness” (2). This guidance goes on to recognize the limitations of the traditional sterility test stating, “We recognize that the compendial sterility tests (USP <71>; 610.12) may not be suitable for all products (e.g., those with limited shelf life),” and “rapid sterility tests may be acceptable for ex vivo genetically modified cells administered fresh or with limited hold time between final formulation and patient administration” (2).
It should be noted that both the Ph. Eur. and the USP both recognize rapid sterility in their respective publications. Chapter 2.6.27 of Ph. Eur., titled Microbiological Examination of Cell-Based Preparations, allows for the use of automated growth-based methods or alternative methods such as a combination of direct detection by alternative methods or other methods based on the harmonized sterility test. The USP has a general Information Chapter <1071> titled Rapid Microbial Tests for Release of Sterile Short-Life Products: A Risk-Based Approach. All of this information supports the concept that ATMPs are different and offer unique challenges regarding sterility. This recognition allows you to pursue options for demonstrating sterility including the use of rapid microbiological/sterility testing equipment.
The best way to proceed forward in getting approval for rapid techniques is to make sure you have performed the proper installation qualification/operational qualification and performance qualification on the equipment and have demonstrated its suitability for use with a complete validation package. In case there is an equipment failure, you should have backup methodologies identified as part of your quality risk management plans. The final word of advice is to make sure you and your organization have a robust, well-documented quality risk management plan that is in line with the concepts set forth in International Council for Harmonisation Q9 Quality Risk Management.
1. EC, EudraLex, The Rules Governing Medicinal Products in the European Union, Volume 4, Good Manufacturing Practice, Guidelines on Good Manufacturing Practice to Advanced Therapy Medicinal Products (November 2017).
2. FDA, Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigations New Drug Applications (INDs), Guidance for Industry (CBER, January 2020).
Vol. 34, No. 8
Pages: 50, 49
When referring to this article, please cite it as S. Schniepp and S. Lynn, "GMPs for Emerging Therapies," BioPharm International 34 (8) 2021.