Sterility testing is mandatory for all medicinal products that are required to be sterile according to the Pharmacopoeia 1 and remains an important criterion for product release. Manufacturers are expected to demonstrate that the finished product is sterile, i.e. entirely free from living organisms of all types.
The question, however, is whether the assurance of sterility of a medicinal product can be demonstrated simply by passing the sterility test? The answer is short and simple: No. Section 2.6.1 of the European Pharmacopoeia describes: “a satisfactory result only indicates that no contaminating micro-organism has been found in the sample examined in the conditions of the test”[1]. Sole reliance for sterility should not be placed on any finished product test.
The key is sterility assurance and achieving this requires providing a high level of confidence that microbial and pyrogen contamination has been excluded in the final drug product. Various guidelines around sterile manufacturing are available, among others the FDA’s Guidance for Industry on Sterile Drug Products Produced by Aseptic Processing [3] and EudraLex Volume 4 – Annex 1 [2]. Annex 1 includes several references to the requirement to apply the principles of Quality Risk Management (QRM) as a pro-active tool for sterility assurance to be part of an effective pharmaceutical quality system. These include references to ICH-Q9 on quality risk management [4] and ICH Q10 on the pharmaceutical quality system [5].
A complex, multi-step process
Sterile pharmaceutical manufacturing generally comprises a complex, multi-step processing system in which significant risks from microbial contamination are presented by diverse sources. To reduce these risks, Annex 1 expects that a holistic contamination control strategy (CCS), based on a risk assessment is developed and implemented. The CCS demonstrates an organization’s understanding of all of their design, technical, procedural and organizational controls and identification of potential risks or gaps that require remediation to improve the overall level of sterility assurance.
The requirement for facilities to have a specific CCS and application of QRM are two of the key features of Annex 1. Developing and maintaining a holistic CCS requires in-depth knowledge and understanding of the pharmaceutical process as a whole including how these processes are subject to change such that all risks can be identified along with the associated contamination controls.
Ultimately, our experience shows that it is the overall effectiveness of the sum of the contamination controls in place that provides a higher level of assurance that a product is sterile. A solid contamination control program using appropriate design, validated control systems, and a scientifically sound environmental monitoring program are more meaningful than the sterility test.
From our experience in the industry, implementation of a robust CCS based on scientific knowledge also provides benefit for the manufacturing of other non-sterile products that require control and reduction of microbial contamination to meet the requirements of product quality.
What challenges has your organization encountered with sterility assurance? And how well do you understand the CCS requirements and assessment of sterility assurance issues? We would be happy to hear about your experiences and any challenges faced. Contact us now!
About the author:
Patrick Nieuwenhuizen is Director and Principal Consultant at PharmaLex and has more than 25 years of experience in the industry across a variety of platforms including Biologics, Sterile Fill Finish and Solid Oral Dose.
References
- European Pharmacopoeia (2024) 11th edition, section 2.6.1: Sterility.
- EudraLex Volume 4 (2022), Annex 1: Manufacture of Sterile Medicinal Products. Accessed through: https://health.ec.europa.eu/document/download/e05af55b-38e9-42bf-8495-194bbf0b9262_en?filename=20220825_gmp-an1_en_0.pdf
- FDA (2004) Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice. Accessed through: https://www.fda.gov/media/71026/download
- ICH (2023) ICH guideline Q9 (R1) on quality risk management. Accessed through: https://www.ema.europa.eu/en/documents/scientific-guideline/international-conference-harmonisation-technical-requirements-registration-pharmaceuticals-human-use-ich-guideline-q9-r1-quality-risk-management-step-5-revision-1_en.pdf
- ICH (2008) ICH guideline Q10 on pharmaceutical quality system. Accessed through: https://www.ema.europa.eu/en/documents/scientific-guideline/international-conference-harmonisation-technical-requirements-registration-pharmaceuticals-human_en.pdf