What are the biggest challenges in achieving and maintaining sterility assurance in pharmaceutical manufacturing?
The first thing to realise is that sterility of a product cannot be 100% guaranteed and sterility assurance is about the probability that a product is rendered sterile.
Identifying and recognising the risk of where contamination could present itself in a Company’s facility, its utilities, equipment and associated processes is of high importance and equally how to prevent this from happening. This is to be augmented with a scientific sound detection program that is capable of providing early indications if a system is not performing in accordance with its predefined limits or capabilities to allow for adequate follow-up in order to take action and prevent a potential issue with the sterility assurance. Then, in the unfortunate situation an issue would arise, how is it followed up and identified what the learnings are to prevent reoccurrence.
Can you highlight some key components of a robust sterility assurance program?
Knowledge and the ability to manage and share this knowledge cross functionally about how the different elements that ultimately produce the sterile product interact with each other, and what controls are in place to prevent issues from occurring or detect them in an early manner. It is important that components complement each other and that a single failure of a control element does not lead to an impact of the sterility assurance. It allows a Company to develop and maintain a sterility assurance program that covers the end-to-end process which is understood and endorsed by different disciplines.
What role does environmental monitoring play in sterility assurance, and how do companies effectively manage this aspect?
A well-designed environmental monitoring (EM) program can generate data that provides direct feedback on the effectiveness of the sterility assurance program. To establish a comprehensive and meaningful EM program a risk assessment should be conducted to identify the sample frequency, locations and type of monitoring performed, based on the activities performed and proximity and risk to the critical zones. Again, knowledge about the facility and processes is key to establishing such a program.When a program is introduced, it creates data. Individual sample results give an indication of the cleanroom performance at the specific sample time, however individual data doesn’t give any indication if the cleanroom can maintain microbial and particulate levels in a controlled state over a prolonged period. Hence, monitoring programs are expected to have procedures in place to detect adverse trends, with alert and action levels to address these. Trend reports should be compiled at suitable frequencies with appropriate review and interpretation of the data. In any situation where an excursion or adverse trend is reported, root cause analysis and product impact assessments are to be completed with corrective and preventive actions taken where required.
How do regulatory requirements impact sterility assurance strategies, and how do you ensure compliance across different regions?
Regulatory requirements and guidance have always been there to provide information on how to design, operate and control a sterile manufacturing process. There are expectations about facility design, cleaning and sterilisation of equipment, operator training and qualification, and guidance how to monitor their performance to name a few. Excellent references are EudraLex Annex 11 and the 2004 FDA Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing2. All relevant elements should form part of a holistic sterility assurance strategy. How these requirements are implemented into the unique processes of a Company is another challenge as regulatory requirements are not too prescriptive, and it is up to the Company to identify which apply and justify how the requirements are compliant. As this cannot reside with one person or department, the subject matter experts require knowledge about the specific regulations and how these apply to their area of expertise with support and oversight of the Quality unit.
What are some common misconceptions about sterility assurance that you encounter?
What is often seen is that sterility assurance is the responsibility of the Microbiology laboratory who are to tell how to assure sterility of the product. Companies focus predominantly on the performance of critical areas where their sterile products are manufactured and not so much on ancillary areas, utilities and processes as these are not deemed direct impact. However, this is a misconception as it is the sum of all elements that make a sterility assurance program work where the knowledge and input from different experts is required. It starts by taking care of the periphery and all supporting systems that eventually provides the largest protection of the product getting contaminated.
How does the design of a facility impact sterility assurance in pharmaceutical environments?
Quality of a product, and as such its sterility assurance, cannot be tested into a product. A passing sterility test simply indicates that no microbiological contamination was detected in the sample tested. Hence, preventing the likelihood of microbial ingress into the facility, utilities and equipment, and ultimately in the product is of most importance. Facility design and how it is operated plays a key part the overall sterility assurance. Besides the design of the facility, pressure cascades, location of equipment, personnel and material flows all play an important role in the prevention of micro-organisms having a disastrous impact on product quality and as such jeopardize patient safety.
References:
- EudraLex Volume 4 Good Manufacturing (GMP) Guidelines – Annex 1, Manufacture of Sterile Medicinal products (2022). Accessed through: https://health.ec.europa.eu/system/files/2022-08/20220825_gmp-an1_en_0.pdf
- FDA Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice (2004). Accessed through: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/sterile-drug-products-produced-aseptic-processing-current-good-manufacturing-practice
