Sterile filter integrity testing and a contamination control strategy (CCS)
What is the meaning of PUPSIT, and why does it matter?
PUPSIT and EU GMP Annex 1 guidelines
What is the global regulatory position on PUPSIT?
A holistic approach to risk during process validation
When manufacturing medicinal products, aseptic processing is an essential step to ensuring the safety, purity, and quality of a medicine. While aseptic processing includes both finish (filtration) and fill (putting product into containers such as vials), this article will focus on the filtration step. In this critical step, sterilizing-grade filters are used, and these filters need to be integrity tested to confirm that they have performed as expected. Sterile filter integrity testing, whether it’s done pre-use, post-sterilization, and/or post-use, helps confirm the structural integrity of a filter and ultimately reduces the risk of contamination of the drug product. Regulatory bodies across the world continue to amend their guidelines to include higher aseptic processing standards. In the context of filtration, the latest guidance highlights a requirement to perform pre-use, post-sterilization integrity testing (PUPSIT) if possible.
Sterile filter integrity testing and a contamination control strategy (CCS)
A critical step in aseptic processing is developing an effective contamination control strategy (CCS), which seeks to identify, evaluate, and control potential risks to the quality of the drug product. Filters and filter integrity testing are parts of the CCS. Manufacturers are encouraged, and sometimes required, to perform filter integrity tests at various points in the process , informed by the results of a risk assessment and the criticality of the filter in question.
Regulatory bodies across the world continue to update their aseptic processing guidelines to include stipulations for when to perform filter integrity testing. Testing can be done pre-use, post-use, and/or pre-use post-sterilization. Currently, US Food and Drug Administration (FDA) guidelines require post-use integrity testing to release a batch; however, European Union (EU) regulatory requirements mandate that manufacturers in the EU perform PUPSIT unless the end user can justify not doing it based on a thorough risk assessment.
What is the meaning of PUPSIT, and why does it matter?
As part of a CCS, pre-use, post-sterilization integrity testing (PUPSIT) is one way by which manufacturers can help ensure the sterility of their aseptically-filled medicinal drug products. PUPSIT determines the integrity of the sterilizing-grade filter and assembly, including filter housing, support structure, and connections, after the assembly has been installed and sterilized but before it is used to filter product.
PUPSIT is carried out to help ensure that the filter has not been damaged during shipping, handling, installation, and sterilization prior to use. A damaged filter could result in a non-sterile product, which can ultimately affect drug safety.
PUPSIT and EU GMP Annex 1 guidelines
While not absolutely required, performing PUPSIT is expected in many countries. Recently, European regulators have amended the Guidelines for Good Manufacturing Practice (GMP) for Medicinal Products for Human and Veterinary Use, Annex 1: Manufacture of Sterile Medicinal Products (1) to include the option to perform a risk assessment if a manufacturer determines that PUPSIT is not possible. This risk assessment should consider the impact and/or risks of performing integrity testing, which could include damage to the filter setup and a potential breach to the sterile pathway through the process of performing PUPSIT.
In other words, Annex 1 requires manufacturers to perform integrity tests both pre-use post-sterilization, then again post-use, for filtration of liquid drug product. Different approaches to PUPSIT can be taken, including bubble point, diffusive flow (also known as forward flow), or pressure hold test. In cases where integrity testing can’t be performed, Annex 1 requires the manufacturer perform a risk assessment.
The recent update to Annex 1 provides greater clarification on PUPSIT implementation and puts quality risk management and periodic review of the CCS at the heart of this guidance. You can view our eBook, titled, Manufacturing sterile drug product, to learn more about PUPSIT and its role in a CCS.
What is the global regulatory position on PUPSIT?
Even though regulatory bodies in both Europe and around the world are now stipulating PUPSIT should be performed, these regional guidelines and their adoption globally have not been consistent. The US FDA’s Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practice (2) only says that pre-use testing can be performed, but it does not mandate it. Pharmaceutical Inspection Co-operation Scheme (PIC/S) adopted EU Annex 1 into its own guidelines (3). Because PIC/S is a global organization whose aim is to develop common standards in the field of Good Manufacturing Practice (GMP), this effectively means that standards around PUPSIT can impact manufacturers not just in Europe but globally. That said, regional regulatory bodies around the world have instated their own wording around when and how integrity testing should be performed (Figure 1).
Read more about our perspective on global regulatory positions in our white paper, titled, What is the position of the regulatory authorities on PUPSIT?
Fig 1. Regulatory positions on filter integrity testing and PUPSIT.
Risk assessment for PUPSIT
Controlling risks associated with performing PUPSIT is critical. While PUPSIT is designed to detect damage that could occur to the filter during transportation, handling or the sterilization process, if not performed properly, it may introduce a new risk of sterility breach, including but not limited to:
- Additional operator steps to perform PUPSIT (operator errors)
- Increased number of components and connections (leaks)
- Manual operation of PUPSIT
These risks may be further increased where complex filtration systems, such as a system including redundant filtration, are used.
Actions that may mitigate this risk include:
- carefully optimized system design
- control of the bioburden in the wetting fluid used to perform PUPSIT
- operator training to help ensure accurate execution of critical tasks
- the adoption of automated solutions to further control human risk factors
How to perform PUPSIT testing
The addition of PUPSIT without robust process design and usability controls may increase the risk of adulteration of the drug product. This risk-based argument to support the absence of PUPSIT is common. This may even be accepted by some inspectors when it can be shown that there are no practical ways to overcome these challenges. With over 30 years’ experience in performing integrity testing in steam-in-place and as part of a single-use system (SUS) design, Cytiva offers both a manual PUPSIT system as well as a variety of automated solutions. These are designed to control the risk of improper installation and reduce the time of implementation without adding significant risk. Our standard, manual single-use system allows you to confidently meet Annex 1 guidelines in critical downstream applications such as formulation and filling. On the other hand, our automated solutions can be used for a variety of molecules and concentrations, to deliver the simple operation and process consistency. Both systems use the Flowstar integrity test instruments, trusted by thousands of users for its accuracy and reliability.
Manual PUPSIT solutions
Standard single-use PUPSIT system designs are available with single and redundant filtration options incorporating a range of sterilizing-grade filter sizes from 1 in. to 10 in. and a variety of filtration materials. Auxiliary manifolds such as inlet manifolds, flush bags, and sampling manifolds are also available as ready-to-order standard solutions. The flexibility of the manual solution enables one shadowboard to be suitable for all filter sizes and manifold configurations. The flexibility of the manual solution enables one shadowboard to be suitable for all filter sizes and manifold configurations (Fig 2).
Fig 2. Cytiva manual drug product filtration system.
Automated PUPSUT solutions
Our Cytiva drug product filtration system (DPFS) is an automated solution for performing PUPSIT and post-use integrity testing that is suitable for a wide range of batch sizes and optimized for low and high-concentration biologics (Fig 3). This further reduces the chance of operator error and minimizes the requirement for training on how to implement PUPSIT.
Fig 3. Cytiva drug product filtration system, an automated solution for performing PUPSIT.
Automated solutions offer:
- Simple operation
- Shadowboard design for easy, step-by-step installation, guided on the human-machine interface (HMI)
- Process consistency
- Recipe driven with fully editable recipes to help ensure maximum consistency for batch runs
- Minimized risk of errors
- Highly decreased human intervention to dramatically reduce processes most prone to error
- Automated filter integrity testing
- Forward flow and bubble point procedures for PUPSIT and post-use integrity testing
- Batch recording and process trend analysis
- Automatic recording of batch process elements that reduce risk on data integrity
- Enhanced product recovery
- Filters oriented in the vertical position and air bag included to facilitate recovery of fluid in the downstream flowpath
- Filter manufacturer–agnostic design
A holistic approach to risk during process validation
A risk assessment to investigate the potential for microbial penetration through the sterilizing-grade filter as a result of PUPSIT can be done in-house or it can be performed as part of a validation services package. While every biomanufacturer understands the importance of validating their filters, SUS components, and aseptic filter process as a whole, not every organization can perform these tests on their own.
Fast Trak™ validation services cover a wide range of Cytiva sterilizing-grade filters and SUS components. Testing includes:
- Microbial retention testing
- Compatibility testing
- Adsorption testing
- Product wet integrity testing
- Extractables and leachables (E&L) testing and consulting
- PUPSIT risk assessments
- Regulatory support
- And more
References
- EudraLex - The Rules Governing Medicinal Products in the European Union, Volume 4, EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use, Annex 1 – Manufacture of Sterile Medicinal Products. European Commission (EC). August 2022. Accessed October 2024. https://health.ec.europa.eu/document/download/e05af55b-38e9-42bf-8495-194bbf0b9262_en?filename=20220825_gmp-an1_en_0.pdf
- Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practice. US Food and Drug Administration (FDA). September 2004. Accessed October 2024. https://www.fda.gov/media/71026/download
- Guide to Good Manufacturing Practice for Medicinal Products Annexes. Pharmaceutical Inspection Co-operation Scheme (PIC/S). August 2023. Accessed October 2024. https://picscheme.org/docview/8881
- Regulation on Good Manufacturing Practices (GMP) for Medicinal Products. Ministry of Food and Drug Safety (MFDS). November 2016. Accessed October 2024. https://www.mfds.go.kr/eng/brd/m_18/view.do?seq=71530&srchFr=&srchTo=&srchWord=&srchTp=&itm_seq_1=0&itm_seq_2=0&multi_itm_seq=0&company_cd=&company_nm=&page=1
- Guidance on the Manufacture of Sterile Pharmaceutical Products by Aseptic Processing. Pharmaceuticals and Medical Devices Agency (PMDA). April 2011. Accessed October 2024. https://www.pmda.go.jp/files/000153543.pdf
- Good Manufacturing Practice for Drugs (2010 Revision). National Medical Products Administration (NMPA). March 2011. Accessed October 2024. https://english.nmpa.gov.cn/2019-07/25/c_390613.htm