Pre-Use Post Sterilisation Integrity Testing (PUPSIT) in the new EU GMP Annex 1

Recommendation

7/8 May 2024

Annex 2 & Co. - GMP Compliance for Biopharmaceuticals - Live Online Training
Regulatory Requirements and Practical Implementation

PUPSIT is THE most discussed new requirement in new EU GMP Annex 1. But what is the legal basis and what is required? The EU Guidelines for Good Manufacturing Practice Annex 1 outline a requirement for verifying the integrity of a sterilizing grade filter before and after it is used in the production of medicinal products.

What is the exact Annex 1 Requirement?

EU GMP Annex 1 Paragraph 8.87:

The integrity of the sterilised filter assembly should be verified by integrity testing before use (pre-use post sterilisation integrity test or PUPSIT), to check for damage and loss of integrity caused by the filter preparation prior to use. A sterilising grade filter that is used to sterilise a fluid should be subject to a non-destructive integrity test post-use prior to removal of the filter from its housing. The integrity test process should be validated and test results should correlate to the microbial retention capability of the filter established during validation. Examples of tests that are used include bubble point, diffusive flow, water intrusion or pressure hold test. It is recognized that PUPSIT may not always be possible after sterilisation due to process constraints (e.g. the filtration of very small volumes of solution). In these cases, an alternative approach may be taken providing that a thorough risk assessment has been performed and compliance is achieved by the implementation of appropriate controls to mitigate any risk of a non-integral filtration system. Points to consider in such a risk assessment should include but are not limited to:

i. In depth knowledge and control of the filter sterilisation process to ensure that the potential for damage to the filter is minimized.

ii. In depth knowledge and control of the supply chain to include:

• Contract sterilisation facilities.
• Defined transport mechanisms.
• Packaging of the sterilised filter, to prevent damage to the filter during transportation and storage.

iii. In depth process knowledge such as:

• The specific product type, including particle burden and whether there exists any risk of impact on filter integrity values, such as the potential to alter integrity-testing values and therefore prevent the detection of a non-integral filter during a post-use filter integrity test.
• Pre-filtration and processing steps, prior to the final sterilising grade filter, which would remove particle burden and clarify the product prior to the sterile filtration.

How to perform PUPSIT?

PUPSIT is a test that is used to ensure the integrity of a sterilizing filter and its associated components, such as the filter housing, support structure, and connections, after the filter has been installed and sterilized but before it is used to filter product. This test can be performed using a bubble point, diffusive flow, or pressure hold test method. One example of a sterilized filter system that would require PUPSIT is a gamma-irradiated sterilizing grade filtration bag and tubing assembly.

What are the concerns regarding flaws?

The use of PUPSIT is necessary because there are concerns that a sterilizing filter may develop flaws that could allow microbiological contamination to pass through during filtration. These flaws may be blocked or clogged by fluid contaminants or components during the filtration process and remain undetected during post-use integrity testing. This is known as "filter flaw masking." In order to prevent this, it is necessary to test the filter before use in order to detect and address any flaws, which would ultimately reduce the risk of product contamination.

Learn more about PUPSIT

On 28 - 29 March 2023 a conference track of the PharmaCongress will cover this important topic. Read more about the agenda of the PUPSIT Conference Track.