What is Pre-use Post Sterilisation Integrity Testing (PUPSIT)?
PUPSIT stands for pre-use post sterilisation integrity testing. PUPSIT is performed once your sterilising filter is installed to ensure that the sterilisation and installation process has not damaged your sterilisation filter prior to filtration of your product.
What do the regulations say?
PUPSIT was first introduced to the EMA Guide to Good Manufacturing Practice for Medicinal Product in 1997. Since 2002 the Australian Code for Good Manufacturing Practice for Medicinal Product has included a clause that has mandated PUPSIT:
“85. The integrity of the sterilised filter should be verified before use”.
The phrase “sterilised filter” here, indicates that filter integrity test must be performed post the sterilisation process but prior to the filtration of product.
The same clause is mirrored within the following regulations:
- Eudralex Volume 4: WU guidelines to Good Manufacturing Practices Medicinal Products for Human and Veterinary Use: Annex 1 Manufacture of Sterile Medicinal Products: 2008
- WHO Good Manufacturing Practices for Sterile Pharmaceutical Products Annex 6: 2011
Similar clauses are contained within the following guidelines and regulations:
- ISO 13408-2 Aseptic Processing of health care products Part 2: Filtration
- 8.10 “The filtration system should be designed to permit in place integrity testing as a closed system prior to filtration
- 9.5 “Physical Testing of a sterilising filter in situ should be conducted before use after sterilisation where the design of the filtration system permits”
- PICs Recommendation on the validation of Aseptic Processes Clause
- 9.5.2 “Each individual filter used for routine production should b tested before and after use”
- FDA – 2004 Aseptic Processing Guidelines
- “Integrity testing of the filter can be performed prior to processing, and should be routinely performed post-use”
Why is PUPSIT performed?
PUPSIT is performed to combat a phenomenon that is sometimes referred to as “filter flaw masking”. This is the concern that minor filter flaws in the filter membrane resulting from the sterilisation or installation process can become clogged during the filtration process during batch processing.
The result of this masking effect is a non-integral filter passing a post use integrity test as a result of the foulant on the membrane.
In theory, this means the sterility of a portion of your batch could be affected.
How is PUSIT Performed?
PUPSIT is performed once the sterilising filter is in situ for batch filtration processes using the same method that is utilised for post-use integrity testing. Additional components must be installed on your filter housing to perform PUPSIT, these include:
- Hydrophobic filter for sterile wetting of filter
- Gas Filter
- Flush Receiver
- Hydrophobic Vent filters (For filter housing & flush receiver)
PUPSIT assemblies can be installed on single-use or stainless steel filter components. For redundant or serial filtration processes an additional PUPSIT assembly will be required for each filter.
What are the risks of PUPSIT?
The implementation of PUPSIT introduces additional risks to your processes that should be considered, these include:
- Additional aseptic handling required
- Supplementary connections and pipework increase the risk of loss of integrity within the transfer line
- Product dilution, resulting from incomplete filter drying required post integrity test
Correctly designed PUPSIT systems must ensure that they do not increase the risk to patient safety or commercial processes.
Are they any occasions where Pre-use Post Sterilisation Integrity Testing (PUPSIT) is not required?
At present the PIC/S and EMA GMPs state that integrity testing of sterilised filters should be performed prior to filtrations process. Ultimately, this means all processes that include a sterilising filtration step must perform PUPSIT.
This expectation remains a contentious issue within industry. The view of many manufacturers (and filter suppliers) is that the increased risk of product contamination or degradation as a result of performing PUPSIT is greater than the potential risk of filter flaw masking.
The new draft version of Annex 1 released in 2017 appears to offer some relief for small batch manufacturers, allowing a formal risk assessment to achieve compliance without performing PUPSIT.
“8.84 The integrity of the sterilized filter assembly should be verified by testing before use, in case of damage and loss of integrity caused by processing, and should be verified by on line testing immediately after use by an appropriate method such as a bubble point, diffusive flow, water intrusion or pressure hold test. It is recognised that for small batch sizes, this may not be possible; in these cases an alternative approach may be taken as long as a formal risk assessment has been performed and compliance is achieved. There should be written integrity test methods, including acceptance criteria, and failure investigation procedures and justified conditions under which the filter integrity test can be repeated. Results of the integrity tests (including failed and repeated tests) should be included in the batch record.”
This clause attempts to provide some clarification around the necessity for PUPSIT. It can be assumed that the phrase “loss of integrity due by processing” is referring to the sterilisation process, and therefore reiterates the idea that sterilisation and installation of filters can result in the membrane being damaged.
However, the regulators do seem to recognise that PUPSIT may not be appropriate for all manufacturers. A formal documented risk assessment may replace PUPSIT for small-batch processes.
This risk assessment should be robust, based on product knowledge and solid scientific data, but where can you find this information?
PDA/BPOG Working Group on PUPSIT
A consortium between the Parenteral Drugs Association (PDA) and the Biophorum Operations Group (BPOG) has been performing a series of investigations to gather scientific evidence around PUPSIT, the object of these collaborative workgroups is summarised below:
“The overall objective of this collaboration is to perform a series of integrated and interdependent workstreams that will provide industry and regulators alike with information that can be used to make informed decisions on how best to control and prevent sterilizing grade filter failures or improve detection of failures. It is not anticipated that any individual workstream will result in definitive positions, but rather that the output of all workstreams are needed to form a valid, scientific position.”
The results of these workstreams have not yet been completed or peer-reviewed, but the PDA letter on the 29th of August contained an update on these projects. This can be read at the link below
In short, these workstreams have shown:
- That filter masking is a real phenomenon; however, it is extremely unlikely to occur during sterile product manufacturing. The foulant concentration required to produce false-positive results were far higher than what would be expected or even possible during normal manufacturing conditions.
- Filters containing minor flaws from the sterilisation processes are extremely rare (Data gathered from industry).
- Results were consistent between pre and post possessing bubble point tests on sterilising filters (No increase/decrease in bubble point). This indicates that foulant loading on filters from normal processing is unlikely to increase the likelihood of a false positive.
This consortium will also produce a best practice guide and a detailed expert-facilitated risk assessment to help sterile and filter manufacturers identify risk and perform analysis on their processes. The aim of these is to help manufacturers produce robust PUPSIT strategies and document alternative approaches in a formal risk assessment.
What does mean going forward?
As more data becomes available, it is possible that the necessity for PUPSIT for small-batch manufacturing could be mitigated using the scientific data developed by the PDA/BPOG consortium in conjunction with established knowledge of your processes.
Where possible, foulant concentrations and filter loading data should be compiled for your process. A solid rationale mitigating the use of PUPSIT would be reliant on this scientific data and knowledge.
It should be noted that the final wording of the updated Annex 1 has not been released. It is conceivable, in light of the PDA/BPOG studies, that the wording may allow greater emphasis on the risk-based determination of PUPSIT requirements for all manufacturers.