Position Paper Pre Use It Mwj 01 11 1

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– 1 – January 28, 2011

To whom it may concern The enclosed Position Paper Pre-use/Post-sterilization Integrity Test is segmented in an Introduction, Executive Summary, Analysis and Recommendations. Please do not hesitate to contact me, if additional questions arise. I hope the information meets the requirements.

Sincerely,

Maik W. Jornitz Founder BioProcess Resources LLC

www.go-bpr.com, [email protected]

– 2 – January 28, 2011

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Position Paper Pre-use/Post-sterilization Integrity Test

• Introduction • Executive Summary

• Analysis

1. Implications 2. Assumptions versus Data

• Recommendations

• References

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Introduction Sterilizing grade filtration has been used for decades with success,

reliability and accuracy. The reliability of this particular aseptic processing step increased with filter stability improvements, robust integrity test methodologies and especially process validation requirements, which evaluate the performance of a particular sterilizing grade filter under process conditions utilizing either the actual fluid or a placebo, if the fluid is bactericidal or bacteriostatic (1, 2, 3).

To verify that the sterilizing grade membrane filter is unflawed, integrity tests, like Bubble Point, diffusive flow or pressure decay, are used. The integrity test of a sterilizing grade filter has to be and most commonly is performed after the filtration process (post-use) (1, 2). Some filter users test the integrity before the filtration process (pre-use) and before the filter is sterilized. Extremely rare are integrity tests pre-use, post-sterilization, as such test would require downstream, filtrate side manipulation and therefore is considered precarious.

EU Annex 1 (4), paragraph 113. states now “113. The integrity of the sterilised filter should be verified before use and should be confirmed immediately after use by an appropriate method such as bubble point, diffusive flow or pressure hold test….The integrity of critical gas and air vent filters should be confirmed after use. The integrity of other filters should be confirmed at appropriate intervals.” The paragraph, in its first sentence, recommends the rare and risk attached pre-use, post-sterilization integrity test, which we believe is undesirable.

Executive Summary

Performing a pre-use, post-sterilization integrity test has only justification due to a) possible damage to the filter during the sterilization process or b) a minor damage of the filter might be blocked resulting in a integrity test pass due to the blockage. Justification a) has its merits as most commonly filter fail due to excessive steam sterilization parameters, although these damaged filters will be detected by the post-use test. This would mean that the risk within this process is an economical and not a drug quality risk. The batch will be either discarded or reprocessed, if validated so. Justification b), a damaged filter becomes integral during the filtration process is highly unlikely and so far has not been yet established by any major filter manufacturer. These manufacturers have thousands of high burden challenge tests of damaged filters, just failing the integrity pre-use, which still fail the integrity test post-use, even with such high blocking fluids as experienced in bacteria challenge testing (5, 6, 7). This justification does not have any merit nor scientific evidence.

A risk based analysis shows that the risk of performing a pre-use, post-sterilization integrity test is higher than not to perform such test. The potential contamination risk to a sterilized filtrate line, downstream of the filter, causes far more concern to drug quality than the lack of a pre-use integrity test.

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Therefore the recommendation is to leave such decision to the filter user, as the risk not performing a pre-use test is a sole economical risk and does not enhance the drug safety. Contrary it creates a potential drug safety risk, which might not be detected. The ICH guidelines (8) state “The use of the word “should” in Agency guidances means that something is suggested or recommended, but not required” and therefore support the notion to leave the final decision to the filter user.

It would be advisable to rather utilize the FDA Guidance (2) approach, which recommends “Integrity testing of the filter(s) can be performed prior processing, and should be routinely performed post-use.” This again allows the end-user to make the decision on a risk basis.

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Analysis In this section, the implications of the enforcement of a pre-use, post-

sterilization integrity test are analyzed. The balance of benefits versus risk will be described in detail. There have also been assumptions made, which will be considered against a scientific data base.

The detailed analysis of all implications and data will support the recommendations following this section.

1. Implications

Currently filter users are either in-line steam sterilizing filters or utilize gamma irradiated Capsule filters connected to a filtrate bag or manifold. When filters are in-line steam sterilized, the filtrate side is kept under positive pressure after the steam sterilization process to assure that the filtrate line is leak tight and no potential microbial ingress can happen. Any down-stream manipulation or additional attachment commonly raises the risk of flaws, mishandling, leaks or secondary contamination, therefore should be avoided.

The pre-use, post-sterilization test either performed manually or with an automated integrity test system would require manipulation of the downstream side, as the filtrate side requires being under atmospheric pressure. There are different process designs scenarios possible, which are evaluated below, not meaning of being complete, but considered as review point.

Process Scenario Description Evaluation

A 3-way valve is installed to separate the sterilized downstream process from the mani-pulation. The wetting fluid is flushed into the blue retainer vessel, which has vent filter attached. The vent filter assures atmospheric pressure conditions.

The design adds connections to the downstream side, the vessel/ vent filter assembly needs to be sterilized, the vent filter needs to be pre-use integrity tested, the product filter needs to be dried to avoid dilution of the filtered product

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Process Scenario Description Evaluation

Instead of a hold vessel with a vent filter, the system utilizes a 3-way valve and a hydrophobic/ hydrophilic filter combination. The wetting fluid is drained through the hydrophilic section of the filter and the hydrophobic section assures atmospheric pressure conditions

The design adds connection points to the downstream side, the filter requires to be steamed and integrity tested pre-use, post-steaming, which is not possible, since the filter is a hybrid of hydrophobic/ hydrophilic sections and it needs to be wetted with solvents.

Redundant sterilizing grade filtration is used, both filters are validated to retain organism according to ASTM 838-05 (9). Filter 2 acts as a barrier to the downstream process and Filter 1 is the sterilizing grade filter pre-use tested.

The design adds downstream connection, the two sterilizing grade filter mean possible increase in hold-up volume, unspecific adsorption and leachables. Both filters require to be validated and bioburden in front of Filter 1 needs to be <10cfu/100ml. (10)

In this scenario, the actual product is used as wetting agent, flushed into the downstream side equipment (vessel, fill hopper). Then the filter is tested using product wet integrity test limits. The vent filter assures atmospheric pressure conditions.

If the filter fails the product would be lost on the downstream side or, if validated requires to be reprocessed. The downstream side is under atmospheric pressure conditions, which elevates the risk of ingress, if there is a connection leak. The hydrophobic filter requires integrity testing.

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It can be clearly seen that any pre-use, post-sterilization process design is complex, requires elaborate set-up and therefore might elevate the risk of human error. In addition, the steaming process of the new designed process becomes more complex and requires re-qualification. Since the steaming process is critical in regard to pressure/temperature conditions a new set-up requires careful evaluation of the p/t conditions to achieve sterility, but also to avoid any excessive differential pressure conditions. This new set-up would also require re-training of the end-user.

The first three of the design scenarios will also require the re-validation of the filtrate quality as wetting fluids will dilute the filtrate. In case of redundant filtration, the unspecific adsorption might be elevated and again yield requires being determined. The hydrophobic vent filters required in the design schematics also need to be integrity tested and since critical to the process, the integrity test needs may meet the liquid filtration needs.

Overall, pre-use, post-sterilization integrity testing means more complex and therefore risk elevated filtrate designs. The questions required to be posted: “Does the pre-use, post-sterilization integrity test increase drug safety in comparison to the higher complexity of the sterile downstream side ?”. We believe not. We believe from a risk management standpoint and evaluation, that the risk of a downstream manipulation error is by far higher than the lack of a pre-use, post-sterilization integrity test.

2. Assumptions versus Data

Multiple technical assumptions probably led to the current paragraph 113. and the claim that pre-use/post-sterilization integrity tests is necessary. Within this section, we analyze the assumptions and compare these to available data.

a) In-line steam sterilization damages the filter and the failure

can only be found during the post-use integrity test. Data: In fact steam sterilization (in-line, especially in reverse direction) is probably the most stressful situation for the filter element and failures have been experienced (Figure 1.). Having said this, most of the time these failure situations were found when the steam sterilization qualification was insufficient or not performed or when the filter user was not trained properly. Steam sterilization cycles require appropriate qualification to establish the efficiency, but also the parameters to avoid any excessive pressure/temperature profile. If the differential pressure over the filter is too high at elevated temperatures, the filter will be damaged, most commonly substantially. The failed filter would be picked up by the post-use integrity test and the filtered product either needs to be discarded or reprocessed, if validated so. The failure effect is a commercial one, but not a undetected drug safety problem, since the post-use test will detect such damaged filter.

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Figure 1.: Damaged filter due to excessive steam sterilization pressure/temperature condition

b) Enlarge pore or defect after the sterilization process is covered,

plugged, self-repaired or masked and will not be detected by the post-use integrity test. Data: The theory of defect or enlarged pore plugging during the course of the filtration has been discussed many times within the filtration expert group. So far there is consensus that such occurrence has not happened, neither in the industry nor in the filter manufacturers in-house tests. Pre-use failed filters always failed post-use and any defect has to been covered that the post-use test passed. These evaluations are supported by rigid bacteria challenge tests performed by the filter manufacturers during the correlation of integrity test limits to the bacteria challenge test. These correlation tests use a hundreds of filter of different integrity test ranges, are pre-use tested, bacteria challenged at a high level (up to 108 cfu/cm2) and afterwards post-use tested (Figure 2.). The integrity test value might shifts slightly, but a pre-use failed filter always failed post-use. In addition the given integrity test limits have safety margins, which cause a filter integrity rejection even when retentive according to the bacteria challenge test. The integrity test limits are set to include such safety margins to avoid any borderline passes. Furthermore, literature searches in regard to any pre-use fail, post-use pass test results have not shown any merit. There has never been an occurrence of such scenario reported, neither in the scientific field nor anecdotal.

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Figure 2.: Typical bacteria challenge/integrity test limit correlation

(courtesy of Sartorius Stedim)

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One has to understand that the described bacteria challenge test of >108 cfu/cm2 is in most case not found within filtration processes. Excessive filter fouling or blockage of the sterilizing grade filter has to be avoided to process the defined batch. The sterilizing grade filter cannot be exchanged during the filtration process; therefore the scaling of the filter to process scale allows a safety margin for the effective filtration area. Filters are not excessive used and blocked, but remain rather less challenged. This also means that a solid blockage of a filter and therefore defect coverage or masking does not happen in real life processes. Furthermore, guidances (1, 2) recommend evaluating process parameters, which have been utilize for the process specifications and validation. These parameters are differential pressure over the filter, flow rates, total throughput or filtration time. If these parameters fall out-of-specification, the filtration process requires to be investigated. This also means that a flawed filter would show unusual process parameter behaviors, as the flaw would result in higher flow rates, contaminant penetration, lower differential pressures etc. A flawed filter would probably even be recognized by an out-of-specification event.

c) The risk to drug safety and quality is higher, when a pre-use, post-sterilization is not performed. This is not the case. First of all, pre-use, post-sterilization integrity testing is not a common practice, but rather a rare event. This means that many sterilizing grade filtration application perform very successful, processing a sterile filtrate. Incidences of post-use filter failure were detected and the filtered product either discarded or reprocessed. Nevertheless, utilizing the PQRI (11) risk assessment process, the actual risk of a pre-use, post-sterilization activity is higher than the lack of this activity. According to this document the level of risk is calculated as:

Risk = (S) x (F) x (D)

(S): Severity of the event (consequence) (F): Frequency estimation (likelihood of event occurring) (D): Level of detectability

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The three categories are measured as: Value Severity

1 Negligible: Has no potential to have an adverse effect on identity, strength, quality, purity or potency of a drug product

2 Minor: Has minimal potential to have an adverse effect on identity, strength, quality, purity or potency of a drug product

3 Moderate: Has moderate potential to have an adverse effect on identity, strength, quality, purity or potency of a drug product

4 Major: Has a substantial potential to have an adverse effect on identity, strength, quality, purity or potency of a drug product

Value Frequency 1 Highly unlikely: The probability of the event occurring is so low

that it can be assumed that the event will not occur 2 Unlikely: Event not expected to occur, but theoretically possible 3 Likely: Event may occur and/or has occurred in the past 4 Highly likely: Event expected to occur

Value Detectability 1 Readily detectable: Will be detected 2 May be detectable: May be detected 3 Not detectable: No mechanism for detection

The scenario of the pre-use, post-sterilization integrity test performance and the lack thereof are now compared side-by-side: Category Test No Test Rational Severity 4 4 If the filter fails or microbial ingress

happens, it has a major effect in both cases

Frequency 3 2 Microbial ingress into the downstream side has occurred, for this reason the downstream side is commonly held under pressure after steam sterilization. This overpressure is replaced by atmospheric pressure during the pre-use test (3). Since steam sterilized downstream processes are commonly held at overpressure the likelihood of ingress is low (2).

Detectability 3 1 If there is a microbial ingress due to downstream manipulation, when the test is performed, it will not be detected (3). If the filter is flawed due to the steam sterilization process it will be readily detected by the post-use test (1).

Risk Level 36 8 Risk assessment would not recommend a pre-use, post-sterilization test.

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Recommendations

The recommendations resulting from the analysis of the implications and data are to either reword paragraph 113. to ”The integrity of the sterilising grade filter may be verified before use and should be confirmed immediately after use by an appropriate method such as bubble point, diffusive flow or pressure hold...”. The other option would be to utilize the approach of the FDA, which defines the word ”should” as a suggestion or recommendation, leaving the decision to the end-user in the first place. Since post-use testing is of importance to confirm the filters separation performance during the process, the paragraph might be changed to ”The integrity of the sterilised filter should be verified before use and must be confirmed immediately after use by an appropriate method such as bubble point, diffusive flow or pressure hold...”.

Both alternatives leave the decision to the filter user, who has the unquestionable desire to produce and deliver a safe drug product. It might be that the end-user is performing only a post-use test or a post and pre-use, pre-sterilization test or a post and pre-use, post-sterilization test. The important fact is that any of these tests have to show a safety improvement to the drug, not to the process. If the drug is compromised due to a lack of process safety it is undesirable and the inability to detect a possible microbial ingress due to filtrate manipulation receives an elevated risk level.

As many times stated “you cannot test quality into your product, you have to produce it”. References

1. PDA Technical Report 26, Liquid Sterilizing Filtration, Parenteral Drug Association, Bethesda, MD, 2008

2. Food and Drug Administration (FDA), Guideline on Sterile Drug

Products Produced by Aseptic Processing, Division of Manufacturing and Product Quality, Office of Compliance, Center for Drugs and Biologics, Rockville, MD, 2004

3. ISO 13408-2:2003(E), Aseptic processing of health care products –

Part 2: Filtration, ISO copyright office, Geneva, 2003

4. EudraLex Volume 4, EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use, Annex 1, Manufacture of Sterile Medicinal Products, Brussels, 2008

5. Jornitz, M.W., EU Annex 1, Paragraph 113, Pre-use Integrity Testing, Minimizing or Increasing Risk ?, PDA/FDA Joint Regulatory Conference, Washington, DC, 2008

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6. PharmTech, The Debate over Pre-use Filter-Integrity Testing: Making Assurance Double Sure ?, PharmTech.com, 2009

7. Martin, J., Current Topics in Sterilizing Filtration, ISPE Aseptic

Processing Course, Tampa, 2009

8. ICH Q8, Q9, Q10 Guidance for the Industry, FDA, Rockville, MD, 2006, 2006, 2009

9. ASTM, Standard F838-05, Standard Test Method for Determining

Bacterial Retention of Membrane Filters Utilized for Liquid Filtration, American Society for Testing and Materials, West Conshohocken, PA, 1983, Revised 1988, 2005

10.EMEA, Committee for Proprietary Medicinal Products (CPMP), Note for

Guidance on Manufacture of the Finished Dosage Form, London, 1996

11.PQRI, Post Approval Changes for Sterile Products Working Group, 2007

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