Polymeric process components that have an impact on the critical quality attributes (CQA) of the final product must be extensively validated to define the level of performance under the process conditions and to document the safety of any product contact components. In accordance with FDA and EMA expectations, these components need to be qualified to quantify any chemicals that may be adsorptive, additive or reactive to the product. Any potential leachables then require secondary assessment to ensure that they do not alter the safety, quality or efficacy of the product.
Fundamentally, the suitability of single-use components/systems, including filtration, for a process, can be assessed by providing data that helps answer the following questions:
- Does the filter or other single-use components affect the product?
- Does the product or process conditions affect the filter or other single-use components?
Data that answers these questions is at the heart of any risk-based review.
The need for these data packages has grown as the adoption of single-use systems has increased and as industry and regulatory guidance for all polymeric, product contact materials has matured. Pall has always been at the forefront of the development of this guidance and our validation laboratories and scientists offer a variety of services and consultancy targeted at delivering a strong package of data that is ready to support any New Drug Application (NDA) or process revalidation.
White Paper: A Risk Based Approach to Validation Studies for Sterilizing Filtration and Single-Use Systems
A Risk Based Approach to Validation Studies for Sterilizing Filtration and Single-Use Systems
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While many sterilizing grade filters deliver robust bacterial retention under most process conditions, the promise of filter performance does not satisfy the regulatory bodies and quality assurance groups.
Where filters are defined as critical, either as a discrete technology or when used as part of a larger single-use system, performance validation is essential to document that the chosen filter can reliably remove any process bioburden.
Sterility is a critical aspect of the product quality attributes. As such, the performance of any filter that is necessary to assure this state is mandated by many regulatory bodies, and clear industry guidance is provided via the Parenteral Drug Association (PDA) Technical Report 26 Sterilizing Filtration of Liquids. The foundation of all filter validation packages requires process-specific bacterial challenge testing to be conducted. This assesses the ability of the sterilizing grade filter to produce a sterile fluid, even under the worst-case conditions of the process. Pall’s sterilizing filter validation program includes, but may not be limited to:
- Viability Testing – to support the validity of the results by quantifying any bactericidal effects of the drug on the test organism.
- Bacterial Retention Testing – to demonstrate the ability of a filter medium to produce sterile filtrate under the worst-case process conditions with a typical challenge concentration of ≥1 x 107 CFU/cm2 of filter membrane area.
- Bacterial Retention Testing with Process Isolates – for specific organisms of concern known to be potential process contaminants.
Risk Consultancy (SOAR)
Quality Risk Management (QRM) and risk mitigation is central to maintaining Quality by Design (QbD). Increasingly, ways are sought to build quality into production operations, to reduce risk to the patient, and to remove potential delays to the commercialization of a drug product.
While Pall’s sterilizing grade filter portfolio reliably removes process bioburden, some high-risk fluids may increase the likelihood of penetration under the rigorous validation conditions. These occurrences are rare but the growth in the filtration of complex formulations such those containing liposomes, lipids, emulsions and surfactants, means that they are real. Pall recommends a risk assessment is performed as early as possible to review any potential risks to sterility assurance. When identified, we assist with screening studies as part of the Sterility Optimization by Assessment of Risk (SOAR) program to achieve success and deliver a robust validation package that fully meets the current regulatory expectations.
Compatibility testing evaluates filters and single-use components for system integrity after exposure to worst-case fluid and process conditions. These include simulated sterilization conditions followed by exposure to maximum process time and temperature.
It is important that the filters and single-use components/systems selected minimize adsorption and loss of product components. Laboratory-scale tests can be used to generate adsorption profiles to help with filter and single-use component/system selection and process qualification. Tests are typically performed at small scale, which can then be confirmed at large scale during production. Filtration and sampling are performed by Pall, however, the analysis of the samples is best performed by the end user using standard quality control methods. Upon review, the results may be used to establish potential pre-treatment options, operational parameters or membrane polymer choices.
Product Wet Integrity Test Parameter Derivation
Filter integrity testing (IT) is performed on critical filters immediately before and after batch filtration to confirm performance to specification.
The use of the product or other process fluid as the filter wetting fluid during this testing can simplify the design of single-use systems and streamline the filter testing procedures.
Our studies define suitable integrity test parameters to evaluate the filter integrity without the need for dedicated wetting fluids.
Where the reduction of leachables or the recovery of product is beneficial, the necessary flush regime after filtration can be established with an understanding of critical product and process conditions.
Highlighted by the increase in the use of single-use technology, regulatory authorities have expressed their concerns relating to leachables that may migrate into the drug product from process equipment and could potentially affect:
- Safety – by increasing the toxicity of the drug
- Quality – by raising impurity levels
- Potency – by inactivating drug components
Studies to identify and quantify these species apply equally to complex single-use systems and to individual components such as filters. Where drug constituents such as proteins may mask some leachables and interfere with their analysis, placebos, mimics and model solvents may be used and the extraction conditions can be optimized to best simulate the process conditions. Worst-case extraction conditions may also be used to determine and identify any possible extractables that may become leachables, and data may already exist in standard product data packages. Pall can provide quality dossiers with this data and provide consultancy and formal reports that can be used to support a comprehensive risk assessment that may negate the need for process specific leachables studies.
Many of Pall’s critical components are supported by sets of extractables data in model solvents that satisfy guidance issued by the BioPhorum Operations Group (BPOG) and USP <665> Polymeric Components and Systems Used in the Manufacture of Drug Products. These data can be provided through Pall’s validation services department and consultancy is available to help develop a robust rationale to support the use of these data in any process submission.
Where the risk assessment concludes that the process is not adequately modeled by the available data, Pall’s Validation services can recommend a study design, tailored to your unique requirements, and provide a full set of protocols and test reports to ensure that the data generated fully meets all quality and regulatory requirements and is ready for inclusion in any submission.
The following services are available on request:
Product quality is important to end users and certain high-risk applications have stringent criteria to meet. Upon request, Pall can offer particle release testing for filters. The objective of the test is to quantify particles (10 to 25 µm and > 25 µm) that could be released from the filter into the product fluid under worst-case process.
Post-Use Integrity Testing
While most critical processes require post-use filter testing immediately after use, for processes where operational or resource limitations make this impractical Pall can perform post-use integrity testing on behalf of the end-user. Reports are issued in a timely manner and can be incorporated directly into batch release or maintenance documentation.