Test Process and Results of Potential Masking of Sterilizing-Grade Filters.

Pre-use/post-sterilization integrity testing (PUPSIT) has been a widely debated topic for the last several years. To a large extent, the debate is because of the fact that scientific data were not available to provide additional clarity that could inform appropriate risk-based judgements and commensurate actions. To gain clarity, the Parenteral Drug Association (PDA) and BioPhorum Organizations Group (BioPhorum) formed the Sterile Filtration Quality Risk Management (SFQRM) consortium in late 2017. The consortium goals have been to fill existing gaps in scientific data as adequately as possible with studies and industry guidance that would provide professionals and license holders with the ability to make informed decisions about appropriate risk-management strategies. This paper is one in a series of publications that are the result of the collaboration, and these should be considered together and viewed holistically in order to determine the best course of action with regard to PUPSIT. In total, the four papers cover the following areas: (1) data mining to determine the influence of fluid properties on integrity test values, (2) filter masking studies and results (this publication), (3) risk assessment and management from filter production to end use, and (4) points to consider in the best practice of the use of PUPSIT. In total, 25 manufacturers and filter suppliers have contributed to the work of the Consortium, deploying their filtration experts and pooling their collective knowledge and applied science experience to address these questions. This effort has also been supported by many independent experts currently available who have contributed to and driven the Filtration Interest Group in the PDA for many years. Both PDA and BioPhorum have prioritized this program and combined their approaches to deliver this comprehensive body of work. We hope that collectively the publications aid decision making and create greater certainty and confidence and above all alignment between suppliers, manufacturers, and regulators alike on these important questions.

A Review of the Aging Process and Facilities Topic.

Aging facilities have become a concern in the pharmaceutical and biopharmaceutical manufacturing industry, so much that task forces are formed by trade organizations to address the topic. Too often, examples of aging or obsolete equipment, unit operations, processes, or entire facilities have been encountered. Major contributors to this outcome are the failure to invest in new equipment, disregarding appropriate maintenance activities, and neglecting the implementation of modern technologies. In some cases, a production process is insufficiently modified to manufacture a new product in an existing process that was used to produce a phased-out product. In other instances, manufacturers expanded the facility or processes to fulfill increasing demand and the scaling occurred in a non-uniform manner, which led to non-optimal results. Regulatory hurdles of post-approval changes in the process may thwart companies' efforts to implement new technologies. As an example, some changes have required 4 years to gain global approval. This paper will address cases of aging processes and facilities aside from modernizing options.

A consensus rating method for small virus-retentive filters. I. Method development.

Virus filters are membrane-based devices that remove large viruses (e.g., retroviruses) and/or small viruses (e.g., parvoviruses) from products by a size exclusion mechanism. In 2002, the Parenteral Drug Association (PDA) organized the PDA Virus Filter Task Force to develop a common nomenclature and a standardized test method for classifying and identifying viral-retentive filters. One goal of the task force was to develop a test method for small virus-retentive filters. Because small virus-retentive filters present unique technical challenges, the test method development process was guided by laboratory studies to determine critical variables such as choice of bacteriophage challenge, choice of model protein, filtration operating parameters, target log10 reduction value, and filtration endpoint definition. Based on filtration, DLS, electrospray differential mobility analysis, and polymerase chain reaction studies, a final rating based on retention of bacteriophage PP7 was chosen by the PDA Virus Filter Task Force. The detailed final consensus filter method was published in the 2008 update of PDA Technical Report 41. Virus Filtration.

A consensus rating method for small virus-retentive filters. II. Method evaluation.

Virus filters are membrane-based devices that remove large viruses (e.g., retroviruses) and/or small viruses (e.g., parvoviruses) from products by a size exclusion mechanism. In 2002, the Parenteral Drug Association (PDA) organized the PDA Virus Filter Task Force to develop a common nomenclature and a standardized test method for classifying and identifying viral-retentive filters. A test method based on bacteriophage PP7 retention was chosen based on developmental studies. The detailed final consensus filter method is published in the 2008 update of PDA Technical Report 41: Virus Filtration. Here, we evaluate the method and find it to be acceptable for testing scaled-down models of small virus-retentive filters from four manufacturers. Three consecutive lots of five filter types were tested (Pegasus SV4, Viresolve NFP, Planova 20N and 15N, Virosart CPV). Each passed the criteria specified in the test method (i.e., >4 log10 PP7 retention, >90% intravenous immunoglobulin passage, and passing integrity/installation testing) and was classified as PP7-LRV4.

Types of filtration.

There are a multitude of filter designs and mechanisms utilized within the biopharmaceutical industry. Prefilters are commonly pleated or wound filter fleeces manufactured from melt-blown random fiber matrices. These filters are used to remove a high contaminant content within the fluid. Prefilters have a large band of retention ratings and can be optimized to all necessary applications. The most common application for prefilters is to protect membrane filters, which are tighter and more selective than prefilters. Membrane filters are used to polish or sterilize fluids. These filters need to be integrity testable to assess whether or not they meet the performance criteria. Cross-flow filtration can be utilized with micro- or ultrafiltration membranes. The fluid sweeps over the membrane layer and therefore keeps it unblocked. This mode of filtration also allows diafiltration or concentration of fluid streams. Nanofilters are commonly used as viral removal filters. The most common retention rating of these filters is 20 or 50 nm.

Filter construction and design.

Sterilizing and pre-filters are manufactured in different formats and designs. The criteria for the specific designs are set by the application and the specifications of the filter user. The optimal filter unit or even system requires evaluation, such as flow rate, throughput, unspecific adsorption, steam sterilizability and chemical compatibility. These parameters are commonly tested within a qualification phase, which ensures that an optimal filter design and combination finds its use. If such design investigations are neglected it could be costly in the process scale.

Integrity testing.

To ensure that sterilizing grade filters in aseptic processing worked as required, such filters are integrity tested. Integrity tests, like the bubble point, diffusive flow or pressure hold test, are non-destructive tests, which are correlated to a destructive bacteria challenge test. This correlation verifies the integrity test limits the filters have to pass. Integrity tests are required by regulatory authorities. The post filtration integrity test is a must, pre filtration integrity testing is recommended. The different tests have specific limitations therefore there is no overall, best integrity test, which can be utilized for every filtration system.

The mechanics of removing organisms by filtration: the importance of theory.

Very often, the concept of filtration is only considered in terms of sieve retention, which can sometimes be misleading. In this review of the adsorptive particle-capture mechanism, the authors aim to familiarize the filtration practitioner with the possible optimisation of particle retention by the manipulation of factors such as ionic strength, osmolarity, temperature and the use of polymeric filters.