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Russell Madsen, group leader of the Parenteral Drug Association (PDA) Filtration Interest Group, discusses technical and regulatory considerations in filtration for parenteral drug manufacturing
In parenteral manufacturing, filtration is used for particulate control, depyrogenation, and sterilization. Russell Madsen, president of the Williamsburg Group, group leader of the Parenteral Drug Association (PDA) Filtration Interest Group, and member of the editorial advisory board of Pharmaceutical Technology, discusses why filtration is important in parenteral drug manufacturing and related initiatives of the PDA Filtration Interest Group.
Importance of filtration Pharmaceutical Sciences, Manufacturing & Marketplace Report: Why is filtration such a critical issue for parenterals?
Madsen (PDA Filtration Interest Group): Patient safety requires parenteral products to be sterile and free from objectionable levels of particulate matter and endotoxins. Filtration is used to remove particulates, for depyrogenation, and for sterilization of aseptically produced parenteral products. Each of these functions has different control parameters and processing requirements. From a risk-based perspective, sterility assurance is the most critical of these filtration processes. Filtration also can be used to remove viruses from biopharmaceutical process streams and products.
Filtration techniquesPharmaceutical Sciences, Manufacturing & Marketplace Report: What are the major techniques that are used for filtration of parenterals, and what are the benefits and limitations of each?
Madsen (PDA Filtration Interest Group): Broadly, there are three major techniques: depyrogenation, prefiltration, and sterilizing filtration.
Depyrogenation is accomplished by means of ultrafiltration, reverse osmosis, microfiltration using charged filters, and charge-modified depth filters. Prefiltration is used to control the particulate and microbial levels reaching the final filter.
Prefiltration can occur in several stages; for example, a depth filter can be followed by a membrane filter. Controlling particulate and microbial levels prior to sterilizing filtration minimizes the potential for blocking or clogging the final filter in a properly designed system with adequate capacity, [thereby] ensuring filtration efficiency and minimizing changes between pre- and postfiltration diffusive flow integrity test values. The use of two sterilizing-grade filters in series is a special case where the first sterilizing-grade filter acts as a prefilter to stringently control the microbial level presented to the second, final filter.
Sterilizing filtration is used to remove all viable microorganisms from the product stream when other sterilization methods, such as moist-heat terminal sterilization, cause unacceptable levels of product degradation. Stringent controls, including knowledge of the prefiltration bioburden, sterilization of the filter, its housing and associated tubing, and filter-integrity testing, are required to ensure sterility of the filtrate. Validation studies demonstrating the ability of any particular combination of filter, product, and processing conditions to produce a sterile filtrate are required. Typically, these validation studies employ B. diminuta (if viable in the product) at a challenge level of 1 x 107 organisms per cm2 of effective filter area in the product to be filter-sterilized. If the standard challenge organism is not viable, other options are available. (See Sterilizing Filtration of Liquids, PDA Technical Report No. 26 (Revised 2008) for details and recommendations.)
Presterilized, single-use filter assembliesPharmaceutical Sciences, Manufacturing & Marketplace Report: What recent advances have been made in filtration technology and how are they addressing some of the aforementioned issues? What might be in development?
Madsen (PDA Filtration Interest Group): Regulatory agencies, such as FDA and EMA, have stressed the need to have detailed knowledge of the prefiltration bioburden to demonstrate microbiological control of the manufacturing process. The presterilization bioburden should not exceed the limit established during product development and validation of the sterilizing filtration process.
The use of presterilized, single-use filter assemblies simplifies the set-up and sterilization of the filtration system, especially where multiple filters are used in series. This approach is consistent with the increasing use of single-use processing equipment, such as chromatography capsules, processing and holding bags, and sterile connectors, to minimize the risk of cross-contamination while providing operator protection from potent and toxic biopharmaceutical process streams.
Presterilized capsule filters minimize the risks of improper set-up and assembly of filter housings, leaking O-rings, and eliminate the need for sometimes complex and difficult-to-validate steam-sterilization of the assembled units. In addition, single-use sterilizing filter capsules are increasingly available in sizes, configurations, and membrane materials that directly replace conventional stainless-steel housings and cartridge filters while providing increased sterility assurance and minimizing risk.
The future will see increasing use of single-use equipment, including sterilizing filters, tangential flow units, and purification columns. It is conceivable that someday sterile, out-of-the-box systems will be available for parenteral production encompassing compounding to filling.
Prefiltration poststerilization integrity testingPharmaceutical Sciences, Manufacturing & Marketplace Report: Why is prefiltration poststerilization integrity testing so important? What are the issues that must be addressed?
Madsen (PDA Filtration Interest Group): While the European GMPs require prefiltration poststerilization testing of sterilizing filters, the US aseptic processing guidance is largely silent on such testing. However, both documents require post-use integrity testing.
Pre-use poststerilization integrity testing (PUPSIT) is intended to show that a filter in its housing, having been subjected to a sterilization process, passes a validated integrity test and has not been damaged during sterilization. In most cases, the filter has already been subjected to one or more presterilization integrity tests: by the filter manufacturer prior to sale and by the user after having been placed in its housing and flushed prior to sterilization. The purpose of such testing is to demonstrate that the filter is integral and has the appropriate pore-size rating.
However, PUPSIT often requires exposing the downstream side of the filter to atmospheric pressure, potentially compromising the sterility of the unit. From a risk-based perspective, this approach therefore makes little sense as long as the sterilization process for the filter has been validated and shown not to damage or cause loss of integrity of the sterilized filter. If, in fact, the sterilization process damaged the filter, the damage would be detected during post-use integrity testing, minimizing the importance of PUPSIT.
PDA published an article “Pre-use/Post-sterilization Integrity Testing of Sterilizing Grade Filters” in the September–October issue of the PDA Journal of Pharmaceutical Science and Technology. The article recommends that the PUPSIT decision should be “. . . made by the filter user upon thorough, documented risk-based analysis in accordance with ICH guidelines.” PDA is planning a research project designed to evaluate the risks associated with PUPSIT and the likelihood that damage to the filter caused by sterilization would not be detected in post-use integrity testing.
Focus for 2013Pharmaceutical Sciences, Manufacturing & Marketplace Report: What issues is the US PDA Filtration Interest Group tackling in 2013? What do you anticipate might be issues that the group will address over the longer term?
Madsen (PDA Filtration Interest Group): For 2013, the next US PDA Filtration Interest Group (IG) meeting will be held on April 16 at the Peabody Orlando Hotel in Orlando, Floridia. There will be four presentations followed by a discussion of topics of general interest. Monica Cardona, Pall Corporation, will present “Safety Considerations for Gas Filtration in High Temperature and Oxygen Enrichment Applications.” Mandar Dixit, Sartorius Stedim North America, will discuss “Optimizing Total Cost of Ownership for Membrane Filtration.” The title of Lia Jeffrey’s presentation, EMD Millipore Corporation, is “Retention of Mycoplasma and Small Microorganisms,” and Leesa McBurnie, Meissner Filtration Products, will provide an update on the activities of PDA’s Mycoplasma Task Force Filtration Subgroup.
Longer term, the IG [Interest Group] is likely to continue to address PUPSIT issues and support discussions on that topic with European and American regulatory agencies. Single-use filtration technologies and devices will be prominent topics for discussion.