Jerold Martin was the senior vice president of global scientific affairs at Pall Life Sciences and the chairman of the Board and Technology Committee at Bio-Process Systems Alliance.

Jerold M. Martin

This is the first of a series of columns that I have agreed to write on single‑use manufacturing technologies and issues for 

 (PTE), which are sister publications. I want to start by acknowledging former BPhI Editor Laura Bush, who invited me to do this, to welcome Senior Editor Michelle Hoffman, and to thank Managing Editors Chitra Sethi (BPhI) and Fedra Pavlou (PTE), whom I look forward to working with. I also want to acknowledge Andrew Sinclair and Miriam Monge, who did a great job with this column in BPhI over the last several years and who have set a high bar in passing the baton.

I’ve written several editorials and articles for both BPhI and PTE in the past, and I am also a member of the Editorial Advisory Boards for both of these publications, but for those who are not familiar with me, I’ve been in the biopharmaceutical industry for over 31 years and have worked in filtration process development and validation with many pharmaceutical and biotech companies since before the biotech revolution. As an active member of the Parenteral Drug Association (PDA), the International Society for Pharmaceutical Engineering (ISPE), the American Society for Mechanical Engineering — BioProcess Equipment Committee (ASME-BPE) and, more recently, the Bio-Process Systems Alliance (BPSA), I’ve been a contributor or reviewer on numerous industry guides and standards, and have conducted trainings for regulatory agencies in the Western hemisphere, Europe and Asia. In my present role as Chairman of the Board and the Technology Committee of the BPSA, I have had the opportunity to interact with suppliers and users of single-use technologies worldwide and look forward to sharing that perspective here.

During the past 10 years or so, we've seen singleuse technologies explode from production-scale filter capsules, tubing and simple biocontainers to encompass sterile connectors, membrane chromatography adsorbers, bioreactors, mixers, and integrated platform systems with increasing levels of sensors and automated controls. Many articles have been published and singleuse conferences have become regular events, with topics evolving from fundamental technologies to user evaluations and on to process and facility integration.  

The main issues today include: implementation, quality, security of supply, regulatory expectations, system design, integrity/installation testing, QbD, PAT, quality agreements, standardisation, disposal and environmental issues, economic justification, and many more. As this column progresses, let me know what singleuse issues and topics you would like to see further explored. This month, I will touch on some recent developments in standardisation and quality agreements, and provide an update on some of the latest BPSA initiatives in this area.  

Standardisation of singleuse has become a frequent topic in articles, on chat boards and at conferences. Interest has been expressed for standardising materials for films and tubing, as well as the dimensions of sterile connectors, hose barb and sanitary flange fittings. When considering standardisation of singleuse components, it is important to bear in mind that while some aspects of singleuse can be standardised (e.g., approaches to sterilisation, characterisation of extractables, particle and endotoxin testing, tubing ID, hose barb and flange dimensions), it is unlikely that any materials or design features will become a commodity subject to standardisation because of the proprietary nature of many singleuse components. Other than ASMEBPE or ASTM International, none of the primary industry professional or trade associations (PDA, ISPE and BPSA) or regulatory bodies issue formal standards. Pharmaceutical standards bodies, such as the US or European Pharmopoiea or the International Organization for Standardization (ISO), tend to focus more on the final drug product and packaging. These can be extrapolated or adapted to singleuse equipment, but the industry organisations themselves primarily issue best practice recommendations and technical guides rather than formal or obligatory standards. 

One of the key roles of the BPSA, in addition to producing its own best practice guides, is to provide stimulus to other organisations to also develop guides or standards that facilitate singleuse equipment implementation. For example, the BPSA recently submitted a letter to the ASME encouraging a review of the ASME-BPE standard for sanitary flange fittings with regard to using polymeric material instead of traditional metal alloys. The current ASMEBPE Standard for Sanitary Flanges was developed with stainless steel in mind, and specifies dimensions and tolerances that are costly to achieve in a variety of polymers. A modified standard addressing the properties of polymer-based flange connectors that maintains critical fitment requirements, while accommodating the unique properties of molded polymers, could reduce cost of ownership and ensure that all involved parts can interwork with both singleuse and stainless steel systems. For flange connector manufacturers, tooling and production costs could also be reduced if more liberal tolerances were allowed.  

Many singleuse systems integrators now offer standardised singleuse assembly configurations for common functions, or subassemblies that can be customassembled aseptically with sterile connectors by the user. Such rationalisation can help reduce complexity and cost, but further standardisation of designs or materials among suppliers is both practically difficult and would be a barrier to further product developments. Singleuse technology may have moved out of its infancy, but standardisation to create commodities needs to be considered very carefully. Establishing standards for equivalency of designs or materials would stifle innovation and be counter to market demands for improved designs and materials. 

One area that can benefit from a form of standardisation is Quality Agreements. In a recent editorial I wrote for PTE (October 2010; available at 

), I discussed a new initiative by the BPSA to develop a Quality Agreement Template for singleuse suppliers and users. The FDA has provided guidance on establishing quality agreements with contract manufacturers of licensed biologics, and drug manufacturers are seeking similar agreements with all their suppliers, including equipment.

  The Society of Chemical Manufacturers and Affiliates (SOCMA), home to the BPSA, has a Bulk Pharmaceuticals Task Force that has developed a Template for Quality Agreements related to the manufacture and release of substances regulated by the FDA.

  A similar template has been developed by the International Pharmaceutical Consortium on Regulation and Science (IPAC-RS) for use by drug manufacturers and suppliers when addressing raw materials, container closure/device components and packaging materials.

  The BPSA, through its Singleuse System Quality Agreement Template Task Force, is adapting the content of these guides to develop a template specific to singleuse manufacturing. This is intended to simplify and standardise the otherwise timeconsuming and sometimes difficult process of negotiating quality agreements between biopharm or vaccine manufacturers and singleuse system or component suppliers.  

To further discuss this topic and provide opportunity for users and suppliers to provide input, BPhI and the BPSA are collaborating to produce a web seminar on Quality Agreements for single use manufacturing. The seminar is scheduled for Wednesday 2 March (7 am PST; 10 am EST; 3 pm GMT, 4 pm CET). For more details, see: 

http://biopharminternational.findpharma.com/webcasts

The BPSA will also be hosting its inaugural International SingleUse Summit (ISUS) in Washington DC (USA; 27–29 July). The meeting will focus on the future of biopharmaceutical manufacturing, with a specific emphasis on regulatory considerations and perspectives on the impact of healthcare reform on drug markets. Innovations and market drivers affecting the singleuse Industry will also be discussed. More information is available at 

 In my next column, I'll be reporting on global issues, as well as the implementation of singleuse based on participation as a speaker and panelist at several international meetings including the ISPE Japan Sterile Products Processing Community of Practice Meeting in Japan (17 February), the ISPE Aseptic Processing Seminar in Tampa (Florida, USA; 21–22 February) and the IBC Biomanufacturing and SingleUse Systems Asia Conference in China (7–9 March). 

In the interim, feel free to send me suggestions on topics, issues and technology that impact your implementation of single-use. I look forward to hearing from you. 

is Senior VP of Global Scientific Affairs at Pall Life Sciences, Biopharmaceuticals Group, and Chairman of the Board and Technology Committee of the BioProcess Systems Alliance (BPSA). He is also a member of 

1. FDA, Guidance for Industry: Cooperative Manufacturing Arrangements for Licensed Biologics (November 2008). 

2. SOCMA BPTF, Manufacturer's Quality Agreement Template (April, 2010). 

3. IPAC-RS, Quality Agreement Template Toolkit (May, 2009). 

Articles

Over the past 10 years or so, we've seen single-use technologies explode from production-scale filter capsules, tubing and simple biocontainers to encompass sterile connectors, membrane chromatography adsorbers, bioreactors, mixers, and integrated platform systems with increasing levels of sensors and automated controls.

Trends Towards Standardisation

This article is part of a special feature on single-use systems that was published in the October issue of PTE Digital, available at http://www.pharmtech.com/ptedigital1010.

The development of quality agreements between biopharmaceutical companies and contract manufacturers has long been recognised as a critical activity to ensure that a product's quality meets regulatory requirements. Quality agreements are used to clearly establish each party's responsibilities and assure that manufacturing processes are controlled according to mutual understanding. For biological products, this is supported by the 2008 FDA Guidance, 

Cooperative Manufacturing Arrangements for Licensed Biologics

. More recently, biopharmaceutical companies have looked to establish quality agreements with raw material and API suppliers as a means to guard the supply chain from counterfeit or adulterated materials. This drive has led to the recent publication of a 

Quality Agreement Template for API manufacturers

 by the Bulk Pharmaceutical Task Force (BPTF), an affiliate of the Society for Chemical Manufacturers and Affiliates (SOCMA). 

Considering the increased reliance that singleuse manufacturing technology places on suppliers to ensure biopharmaceutical quality, quality agreements have also begun to be established between singleuse process equipment suppliers and users — particularly for critical singleuse equipment, such as filters, biocontainers, tubing manifolds and other integrated singleuse systems. While some companies have negotiated agreements on a casebycase basis, there is a recognised need within the industry for a common Quality Agreement Template (QAT) specific to single-use manufacturing that highlights key performance criteria. With this in mind, the BioProcess Systems Alliance (BPSA; 

), also an affiliate of SOCMA, has formed a Quality Agreement Template Task Force (QATTF) to develop a suitable template for singleuse technologies for the benefit of users and suppliers.  

The BPSA is an industry trade organisation for suppliers and users of singleuse technologies for production of biopharmaceuticals and vaccines. Its primary objective is to facilitate the implementation of singleuse manufacturing through networking, recognition and publication of best practice guides, to provide clarification of current regulatory requirements and to interact with governmental agencies on emerging issues that may impact BPSA members. The BPSA QATTF is composed of quality department personnel from member companies that are system suppliers and end users. This is a global initiative since many BPSA member participants on the committee represent global companies.  

One of the major challenges with quality agreements that users and suppliers have experienced is that no two companies request the same information, resulting in many hours spent filling out and modifying each company's unique forms. Singleuse system suppliers are considered more responsible for the user's processes than stainless steel component or system suppliers because singleuse components could conceivably vary from lot to lot, with users being highly dependent on the quality and delivery (and repeat quality) of such systems. Consequently, users are requesting to be kept more informed of supplier process changes beyond what has been previously acceptable practice. Singleuse equipment suppliers and users must find ways to ensure suitable change notification on custom-assembled systems for users, while enabling sufficient flexibility of suppliers for updating standard products and processes. Based on a BPSA informal survey of singleuse supplier QA managers, the BPSA estimates

that 60–70% of the work undertaken to establish agreements between supplier and user is redundant and does not serve any added value. 

Adoption of singleuse technologies for biopharmaceutical manufacturing is growing every day, and many user and supplier companies have expressed the need for an easier way to execute quality agreements in a more timely and lowcost manner. By streamlining the process, the adoption of single-use technologies can progress more efficiently and rapidly, with a higher sense of process consistency and product quality, at lower cost. The BPSA has already helped the industry significantly by educating and providing best practice guides for the adoption of singleuse technologies. BPSA documents such as extractables/leachables guides, white papers on component quality test methods, irradiation/sterilisation, disposal and the economic advantages of singleuse are good examples of what the BPSA has been able to accomplish in a relatively short period of time.  

The BPSA QAT will be a consensus document that identifies commonalities of various templates existing today and will be more effective as a starting point for negotiations. Application of the BPSA QAT will be voluntary (as a trade association, BPSA has no mandate authority). 

At the moment, the BPSA QATTF is comparing existing templates and will be creating subsections to the document that cover the key points that the QAT must have. Some of the issues to be addressed will be identification of critical changes, change control and notification, subcomponent supplier qualification, component origin information, customer involvement in changes to standard products, levels of disclosure and custom product quality specifications. Rather than hinder uptake, we envision the BPSA QAT will provide higher assurance of quality supply and facilitate faster uptake of singleuse equipment by reducing the time, cost and effort to establish agreements. 

The BPSA QATTF had its first meeting on 12 August 2010. The task group is currently defining a process for developing the document, which is expected to be completed over the next 4–6 months. This template will be another tool that biopharmaceutical companies and suppliers can use to ensure that high quality, safe drug and vaccine products can be delivered to patients at the time they are needed, to save and improve the quality of peoples' lives. Interested parties are invited to contact the BPSA for corporate membership and participation information. 

Based on preliminary feedback from singleuse suppliers and users, we anticipate that, when published, the impact of the BPSA QAT will be positive. Smaller companies are more likely to accept it as offered while larger companies are likely to demand customisation, but the consensus is that the BPSA QAT will facilitate the finalisation of agreements in a more expedient manner. We predict that requests for quality agreements will increase as regulatory agencies come to expect these to be in place between users and suppliers of singleuse process equipment. 

For further information about the BPSA's publications and activities, please visit 

With thanks to Todd Kapp of Renolit, Jamie Ethier of Millipore, Ann Rich of ThermoFisher, and Terry Cusick of Pall for their valuable input. 

 is Senior Vice President, Global Scientific Affairs, Biopharmaceuticals at Pall Life Sciences and Chairman of the Board, Bio-Process Systems Alliance.

The development of quality agreements has long been recognised as a critical activity to ensure a product's quality meets regulatory requirements.

Developing A Quality Agreement Template For Single-Use Systems

What have been the key innovations that have shaped current aseptic practices and techniques?

: The number one consideration for aseptic practices and technique is risk minimization. Since the mid-1990s, the development of isolators and restricted access barrier systems (RABS) has substantially changed how operators interact with sterile drug product and their associated technique. A physical barrier between the operator and the critical zone of the isolator controlled at positive pressure with HEPAfiltered air creates a high level of contamination control. Most interactions through isolators and RABS are done through glove ports, which again limits the risk to the associated product. In addition, the ability to biodecontaminate the critical zone and clean-in-place/steam-in-place (CIP/SIP) contact parts has led to less operator involvement and further reduces risk. 

 Isolation technology is replacing conventional clean room aseptic technology within the most developed areas of the pharmaceutical industry. The technology's major benefit is the higher aseptic conditions that can be achieved and maintained during manufacturing. Isolators provide a complete barrier between product and operators, who are the highest source of contamination in aseptic processing. Isolators also guarantee a higher sterility assurance level after decontamination compared with conventional clean room technology (usually 6 Log contaminants reduction versus 3 Log reduction). This is achieved by means of vaporized hydrogen peroxide.  

Furthermore, in 2008, the European Commission issued a GMP document for sterile drugs preparation stating that the sealing of sterile vials with aluminium caps must happen under Grade A laminar air flow. Consequently, the most innovative machinery manufacturers have reviewed the design of their aluminium capping machines; the latest models incorporate features that make them suitable to work under laminar air flow and that minimize particle generation to maintain the required level of air cleanliness. 

: Key innovations have been singleuse systems (processscale filter capsules, tubing, biocontainers, etc.), which are presterilized (by gamma irradiation) and preassembled to eliminate aseptic connections and cleaning. These systems have been further enabled by the introduction of sterile connectors. Use of singleuse systems and sterile connectors reduces risk of both microbial contamination and chemical contamination from lottolot or producttoproduct carryover or from cleaning agent residues. Because they are closed systems, they can even enable sterile processing to be done outside of isolators or Class A environments. 

Another key innovation is the development of new high capacity 0.1µm-rated filters with high mycoplasma removal capability. These are used for sterilizing filtration of soy peptonebased bacterial culture media used in aseptic filling line validation to ensure the absence of mycoplasma, such as 

, in the sterile media fill validation of the aseptic filling line. 

What are the key challenges to successfully implementing aseptic techniques and technologies?

 Some major key challenges with implementing appropriate aseptic techniques and current technologies are centred around clean room design. Retrofitting a conventional clean room with isolator or RABS technology can be difficult because it will often change the air dynamics and may require changes to the existing heating, ventilation and air conditioning (HVAC) systems. Changes in HVAC are extremely expensive, which often deter companies from installing these types of technologies into existing clean rooms. Another key challenge, is implementing technologies and practices that meet multiple regulatory expectations. Companies who market and sell products globally must meet the compliance expectations of many regulatory authorities.

: Training of operators. Only highly skilled and disciplined operators can ensure the correct implementation of aseptic techniques. Several companies can't (or don't want to) implement aseptic techniques because of inadequate company culture or the inability to establish suitable standard operating procedures (SOPs). These factors sometimes represent real challenges for companies 

: The primary issue in implementing singleuse systems to replace cleanable stainless steel equipment (filter housings, piping, tanks, filling lines) is the development of extractables data from the singleuse plastic equipment to validate that they do not contribute chemical contaminants to the final product. The Bio-Process Systems Alliance (singleuse trade association) has developed recommendations for single-use equipment suppliers to develop generic extractables data that can be referenced by end users implementing the systems. Suppliers such as Pall have developed libraries of extractables data that can enable users to conduct risk assessments without having to initiate new studies. 

What future innovations do you predict in aseptic techniques and technologies during the next 5 years?

: In the next 5 years, I believe there will be additional consideration for reducing manual operator interaction during the manufacturing process and making the process more automated. Manual aseptic operations provide a number of uncertainties and risks. Currently, a popular topic for regulatory agencies is risk management of aseptic operations. I believe there will be a large demand to make the process fully automated and thus reduce the associated risk. 

: The use of sterile ready-to-fill vials (as it has already taken place with prefillable syringes). Also, I believe we will see an increased use of plastic, such as cycloolefin copolymer, containers as an alternative to glass. 

: Rapid microbiology methods will increasingly be employed for bioburden analysis and, in some cases, sterility testing. In addition, automation (robotics) will minimize operator interventions to further reduce the incidence of false positives. 

Changes to Annex 1 (manufacture of sterile medicinal products)			

Pharma fails to comply: top tips from the MHRA			

Manager, Sterile Filling, Ben Venue Laboratories, Inc. 

Macofar Product Line Manager, Romaco Group

Senior Vice President, Scientific Affairs, Pall Life Sciences

Aseptic challenges: the experts' view

Membrane filters designed to sterilize liquids and gases have performed successfully in a broad range of process applications. As economic and market conditions lead pharmaceutical, biotechnology, and vaccine manufacturers to search for ways to improve profitability by decreasing process costs, re-using sterilizing-grade filters may be considered. Although liquid sterilizing-grade filters are generally developed and recommended for single batch or campaign use, there are many applications where they may be subjected to multiple usages (i.e., re-use). This article focuses on the re-use of hydrophilic- or hydrophobic-membrane sterilizing-grade filters applied in liquid-sterilizing applications. The author reviews different approaches that may be defined as re-use, discusses factors to consider when deciding whether to re-use sterilizing-grade filters, and provides a case study that highlights potential risks and considerations for process validation in filter re-use applications.  

Suitability of re-use of sterilizing-grade filters in liquid sterilization applications ultimately depends on the requirements of the specific application, the supplier's core filter product-validation studies, and the end user's filtration process validation. This evaluation includes assessments of re-use risk and effects that may compromise the filter's ability to completely retain bacteria and thus sterilize the process fluid. 

It is generally accepted that when a nondestructive physical integrity test (e.g., a forward-flow diffusion test or bubble point-type test) of a sterilizing-grade filter is correlated to bacterial retention, re-used filters can be relied on to provide a sterile effluent as long as they continue to demonstrate integrity upon repeated testing. Both forward flow and bubble point-type test methods are highly capable of detecting filter manufacturing defects such as holes in membranes or bypass of membrane cartridge seals due to inadequate installation. It is often overlooked, however, that membrane degradation can occur under incompatible re-use conditions that may compromise the filter's bacterial retention properties. Such cases of membrane degradation are not modeled by filter manufacturers' core validation studies and may not  be detectable by common production integrity tests  correlated to retention under those model conditions. The case study provided in this article illustrates this point. 

The use and re-use of sterilizing grade membrane filters, rated at 0.2 μm and even 0.1 μm, occurs often in nonsterilizing liquid-service applications such as those carried out for bioburden or particle reduction or control. In these applications, the filters may or may not be integrity tested because they are not necessarily expected to remove 100% of incident bacteria with validated assurance (i.e., sterilize) and their filtrates are not claimed to be sterile. They may be used as prefilters or as final filters to control bioburden that may already be very low in the influent fluid. Although such filters have been validated by their manufacturers for quantitative bacteria removal when integral under standard conditions, the risk of marginal, or in some cases, gross failure, carries much less consequence than a risk of nonsterility in the production of a sterile drug or maintenance of a sterile process. Despite the less critical nature of these applications, many of the risks that come with the use of sterilizing-grade filters in sterilizing processes may be applicable and can be used in risk assessment.  

Hydrophobic sterilizing-grade membrane filters for air, gas or vent service, typically manufactured with 0.2 μm pore-rated polytetrafluoroethylene (PTFE) or polyvinylidene fluoride (PVDF) membrane, have also traditionally been re-used in  multiple batch service with autoclave or 

 steam (i.e., steam in place, SIP) sterilization between batches or campaigns. Because this article focuses on liquid-sterilizing filtration applications, the re-use of air, gas, and vent filters will not be addressed.  

In general, one can consider re-use of sterilizing-grade filters as applying to filtration of multiple batches of product or other process fluid. This approach is consistent with applications of re-use of air, gas, and vent sterilizing filters in multiple batches or campaigns. However, in the case of liquid sterilizing filtration, there are many interpretations of re-use. Each interpretation has different implications on filter performance. Filters can be considered re-used when they are employed for multiple batches in the following instances: 					

Without removal, rinsing, cleaning, sanitization, or resterilization

With inter-batch rinsing and resterilization

With inter-batch rinsing, cleaning, and resterilization

Intermittent use with inter-batch drying.

In the first case of re-use, defined as "without removal, rinsing, cleaning, sanitization, or resterilization," the filters are initially sterilized and left in place with no interference as multiple batches of fluid pass through them. Although additional stress on the filter from re-use is minimal with this approach, a significant risk factor is that bacteria from the first batch and subsequent batches, may remain viable on the membrane during the re-use cycles. These bacteria could potentially produce smaller cells while dividing and migrating through the largest pores of the filter media until they contaminate the filtrate and compromise the sterility of later batches. This time-dependent bacterial penetration, sometimes referred to as "grow-through," has been reported for integral 0.2 μm-rated sterilizing-grade filters even for single batches that are run for extended periods of time (> 8 h). The results would be no different if a single batch were simply subdivided into multiple batches of product, each processed through the same installed filter in shorter consecutive periods of time. This risk becomes greater, however, when the filters are allowed to stand unused for additional time between processing of consecutive batches. Risk of time-dependent bacterial penetration cannot be assessed by filter-integrity testing because there is no additional stress on the filter.  

 A second and similar process of sterilizing-grade filter re-use occurs when the filters are subjected to water or other solvent rinse between each use to minimize carryover of process fluid components from one product to the next, or one batch to the next. While this type of re-use benefits from reduced batch-to-batch cross-contamination of process fluid components and may slow the ability of retained bacteria to multiply by removing some process fluid-derived nutrients, the risk of time-dependent bacterial penetration remains. This risk remains because retained viable bioburden can continue to divide even under starvation conditions, forming biofilms comprised of cells and cell-derived adhesive secretions that are difficult to rinse away. If the bioburden load from the previous batch is significant, or a biofilm develops on the filter membrane, there is additional risk of downstream contamination with bacterial byproducts such as endotoxins, where the rinse fluid can stress the retained bacteria. 

With inter-batch rinsing and resterilization. 

The third type of re-use (inter-batch rinsing and resterilization) can limit the risk of extended time-dependent bacterial penetration beyond a single batch processing time and control possible development of biofilm. If the filter is not sufficiently rinsed after each re-use cycle before resterilization and introduction of the next batch, however, the resterilization can degrade retained bacteria and leave increased levels of leachable bacterial endotoxins and other cellular byproducts that can contaminate the subsequent processed batch. This type of re-use also imposes additional physical stress on the filter during resterilization. Most sterilizing-grade filters are qualified by their supplier to withstand several steam autoclave or SIP cycles without compromise to integrity or bacterial retention capability. It should be noted, however, that filter-supplier qualifications are typically conducted on intact filters wet only with water, subjected to multiple laboratory steaming cycles, and then tested. Although indicative of filter robustness, these tests do not necessarily model the additional chemical degradative stresses on the filter that may occur when residual product or cleaning agent is insufficiently rinsed out before subjecting a filter to steaming conditions. The tests also do not take into account that a particular end-user sterilization cycle may be more stressful to the filter than the controlled laboratory sterilizations conducted by the filter manufacturer to support product claims. 

With inter-batch rinsing, cleaning, and resterilization. 

The fourth type of re-use (incorporating inter-batch rinsing, cleaning, and resterilization) further reduces risk of cross-contamination or leaching of retained bacterial byproducts during rinsing and cleaning. Despite the reduced contamination risk, this type of re-use becomes more severe in terms of potential stress to the filter and risk of filter damage that may not be detectable by routine integrity testing. In addition to rinsing out the process fluid with a suitable solvent, this type of re-use subjects the filter to an aggressive cleaning fluid intended to dissolve or degrade retained contaminants. Compatibility of the filter membrane and other component materials must be determined beyond only the batch process fluid in this situation to also consider the cleaning fluids and regimens, cumulative contact time, and so forth. Residual products or cleaning agents retained within the filter due to inadequate rinsing after cleaning and before steam exposure for resterilization can be more aggressive at the elevated temperature conditions of the resterilization process. An example of the potential impact of such conditions is provided in the case study discussed later in this article. 

The fifth category of re-use entails a different form of stress incurred by drying the membrane between batches. Some membranes may be damaged by repeated drying cycles, particularly if dried in hot-air ovens. Residual contaminants, cleaning fluid, or residue can be concentrated within the filter during drying, exerting further chemical stresses on the membrane and compromising its functionality without being detected by routine integrity tests. 

In each of these cases where an end user considers re-use to economize on filtration costs, it is incumbent that all process and re-use conditions be properly validated for filter performance and leachables. It is critically important that  the filter's ability to retain bacteria and the filter integrity tests' ability to predict filter integrity not be compromised. 

In addition to process conditions, the risk of re-use, including the criticality of the filtration process, should  be assessed for each application. Some processes may be considered less critical than others and may not require the highest levels of sterilization assurance. Such processes use sterilizing-grade filters for particulate and/or bioburden control but do not claim sterility of the effluent. In these applications, a user may consider re-use of those filters more aggressively. Other processes require a reasonable level of sterilization assurance, suggesting greater risk in re-use. The most critical applications require the highest levels of sterilization assurance achievable and are often done by combining sterilizing-grade filters with effluent from bioburden control filters and, in some cases, use of serial filtration with double 0.2 μm, 0.2 μm to 0.1 μm, or double 0.1 μm sterilizing-grade filters. With such redundancy, there may be a balance between re-use of upstream filters and single use of final filters, or re-purposing of prior batch final filters as upstream filters for subsequent batches. In each case, any perceived economic advantage to re-use of the filters should be weighed against the risk of failure, which can be caused by premature plugging, loss of integrity, increased leachable contamination, or bacterial penetration. 

Examples of applications for sterilizing-grade filters used as either nonsterilizing particle or bioburden control filters or as sterilizing filters, or both, include filtration of:  					

Fermenter or cell-culture bioreactor culture media

Nonsterile active pharmaceutical ingredients (APIs)

Sterile culture media for aseptic filling validation

Aseptically filled sterile topicals and ophthalmics.

Each of these applications has its own requirements and risk factors for bioburden control and/or sterilizing filtration. In addition to the conditions of re-use (rinsing, cleaning, resterilization, drying), each application for re-use should be considered independently based on its criticality for sterilization assurance and any other influence on the filtered effluent. 

Regulatory guidance on re-use of sterilizing-grade filters

A review of API and nonsterile drug manufacturing guidance from the US Food and Drug Administration and European Medicines Agency (EMEA) indicates that neither use nor re-use of sterilizing-grade filters is specifically covered for nonsterile APIs or nonsterile finished drug products (1–2). Such guidance would also apply to use of sterilizing-grade filters in manufacture of nonsterile API and biotech APIs from fermentation to downstream purification, including sterile-filtered media, additives, buffers, and process intermediates. Although use of sterilizing-grade filters in nonsterile API and nonsterile drug manufacturing (e.g., for bioburden control) may be considered current good manufacturing practice (CGMP), specific guidance for use and re-use of sterilizing-grade filters is only provided under guidance for sterile drugs.  

Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients 

that can be considered applicable to the re-use of sterilizing-grade filters even with nonsterile APIs. ICH Q7A states, "Equipment should be constructed so that surfaces that contact raw materials, intermediates, or APIs do not alter the quality of the intermediates and APIs beyond the official or other established specifications" (2). Under this guidance, the potential impact of sterilizing-grade filters on the API, including extractables data that may be provided by the filter manufacturer, in cases where filters are re-used in API manufacturing, the end user should also consider the potential impact on the product of retained bacteria and insufficiently removed product or cleaning agent residues on the filter surface. 

With regard to sterile drug manufacturing, a corresponding statement can be found in 21 

 211.65(a) on CGMP for finished pharmaceuticals,  which states,  

"Equipment shall be constructed so that surfaces that contact components, in-process materials, or drug products shall not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements" (3). 

The same consideration for potential impact of surfaces of re-used filters would apply. 

Guidance for Industry on Sterile Drug Products Produced by Aseptic Processing—Current GMP 

presents two views with regard to use and re-use of sterilizing filters. For sterile drug products, the guidance states, "Sterilizing filters should be routinely discarded after processing of a single lot" (4). Although this statement appears nonsupportive of re-use of sterilizing filters, it is followed by the statement, "However, in those instances when repeated use can be justified, the sterile filter validation should incorporate the maximum number of lots to be processed." This allowance indicates that where sterilizing-grade filters are to be re-used, the sterilizing filtration process validation should assess the impact of cleaning and resterilization in the end-user's process. The guidance goes on to state, "It is important that integrity testing be conducted after filtration to detect any filter leaks or perforations that might have occurred during the filtration." This guidance applies to individual batches and campaigns of batches. Of critical interest is that the guidance suggests that filter leaks or perforations presumably capable of compromising sterilizing performance will be detected by integrity testing. 

Guidelines to Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use (Annex 1 on Manufacture of Sterile Medicinal Products)

, states, "The same filter should not be used for more than one working day unless such use has been validated" (5). While this statement seems to allow extended use and potential re-use of filters, process validation should include consideration of any re-use effects on the filter. The guidance goes on to state, as in the API guides, that, "The filter should not affect the product by removal of ingredients from it or by release of substances into it." Here again, the leaching of contaminant or cleaning residue from used filters before re-use should be considered and absence of any such effects should be validated. 

 Industry recommendations on re-use of sterilizing-grade filters have been limited to date. The first edition of the Parenteral Drug Association (PDA) Technical Report 26, "Sterilizing Grade Filtration of Liquids" in 1988 focused exclusively on final drug sterilization and did not address re-use of sterilizing-grade filters (6). The 2008 revision of this document considers applications of sterilizing-grade filters in biotechnology and pharmaceuticals manufactured outside the US, and states, "Sterilizing filters should be routinely discarded after processing of a single lot." But the revision also elaborates on FDA's aseptic processing guidance on re-use by stating,  

"However, in instances where repeated use can be justified, the sterile filter validation, including integrity testing, bacterial challenge and cleaning should incorporate the maximum number of lots to be processed" (6). 

As a co-author of both PDA documents, this author supports PDA's recommendation to subject filters at the extent of re-use and cleaning cycles to a bacterial challenge. 

 FDA has actively enforced its guidance on re-use of filters under GMP. An FDA Warning Letter to a sterile pharmaceutical manufacturing facility has stated, "Failure to validate the extended re-use period of the (redacted) filters used for many different injectable product formulations and batches. Validation rinse data was inadequate to support that ingredient residues from the previous batch are removed... Your response (to the 483) failed to ensure that products (redacted) do not contain unacceptable residues from prior batches of different products that used the same filters. The inspection found inadequate validation rinse data to support that drug residue from the previous batch was removed. We are concerned of the possibility of cross-contamination" (7). 

Another FDA Warning Letter to a sterile ophthalmics manufacturer stated, "According to the establishment inspection report you re-use sterilizing filters as long as they perform to the manufacturer's filter integrity standards of (redacted) or for a maximum of your internal specification of 50 re-uses. We are concerned about the effectiveness of your filters after being re-used and autoclaved 50 times. We understand that you conduct a filter integrity test by the (redacted) method before and after each batch. However, in order to justify 50 re-uses, we would like to see bacterial retention validation studies using product both upon the initial use of the filter and after the 50th re-use. Further, it is unclear to us whether you have conducted filter extractable and leachable testing with product. If you have this data, provide it to us. If not, let us know when you will be able to provide it to us" (8).  

				An FDA reviewer has stated publicly that reuse of sterilizing filters is "discouraged for sterile drug product," while simultaneously recognizing that sterilizing-grade filter re-use is "common for API production" (9). The reviewer recommended, "Microbial retention validation should incorporate multiple filtration and sterilization processes" and "correlate microbial retention validation, filter integrity testing following multiple sterilization/filtration cycles, and sterility of API/product" (10). FDA is now requesting that batch records indicate when sterile filters have been previously re-used, as stated in an October 2008 483 observation (10).			

The author examines re-use of hydrophilic- or hydrophobic-membrane sterilizing-grade filters in liquid sterilizing applications.

Considerations on Re-Use of Sterilizing-Grade Filters

Single-use disposable technologies have been available long before the advent of biotech. Research, drug development, analytical and QC labs transitioned into disposables during the 1970s, and at the start of today's biotech industry, over 25 years ago, early manufacturing applications included small capsule filters for vents and liquid capsule filters for product and buffer filtration. 

The biotech sector continues to expand the use of disposable technology in processing operations. More recent applications extend beyond filtration and storage to include membrane chromatography (in single-use disposable capsules) and tangential flow filtration (TFF) systems. Some benefits of single-use systems are described here.  

 During the early stages of biotech product development, it is important to evaluate technologies and make preclinical and clinical batches quickly. The use of disposable products can help to streamline operations during these stages.

By streamlining operations with preassembled, presterilized systems, time savings can be achieved throughout the production process — from initial assembly to disassembly post-use. 

 or autoclave sterilization can be eliminated completely, which saves time and also reduces or eliminates maintenance required for steaming equipment. Additionally, time between manufacturing campaigns can be decreased. 

 Sterilized reusable systems also require sterilization validation; and both sterilized and nonsterile reusable systems require cleaning validation and removal of cleaning agents. These operations can require considerable time and labour. Sterilization validation of presterilized assemblies, however, can be conducted by the supplier, which eliminates the need for autoclave or steam-in-place (SIP) process validation by the user. In some cases, this can even eliminate the need for an autoclave or steam generator. The disposability of these systems also eliminates cleaning validation for this process step and may significantly reduce overall cleaning validation.  

 Safety is always an important consideration and disposable systems can provide increased personnel safety as SIP operations are not required, and operator contact with process fluids and cleaning agents can be reduced or eliminated. Disposable components are typically lighter than equivalents used in hard-piped systems, making operator handling easier and safer.  

These drivers have led to increased use of disposable technology, causing biotech suppliers to offer an on-going stream of new disposable capabilities. There are new disposable methods for sampling as well as for making aseptic (sterile) connections. New technologies that are good examples of recent enabling technologies for single-use processing include: 

Disposable membrane chromatography systems.

 Membrane chromatography is an increasingly applied new technology where chromatographic separations are performed at the interior and exterior surfaces of microporous membranes. This offers significant advantages compared with traditional beaded resin column chromatography in terms of footprint, process time and, in particular, capacity for large biomolecules.  

 Tangential flow ultra-and microfiltration systems have continued to be performed in hard-piped systems with piping and membrane cassettes repeatedly cleaned and reused. Concerns of cleaning efficacy and batch-to-batch carry-over of contaminants from TFF systems has driven interest in single-use for these systems.  

 Components are currently available for fully disposable processes with initial batch sizes up to 2000–3000 L. This makes disposables ideally suited for pilot-scale operations and clinical batches, as well as production of patient-specific drugs, gene therapies, vaccines, high potency recombinant proteins and cytotoxic agents. Because disposable systems offer benefits that can impact the time for development as well as for the cost of production, the biotech sector is expected to continue to use these technologies and increase demand for further developments of disposable processing approaches.

Is a senior vice president at Pall Life Sciences, USA. 

Because disposable systems offer benefits that can impact the time for development as well as for the cost of production, the biotech sector is expected to continue to use these technologies ...

The Future is Disposable

This paper discusses the most important factors that a filter user must take into account when making a filter selection.