Peter Soelkner is Managing Director of Vetter Pharma International GmbH, Germany.

Peter Soelkner

	The pharmaceutical and biotechnology industries have received a fair amount of attention in recent years. For companies to be successful and maintain their position in the market, keeping abreast of industry trends is imperative. 

	But what are some of these trends and how have they affected the industry today? What can the industry expect in the future? From a contract development and manufacturing organization’s perspective, one can see a rapidly changing pharmaceutical and biotechnology market primarily due to a variety of factors. 

	On the macro level, the industry is witnessing the combination of digital health with mobile lifestyles, which includes using more convenient technology to deliver medication and information to patients and healthcare providers. This is a significant trend because approximately two-thirds of the world’s population already own a ‘smart’ mobile phone.

	From a therapy perspective, breakthrough therapies for medical needs are quickly on the rise. Looking at the injectables market, in particular, nearly 40% of breakthrough therapies are monoclonal antibodies (mAbs), most of which are used to treat cancer and orphan diseases. Additionally, diseases such as diabetes are also on the rise worldwide, leading to an increased number of patients that require access to parenteral therapies.

	What do the outlined market developments mean as a consequence for pharmaceutical service providers? Service providers are advised to adhere to the following practices in order to continue market success: 

		Adapting and enhancing the service portfolio 

		Partnering with others with complementary expertise, which means working in teams comprised of various companies that are able to address complex market requirements

		Supporting customers in the development of breakthrough therapies by providing speed, flexibility, and valuable expertise with complex high-value therapies.

	Looking at the injectable market, a ResearchAndMarkets report estimates that the global injectable drug delivery market is expected to grow from US$404.14 billion in 2017, reaching nearly US$1200 billion by 2026, with a Compound Annual Growth Rate (CAGR) of 12.8% (1). In geographical terms, North Americais still estimated to be the holder of the largest share for the market during the forecasted period. This growth is attributed to the rising dominance of chronic diseases, as well as the number of companies that are focused on collaboration and partnerships that enable the availability of high-value products. 

	With venture capital funding accelerating in 2017, smaller biotech companies are in good financial shape and have the ability to maintain their pace of outsourcing expenditure. It helps that the injectable share of all therapeutic New Drug Application (NDA) and Biologic License Application (BLA) approvals has increased in recent years, with further positive development expected until 2024. The orphan drug sector will also double in size by 2024 with venture capital funding taking aim at oncology, rare diseases, and high prevalent chronic diseases. 

	Various digitalization activities are widespread in our market as well. This involves primarily pharma and biotech companies, but also their partners and suppliers. The earlier the suppliers engage themselves in digitalization projects, the quicker they can act as a valuable partner at ‘eye level’. Sample digitalization activities in the drug product manufacturing process include efforts in the field of electronic batch recording and, in general, establishing paperless processes. Overall, being active in connected health initiatives is a core trend as the healthcare industry is focusing on patient-monitoring as well as supporting patient engagement and adherence through software services connected to medical devices (

	From an indication perspective, the industry is also experiencing that the ‘

mainstream approach of molecules that are simple to manufacture is becoming more and more outdated’

. This is due to the fact that more and more drugs are targeted to small, specific subgroups, and that ever-more therapeutic biologics have been approved in the market over the past few years. By their very nature, these compounds are complex to handle. Vetter is also receiving project inquiries with minimal filling volume requests, for example, products that are administered via an injection into the eye. Vetter estimates RNA and DNA therapeutics to increase in the future, with Big Pharma investing heavily in these forms of gene therapy solutions (

	An increasing number of parenterals are being supplied in more patient friendly drug-delivery systems, such as prefilled syringes or auto-injectors. Additionally, many component suppliers are providing ready-to-use components that offer advantages to manufacturers. 

	Nevertheless, this still requires tight oversight of the involved suppliers. Overall, thesupply chain of a drug product is increasingly challenging due to the global nature of the business. Active ingredients, components, and excipients, for example, often come from many various suppliers around the world.

	Obviously, there is a huge difference between a therapy that treats thousands of patients and one that treats a few. Nevertheless, both blockbusters and personalized therapies will continue to be needed in the future. The entire industry, including both pharma and biotech companies along with their partners in the supply chain, must retain the flexibility to discover, develop, manufacture, and market therapies in both fields.

	There have always been a wide variety of trends that have influenced our industry. Most likely, this will continue into the future as well. As an industry, we will always do our best to meet these needs successfully. And, we will be able to master the future with the support of industry experts and their promising solutions, be they analogous or digital.

Injectable Drug Delivery Market Size, Share, Report, Analysis, Trends & Forecast to 2026

	Peter Soeklner is managing director at Vetter Pharma-Fertigung GmbH & Co. KG and Vetter Pharma International GmbH.

Articles

Keeping abreast of the latest industry trends and retaining flexibility are key to maintaining a strong market position.

A CDMO’s Perspective of Important Bio/Pharma Industry Trends

	Given the very nature of its business, the bio/pharmaceutical industry is continuously faced with challenges such as cost aspects and stricter regulations, to name but a few. Often, these challenges are met with new trends that help navigate these issues and lead to new growth opportunities. Never one to shy away from a challenge and embrace a new trend, the industry’s response has been the creation of novel approaches to treat diseases, or the development of new delivery techniques to overcome obstacles and move the industry forward to the benefit of all. But what is the outlook of the industry today and where is it heading in the future?

	From a macro view, globalization has resulted in growth that creates opportunities for expanding the market reach of existing drug products. A report on global spending by IMSQuintiles (now IQVIA) noted that there has been a 4–7% per year growth in financial spending on medicines (1).

	In terms of new products, there are more biologics entering the clinic and eventually coming to market. Due to continuous advances in the discovery of how the human body works, many of these new biologics are quite novel, focusing on individual treatments that target smaller markets, such as the orphan drugs do. BioPlan Associates noted a 14–15% growth in the biopharmaceutical sector of the industry in its 2017 report and survey (2). This growth is expected to further increase in the future, according to EvaluatePharma, with biologics comprising 50% of the top 100 drugs by 2021, compared to current figures of approximately 20% (3).

	From an industry’s perspective, the biotech sector shows great promise. A number of the companies working in the biotech space are virtually operated companies; consequently, they tend to outsource most, if not all of their development and manufacturing operations. One of the key drivers of outsourcing is the rising cost to develop and manufacture new drugs, hence, creating the demand for contract development and manufacturing organizations (CDMOs) with a wide range of capabilities. As a result, there has been a good deal of mergers and acquisitions over the past few years-the players continue to seek opportunities to expand their portfolio of offerings by merging with or acquiring service providers with different expertise. This includes pharma companies merging with smaller biotech companies, as well as service providers from different fields merging to enlarge their portfolio. Competitive service providers within the same fields are also looking to gain more market share and benefit from the synergies inherent in a partnership or merger.  

	The large and mid-size pharmaceutical companies, on the other hand, are constantly faced with the pressure to refill their drug pipeline. To do so, they continually rely on acquisitions or in-licensing from smaller biotech companies to gain access to new innovation in general, and more innovative drug candidates in particular. Further, due to ever-increasing costs of bringing drugs to market, larger pharma and biotech companies are constantly searching for manufacturing strategies to realize more effective development and manufacturing operations. There is an ongoing demand for increased production efficiency not only from a technological aspect, but also in terms of yield of high-value products. What this means for the industry is a greater adoption of single-use systems, for example, as well as more automation, monitoring, and tighter process control. Given the highly regulated nature of the aseptic manufacturing sector, expectations for quality continues to remain high. Today, pharma and biotech customers expect a great deal of oversight to realize the necessary and requested high quality for their valuable products.

	According to the 2017 CPhl annual report (4), there is a trend towards the integration of outsourcing activities. Single-source development and manufacturing providers are increasingly preferred, primarily in an effort to reduce business complexity. Sponsor companies are continuously in search of a few well-chosen strategic partners to help them accelerate their drug development and commercialization process and by doing so, decrease their time to market. A large number of pharma and biotech companies are using outsourcing as a manufacturing strategy as well as a means of adding flexibility to their capacity. Additionally, innovative pharma and biotech companies often rely on external partnerships with solution providers such as independent CDMOs. This approach reduces direct costs from their supply chain, helping them remain flexible and able to quickly react to changing situations within the development and manufacturing process.

	With the many challenges occurring within the industry, outsourcing of various development and manufacturing operations to CDMOs is expected to continue, especially with the increasing number of smaller companies striving to enter the market and have their innovative products move through the development process as quickly as possible. The means by which service providers are willing to work with customers is also changing and will continue to do so well into the future. In addition to experience, state-of-the-art technology, capacity, and flexibility, the innovation and creativity that a CDMO can provide will play an important role in setting it apart from competitors.

	There is little doubt that the market will continue to grow, and this growth offers promising opportunities for those solution providers that are well-orchestrated and prepared to meet the needs of their large and small pharma and biotech customers today and in the future.

		QuintilesIMS Institute, Outlook for Global Medicines through 2021 (December 2016).	

 Annual Report and Survey of Biopharmaceutical Manufacturing (April 2017).	

		EvaluatePharma, World Preview 2016, Outlook to 2022 (September 2016).	

		UBM, CPhI Annual Report 2017 (October 2017). 

 is managing director of Vetter Pharma International GmbH.

Flexibility, innovation, and creativity are critical for success in navigating the challenges facing the bio/pharmaceutical industry.

A Changing Industry Brings New Challenges, but also Opportunities

	Over the past several years, the global contract pharmaceutical manufacturing market grew at an average annual rate of 7.5% according to the business information portal Visiongain (1). The reason for this growth, among other things, was the growing demand for biotechnological drugs that have established themselves in the treatment of a variety of diseases, as well as the emergence of a number of small pharma companies that have limited capacity to fill their product. And with the global market expected to continue expanding in 2017, the future remains optimistic. According to estimates by the market research firm IMS Health, the market for biological products will reach the $390 billion mark by 2020 (2). It is important to note, however, that companies wanting to exploit this trend will be facing new challenges.

	Beginning in 2017, regulatory agencies from many countries will be tightening their guidelines to fight drug counterfeits and are calling for the serialization of drugs in their domestic markets to do so. Using distinctive markings on the sales package, the drugs can be tracked as they pass through the supply chain, from final packaging to distribution, on through to the pharmacy. In some countries such as Turkey, India, China, and Argentina, regulators are already demanding that drugs be serialized. Saudi Arabia and the United States will follow suit in 2017. Starting November 2017, FDA will make serialization of drugs a requirement, with drugs being given a national drug code (NDC), a serial number, a batch number, and a sell-by date. Because serialization requirements differ among countries, pharmaceutical and biotech companies must find flexible solutions that can easily adapt to the demands of individual regulatory authorities.

	In the future, international pharmaceutical and biotech companies will be seeking better solutions to predict demand and build flexible supply chains. Because they will be transforming supply-chain management, they must also take digital innovations into consideration such as cloud storage, which has the potential to create a flexible supply chain. In addition, the data gathered from the supply chain can be evaluated and used to make predictions. Production and sales planning can, therefore, be carried out far more accurately using big data analysis.

	However, it is not all about software. In coming years, innovative solutions will make it easier to administer drugs to patients. The use of prefilled syringes will increase because they are easier and safer to use, facilitating application and lowering the risk of dosage error. Autoinjectors and pens offer options with even greater convenience. The reason is simple; user convenience is becoming increasingly more important. Patients place high value in applications that they can self-administer. That is why the homecare sector will continue to grow and more medical care will be performed in the home.

	The one core challenge that remains for drug manufacturers is digitalization; they will be working hard to develop solutions that make effective use of the digital transformation of the industry. Internal paper-based processes will increasingly be replaced by digital images that will allow for a great deal of potential for improvement. Large amounts of data, widely referred to as big data, will be systematically collected, stored, and analyzed, for example, to ascertain the current status of production orders in real time, or to know the state of a particular machine. Work processes are increasingly being controlled using mobile devices, or even automated.

	Pharmaceutical and biotech companies need partners that address their needs in a more personalized manner and support them with custom-designed, flexible solutions and services. They must grapple with the issue of how to innovate and continue to remain a step ahead of the game. Strategic innovation management puts companies in a position to foresee what their customers want, identify process innovations, and implement them. One possibility is working alongside other innovative partners to combine competencies and design new innovation projects.

	In the final analysis, there have always been a wide variety of trends that have influenced the bio/pharmaceutical industry. And newer trends will also leave their imprint on the industry in the future, being part and parcel of the economic sector. The trends in the year 2017 will present the industry with new challenges, and companies will be able to meet them successfully if they focus on the issues at hand.

	1. Visiongain, Pharmaceutical Contract Manufacturing World Market To Reach $79.24bn In 2019, Press Release, February 10, 2015.

	2. IMS, Delivering on the Potential of Biosimilar Medicines – The Role of Functioning Competitive Markets (March 2016).

 is managing director at Vetter Pharma International GmbH.

The trends in the year 2017 will present the industry with new challenges, and companies will be able to meet them successfully if they focus on the issues at hand.

Past, Present, and Future Trends Affecting the Bio/Pharmaceutical Industry

Contract manufacturers must view their relationships with clients as a partnership, which lasts beyond the fulfillment of a particular project, and not simply as a single transaction. To do this well requires the identification and understanding of how we can help our customer’s entire business to become more successful, rather than just focusing on the success of a single product. We need to understand their strategy and learn more about their entire portfolio and business model. This level of trust requires a mutual effort towards open, honest and continuous communication and the careful management of expectations.  

Virtually any breakdown in the business relationship can be traced to a breakdown in communication or the failure to capitalise on lessons learned. 

Every relationship must begin with the understanding of a customer’s overall goals beyond the project at hand and the development of processes that address these goals. We must instill confidence in our customers that their project is as important to us as it is to them and we must demonstrate this confidence through the action of adding value in each step of the process. How this is executed in a tactical manner is critical to the management of the relationship and depends primarily on the nature of the project and the business model of the customer. This is why every effort should be made from the beginning to cultivate comprehensive partnerships that evolve in trust and a collaborative environment between the CMO and the customer. Anticipating the customer’s needs as the relationship evolves, and addressing and explaining challenges as clearly and as early in the process as possible will also help minimise misunderstandings and strengthen the relationship between the CMO and the customer. 

Lack of communication, failure to manage expectations, inconsistency in communicating with “one voice”, and a lack of creative and innovative approaches to difficult projects will challenge any relationship. Managing the expectations of clients is the foundation of good customer relationships. Projects cannot, and should not, proceed without the customers’ needs anticipated. Creative solutions to problems must be provided immediately as the product is being developed and produced. Adherence to the production schedule must be carefully monitored and any delay immediately communicated and explained to the customer. Open channels of communication should address any problem before it becomes critical, and also instills confidence in the CMO and adds value for the client. 

Properly managed, the benefits of effective CMO–customer relationships will result in optimised costs, improved efficiency and mutual success. We have found that peer-to-peer relationships, regular team meetings to ensure ongoing and consistent communications and ongoing team building at all levels are imperative success factors inherently found in projects with good outcomes. 

To hear Peter Soelkner discussing Vetter’s expansion into North America through the opening of its new facility in Chicago, please go to 

Contract manufacturers must view their relationships with clients as a partnership, which lasts beyond the fulfillment of a particular project, and not simply as a single transaction.

Successfully managing CMO-client relationships

Sterilizing grade membrane filters are widely used for the intermediate and final filtration of liquid drug products. Their function is either to reduce the bioburden level within intermediate production steps or to sterilize the final filled product. In 1918, Nobel Prize winner Richard Zsigmondy invented membrane filters that found commercial use in the pharmaceutical industry during the 1930s as flat filter devices (mainly 293 mm discs) and during the 1960s as pleated filter cartridges. When Pseudomonas diminuta (now Brevundimonas diminuta) penetrated 0.45 Âµm rated filters, the standard for sterilizing grade filters became 0.2 Âµm. In 1982, the Health Industry Manufacturers Association (HIMA) stipulated that these filters must retain 107 per cm2 B. diminuta; this is now (since 1988) required by the American Society for Testing and Materials (ASTM).1,2 Since this time, appropriate process validation has received greater priority than pore size ratings; under process conditions, such validation has provided a catalyst for improvement. This article evaluates performance developments of sterilizing grade filters during the last decade and the unfulfilled optimization potential of these systems compared with revalidation costs.	

Materials. Flat 293 mm disc holders (Figure 1) or manifolds were used in process filtration before pleated filter cartridge devices (Figure 2) were developed. Such manifolds had disadvantages including a large footprint, possible leaks, cross-contamination and difficult assembly. The first pleated filter cartridge devices were designed and built to provide a larger filtration area within a smaller filter. These devices had a filtration area of approximately 4000 cm2 and a cylindrical pleat pack that was resin-bonded to the end caps.

Figure 1:  A 293 mm flat filter holder.				

Polyester materials were commonly used in the prefilter and support fleeces in the filters. Both the polyester and the resin (used to bond the membrane to the end cap) gave the filters low chemical and thermal resistance because of oxidative degradation during use. Furthermore, the fleece and resin components added to increasing extractable levels, which would be unacceptable under current standards. Cellulose acetate, cellulose nitrate, mixed cellulose esters, polyamide and polyvinylidenefluoride were the most commonly used filter membrane materials. These materials usually included surfactant or membrane surface treatments to achieve pleatability, wetability and membrane stability. Large water flush volumes were required before the filter could be used to wash out any residual surfactant or treatment.		

Figure 2:  A resin-bonded filter cartridge.			

Optimization. The next development phase to optimize sterilizing grade filter products was replacing the resin bonding with heat welded thermoplastic materials used in the end caps, core, outer support and bonding materials (Figure 3). These filters demonstrated higher chemical, thermal and mechanical resistance, but still generated membrane weaknesses or potential membrane damage if an excess of welding material (commonly polypropylene melt) was forced into the tight pleats of the membrane. This could create hydrophobic spots that showed false negative integrity test results. Pleating of the membranes and the support layers developed further, and a higher pleat density was achieved resulting in significantly increased effective filtration areas from 0.4 m2 to up to 0.75 m2. To avoid inefficient use of the entire pleat pack, new fleece structures were developed to gain a wide enough gap between the pleatings. 	

Configurations. In addition to optimized prefilter fleeces, different membrane filter configurations were utilized as a single layer (for example, 0.2 Âµm only), a homogeneous double layer (for example, 0.2/0.2 Âµm) or a heterogeneous double layer filter (for example, 0.45/0.2 Âµm). Depending on the filter configuration, these filters displayed an effective filtration area of up to 7500 cm2. This represented a 15 fold increase compared with the 293 mm disc filter area and a 1.9 fold increase compared with the first pleated filter. The development of an effective filtration area resulted in a tremendous increase in total throughput for the industry; heterogeneous double layer membrane configurations increased the total throughput furthermore because of a fractionate retention of any contaminant. The contaminant load no longer restricted itself to the 0.2 Âµm final filter membrane.		

Figure 3:  A high pleat density filter cartridge.			

Ultrasonic technology. To avoid heat welding weaknesses, ultrasonic welding was utilized and is still currently used. This allowed the mechanical and thermal stability to increase to an extraordinary level, considering the fragility of the membrane material. With polymer evolution, additional treatment steps and new membrane refinements eliminated the use of wetting agents and surface treatments that previously caused increased extractable levels and high flush volumes. 	

Surface treatments were included within the membrane production process, leading to chemical integration in the membrane matrix instead of having an individual membrane modification step. This also meant that the hydrophilicity of the membrane was retained even under stringent conditions such as steam sterilization or sodium hydroxide contact. The leachable level of such membranes was greatly reduced because of bonding between the surface treatments and the membrane. End caps. Eventually, polyester end caps became obsolete in multiple use applications such as air filtration because of the oxidization and degradation of the polymer. The most common end cap and support material is now polypropylene, which complies with regulations; some new poly-propylenes are also gamma irradiation stable. Safety was also enhanced by improving the designs of filter cartridge adapters, which are now tightly installed into the recess of filter housings. Instead of a double step adapter (where one O-ring is smaller than the other [also known as 2216 and 2218]), adapters with double O-ring seals of similar size (also known as 2226) and with bayonet locks are commonly used.3,4 This type of adapter is more secure because of the firm seat of the filter cartridge housing, particularly during variable pressures, back pressures and steam sterilization conditions. The increase in effective filtration areas and the new membrane configurations allowed higher flow rates and total throughputs, which still incorporated the same geometric dimensions as the first filter cartridges (Figure 4). 	

Today, the design and construction of sterilizing grade membrane filters are optimized to fulfil the ever changing and increasingly stringent requirements of regulatory authorities and the biopharmaceutical industry. Optimization is continually evolving and has led to the following features of modern sterilizing grade filter elements:				

steam sterilization resistance up to 134 ÂºC and gamma irradiation resistance

mechanical resistance of 5000 pulsations at 5 bar differential pressure

optimal total throughputs to significantly reduce costs per litre

optimized flow rates to reduce the processing times or effective filtration area

integrity testing of common non-destructive tests, such as diffusive flow, pressure decay, water intrusion or bubble point

full validation documentation and individual process validation under process conditions with the actual drug product.

Major filter manufacturers not only improved their production processes, but also asked the biopharmaceutical industry to help find reliable solutions. Research and development (R&D) investment in filter elements enhanced aseptic process security and also improved production economics. Today, filter production is undertaken to the highest pharmaceutical quality standards. By receiving input from the industry and regulatory authorities, filter manufacturers are able to produce a wide range of optimized filter products.	

Table I:  Total cost calculation of a historic and modern optimized filter system.			

Savings. The total throughput of commercially available filters today is double compared with filters supplied 10 years ago (Figures 5 and 6). Improvements to reduce the effective filter area have resulted in a decrease in the running costs per litre and associated capital costs. Expensive multi-round stainless steel filter housings can now be replaced by single-round housings; a particular application that required a 3320 in. housing a decade ago, today only requires a single-round 30 in. housing. This, potentially, means a capital cost reduction of up to 70%. A similar cost calculation for filter elements can be demonstrated; assuming that a 10 in. filter element costs $150 and the filtration system is used for 200 days, then the consumable expenditure of multi-round versus single-round would be $900 and $450, respectively. This would give annual savings for consumables of up to $90000 (Table I). 	

Additional savings can be made but are often overlooked; for example, the integrity testing of multi-round housings (large volumes) is difficult and can result in longer downtimes, particularly in high water flush volumes. Assuming the net volume (housing including filter elements) of a 3320 in. multi-round housing is 6 L and that of a 1330 in. housing is 2 L, an additional 4 L are required just to fill the multi-round housing. Also, the assembly of 3320 in. filter elements requires a minimum of double the flush volume compared with a 1330 in. element. This would be 30 L more if it is assumed that there is only a 10 L flush volume per 10 in. filter cartridge. Therefore, the total amount of higher flush volume of water for injection (WFI) would be 34 L more at every filtration run, which would result in additional WFI usage of 6800 L.		

Figure 4:  A flow rate comparison of different sterilizing grade filter developments. Membrane material is 0.2 ÃÂµm cellulose acetate and Figure 5:  Total throughput comparison of 0.2 ÃÂµm sterilizing grade filter cartidges with polysulfon (PS) membrane materials.			

Savings differ greatly from application to application. In some, the throughput does not have much importance; however, processing time (flow rate through the filter element) is important. Some applications require a high batch volume filtration; therefore, an improved filter cartridge with enhanced flow rates allows high batch volumes to be processed faster without changing the equipment dimensions.	

Although membrane filter performance has greatly improved, some aseptic processes that utilize the filters have not advanced significantly. Filters resembling those used more than a decade ago are still used today - possibly because of regulatory implications or a reluctance to change.				

Obsolete filter products still seem to find a use, despite revalidation becoming easier5,6 and the savings that could be made by upgrading. All major filter manufacturers offer validation services and some provide a range of additional support services. Previously, such services and guidance were not available. Now, however, process validation and revalidation are necessary requirements that are well documented.	

Support services are additionally available when conditions change during stability tests. Filter manufacturers have also established thorough testing procedures, such as monitoring adsorption levels of individual membrane polymers.			

Figure 6:  Total throughput comparison of 0.2 ÃÂµm sterilizing grade filter cartidges composed of polyvinylidenefluoride (PVDF) membrane materials and Figure 7:  Throughput trials with different prefilters (47 mm discs).			

Because of economic pressures and the need for increased efficiency, the biopharmaceutical industry is looking to use the most up-to-date equipment whenever possible. This has meant improved quality systems being installed within the filter manufac-turing process. Although the performance of individual equipment can be improved, this does not imply that such improvements can only be achieved by exchanging types of filters. Improvements made to sterilizing grade membrane filters has meant that prefilters have also been thoroughly reviewed by manufacturers (Figure 7).3,7 Performance and economic improvements can be enhanced by finding the optimal solution or combination of pre- and final filter. To find this optimum, filter manufacturers have established software-driven, highly effective filterability test systems and methodologies.				

Initial trials are normally performed with 47 mm filter disc composites to establish the optimal retention rate/pore size combination. Once this optimal combination has been found, filter trials are performed with small-scale pleated filter devices. Filterability trials are useful in identifying the correct filtration combination and size; moreover, the filtrate of these trials can be used to test for any yield or activity losses resulting from unspecific adsorption. Yield losses, because of unspecific adsorption and undetermined dead volumes, must be avoided, particularly with low volume/high value products; for example, monoclonal antibodies or blood fractions. Any yield loss reduces the available production capability and product profitability. Evaluating filter size and material is a priority during the development and scale-up phases, and both should be evaluated within an existing filtration process.	

In addition to improvements in filter equipment, filter systems have developed to become disposable, such as capsule filters. These are available in larger sizes with up to 1.8 m2 of effective filtration area. The benefit of such systems is the reduction in cleaning and downtime, resulting in reduced costs. Operator protection is enhanced because the user is not exposed to the filter and separated contaminant during filter exchange. Installing disposable filter systems is easier and avoids the risk of possible O-ring damage, which can occur in classical filter systems.	

Sterilizing grade filters have experienced remarkable improvements during the last decade (such as thermal and mechanical stability), resulting in reliable, cost-effective filter units. Previous concerns regarding leachables from resins and surface treatments have almost been eliminated because of raw material and production process improvements. Additionally, the performance of sterilizing grade membrane filters (throughput and flow rates) has doubled, equating to lower costs per litre, and reduced downtimes and production times. Filter manufacturers are also providing a range of support services, and validation and revalidation support. 				

1.	ASTM Committee, "Standard Test Methods for Determining Bacterial Retention of Membrane Filters Utilized for Liquid Filtration," Annual Book of ASTM Standards (American Society for Testing and Materials, Philadelphia, Pennsylvania, USA, 1988) pp 790-795.				

2.	"Microbiological Evaluation of Filters for Sterilizing Liquids," HIMA Document 3, Volume 4 (Health Industry Manufacturers Association, Washington DC, USA, 1982).	

3.	M.W. Jornitz and T.H. Meltzer, Sterile Filtration - A Practical Approach (Marcel Dekker, New York, New York, USA, 2001).	

4.	P. Soelkner and J. Rupp, "Cartridge Filters" in T.H. Meltzer and M.W. Jornitz, Eds., Filtration in the Biopharmaceutical Industry (Marcel Dekker, New York, New York, USA, 1998).	

6.	PDA Technical Report No. 26, "Sterilizing Filtration of Liquids," PDA J. Pharm. Sci. Tech. 52(Supplement Number 1), 1-34 (1998).	

7.	R.V. Levy, "Sterile Filtration of Liquids and Gases," in S.S. Block, Ed., Disinfection, Sterilization and Preservation (Lippincott Williams and Wilkins, Philadelphia, Pennsylvania, USA, 2001).	

Sterilizing grade filters are widely used in the biopharmaceutical industry and were once thought of as being perfect. However, these filters have experienced rapid developments and improvements during the last decade, which have resulted in enhanced thermal and mechanical resistance. Moreover, their performance levels have been raised, which has led to significant cost savings within production processes.