The pharma industry has reached the longdreaded patent cliff and profits for branded medicines are plummeting because of generic erosion. For copycat products, on the other hand, business is booming. Analyst firm Frost & Sullivan has recently released two reports examining the markets for generic drugs and biosimilars respectively, and has predicted huge growth for both in the lead up to 2017. 

Generic Pharmaceuticals Market — A Global Analysis

, pharmaceutical products worth $150 billion will go off patent between 2010 and 2017, which will propel the generic-drugs market from revenues of $123.85 billion in 2010 to an estimated $231 billion by 2017.  

However, as competition intensifies, genericdrug manufacturers will need to carefully consider their product segments and the appropriate time for market launch. Companies will also have to deal with increasingly harsher costcutting measures from governments and healthcare service providers. Although generic products are often favoured over branded medicines because of their lower cost, the profit margins of generic manufacturers are still likely to be squeezed. According to the report, many generic manufacturers, including Teva, Sandoz and Mylan, are opting to produce higher value products, such as difficult to produce generics, specialty products and biosimilars.  

In a press statement, Aiswariya Chidambaram, a research analyst at Frost & Sullivan, advised, "Large multinational generic firms need to adopt a differentiated approach by opting for products with technologically challenging formulations, products which require significant regulatory support and products with limited availability of active pharmaceutical ingredients." 

Another strategy being adopted by genericdrug companies is to forge alliances with branded pharma for marketing and exclusivity rights to certain generic blockbusters, such as Lipitor and Crestor, among others.  

The global biosimilars market earned revenues of around $172 million in 2010, but this is estimated to jump to $3987 million in 2017, with the industry growing at a compound annual growth rate of approximately 56.7%. According to Frost & Sullivan's 

 report, impending patent expiries are expected to provide impetus to the market development of several new biosimilars. 

But strong growth doesn't necessarily mean that there will be a sudden boom of new developers seeking to enter the market. Although biosimilars offer "lucrative growth prospects," high investment is also required because of the complex production processes, expensive biological and chemical materials, rigorous clinical trials and stringent quality and safety tests, which are all needed for development. High manufacturing costs can also act as a barrier to market entry, but this can be overcome by using license agreements between companies.  

"The need for considerable financial outlays will hinder the entry of small biotech firms in particular," Frost & Sullivan analyst Srinivas Sashidhar said in a press statement."On the other hand, specialty pharmaceutical companies with biotech expertise and financial capabilities are well positioned to venture into the biosimilars market." 

As with generic smallmolecule drugs, biosimilars are likely to be used in healthcare programmes in place of branded biopharmaceutical products for cost reasons. However, developing a biosimilar is much riskier than a traditional pharmaceutical. Biosimilars are highly complex and there is no guarantee that regulators will accept the product's similarity to its biological counterpart. In the US, in particular, the regulatory pathway for biosimilars is still very new. Uncertainty also remains about how successful a biosimilar will be in the market. According to Frost & Sullivan, one important factor to help achieve success will be effective communication with the scientific community, including close interaction with doctors and pharmacists to promote the benefits of biosimilars and increase uptake. 

The EMA has published an implementation plan for Europe's new pharmacovigilance legislation, which comes into force in July. The legislation will improve the safety and risk–benefit monitoring of drugs and represents the biggest change in the EMA's legal framework. 

Pfizer, Sanofi, GlaxoSmithKline and other major companies and global healthcare organisations have joined forces and pledged to defeat 10 neglected tropical diseases by 2020. The companies will donate an average of 1.4 billion treatments each year, while new collaborative R&D is expected to lead to new treatment options. 

AstraZeneca has announced restructuring initiatives that could lead to 7300 job losses. Positions affected include those in selling, general and administrative areas, as well as operations and neuroscience R&D. The restructuring is expected to deliver around $1.6 billion in annual benefits by the end of 2014. 

The FDA has released a draft guidance for API manufacturers that provides recommendations for procedures to ensure that crude heparin does not contain oversulfated chondroitin sulphates or nonporcine origin material. The guidance is titled 

Heparin for Drug and Medical Device Use: Monitoring Crude Heparin for Quality

Articles

News

The pharma industry has reached the long-dreaded patent cliff, but for copycat products, business is booming.

News: Market Boom for Generics

Despite receiving increased regulatory attention, counterfeit medicines remain a serious and ongoing global health threat. The World Health Organization (WHO) defines them as medicines that have been deliberately and fraudulently mislabelled with respect to their identity and/or source (1). Such illicit products range from random mixtures of harmless, inactive substances to toxic preparations that can result in death. Counterfeit medicines are found everywhere in the world, although the scale of the problem varies from region to region.  

Criminal gangs are attracted to pharmaceuticals because of the high value of medicines and the relatively low risk of prosecution (2); as the counterfeiting business operates on an international scale, it is difficult to tackle the source of the problem and apprehend the parties involved. Furthermore, since many countries have failed to enact deterrent legislation, counterfeiters have felt free to act with impunity and have often managed to evade justice. 

Counterfeiting has traditionally been most prevalent in regions where the regulatory and enforcement systems for medicines are at their weakest, which includes many African countries, as well as parts of Asia and Latin America. In contrast, counterfeiting levels in most industrialised countries (e.g., EU countries, the US, Australia, New Zealand, Canada and Japan) tend to be low thanks to effective regulatory systems and market control. Consequently, many anticounterfeiting strategies have tended to focus on the areas where counterfeit pharmaceuticals are most prevalent.  

However, the supply chains of industrialised regions are now under threat, with several highprofile court cases in 2011 highlighting the efforts that counterfeiters are willing to make to break into high-value pharmaceutical markets. These cases have brought a renewed sense of urgency to the fight against counterfeiters. 

In 2011, the Medicines and Healthcare products Regulatory Agency (MHRA) revealed the extent to which the UK is now being targeted by counterfeiters. In one country-wide crackdown, the agency reported that over a million doses of medicines worth approximately €2.4 million were seized in raids by enforcement investigators (3). Counterfeit Valium and Viagra were the most commonly sold fakes, but counterfeiters were also targeting major therapeutic areas such as cancer, cardiovascular disease, respiratory disease and depression. 

The MHRA's success against counterfeiters was illustrated by the culmination of a case that has been described as the most serious counterfeit medicine fraud in the EU (4). A criminal gang had attempted to target the UK by bringing in two million doses of counterfeit drugs from China. The plot was highly sophisticated, with the products closely resembling genuine medicines, and was considered the worst breach of the UK's regulated medicines system. Approximately 72000 packs of counterfeit medicines with a retail value of around €5.6 million actually managed to enter the UK supply chain between December 2006 and May 2007. It was only thanks to international cooperation over a tip off that the criminal network was broken up. In May 2007, a licensed pharmaceutical packager in the UK was repacking a wholesale consignment of the antipsychotic drug Zyprexa when he noticed anomalies in the packaging (5). He informed the drug's manufacturer, Eli Lilly, who were suspicious about the findings and immediately contacted the MHRA. The regulator's enforcement team then impounded the consignment. Upon testing, it was found that the fake Zyprexa tablets contained various impurities, as well as only 55–80% of the API (5). This led to the MHRA's first ever Class One Drug Alert recall for the fake batch of Zyprexa as it ordered all pharmacies and healthcare staff to ensure that the product was taken off the shelves. Over the following months, the investigation revealed a complex international supply route that led from Ireland via Belgium and Mauritius, and then to a location in London. At the same time, US investigators began to investigate the matter and revealed the Chinese source of the counterfeits.  

Despite this success, the UK's BBC news has recently reported that not all the counterfeit products that entered the country's supply chain have been recovered. Following questioning of the MHRA using a Freedom of Information request, the regulators admitted that although the vast majority of counterfeit products had been recovered, some had been dispensed to patients (6). Eight patients who had received counterfeit Zyprexa or Plavix were identified, but the authorities are continuing to look for other patients who may have received such products. According to the BBC, the numbers could run into the thousands.  

There are also continuing reports of other breaches of the system. At the end of last year, the MHRA announced that counterfeit versions of the HIV medicine Viread had been discovered in the UK market alongside earlier-reported Truvada counterfeit products (7). At around the same time, a Danish parallel importer withdrew stocks of Truvada following consultations with the Danish regulatory agency. So far, full details of the nature and source of the products have not been made public and there is no evidence that they reached patients. 

Illegal online pharmacies have been a particular problem for the authorities. In November 2011, two men who had been running an illegal online pharmacy business were sentenced to 24 months in prison. The MHRA had run a 2-year surveillance initiative called Operation Aimee to expose the set up (8). Over this period, MHRA intelligence officers made large numbers of online test purchases of products to build up evidence for their case. When raids were finally conducted, 99220 tablets of counterfeit Viagra, Cialis and a number of other controlled substances were seized. 

Fortunately, the MHRA were able to expose and close down this particular criminal network, but the consequences of the illegal online trade ended up being deadly for one unfortunate victim. In a tragic case, a young paramedic who was having trouble sleeping between shifts decided to look online to get quick access to medication. She bought an anti-depression drug that is also used for insomnia from an online site, but died after taking a few tablets (3). The case served as a reminder of the fine line between success and failure against the counterfeiters and the need for concerted action. 

The fact that counterfeit products have managed to enter highly regulated markets has led to renewed efforts to tackle counterfeiting. Much hope has been placed in Europe's Falsified Medicines Directive, which will come into force in January 2013 and increase controls across the EU. The Directive was approved by the European Parliament last year and introduces new rules that will require prescription medicines to have safety features that enable verification of individual packs throughout the supply chain (9). Under the new system, all importers, manufacturers and distributors will become brokers of medicinal products, which confers greater responsibility on them to be vigilant and proactive. The Directive also targets illegal online pharmacies, which remain a major threat. In the future, all websites offering medicines for sale will need to be clearly linked to the website of the competent authority in that particular country. The regulatory body will also display a list of approved online sales sites, which will be required to display a common, recognisable logo (9, 10). 

The pharmaceutical industry has also been working on a number of initiatives with other stakeholders. In January 2012, the European Federation of Pharmaceutical Industry Associations (EFPIA), the European umbrella organisation of pharmaceutical full-line wholesalers (GIRP), the European Association of Euro-Pharmaceutical Companies (EAEPC) and the Pharmaceutical Group of the European Union (PGEU), which represents pharmacists, issued a joint press release calling for practical and cost-effective solutions to implement the requirements of the EU's Falsified Medicines Directive (11). The organisations have been developing a European Stakeholder Model (ESM) that can be adapted to individual national systems. ESM employs a product verification system that is run by pharmaceutical manufacturers, pharmacists and wholesalers, as well as parallel distributors. A unique serial number will be featured on each product pack that can be checked with ease against a central database at the point of dispensing. A pilot of the system was conducted in Sweden during 2009 to 2010 and a further pilot is planned for Germany in 2013 (11). 

Another major development that has received the industry's backing is the MEDICRIME Convention launched by the Council of Europe. In December 2011, a high-level conference was held in Moscow where members signed up to binding international legal agreements to combat counterfeiting. In particular, it was felt necessary to tighten the definition of what constituted a counterfeit in order to fill gaps in certain national legislation. For example, in certain countries, it has been difficult to bring legal action against those manufacturing, distributing and selling falsified medicines because the existing legislation only covered breaches of trademark and patent legislation (12). EFPIA hopes that the timing of the MEDICRIME initiative will boost efforts at the EU level and has also stated that it is ready to help any members in meeting their obligations for the MEDICRIME Convention (12). 

The threat posed by counterfeits to the European supply chain cannot be underestimated and the number of cases in the UK alone last year shows that counterfeiters are continuing their efforts to break into regulated markets. On a positive note, the level of international cooperation to defeat the criminals behind counterfeiting is at an all-time high. The EU's Falsified Medicines Directive, the MEDICRIME Convention and the ESM initiative by industry stakeholders are just some of the notable cooperative measures that are set to improve protection of the supply chain. 

1. WHO, "Medicines: spurious/falsely-labelled/ falsified/counterfeit (SFFC) medicines" (WHO website, 2010). 

3. T. Symonds, "Fake medicine trade: UK crackdown on drug importers" (BBC News, 2011). 

4. BBC News, "Man jailed for £4.7m counterfeit medicine fraud" (BBC News Website, 2011). 

5. N. Siva, "How investigators unravelled Europe's biggest-ever fake-medicine scam" (Wired, 2011). 

6. P. Kemp, "Fake drugs given to NHS patients still untraced" (BBC News, 2012). 

7. MHRA, "Counterfeit drug peddlers sentenced" (MHRA Press Release, 2011). 

8. P. Taylor, "Counterfeit Viread also on market, says MHRA" (Securing Pharma Website, 2011). 

9. G. MacDonald, "EU falsified meds act formally adopted" (In-Pharmatechnologist Website, 2011). 

10. "Q&A: Directive on falsified medicines" (European Commission, 2011). 

11. EFPIA, "EAEPC-EFPIA-GIRP-PGEU working for better Patient Safety" (EFPIA Website, 2011). 

12. EFPIA, "MEDICRIME Convention Position Paper of the European Federation of Pharmaceutical Industries & Associations" (EFPIA Website, 2011). 

Industry Insider

Traditionally more prevalent in less industrialised regions, counterfeit medicines are now more frequently entering the heavily regulated supply chains of EU countries.

Stepping Up the Fight Against Counterfeits

Q. What is the difference between parametric release and real-time release testing?  

Compliance with release specifications can be demonstrated by performing a complete set of tests according to approved specifications before the final product is released onto the market. Under certain conditions, however, it is possible to use an alternative strategy called parametric release. Rather than conducting an approved sterility test, parametric testing involves utilising information collected during the manufacturing process to demonstrate that the product was made according to defined GMP and sterilisation procedures (1). 

Parametric release can only be applied to products terminally sterilised in their final containers by steam, dry heat or ionising radiation, but recent guidelines adopted in the International Conference on Harmonisation (ICH) context (ICH Q8, Q9 and Q10 Guidelines) now enable a similar release strategy to be adopted for other tests too (2). This approach is called real-time release (RTR) testing, and can be applied to both new and established products. As with parametric release, RTR testing provides assurance of final product quality based on information collected during the manufacturing process. The basis for establishing RTR testing mechanisms involves combining quality riskmanagement principles, enhanced product knowledge and process understanding, as well as applying an adequate pharmaceutical quality system. It is important to note that the other products mentioned may be chemical products such as excipients, active substances, pharmaceutical intermediates and finished products. 

To demonstrate, a combination of in-process tablet weight, blend content uniformity measurement, drug substance purity and particle size could serve as a control strategy for ensuring the drug content of a highdose tablet, if the relationships has been demonstrated. In this example, the above-mentioned factors would serve as the RTR tests. Based on the outcome of these tests, as well as other required tests in the product specification, and GMP compliance, the production batches are released by the qualified person.  

Q. What preconditions have to be given for parametric release of sterile medicinal products?

Parametric release is defined by the EMA as a sterility assurance release programme where a demonstrated control of the sterilisation process enables a company to use defined critical process controls in lieu of the sterility test to fulfil the intent of 21 

Compared with performing sterility tests of units drawn from a finished batch, meeting parametricrelease requirements can provide greater assurance of a product's sterility. Traditional sterility testing methods are limited in their ability to detect contamination because the small number of samples required restricts the ability to capture microorganisms dispersed in large volumes. Additionally, the prescribed culture media has only a limited ability to stimulate the growth of all potential microorganisms. The sterility tests described in the European pharmacopoeia, however, provide an optimised approach by taking into account different culture media, and their respective incubation temperatures and incubation times. Even so, sterility tests typically only detect major errors in the manufacturing process that stem from the contamination of a large number of product units. Data derived from in-process controls of a validated terminal sterilisation process, on the other hand, can provide more accurate information regarding product sterility because the probability of product bioburden surviving the sterilisation process in any single unit of a product can be calculated to less than one in a million. 

At the very beginning, the accurate monitoring of relevant sterilisation cycle parameters, such as temperature, pressure, time and the fθ value, were sufficient for a parametric release. However, further requirements soon became mandatory. Today, the entire sterilisation process must be described, and process validation reports have to comprise heat distribution and heat penetration studies for at least three runs for each load pattern used, according to good validation practices. Microbiological qualification must also show sufficient efficacy at the minimum level of the cycle, including information on the biological indicators used (type, D-value, Z-value and stability) and bioburden characteristics (number, type and resistance), as applicable. 

The effort involved in the preparation phase of parametric release is high and a large amount of documentation is necessary, but in most cases, the same effort is also required when following the usual application processes for sterilised drugs. Sterility tests require large additional investments, but also offer additional protection in case of legal claims. The biggest advantage of using parametric release, besides quality assurance, is that it can shorten processing times by a few weeks. Depending on production costs, batch sizes and the amount of batches released, this can lead to significant financial savings. However, manufacturers also need to bear in mind that not all countries accept parametric release.  

Q. Will real-time release testing replace the final release procedure? 

The main benefit of RTR testing when combined with Quality by Design and PAT tools is increased quality assurance for patients. In addition, such a strategy can lower manufacturing costs through improved yields, less waste, faster cycle times, and fewer deviations and rejects. 

Process understanding and the definition of a robust control strategy are key aspects of RTR. The interaction of material parameters and attributes, as well as the dynamics of processes, must be taken into account, and are one important part of submission dossiers for marketing authorisations. As such, when implementing RTR systems it is essential to use PAT to efficiently monitor and record all quality-relevant parameters. In this area, there have been a number of improvements, including advances in NIR- and Raman microscopy, fluorescence microscopy, image analysis and laser-based methods. Using chemometics and multivariate analysis, it is now also possible to monitor production processes in real-time. However, a move towards RTR is not only about using advanced analytical and physical measurement techniques, but also involves performing statistical calculations on the resulting data masses. Importantly, regulatory authorities worldwide have to accept the move from final product testing to RTR applications. RTR has to be accepted by all regulatory authorities because the current varied acceptance can be a major issue. The equivalence between RTR-testing and pharmacopoeial testing must also be explained.  

If you do wish to implement new tests and procedures, then you will need to adapt the whole QA system. This is mandatory for compliance. The new quality system must also be aligned with ICH Q10. 

These steps constitute the transition from rigid to risk-based cGMP, and a mindset change from reactive to proactive quality thinking, which could be quite a challenge. In particular, there will be a huge impact on qualified persons or other persons responsible for product release. Specifications will need to be elaborated carefully, and the definition of deviations that require investigation and the process to declare analytical results as outliers or invalid data must be described in SOPs. 

RTR will be implemented over time as industry understanding increases and regulatory expectations are clarified. There is a long road ahead, but as the saying goes: a journey of a thousand miles begins with a single step. 

 Head of quality systems excellence at Boehringer Ingelheim GmbH (Ingelheim). 

1. EMA, Note for Guidance on Parametric Release (March 2001). 

2. EMA, Guideline on Real Time Release Testing (February 2010). 

3. FDA, CFR — Code of Federal Regulations Title 21 (April 2010). 

Ask the Expert

Boehringer Ingelheim's Heribert Häusler tells us about parametric release and real-time testing.

Parametric Release and Real-Time Release Testing

By Kashyap R. Wadekar, Mitali Bhalme, S. Srinivasa Rao, K. Vigneshwar Reddy, L. Sampath Kumar, E. Balasubrahmanyam

The public and the pharmaceutical industry are placing greater attention on impurities in drug as evidenced by the attention given to pharmaceutical impurities in books, journal articles, and national and international guidelines. The health implications of impurities can be significant because of their potential teratogenic, mutagenic, or carcinogenic effects. Controlling and monitoring impurities in APIs and finished drug products, therefore, is a crucial issue in drug development and manufacturing. 

This article was also published in our US sister publication 

Peer-Reviewed Research

In Part II of a three-part article, the authors examine impurities from chiral molecules, polymorphic contaminants, and genotoxic impurities.

Evaluating Impurities in Drugs (Part II of III)

Although the problem of counterfeit drugs traditionally has centered on solid dosage drugs, recent drug shortages for injectable cancer medications have triggered concerns over counterfeit versions of these types of drugs. In January 2012, FDA advised that current shortages of injectable cancer medications may present an opportunity for introduction of non-FDA approved products into the drug supply. FDA advised healthcare providers to obtain and use only FDA- approved injectable cancer medications purchased directly from the manufacturer or from wholesale distributors licensed in the United States. 

Ingredients

Regulatory bodies, standard-setting organizations, and industry seek to tackle the problem of counterfeit drugs and securing the flow of pharma ingredients.

Securing the Pharma Supply Chain

Two fundamental cornerstones of the new bio/pharmaceutical business model are the end of the blockbuster product and the need to accumulate and conserve cash. These two realities have major implications for bio/pharmaceutical manufacturing strategies and technologies and create new challenges for CMOs. It is widely understood and accepted that the new products coming out of the bio/pharmaceutical pipeline will be sold in smaller volumes than the products introduced a generation ago (albeit at higher prices). This situation partly reflects the failure of bio/pharmaceutical R&D laboratories to come up with safe and effective drugs suitable for broad populations. More importantly, it also reflects the growing understanding of how drug effectiveness varies within patient groups, the ability to develop biomarkers to identify patients for whom new drugs will work best, and the expectation of regulatory authorities that new drugs will incorporate that knowledge into clinical regimens. The classic example is Roche's/Genentech's Herceptin (trastuzumab), which is highly effectively for the 20% or so of breast-cancer patients that test positive for expressing the HER-2 gene. 

Outsourcing Review

The evolving bio/pharmaceutical business model poses risk for CMOs.

CMOs Face a Kodak Moment

Increased regulatory expectations and the need to mitigate risk have popularised the use of redundant filtration for bulk and final fill operations. Single-use redundant filtration (SURF) assemblies are an efficient and flexible alternative to stainless steel systems because they eliminate clean in place (CIP), sterilisation steps and the associated validation protocols. Preparation time can also be significantly reduced when using single-use assemblies because of their pre-sterilised format and the ease with which they can be handled. Redundant filtration operations in multi-product facilities can be performed without spending the extra validation time that is often required for non-disposable systems.

Credit to Ingram Publishing/the Agency Collection/Getty Images 

This article identifies a suitable design for redundant filtration operations using single-use technology and standardised assembly components. The design was finalised with input from a global technical and quality team with consideration given to international regulatory requirements. The article also demonstrates the capability of the assembly to withstand the high pressure that is used for integrity testing and drying. Pre-use integrity testing was performed on both filters. Using hydrophilic/hydrophobic filters on the assembly outlet eliminated flush volume limitations caused by catch bag size. Assembly specifications, such as leachables and extractables, hold up volume and flushing requirements, were established for a single-use assembly. 

As defined in PDA Technical Report 26, redundant filtration is a "type of serial filtration in which a second sterilising-grade filter is used as a backup in the event of an integrity failure of the primary sterilising filter." The pore size of the sterilising-grade filters may be the same or tighter than the primary filter (1). Other regulatory bodies (e.g., FDA, EMA and SFDA) have also issued their own guidelines for sterile filtration. According to the FDA's aseptic processing guidelines published in 2004, it is recommended that redundant filtration should be considered in many cases where liquid is sterilised by filtration (2). The EMA's 2008 GMP guidelines state that because of potential risks of sterilisation by filtration, a second filtration step as close to the filling point as possible is advisable (3). 

Designing a redundant filtration system that meets regulations and recommendations is challenging. For stainless steel systems, the EMA recommends that integrity testing should be performed on sterile filters before use. To do this, filters must be fully wetted without breaching the sterility on the downstream side of the assembly. Many conventional stainless steel facilities employ a "catch can" with a sterile vent filter to collect the initial flush liquid from the wetting step. Prior to use, additional time is required to sterilise, maintain and store the catch can. In addition, use of a catch can constrains the total flush volume that can be used if the filters need to be rewetted (e.g., in a repeated filter integrity test).  

Disposable or single-use redundant filtration (SURF) assemblies offer a flexible solution for this relatively complex operation (4). These assemblies can be presterilised by the supplier using gamma irradiation and there is no need for cleaning after use because assemblies are self-contained and entirely disposable.  

Proposed single-use process solution: design considerations

Many biopharmaceutical companies already use variations of SURF assemblies for final and bulk fill operations. However, preparation and utilisation sequences may differ across processes and geographies because of differing national guidelines.

 Figure 1: Utilisation sequence options for single-use redundant filtration assemblies. F1 is the first liquid filter. F2 is the second liquid filter. 

This study reviewed different redundant filtration assembly designs and operating sequences, and proposes a new SURF assembly that has greater operational robustness and minimises the risk of product contamination. Below are the major design considerations for the assembly (see 

A barrier filter (0.2 µm, EMD Millipore) was included in the design as a combined liquid and gas outlet. The barrier filter contains both hydrophilic and hydrophobic sterilising-grade PVDF membrane, which can exhaust both air and water from the assembly. As a result, it can be used as the initial filter flush outlet and as a sterile air outlet during integrity testing and the filter drying step. Such a filter further solves the problem of flush volume constraints imposed by the catch bag/tank size. The assembly can be wetted and tested for integrity multiple times without breaching the sterile envelope. 

Catch bags were attached to the vents of the liquid filters to collect liquid during venting. 

Gamma stable vent filters were attached to the bags to enable passage of air during venting. 

A hydrophobic PVDF filter was added on the air inlet line to ensure sterility of the air coming into the assembly for integrity testing. 

Single-use sterile connectors were used at the assembly's inlet and outlet to assure sterile connections during operation. 

In-line liquid filter capsules were selected (as opposed to T-line capsules) to reduce the hold-up volume. 

The assembly was used in the vertical orientation to achieve better draining after wetting and during product recovery after filtration.

The catch bag on the first liquid filter is primarily in place to avoid the liquid spill that can occur during venting for water flush and product filtration. With some minor modifications, the catch bags on both the first and second liquid filters can also be used for in-process sampling. The catch bag on first liquid filter and the separate air inlet line (with an air filter near the feed inlet) are additional features that are incorporated to ensure cleanliness and ease of operation.  

Pre-use, post-sterilisation integrity testing of a redundant filtration setup can be challenging. With either stainless steel or a singleuse assembly, it is critical to maintain setup sterility during every step. The efficiency of the filter wetting step is also important to avoid false negative integrity test results. For highvalue products, the drying step after integrity testing is crucial to minimise product dilution. 

 outlines the utilisation sequence for SURF assembly before use. Along with the points mentioned above, operator convenience and regulatory compliance were also considered.  

A flushing test was conducted to record the reduction of total organic carbon (TOC) and conductivity with flush volume. The filters and assembly were flushed with deionised (DI) water at a flow rate of 250 mL/min for a total of 20 L. The assembly effluent was sampled at 1 L intervals and tested for conductivity and TOC. Analytical results for flush filtrate samples are summarised in 

. At the end of 20 L reverse osmosis (RO)/DI water flush, TOC and conductivity were 0.231 ppm and1.1 µS/cm, respectively. 

Figure 2: Total organic carbon (TOC) and conductivity (ÂµS/cm) versus flush volume (mL). 

Traditionally, the comparison of single-use versus stainless-steel processes is made on the basis of consumable cost versus capital cost, but other costs must also be taken into account to make an accurate comparison, including labour, validation and quality. Selection of the cost minimum option depends on the specifics of the application and accurate accounting of the associated costs of each technology. Labour rates and process costing assumptions are taken from Biosolve cost modelling software (Biopharm Software Solutions). 

 summarise the results of the cost analysis for a typical redundant filtration process using two 10 in. cartridges. The costs assumed here are representative of industry costs; it is assumed that difference in cost for utilities and materials (e.g., CIP solution, water for injection) does not significantly affect the cost comparison. The costs of pump and extractables–leachables validation are similar for both stainless steel and singleuse setup, so these costs were excluded from the analysis. 

Table I: Capital and validation cost. Capital and validation costs are taken over 10-year expected lifetime of the facility. 

SURF assemblies offer further benefits over stainless-steel setups. Equipment turnover for new products is quicker with single use assembly. For example, additional testing and cleaning time associated with equipment release and documentation is reduced or eliminated if singleuse technologies are used. It also provides more production flexibility because single-use assemblies can be made to order in the size and configuration required with the need for additional equipment or validation. It also eliminates the need to have multiple setups in place to meet the production demands of different products. 

Table II: Cost per batch. The cost calculations in this table are based on 12.5 h batch time for stainless steel setup and 6.5 h batch time for single-use assembly. The batch time is lower for single-use assembly due to elimination of preparation steps, cleaning procedure and ease of handling. 

This study identified a suitable design for redundant filtration operations by utilising single-use technology. An optimised utilisation sequence for preparatory steps was designed and tested. Conducting a pre-use integrity test on a pre-sterilised redundant filtration setup can be challenging, but an effective filter wetting step is important to avoid false negative integrity test results. For highvalue products, the drying step after integrity testing is crucial to minimise product dilution. All preparatory steps and filtration operations can be successfully performed on a single-use assembly. SURF assemblies are robust and efficient disposable solutions for bulk and final fill processes. 

Journal of Pharmaceutical Science and Technology

Sterile Drug Products Produced By Aseptic Processing—Current Good Manufacturing Practices (Guidance for Industry)

"Guidelines to Good Manufacturing Practice—Manufacture of Sterile Medicinal Products," Annex 1

Special Feature

The authors describe a new assembly for bulk and final drug product filling operations.