	Host-cell proteins (HCPs) constitute a major part of process-related impurities during biologics production. The amount of residual HCPs in drug product is generally considered a critical quality attribute (CQA), due to their potential to affect product safety and efficacy. Therefore, it is a regulatory requirement to monitor the removal of HCPs in drug product during bioprocess development.

	HCPs are proteins produced or encoded by the host organisms used to produce recombinant therapeutic proteins (1). Recombinant therapeutic proteins are usually produced by genetically-modified prokaryotic or eukaryotic host cells using cell culture/fermentation technology (2). Genetic engineering allows the host cells to be transformed to produce a protein of interest selectively. During the recombinant protein production, host cells also coproduce proteins related to the normal cell functions such as cell growth, proliferation, survival, gene transcription, protein synthesis, and etc. Other non-essential proteins may also be released to the cell culture/fermentation as a result of cell apoptosis/death/lysis. In general, apart from the therapeutic protein of interest, all endogenous proteins co-expressed by the host cells are called host-cell proteins (2).

	HCPs constitute a major group of process-related impurities in a drug product. The risks associated with HCPs are primarily immunogenicity. HCPs are complex mixtures with diverse physiochemical and immunological properties (2). Almost all HCPs carry clinical safety risks as foreign proteins due to the potential to elicit immune response in humans. In addition, some HCPs can also act as adjuvants to enhance immune response to a drug product (1, 3). Certain HCPs with proteolytic activity can also affect drug product stability and efficacy if not adequately removed or inactivated (4). HCPs have the potential to affect both the safety and efficacy aspects of a given drug product.

	The risks associated with HCPs are often assessed by a combination of downstream process capabilities, residual HCPs levels, the (maximum) dose, route of administration, dosing frequency, toxicological data, and clinical data (1). Although it is a common understanding that HCPs pose clinical safety risk due to their potential to elicit an immune response, it is difficult to demonstrate which HCP and in what concentration may cause immunogenicity problems in humans (1). Theoretically, preclinical pharmacological and toxicological evaluations can be performed with the presence of different amounts of HCP impurities; however, the evaluation results are mostly irrelevant because the magnitude and nature of the immune response depends on the homology of the amino acid sequence, residual HCPs amount, and product dosing regimen. For this reason, a risk control strategy is applied through the development of robust downstream bioprocess to remove HCPs to as low a level as possible or to “undetectable” levels in drug substance/product (1, 3, 5). The detectability of residual HCPs, however, also depends on the method of detection’s sensitivity. Industry addresses this risk by meticulous method development and the use of multiple technologies to evaluate all potential HCPs that might coproduce or copurify with drug product during bioprocess development. 

Regulatory Requirements for HCPs Measurement and Control 

	According to International Conference on Harmonization (ICH) guidelines Q6B, “For host-cell proteins, a sensitive assay (e.g., immunoassay, capable of detecting a wide range of protein impurities) is generally utilized. In the case of an immunoassay, a polyclonal antibody (pAb) used in the test is generated by immunization with a preparation of a production cell minus the product-coding gene, fusion partners, or other appropriate cell lines” … “Clearance studies, which could include spiking experiments at the laboratory scale, to demonstrate the removal of cell substrate-derived impurities such as nucleic acids and host cell proteins may sometimes be used to eliminate the need for establishing acceptance criteria for these impurities” (6). FDA expects “Whenever possible, contaminants introduced by the recovery and purification process should be below detectable levels using a highly sensitive analytical method” (7). The European Medicines Agency (EMA) guideline 

 states, “In summary, for HCP, whatever the product and production system, residual HCP have to be tested for on a routine basis”…“As such, it is currently required that HCP be routinely monitored at the purified bulk level, using suitable analytical assays. Results from batch to batch should be consistent and meet specification limits” (8).

	Regulatory agencies from other countries and emerging markets may have their own wording on HCP control, but it is generally accepted that a sensitive, validated method is required to monitor residual HCPs in accordance with ICH guidelines. The allowed amount of residual HCPs in final bulk material is determined on a case-by-case basis, commonly in the 1 to 100 ng/mg range.

	To date, immunoassay, commonly in the form of sandwich enzyme-linked immunosorbent assay (ELISA) (see Figure 1), remains as the industry gold standard for HCP measurement due to its high sensitivity and high throughput (3, 5). The HCP composition and abundance are unique to their respective host and the manufacturing process used for biologics production. Meanwhile, different host cells and manufacturing processes may produce certain HCPs in similar abundance. The number of proteins derived from host cells varies significantly from host to host. For example, 

) has ~4300 genes, whereas Chinese Hamster Ovary (CHO) cells have ~30,000 genes (1). Although not every host gene will be transcribed and translated to protein, the complexity of host genome and the post-translational modification present in mammalian cells make it almost impossible to understand the complete HCP composition in a given manufacturing process. Because these HCPs are potentially immunogenic, a commonly accepted method to evaluate the presence of HCPs is through an immunoassay. In theory, an HCP mixture injected into an animal, such as a rabbit, goat, or chicken, will elicit an immune response, and the animals will generate anti-HCP antibodies against these foreign proteins. Although the identities of all HCPs are not known, the polyclonal antibodies raised in animals should be able to recognize most, if not all, of the proteins contained in the HCP mixture. Using these polyclonal antibodies, a multi-analyte sandwich ELISA can be developed (see Figure 1). In Figure 1, capture antibodies enrich the HCPs from sample and immobilize them to a 96 (or greater)-well plate. Then, detection antibodies, conjugated directly with an enzyme or through a biotin-avidin magnification, bind to the captured HCPs. An enzyme, commonly horseradish peroxidase (HRP), can catalyze the substrate to generate a colorimetric, chemiluminescent, or fluorescent signal that correlates with the amount of HCPs in the test sample (5).

					Figure 1: Schematic view of sandwich enzyme-linked immunosorbent assay (ELISA) used for host-cell protein (HCP) detection and measurement.

	Generic HCP ELISA developed using polyclonal antibodies raised against parental cell lysate or cell culture supernatant allows the detection of a majority of HCP species, but may not be able to detect a subgroup of proteins specific to a certain manufacturing process. A generic ELISA kit is commercially available and has the advantage of eliminating lengthy assay development time as indicated in Figure 2, with only steps pointed in yellow being required before its use for process development. This makes the kit good for early phase development. In late phase (Phase III or commercial), cell line-specific platform assay or upstream process-specific ELISA assay is often required to mitigate the risk associated with a more generic commercial assay. The development cycle for an in-house HCP assay is shown in Figure 2 following the flow of green arrows. Commonly, platform- or process-specific HCPs are generated by growing a null cell culture (mock) without the product-encoding gene under similar upstream processes to represent HCPs from a (platform) production culture. PAbs generated by immunizing animals with these HCPs will be used for ELISA development upon qualification by a 2D-coverage assessment. The pAbs should recognize a large majority of HCPs coproduced with drug product. When less-than-ideal coverage is observed, different strategies (as represented by the orange arrows) can be used to improve the coverage or qualify the ELISA at risk and supplement the ELISA with orthogonal methods to characterize HCP process clearance (see Figure 2). Upon qualification and validation, HCP ELISA can serve as a QC release assay for drug substance, and in-process pool testing results can guide the downstream process development (see Figure 2).

					Figure 2: Schematic view of host-cell protein (HCP) assay development cycle.

	In a typical recovery process for a therapeutic monoclonal antibody, the highest concentration of HCP is detected in the harvested cell culture fluid (HCCF), and then cleared through additional downstream purification steps, with typically low (1-100 ng/mg, or ppm) levels of HCPs observed in final bulk drug substance (5).

	Due to the heterogeneity of HCPs, proteins of high abundance/immunogenicity often dominate the multi-analyte ELISA signals, whereas proteins of low abundance/immunogenicity don’t have enough antibodies to recognize them. In addition, copurifying HCPs enriched in drug substance may also have limited antibody to detect them, resulting in dilutional nonlinearity and potentially an underestimate of residual HCPs. Furthermore, due to the fact that not every HCP is immunogenic in animals, even the best process-specific HCP ELISA cannot detect 100% of HCPs coproduced with the recombinant protein. Supplementary to HCP ELISA, traditional HCP separation and visualization methods, such as 1D and 2D sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), remain useful tools for HCP characterization. Other technologies, such as 2D-differential in-gel electrophoresis (DIGE), capillary zone electrophoresis-electrospray ionization-tandem mass spectrometry (CZE-ESI-MS/MS) or two-dimensional-liquid chromatography-tandem mass spectrometry (2D-LC-MS/MS) also emerged as orthogonal methods for HCP characterization (1, 2, 9-12).

	Zhu-Shimoni et al from Genentech published a comprehensive review on the limitations of HCP testing by ELISA with some examples from their process development (5). One example is a HCP named GST-α. GST-α causes no or low immune response in the animals being immunized and thus doesn’t generate an antibody in the polyclonal antibodies used for HCP ELISA. However, this protein was detected on capillary electrophoresis-sodium dodecyl sulfate (CE-SDS) as an impurity peak with a ~2000 ng/mg relative concentration in bulk drug substance. Additionally, some of HCPs may copurify with recombinant protein and thus become enriched in the final bulk; however, the antibodies against these HCPs in the polyclonal antiserum raised against a mock HCP pool may have limited quantity to accurately detect them. Furthermore, steric hindrance and the lack of multiple epitopes to bind the same antibody (capture and detection) can cause inaccuracy on HCP measurement (5). The lack of appropriate calibration standards also limits the accuracy of HCP quantification. These limitations of HCP ELISA mentioned previously can be overcome using orthogonal methods. 

	A large amount (> 0.1%) of residual HCPs present in final drug substance can be detected by size exclusion (SEC), ion exchange (IEX), or reversed phase (RP)-high performance liquid chromatography (HPLC), SDS-PAGE, CE-SDS, isolectric focusing capillary electrophoresis (iCE), and other analytical methods and confirmed with LC-MS. However, most HCPs are present in the final drug substance at very low levels and require much more sensitive method for detection. Analytical methods mentioned previously often don’t have the sensitivity and resolution to separate and detect individual HCP. Immunoassay-based methods, such as slot blot assay and western blot assay, have the sensitivity but often are only semi-quantitative (1, 3, 13). Protein separation and visualization methods, such as 2D-SDS-PAGE, supplement HCP ELISA by providing information on individual HCP properties. 2D-SDS-PAGE with silver stain or other sensitive staining method, such as Sypro Ruby (Life Technologies, Grand Island, NY), has traditionally been used to analyze complex protein mixtures due to its ability to separate proteins by both isoelectric point (pI) and molecular weight (MW). Silver stain has a detection sensitivity of ~0.2-0.5 ng/protein spot, thus can detect protein of very low abundance, but has a lengthy and tedious staining procedure as well as gel-to-gel variations. To overcome the gel-to-gel variation, two or three samples can be run on the same gel using DIGE, with each of the samples pre-labeled with different fluorescent dyes (2). Analyzing drug substance or in-process pools with 2D-DIGE can give the laboratory scientist a snapshot of the HCP profile, and an easy comparison of the HCP composition differences between two samples (see Figure 3). Coupled with spot picking and LC-MS, 2D-DIGE provides direct information on the HCP properties (pI, MW, abundance, and identification), which can help improve HCP removal strategy in downstream process development.

					Figure 3: An example on the use of 2D-differential in-gel electrophoresis for hostcell protein profile comparison between a null cell culture (mock, green) and a monoclonal antibody production harvest cell culture fluid (HCCF, red).

	In the past five years, 2D-LC-MS has emerged as a new orthogonal method for HCP characterization, with the advantage of being sensitive, specific, gel-free and automatable. With an additional separation dimension by high pH reversed phase, ion-exchange, or size-exclusion before LC-MS/MS identification, 2D-LC-MS reduces the interference from dominant peptides digested from recombinant protein and maximizes the detection of low abundance HCP-related peptides (9, 11, 14, 15). Additionally, with the 2D-LC-MS identification of potential residual HCPs, a targeted multiple reaction monitoring (MRM)-LC-MS-based method can be developed to quantify multiple HCPs in a drug substance (5, 11, 16, 17).

	Adequate HCP removal is an important indication of robust and well-controlled bioprocessing. Due to the generally low abundance of HCPs in drug substance, however, it is quite a challenge to detect and measure HCPs in a matrix dominated by the recombinant protein. HCP ELISA has the sensitivity to detect ng/mg level of residual HCPs in drug substance but is limited by the pAbs used in the assay. Often, the pAbs are raised against an HCP population present in the upstream of the bioprocess or a more generic host-cell proteome. These antibodies are not specific enough to the downstream process and thus, the amount of available antibodies present are not correlated with the amount of HCPs in drug substance, which results in antigen excess and lack of dilutional linearity. On the other hand, downstream process-specific ELISA can miss certain HCPs that leak through the particular downstream purification process and/or when downstream processes change. Developing a process-specific HCP ELISA for each biologic is also costly and time-consuming, given the time required to generate process-specific reagents, antibodies, and to develop and validate the assay. For this reason, a multi-product platform assay is more feasible and cost-effective if using the same cell line or cell lines with similar HCP profiles. Data indicate that different upstream processes only change the expression/secretion of a very small subgroup of HCPs within thousands of proteins (18). Using either platform HCP ELISA or process-specific HCP ELISA for HCP testing and control is a strategic decision balancing the benefit and risk of each. No matter which process is chosen, careful qualification of the antibody reagents used in ELISA for each program is necessary to demonstrate their coverage of the large majority of HCPs potentially coproduced with a therapeutic protein. In addition, orthogonal methods such as 2D-DIGE and 2D-LC-MS can be used to provide additional evidence on the process robustness in HCP clearance. These methods are also able to characterize HCPs copurified with recombinant protein that do not elicit an immune response in animals.

	When used together with HCP ELISA, the aforementioned characterization methods reduce the risk of HCP oversight and offer valuable information on the HCP properties and identities to guide downstream process development. Furthermore, single- or multi-analyte ELISA can be developed to target copurified HCPs upon LC-MS/MS identification and the understanding of antigen excess in platform- or process-specific HCP ELISA.


	The authors would like to thank Drs. Steve Farrand, David Chin, and Zhi Chen for their thorough review of this manuscript.


	1. X. Wang, A.K. Hunter, and N.M. Mozier, 

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	2. M. Jin, et al., 

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	3. L.C. Eaton, 

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	4. F. Robert, et al., 

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	5. J. Zhu-Shimoni, et al., 

 111 (12), pp. 2367-79, 2014.
	6. ICH, Q6B, 

Specifications: Test Procedures And Acceptance Criteria For Biotechnological/Biological Products

www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q6B/Step4/Q6B_Guideline.pdf

 Points to Consider in the Manufacture & Testing of Monoclonal Products for Human Use 

www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatory-Information/OtherRecommendationsfor-Manufacturers/UCM153182.pdf


	8. The European Agency for the Evaluation of Medicinal Products Human Medicines Evaluation Unit, London, June 10, 1997, 

www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003322.pdf

35 (10), pp. 1448-52, 2014.
	10. A. L. Tscheliessnig, J. Konrath, R. Bates, et al., 

 8 (6), pp. 655-70, 2013.
	11. M.R. Schenauer, G.C. Flynn, and A.M. Goetze, 

428 (2), pp. 150-7, 2012.
	12. C.E. Hogwood, D.G. Bracewell, and C.M. Smales, 

30C, pp. 153-160, 2014
	13. D. Zhu, A.J. Saul, and A.P. Miles, 

, 306 (1-2), pp. 40-50, 2005.
	14. M.R. Schenauer, G.C. Flynn, and A.M. Goetze, 

29 (4), pp. 951-7, 2013.
	15. J. H. Thompson, et al., 

28 (8), pp. 855-60, 2014.
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. 4 (1), pp. 24-44, 2012.
	18. D.C. Krawitz, et al., 

 When referring to this article, please cite it as F. Wang, D. Richardson, and M. Shameem, “Host-Cell Protein Measurement and Control” 

Articles

Features

This article reviews the definition of HCPs, risks posed by HCPs, regulatory concerns, commonly accepted ELISA methods for HCP measurement and their limitations, and orthogonal methods available for HCP characterization.

Host-Cell Protein Measurement and Control

It is hard to believe, but the biopharmaceutical industry is already old enough to have aging facilities that are decades old. FDA’s focus on the need for updates is creating both opportunities and challenges for biologics manufacturers involved in the scale-up and transfer of production technologies. Single-use and modular technologies, along with continuous processing approaches, are helping the industry both modernize old processes and facilities and minimize the risks associated with making significant changes to existing systems.


	Just as time passes more quickly as people age, it seems time goes by more rapidly as industries mature. While the biopharmaceutical industry is young compared to the small-molecule pharmaceutical sector, it has been of significance for several decades. Some of the processes that are running today utilize the technologies developed when the industry was first established. “Many of these processes were licensed long ago and are quite complex, contain open steps, and are inefficient in many places,” notes Parrish Galliher, CTO of BioProcess Upstream at the Life Sciences business of GE Healthcare.

	FDA has recognized the need to upgrade these older processes and facilities and is imposing updates (1). Equipment suppliers are working closely with biopharmaceutical manufacturers to develop plans for implementing the needed changes. “This situation provides a great opportunity to update those systems, facilities, and practices, but also presents the challenges associated with changing any process, including the risk of affecting product quality in some way. Fortunately, by working closely with tools and technologies suppliers and the regulators, biopharmaceutical manufacturers are better positioned to overcome such challenges,” Galliher asserts. 


	One of the most efficacious ways to revamp older processes as required by FDA is to upgrade with single-use technologies, according to Helene Pora, vice-president of single-use technologies at Pall Life Sciences. “Single-use systems have proven to not only reduce capital investment, but also minimize turndown time, resulting in more effective and higher-quality manufacturing processes for scale-up and tech transfer,” she states. In fact, biopharmaceutical contract manufacturers routinely assess single-use technologies as options when new equipment is introduced to meet a process need, according to Paul Bird, head of the manufacturing engineering group at Fujifilm Diosynth Biotechnologies’ Billingham, UK site.

	Fujifilm develops and manufactures biologics using both microbial and mammalian production systems, and although single-use technology is a relatively new introduction, it has had an impact on mammalian manufacturing at the company. Mammalian cultures do not tend to be intensive; they do not have high oxygen demand and do not grow in very high cell densities, Bird explains. In addition, the culture growth takes place over a long period of time. As a result, a reactor for mammalian cell culture is not required to have high heat removal or provision for high oxygen supply; as such, single-use systems are well suited.

	The situation is different for microbial cultures based on 

 and yeast, for example. These processes have high growth rates and densities, and thus the demand for oxygen is high, making it difficult to replicate a high-productivity process in a disposable reactor, according to Bird. “Because these cultures require very good heat removal, high oxygen transfer, and other rigorous conditions, stainless steel tends to remain the best possible option for microbial processes today,” he notes. Advances in single-use technologies designed specifically for microbial systems may, however, lead to their greater use in the future.

	Galliher agrees that single-use technologies are not a panacea for the upgrading of older processes. “Most older facilities use stainless-steel manufacturing systems, so the conversion to disposable technologies is not automatically straightforward,” he observes. When single-use systems are chosen, however, he adds that they are fairly rapid to install and start-up, particularly relative to older legacy technologies, so the impact on facilities and utilities support systems is minimized. In addition, because the running costs are less for single-use systems, they can be considered enabling technologies.


	While modular systems are a well-established concept and have been available in some form for several decades, they are attracting increasing attention in the biopharmaceutical industry today. In fact, the increasing availability of modular processing units is bridging the gap for many manufacturers with both established traditional facilities and new sites under construction, according to Pora. “For established facilities, modular processing units enable a quick and easy transition to the hybrid facility format, while for new facilities, they are making the fully flexible single-use facility a reality,” she says.

	The popularity of modular systems is not just being driven by FDA mandates; Pora also notes that manufacturers have realized that modular solutions can help them overcome bottlenecks and become more efficient with less investment of time and money.

	The global interest in standardizing facilities, harmonizing designs, and moving to a distributed facility model with a series of smaller identical facilities around the world is also driving interest in modular systems. “For this model to be successful, the facilities need to be identical in order to facilitate tech transfer, documentation, training, and essentially everything that needs to be commissioned to run these facilities in remote territories. Due to this trend, the demand for duplicate cookie-cutter-type modules has increased,” Galliher comments.

	Another trend driving interest in modular technologies is a reduction in production volumes due to the switch to distributed production, increasing yields, and the trend towards personal medicine. “Smaller facilities require smaller production systems, which makes modularity increasingly possible,” says Galliher. He does note, however, that modularity will compete with stick-built facilities in places where labor is cheap. “Companies will have to consider the quality standards they want to reach and whether modules already constructed to meet cGMP and other industry requirements will better meet their needs,” he adds.

	Modular technologies are also increasingly available on the production equipment level and are used to build systems and processes that are identical in different locations, which again simplifies maintenance, documentation, training, and validation. “The modular nature of machinery makes modifying or adding options possible; their plug-and-play designs allow for easy modification with additional or different functions,” Galliher observes.

	Fujifilm is a good example of a biopharmaceutical manufacturer that is taking advantage of modular production systems. In particular, the company designed a single system for the final bulk filling of cGMP products that replaces numerous existing filling systems. “By adopting a modular technology approach, we generated a unique capability for biologic drug product filling that for the first time provides flexible and adaptive manufacturing,” asserts Bird. He notes that the system is flexible because the production process supports bespoke operations meeting customer requirements in full, and adaptive because the modular nature of the system enables point-of-use increases or decreases in production capacity. “This ambitious project has extended the benefits for the most critical unit operation--final bulk filling--and has standardized the operator experience without impacting the flexibility to meet customer requirements,” he adds.

	Consistent, flexible, yet rigorous business processes that introduce dependable operations on-time and in full are necessary for effective technology transfer, according to Bird. “In addition to effective technology transfer between R&D sites and various business units, companies must have the ability to site, develop, and deliver into manufacturing correctly the first time. The collaboration of highly motivated and highly skilled people across multiple programs of activity is the key to success in both areas,” Bird states.

	As one example of how Fujifilm is using technology to address current challenges, Bird cites the company’s “TAG” system for digitally managing the capture, conveyance, and retention of manufacturing knowledge to improve technology transfer, which provides controlled publication and distribution of manufacturing system standards and operational best practice.

Scale-down modeling for successful scale-up and tech transfer


	One of the benefits of the use of smaller production facilities is a reduction in the scale-up factor for many biopharmaceutical processes. No longer are manufacturers required to scale-up from the lab to 20,000 L; more commonly processes are scaled up to 2000 or sometimes 5000 L. As a result, scale-up is less of a technological leap and therefore more predictable and lower-risk than in the past, according to Galliher.

	The use of scale-down modeling, in which a large-scale system is reverse-engineered down to the lab scale so that it can be operated to model the large-scale process, has also significantly reduced the difficulties associated with process scale-up. With this approach, data that are representative of large process behavior can be collected early in the development process and at lab-scale costs, according to Galliher. He adds that better-designed model bioreactor, chromatography, and filtration systems are allowing for even smoother scale-up and tech-transfer operations.

	Raw material choices are also being adjusted to improve scale-up processes. “Instead of buying small amounts of lab quality reagents and then moving to large-scale suppliers once a process has been developed, today some manufacturers are beginning the development process with materials purchased from their eventual large-scale suppliers. This approach eliminates the need to change their raw materials at the point of tech transfer and scale-up and thus avoids any potential impact on performance and product quality,” Galliher explains.

Continuous processing has potential to overcome scale-up and tech-transfer issues


	The adoption of continuous processes and intensified manufacturing may have a significant impact on technology transfer and process scale-up. Pora believes that single-use technologies can also be aligned with the concept of continuous processing to address scale-up issues. “Many of the recent investments at Pall have been driven by this expectation, and our new single-pass tangential flow filtration modules and systems and inline concentrator are examples of technologies that have resulted from our recent efforts,” she says.

	Galliher sees both advantages and disadvantages associated with continuous processing, and he remains uncertain whether these techniques and technologies will graduate to the commercial manufacturing stage. He does, however, believe that with their knowledge and skills, service providers can support biopharmaceutical manufacturers with the assessment of these new technologies and help them with scale-up and tech transfer into their own facilities. “When you drill down,” concludes Pora, “the particular challenge is reducing complexity.


	1. J. Wechsler, “Modern Manufacturing Systems Key to FDA Quality Initiative,” 

:
	When referring to this article, please cite it as C. Challener, “Advanced Technologies Facilitate Scale-Up and Technology Transfer,” 

Cover Story

Single-use and modular technologies plus continuous manufacturing are increasingly important to biopharma scale-up and tech transfer.

Advanced Technologies Facilitate Scale-up and Technology Transfer

	There is still some uncertainty surrounding whether a biosimilar will share the same compendial identity-or biological product monograph-as its reference product. It has been reported that FDA determined that the United States Pharmacopeial Convention’s (USP’s) monograph for filgrastim does not apply to the first-ever approved biosimilar product, Zarxio (filgrastim-sndz). This determination may ultimately factor into future FDA policy or guidance documents on biosimilar naming. While FDA and USP work closely on nomenclature policy, “USP naming is not directly implicated under either USP rules, or Federal law, until a compendial standard applies to an article,” according to presentation notes from USP, and “shared compendial identity does not necessarily imply or mandate an FDA determination of sameness or interchangeability” (1). 

 spoke to USP to find out a bit more about how the naming process for a drug occurs and who truly will have the final say when it comes to biosimilar nomenclature.
	
	

 What is current practice for small-molecule generic drugs in terms of a product’s name and its monograph? How do monograph and name typically relate?
	
	

 USP’s mission is to improve global health through public standards and related programs that help ensure the quality, safety, and benefit of medicines and foods. Our flagship compendia of public standards-

)-play a key role in the adulteration and misbranding provisions of US federal food and drug law.
	
	International Nonproprietary Names (INNs) are given to most drugs early in the drug-development process, even though many of these drugs never make it onto the market. The INN is established by the World Health Organization’s expert group on nonproprietary names. In the United States, the United States Adopted Names Council (USAN) next names medicinal articles, usually also well before approval. When FDA approves a product, it assigns an interim established name, and generally (but not always) follows the USAN name. While USP provides expert representation in both INN and USAN deliberations, USP’s role in naming comes into play after approval of a drug, when a USP monograph is developed and is given an official title, which then becomes the established name for that drug.
	
	Small-molecule generic drugs fall under the same USP monograph and must use the same name as the innovator product (assuming a monograph exists for that product) because they share the same compendial identity. Whenever two products share the same compendial identity (meet the same identification tests and other aspects of identity in the monograph), they are covered by the same monograph-understanding that the monograph tests and acceptance criteria describe a subset of the quality attributes of the articles in question and do not make a statement about their regulatory status, clinical attributes, or interchangeability, all of which are for FDA to determine. Once a product is determined to share the same identity as a drug recognized in the compendium (a drug for which there is an existing monograph), it is required to use the same monograph title (the official title) as its non-proprietary name, unless FDA chooses to establish a different name via regulation. Conversely, if a drug does not share the same identity as a drug recognized in the compendia, it must use a ‘clearly distinguishing and differentiating name.’ For details, see 21 

 Who has the final say when it comes to naming? USP or FDA?
	
	

 FDA has the final say, but only if it chooses to establish a name via notice and comment rulemaking. Under section 502(e) of the Food Drug and Cosmetic Act (FDCA), a drug is misbranded if its label does not include the ‘established name’ of the drug and of each ingredient. Section 502(e) specifies that the ‘established name’ of a drug or ingredient is:
	
	(A) The official name designated by FDA in accordance with section 508 of the FDCA;
	(B) The official title used for the drug or ingredient in an official compendium such as 

, if FDA has not designated a name under (A); or
	(C) If no name has been established under (A) or (B), the common or usual name of the drug or ingredient.
	
	Under this provision, unless FDA has designated an ‘official name’ under section 508, the ‘official title’ used in the USP-NF becomes the established name. In order to designate an official name under section 508, FDA must go through a multi-step process including rulemaking, and it has never done so. Recent case law confirmed that while FDA might assign a name upon drug approval, this name is considered an ‘interim’ established name until an established name is provided in the 

Will naming conventions for biosimilars merely be suggestions, or will they be enforceable by law?
	
	

The statutory and regulation provisions described previously relating to naming apply the same way to biosimilars as they do to other drugs, and USP’s role in establishing standards and names for products similarly is the same with respect to biosimilars as it is for other drugs. USP has no role in enforcement, which falls under the purview of FDA and other regulatory bodies.
	
	

 How will the naming of a biosimilar interplay with an innovator product’s monograph?
	
	

As stated previously, if two products share the same compendial identity, they must use the same monograph title as their nonproprietary name. This is true for all drugs regardless of their regulatory status; as noted previously, compendial identity speaks to common quality attributes and does not make any statement about regulatory status.
	
	


	1.  M.B. Van Hook, "Role of USP Quality Standards in the Nonproprietary Naming of Biologic Drugs," webinar on Biosimilar Naming & Substitution through FDLI–Food and Drug Law Institute, March 10, 2014, 

www.fdli.org/docs/default-document-library/combinedvan-hook-naming-slides.pdf?sfvrsn=0

www.gpo.gov/fdsys/pkg/USCOURTS-caDC-04-05414/pdf/USCOURTS-caDC-04-05414-0.pdf

: When referring to this article, please cite it as R. Hernandez, "What’s In a Name? For Biosimilars, A Lot," 

Inside Standards

Will biosimilars share a compendial identity like generic drugs do?

What’s In a Name? For Biosimilars, A Lot

	In many circumstances, sterile filtration is necessary to remove particles or microorganisms that may affect the safety or efficacy of a biologic. Various processes and tests can be implemented to ensure that filtration is successful. 

 spoke with Dr. Jens Meyer, product manager, filtration technologies at Sartorius Stedim Biotech; Cindy Neeley, PhD, application scientist at Thermo Fisher Scientific; and Tom Watson, global product manager at Pall Corporation, about ensuring filter validation, determining the correct filter pore size, and the importance of keeping filtration processes up to date.

: How can one ensure that all sterile filtration equipment and processes are up to date?

: Because sterilizing-grade filters consist of a very thin membrane that functions as a sterile barrier, any mechanical impact must be avoided as much as possible. In addition, wetting of a filter membrane plays a crucial role in integrity testing. Due to limitations on temperature and differential pressure, all sensors need to be routinely calibrated and checked. Obviously, the entire equipment and product-contacted surfaces have to be steam-sterilized before starting a filtration run.

: A well-designed filtration system begins with choosing a filtration membrane appropriate for your fluid. Differences in how a filter is manufactured, the material components used, and how it performs will have a direct impact on your work. Always double-check the type of containers you entrust with valuable samples and solutions. Storage bottle and cap systems, such as the Thermo Scientific Nalgene bottles and caps, are constructed to minimize gas permeability and maintain sample integrity over time.
	
	

: Given the continuing and rapid adoption of single-use systems, it is important that any filters currently being tested at benchtop or pilot scale are available in configurations that are compatible with gamma irradiation. Their performance should be validated by the filter supplier, and any process-specific filter validation studies should be performed using filters that have been sterilized by the method intended at process scale.

	From an applications standpoint, newer, complex parenteral formulations using nanoparticles and liposomes tend to be harder to filter than traditional formulations. For those engaged in the manufacture of hard-to-filter formulations, it is worthwhile to identify a sterilizing-grade filter that will have good throughput capacity for these fluids. It’s also critically important to ensure that bacterial retention is confirmed early through filter validation studies.

	In addition to securing a reliable sterilizing-grade filter, it can be useful to work with suppliers who can offer state-of-the-art integrity test equipment, a whole suite of complementary single-use technologies combined with systems know-how and a high level of validation expertise.

: What methods are used to determine the pore size of a filter needed to thoroughly remove all microorganisms?

: According to a current American Society for Testing and Materials (ASTM) standard (F838-05), a sterilizing-grade filter must completely retain 

 bacteria per cm² of filtration area. Standard integrity tests applied by end-users, such as the bubble point or diffusion tests, have to be correlated with the bacterial challenge tests. In principle, porometric investigations can be used to confirm a filter’s pore size distribution around 0.2 µm. For mycoplasma retention, 0.1-µm-rated membrane filters are used.

: At Thermo Scientific, membrane bacterial retention tests are performed to determine the microbial retention capabilities of a filter with a certain pore size. Following a challenge of microorganisms of a certain level, the microorganisms are recovered from the filtrate and counted after an incubation per protocol (e.g., ASTM F838-05). The 0.2-μm filters typically used to remove bacteria are certified to retain a challenge of 1 x 10

: The method used to determine whether or not a sterilizing-grade filter of a given removal rating will produce a sterile effluent in a manufacturing process is a process-specific bacterial challenge study. Ahead of such a study, it is recommended that the filter end-user begin with the selection of a filter that has been validated by its manufacturer as retentive for 

 in accordance with test method ASTM F838-05 at a challenge level of 10

 effective filter area. Typically, filters rated at 0.2 µm and 0.1 µm sterilizing-grade make this generic microbial retention claim.

	The subsequent process-specific bacterial challenge study, performed with an appropriate challenge organism at the same challenge level, yet under ‘worst-case’ operating conditions, can confirm whether or not a selected filter will deliver a sterile final drug or vaccine product.

: What are the advantages and disadvantages of using multiple filters?

: In most cases, a single filter sufficiently ensures the sterility of a final product. For fluids containing particles, a cascade of prefilters and final filters increases filtration capability. Redundant filtration using two sterilizing-grade filters sequentially is often believed to prevent the loss of a product batch if one filter fails an integrity test. However, this approach increases safety at the expense of filtration performance, which is lowered due to loss of pressure across the first filter.

: Manufacture certification guarantees removal of microorganisms to a certain level, even with a single filtration process. Within the manufacturer’s guidelines, single-filter filtration can be effective, economical, and environmentally friendly. Multiple filters should be used if the filtration volume or bioburden exceeds the capacity recommended by the manufacturer for a single filter.

: The additive effect of multiple filters can have a positive impact on process cleanliness and safety. In the case of sterilizing-grade filters used in parenteral fill/finish applications, multiple filters (i.e., two or more identical filters positioned sequentially in a system) may be installed for different purposes. In some cases, two identical sterilizing-grade filters may be necessary because a single sterilizing-grade filter may not be able to achieve complete bacterial retention during process-specific validation studies. In such ‘serial filtration’ or ‘double filtration’ set-ups, both filters would be expected to pass an integrity test for batch release. Alternatively, a sequence of identical filters can incorporate a redundant filter. For example, in a process where a single sterilizing-grade filter has been validated to produce a sterile effluent, a redundant filter would be a duplicate of this, installed in-line.

	Aside from the direct cost implications of using multiple filters, there are further considerations around the impact of extractables, adsorption, and integrity testing complexity. However, concerns over increasing costs and other factors should not detract from the economic and safety benefits that can result from more intensive filter usage. A risk-based approach with support from filter suppliers may help the filter user arrive at the appropriate filtration schematic, with the appropriate balance of safety and economy.

: What tests, if any, are conducted to determine the compatibility and interactions between the end product and filter?

: The chemical compatibility of the different membrane materials and of the most frequently used product ingredients is known and published by filter suppliers. If compatibility with a particular ingredient is unknown or doubtful, specific tests can reveal structural changes to the membrane, the effects on integrity test values, or the potential impact on a membrane’s bacterial retention. Process-specific filter validation allows identification of potential effects on the final product, such as by verifying the concentration of the ingredients in the first vials.

: In general, binding tests are performed to ensure that the filter membranes do not remove any valuable components from the end product (e.g., the protein). Extractable and leachable tests of the filter membrane ensure the end product is not contaminated with the filter material. A chemical compatibility test is crucial to meet the requirements of organic solvents, or certain pH conditions. Furthermore, flow-rate tests are important for filtering fluids with high viscosity.

: How do environmental variables within the laboratory affect the process of sterilization?

: General environmental parameters like room temperature and humidity will not affect the sterilization process itself. For integrity testing, all auxiliary media and equipment should be room temperature. In very rare cases, it has been shown that exposure of stainless-steel filter housings to direct sunlight might interfere with the procedure. The same could happen when hot or cold water is used for performing water intrusion tests. However, this only appears rarely and is not considered a main concern during the filtration process.

: Sterilization by filtration is achieved when the filtrate passes through the sterilizing (usually 0.2 μm) membrane into a sterile collection vessel. Until this point, the solution is not considered sterile and does not specifically need to be handled as such, unless the work environment requires this to prevent cross-contamination. Therefore, an environment with positive air pressure (e.g., a biological safety cabinet or a clean room) is preferable.

: When referring to this article, please cite it as A. Roberts, “Sterile Filtration Techniques for Optimal Microbial Retention,” 

Downstream Processing

Removal of microorganisms is crucial when working with biologics. Sterile filtration offers a reliable, safe, and effective way to ensure product integrity.

Sterile Filtration Techniques for Optimal Microbial Retention

 	 	The submission and review of manufacturing supplements is costly and time consuming for biopharmaceutical companies and for regulatory authorities in all regions, and a concerted effort is underway to devise more efficient approaches. There’s renewed support for developing an international quality standard for regulating postapproval changes. And new policies and procedures at FDA aim to streamline oversight of manufacturing changes for firms that adopt modern production methods able to ensure the continued safety and efficacy of products after alterations in systems, formulations, or test methods.	 	These developments reflect the struggle for regulators trying to review thousands of supplements, and for manufacturers implementing changes in products and manufacturing facilities around the world. Pfizer is involved with some 24,000 postapproval changes a year for its 30,000 products, noted vice-president Roger Nosal at the April 2015 CMC Workshop sponsored by the Drug Information Association (DIA). 	 	FDA officials have long proposed that manufacturers implementing quality-by-design (QbD) approaches and quality controls should be able to manage postapproval changes with less regulatory oversight. This goal has not been realized, though, as seen in a continued rise in manufacturing supplements that require agency approval, and in multiple drug shortages linked to low quality manufacturing operations. 	 	The review of manufacturing supplements by the Center for Drug Evaluation and Research (CDER) has increased over the past decade, partly due to the practice of “locking in” an applicant’s manufacturing process before it is fully optimized. Field inspection is not connected to knowledge gained from product review, and there can be a significant disconnect between clinical batch data and commercial production.	 	CDER’s new Office of Pharmaceutical Quality (OPQ) seeks to tackle these problems through more seamless integration of review, inspection, and surveillance throughout the product lifecycle, commented OPQ deputy director Lawrence Yu at the DIA workshop. The goal for OPQ is to ensure that all new and generic drugs meet the quality standards and clinically relevant specifications through pre- and post-approval. Robert Iser, senior scientific advisor in OPQ’s Office of Process and Facilities (OPF), acknowledged that confusion over the level of detail needed to support postapproval changes leads to unnecessary submission of supplements and discourages continual improvement in drug manufacturing processes. 	 	OPF acting director Christine Moore noted that differing change filing requirements among multiple health authorities are costly and discourage adoption of “continual improvement” models. She emphasized the importance of appropriately evaluating the potential risks of changes and of rewarding responsible quality management by allowing manufacturers to make changes under quality systems with little or no prior approval.	 	


	Manufacturers have been looking for FDA to streamline the post-approval change process by “down-regulating” reporting requirements for low-risk changes. Industry seeks a “do-and-tell” approach that permits companies to make changes and then list them in annual reports or in changes-being-effected (CBE) supplements. FDA issued a guidance in March 2014 that sought to expand the range of manufacturing changes that can be documented in annual reports, but the list was fairly limited, and industry has found it inconsistent and confusing (1).
	
	In most situations it’s easier to design a new drug than to update existing analytical methods and technology, noted Ganapathy Mohan, head of global CMC at Merck, Sharp and Dohme. Global approval of a manufacturing change can take more than five years, he said, and changing a polymer supplier or reformulating an oral solution can be complex, particularly for products manufactured at multiple sites that have to meet differing regulatory requirements. 	 	FDA officials plan to try again to offer regulatory relief in filing supplements and also in undergoing plant inspections for those biopharma companies that implement QbD and advanced manufacturing technologies. New draft guidance is expected this year that will clarify which elements of an application are considered “established conditions” (or regulatory commitments) and should help manufacturers manage postapproval changes in a general way. FDA also hopes to revise guidance on providing CMC information in comparability protocols for approved drugs to encourage adoption of innovative test methods and new approaches to change management.	 	


	Regulatory authorities and manufacturers also are collaborating through the International Conference on Harmonization (ICH) to produce a new Q12 quality standard for managing  postapproval manufacturing changes over the lifecycle of drugs and biologics. An ICH expert working group discussed a Q12 concept paper in Lisbon, Portugal in November 2014, and a more detailed proposal is scheduled for further discussion at the June ICH steering committee meeting in Japan. The aim is to publish a document by June 2016 that builds on other ICH quality guidelines to strengthen quality assurance through harmonized management of post-approval CMC changes. 
	
	Agreement and publication of Q12 is a high priority for both industry and regulators, said Moheb Nasr, vice-president for CMC regulatory strategy at GlaxoSmithKline, a former FDA official and rapporteur for the Q12 working group. Nasr observed at the DIA workshop that lack of agreement on change management regulation has inhibited continual improvement and manufacturing innovation and has increased regulatory workloads for both industry and authorities. While previous ICH quality standards have focused on using science- and risk-based approaches in new drug development, the Q12 document aims to address more directly the commercial manufacturing phase of lifecycle product management. 	 	A more flexible change management approach has been encouraged in the European Union as part of an effort to reduce “variations” that require prior approval, pointed out Jean-Louis Robert, head of the pharmaceutical chemistry unit at the National Health Laboratory in Luxembourg. Many minor changes can be implemented under a do-and-tell approach, while manufacturers contemplating more complex changes over the product lifecycle are encouraged to prepare a post-approval change management protocol (PACMP) to accelerate and gain more predictability in regulatory response. PACMPs may be appropriate for certain changes to biological products, such as adding a new cell-culture facility, and should be most useful for drugs developed using QbD principles, Robert commented.	 	

	In the US, the new OPQ structure aims to better combine oversight of drug development with postapproval changes to achieve a more seamless adherence to quality standards throughout the life of a drug or biotech therapy. OPQ’s Office of Lifecycle Drug Products (OLDP) now is responsible for assessing post-approval changes for new drugs and generic drugs, as well as CMC submissions for generic drugs. The plan is for reviewers in OPQ’s Office of New Drug Products (ONDP) to hand off to OLDP oversight of new molecular entities (NMEs) after three years, and for standard new drugs after one year. This plan will allow the original reviewers to evaluate initial scale-up and formulation changes for more innovative products. Post-approval changes for biotech therapies will continue to be managed by OPQ’s Office of Biotechnology Products.	 	A smooth hand-off from new drugs to lifecycle is important, commented ONDP acting director Sarah Pope-Miksinski, as is close collaboration with Moore’s OPF to ensure parity in oversight of changes involving drug process, facility, and sterility. OPF evaluates drug manufacturing process design and controls for commercial production and participates in pre-approval inspections to ensure appropriate implementation of control strategies (2). 	 	

Guidance for Industry, CMC Postapproval Manufacturing Changes To Be Documented in Annual Reports 

www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM217043.pdf

.
	2.  More information on OPQ operations provided in CDER “Pharmaceutical Quality Oversight” report, April 2015, 

www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM442666.pdf

 When referring to this article, please cite it as J. Wechsler, “Quality Systems Key to Lifecycle Drug Management,” 

Regulatory Beat

Regulators and industry seek to streamline and harmonize oversight of postapproval changes.

Quality Systems Key to Lifecycle Drug Management

	A number of recent workforce surveys have shown that professional workers are continuing to put in longer hours. The Great Recession is partly to blame; professional workers were laid off, and those remaining today continue to do the work of two or more.  But as the global economy has improved, the number of employees has not.  Therefore, to get the needed productivity, outsourcing is becoming a standard strategy. 
	
	Biopharmaceutical manufacturers already outsource plenty of activities, and they’re clearly indicating this trend is not likely to be reversed. According to BioPlan Associates’

12th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production

 (1), the push to outsource is being institutionalized. Non-core functions, such as assay testing, are a bellwether: Once again, the industry has voted this activity the most likely to be dumped.

	Each year, BioPlan’s survey brings in more than 200 qualified biopharmaceutical manufacturers who share their perspectives on market trends and opportunities. Back in 2012, the survey showed a large jump in the share of survey respondents who projected significantly greater levels of outsourcing of bioassay testing. Since then, this has consistently ranked as the top area of projected outsourcing increases.

	In the 2015 survey, however, bioassay testing stands out relative to 24 other common bioprocessing activities. Indeed, when respondents were asked which activities will be outsourced at significantly higher levels at their facility during the next 24 months, 40.9% of the industry cited “analytical testing: other bioassays.”  This percentage was double the share of respondents indicating they expect greater levels of fill/finish outsourcing (19.7%), the next highest activity in terms of future outsourcing growth. Beyond assay testing and fill/finish, other activities in the top five for future outsourcing activity include downstream process development, validation services, and API biologics manufacturing (see Figure 1).

					Figure 1: Selected activities: Future outsourcing growth.

	Furthermore, of the 10 most popular activities projected for future outsourcing growth, only three were cited by a higher share of respondents in 2015 compared to 2014. Aside from bioassay testing (40.9% vs. 33.9% in 2014), the others were cell-line development and upstream process development, each with only slight increases. In other words, while enthusiasm for outsourcing appears to have flattened out for most activities, it’s still going strong for analytical testing of bioassays.

	Most likely, this may be the result of continued outsourcing of analytical methods based on the need to have costly, high-maintenance equipment in almost constant operation, as well as the need for specialized staff able to run the assays and prepare the requisite regulatory filings, which may occur only intermittently.
	
	


	
	Staffing requirements may be a larger influence in Europe than in the United States. In the 2014 study, Western European respondents were twice as likely as US respondents to report difficulties in hiring high-tech assay staff (15.8% vs. 7.3%) at their facilities. Perhaps it’s not a coincidence that in the 2015 survey, European respondents were particularly enthusiastic about future outsourcing of assay testing, at almost four times the rate of any other activity. While this activity was also projected for future increases by the largest proportion of US respondents, it didn’t distance itself from the pack at nearly the same level.
	
	Future increases in outsourcing of assay testing may also be due to most companies currently only outsourcing this activity to a minor degree (see Figure 2). While assay testing is again the most commonly outsourced activity, it tends to be outsourced at fairly low levels in relation to other activities. A look at the five most commonly outsourced activities reveals that:

		Approximately 86% of respondents are outsourcing analytical testing of other bioassays to some degree, and an average of 27% of these operations are outsourced.

		73% are outsourcing validation services, with an average of 18% of this activity being outsourced.

		An equal 73% are outsourcing some fill/finish services, but with these respondents estimating outsourcing an average of 35% of these operations overall.

		Some 72% outsource toxicity testing, for an average of 26% outsourced. 

					Figure 2: Average percentage of activity outsourced.

	These results indicate that while toxicity testing is a less commonly outsourced activity, it is outsourced on average to almost the same degree as assay testing. Meanwhile, more than one-third of facilities’ fill/finish operations are currently being outsourced, despite nearly three-quarters outsourcing this activity to some degree.

	As such, the increase in future assay testing outsourcing may be the result of those already outsourcing this activity planning to do so at higher levels in the future.
	
	

	The BioPlan survey shows that the popularity of some outsourcing activities has flattened out, a fairly understandable result given the extent of growth witnessed in recent years. Some notable declines in terms of outsourcing popularity include toxicity testing (72% outsourcing to some degree, down from 87% in 2014) and fill-finish operations (73%, down from 80% in 2014). Still, higher proportions of respondents this year reported having outsourced activities including:

		contract research-laboratory (66%, up from 59%)

		project management services (52%, up from 43%)

		downstream process development (41%, up from 36%).

	In terms of outsourcing levels, most activities appear to be outsourced to a slightly lesser degree in 2015, with the only standouts in terms of decreased levels being toxicity testing (26.1% of these activities on average being outsourced, down from 35.4%) and cell line stability testing (13.4% on average, down from 19.6%). Nevertheless, for the most part, reported levels of outsourcing are in the range set in prior years.

	Additionally, it is expected that the slight dip in levels of validation services being outsourced will be temporary, as the increasing penetration of single-use devices will likely spur more spending in this area. Finally, while more respondents are outsourcing design of experiments (DoE), this activity is being outsourced to a lesser overall degree, suggesting that companies newly outsourcing this quality activity are testing the waters. 

	Although survey results suggest that the market growth for outsourcing of certain activities is flattening, the overall outsourcing market appears to be healthy, as many respondents predict spending increases to come. In fact, a slight majority forecast some level of spending increase, though most of those will be limiting their increases to less than 25%. Overall, it is estimated that spending on outsourcing of R&D and manufacturing will grow by 13% in 2015; this is a healthy growth rate, and it’s consistent with the growth in overall biopharmaceutical sales. 

	While some increases in outsourcing budgets are targeting the more common outsourced services, such as assay testing and fill/finish operations, other activities are showing increasing importance, such as DoE and quality by design. These activities represent smaller budgets, so in years to come, their growth rate may likely be even greater than the big-ticket outsourcing activities.

 When referring to this article, please cite it as E. Langer, “Another In-House Operation Gets Outsourced,” 

Perspectives on Outsourcing

Biopharma companies on both sides of the Atlantic ship more of their assay testing to outside service providers.

Another In-House Operation Gets Outsourced

Meritech’s CleanTech 2000SCA Automated Handwashing System delivers a 12-second wash and rinse cycle that removes 99.98% of dangerous pathogens from bare skin and gloves. The compact system features a clean-in-place design and turnstile-controlled access that automatically opens at the end of each handwashing cycle.
	The system requires 75% less water and soap and produces less discharge waste. A stainless-steel supporting wall and hand dryer or paper towel dispenser can be added optionally.
	
	

Product Spotlight

Meritech’s CleanTech 2000SCA Automated Handwashing System delivers a 12-second wash and rinse cycle that removes 99.98% of dangerous pathogens from bare skin and gloves.

Automated Handwashing System Increases Efficiency

Hamilton’s EasyFerm Bio biocompatible pH sensor is designed for cleaning in place (CIP), sterilization up to 140 °C, autoclavable temperature up to 130 °C, has a pressure range up to 6bar, a 120 mm a-length, and a 12 mm diameter.

	The sensor is made with pH glass and a reference HP-Coatramic diaphragm, and can withstand frequent autoclaving, steam sterilization, and CIP. The sensor has a measuring range from pH 0 to 14 with a NTC 22 kOhm temperature sensor.
	
	

Hamilton’s EasyFerm Bio biocompatible pH sensor is designed for CIP, sterilization up to 140 °C, autoclavable temperature, and a pressure range up to 6bar.

Biocompatible pH Sensor Ensures Reliability

	FDA’s Center for Drug Evaluation and Research (CDER) has been encouraging industry to invest in quality drug production methods and improve processes, facilities, and equipment. Such advances in processing are built on an exchange of scientific and technical information.

	Players in biopharmaceutical development and manufacturing-from biopharma companies and industry suppliers-have a wealth of scientific and technical expertise about biopharmaceutical formulation, development, and manufacturing. Sharing this knowledge-in an objective format-is vital to the growth and improvement of the biopharma industry.

 was founded with the purpose of sharing information about emerging biopharmaceutical development and processing methods, technologies, and practices. With a dedication to providing objective, informed content, the magazine and 

 are excellent media channels for this information exchange. 

	Article formats vary from peer-reviewed papers, non peer-reviewed technical papers, and business-focused articles. The editors welcome contributions from experts in the biopharmaceutical development community, with these four key guidelines in mind:


	Articles and papers must be based on technical and scientific fact, supported by references to published literature or data. Marketing-driven content, unsupported claims, or promotional language are not acceptable in editorial features.


	Manuscripts are reviewed with the understanding that the content has not been published previously in any format, including print or electronic publications, conference proceedings, whitepapers, application notes, posters, or company-created marketing or sales literature. In addition, the submission should not be ghostwritten or under consideration for publication elsewhere, including on the Internet.


	The author must own the rights to the submitted content, including all images, tables, and figures. Graphics from other sources or third-party sources will not be accepted for publication. Before a manuscript is accepted for publication, all authors must sign a license agreement to provide BioPharm International permission to publish the original article and its associated figures/tables in print and online. Authors retain the copyright to the article, as it was originally submitted.


	The editors seek objective articles on technical and regulatory subjects including upstream processing functions of protein expression, fermentation and cell culture; downstream processing including separation and purification; process development; drug formulation and delivery; validation; GMP compliance and quality control; analytical technologies; scale-up strategies; and facilities design. The magazine also covers business topics such as supply-chain management, sourcing and outsourcing, project management, partnerships, and intellectual property management.


	If you have an important technical, regulatory, or process improvement topic to share with peers in the industry, I encourage you to share it through 

. To learn more about contributing a peer-reviewed or technical article, view 

 and review the author’s guidelines and editorial calendar. Then, send me a message or give me a call. I would be happy to discuss your ideas for contributions.

:
	When referring to this article, please cite it as R. Peters, “Your Insight Can Create Industry Benefits,” 

From the Editor

Objective, peer-reviewed papers and technical articles can help advance biopharmaceutical development.

Your Insight Can Create Industry Benefits

Issue PDF

Click the title above to open the BioPharm International June 2015 issue in an interactive PDF format.

BioPharm International, June 2015 Issue (PDF)

The pharmaceutical industry is grappling with pressures including changing business models, a more competitive market, shifts in customers’ demands (e.g., patients and providers), major patent expiries, shifting technology, constrained budgets, increasing scrutiny from payers and regulators, and fundamental questions regarding the industry’s integrity. Many of these internal and external pressures exist in emerging and developed markets alike, forcing manufacturers to reconsider their approach to bringing new products to market (1-3).
	
	Australia is a country that has challenged pharmaceutical manufacturers in recent years with extensive government reforms in drug pricing, unpredictability around reimbursement and pricing decisions, and other structural changes.

	Despite these challenges, the Australian market still offers a number of opportunities for manufacturers. Ongoing changes in Australia’s population and economy have contributed to a shift in the country’s epidemiological profile. That shift has increased the need for more effective population health management practices, and medications that address complex, chronic conditions. Manufacturers will not only find new and expanding target patient populations for their product portfolio in Australia, but also opportunities for broader approaches to managing disease and wellness. And despite some recent setbacks in the growth of Australia’s own biotechnology R&D sector, the country remains a powerhouse for medical science innovations (4).

	Understanding these complex market dynamics will be crucial for manufacturers exploring new and existing opportunities for growth in Australia.

 According to the Organization for Economic Co-operation and Development (OECD) Better Life Index, Australia’s universal healthcare system should be viewed as one of the best in the world. As a nation, Australians live longer than most populations around the world. Over the past 30 years, life expectancy has greatly increased and preventable deaths have been reduced (5).

	The country’s current expenditure in health is modest in relation to OECD standards, and their system aims to guarantee access for essential health services to everyone, regardless of their socioeconomic status. While more Australians are living longer, age and sedentary behaviors similar to those practiced in other developed economies, however, have contributed to mounting rates of chronic conditions such as arthritis, diabetes, heart failure, and asthma among others (see 

	To meet the demands of this epidemiological shift, healthcare providers throughout the country need to think about patients and the care continuum in new ways. Of necessity, greater attention  is required for the preventive and chronic care needs of patients in defined populations. The Australian Government is playing a role in this paradigm through reform initiatives. Specifically, these initiatives aim to facilitate partnerships to improve care coordination across healthcare settings and throughout communities (e.g., Medicare Locals now being replaced with Primary Care Networks); introduce a national personally controlled electronic medical record; enhance the utilization of home-based care and telehealth technology, and improve medication management (7).

	Two other commonly cited challenges of Australia’s healthcare delivery sector include long waiting lists for many hospital medical procedures and the concern there is a shortage of primary-care physicians. This concern is despite the fact that there are more than 43,440 primary physicians compared with 25,400 specialists covering all disciplines (8). Also, wait times for elective procedures are a major concern in many OECD countries. In Australia, median wait times for patients treated have increased over the past decade for a number of common procedures, sometimes significantly (e.g., knee replacement, hysterectomy, cholecystectomy by 32-47%, prostatectomy and hernia by 41-58%) (9). According to the Commonwealth Fund, over the past several years
	Australia, along with Canada and the United States have ranked poorly with respect to overall accessibility of appointments with primary care physicians (10).
	
	


	
	The country’s healthcare expenditure continues to grow faster than population growth, spurred by societal changes such as population aging, treatment and technology advances, and consumers’ increasing awareness of health-related issues. Healthcare spending in 2013 was an estimated 9.67% of gross domestic product (GDP) (17.4% US/9.4% UK), with two-thirds of the total coming from the government (11).

The Australian pharmaceutical market offers opportunities for manufacturers despite challenges.

BioPharm International-06-01-2015