	Glass has long served as the traditional primary package for parenteral products. Unfortunately, glass breaks relatively easily and has been known to cause particulate contamination, to delaminate, and to interact with the drug product. 

	“Current issues with borosilicate glass containers such as breakage, cracks, and particles can lead to patient harm due to contamination, decreased drug efficacy, and drug shortages, as a result of recalls and manufacturing inefficiencies,” says John Tobin, vice-president of Commercial Operations at Corning. 

	He notes, “Current glass packaging has not innovated at the same or even a comparable pace to the scientific breakthroughs in biologic medicines and vaccines throughout the industry. Corning first became aware of glass quality issues with current pharmaceutical packaging for injectable drugs when a major pharmaceutical company and long-time customer asked us to develop a substantially more robust glass solution that also eliminates delamination and reduces particles. At the time, the United States Food and Drug Administration (FDA) had recently issued an advisory regarding the formation of glass lamellae in certain injectable drug containers. It became very clear to Corning that the industry needed a 21st-century glass package that provides the enhanced quality required to protect 21st-century drugs and, more importantly, provide more reliable access to vital medicines for patients around the world.” 

	To target the problems encountered with Type I borosilicate glass, Corning’s glass experts worked in collaboration with Merck and Pfizer to develop Valor Glass, an aluminosilicate glass, which is now commercially available. As a drop-in replacement for borosilicate glass, the new glass type is compatible with existing stoppers, caps, labels, and fill/finish lines.

	Corning used glass chemistry and an ion-exchange process, and lowered the coefficient of friction of the surface to produce a glass that is inherently strong and damage resistant (see 

). Traditional borosilicate Type I glass contains a significant amount of boron. However, Tobin says, “When introduced to heat, such as during the converting process, the boron in the glass network becomes volatile and evaporates out of the glass, creating surface heterogeneities (regions of non-uniform glass composition) on the interior drug-contacting surface of the package. Corning intentionally removed boron from the Valor Glass composition because of its volatility, which can cause delamination. The other glass components are the same but the ratios are slightly altered to enable a high degree of chemical durability. As a result, Valor Glass has a pristine, chemically durable drug-contacting surface both before and after the converting process, effectively eliminating the root cause of delamination.” 

	An ion-exchange process also minimizes issues such as breakage, cracks, and particulate contamination. Despite the difference in chemistry, Valor Glass meets the current 

Type I hydrolytic criteria and has low extractable concentrations. Work is underway at 

 to broaden the definition for Type I glass to include Valor Glass. 

	A protective coating on Valor Glass lowers its coefficient of friction and eliminates cosmetic flaws. Eliminating high-friction vial-to-vial contact protects the surface of the containers, results in a more uniform container flow, and enhances machinability. As a result, vials and cartridges run smoothly on fill/finish machines. Incidents with downed vials, jams, and broken containers are virtually eliminated, and throughput increases. For drug manufacturers, fewer line interventions mean less downtime and a decreased risk of contamination and quality defects. Trials on commercial filling lines have confirmed performance and shown a 96% reduction in peak particle counts, according to Corning.  

	Valor Glass has drawn the attention of more than 40 pharmaceutical companies. Tobin reports, “We initially thought interest would be for pipeline products, but it’s being looked at for marketed drugs as well. Corning has filed a drug master file for Valor Glass with FDA and will continue to work closely with pharmaceutical manufacturers to provide supporting information to facilitate adoption.” 

	Merck has announced plans to convert several products to Valor Glass pending regulatory approvals. At a press conference on July 20, 2017, Kenneth C. Frazier, Merck’s chairman and CEO, said, “Biologics today are on the leading edge of scientific innovation, and Valor Glass represents a similar advancement in materials science: glass that is purpose-built for medicines and vaccines.” At the same press conference, Valor Glass was described as a potential game changer. “Our initial trial results with Valor Glass show promise, and we are working with Corning to assess the full potential of this glass solution on products at several of our manufacturing sites,” said Ian C. Read, chairman and CEO at Pfizer (1). 

	As the designer of the composition, technology, and manufacturing platform, Corning manufactures and sells Valor Glass and oversees all purchases of it. In addition, established partners, such as Gerresheimer and Stevanato Group, are providing converting and related expertise to speed delivery to the industry and patients. 

	With usage of prefilled syringes continuing to rise, Schott has doubled polymer syringe production at its syringe competence centre in St. Gallen, Switzerland. The new capacity started up in June 2017 and builds on a previous expansion. Additional capacity is being installed and will be operational in 2018 (2).  

	“Schott has optimized singular process steps based on our existing quality and production experience,” says Tom van Ginnecken, global product manager, Polymer Syringes at Schott. He notes, “Typical improvements involve the state-of-the-art technologies for transportation and handling to further reduce the risk of cosmetic defects. In addition, Schott is getting prepared for future pharma requirements in automation and data exchange.”

	He explains, “We see a growing trend toward customized delivery systems. The first reason for this trend is the focus of pharmaceutical companies on orphan diseases. With a highly individualized injection solution, the pharmaceutical companies try to increase patient comfort and increase drug adherence by offering a tailor-made solution that is compliant with the patient group’s impairments and abilities. Another driver for more customized delivery systems is the need for product differentiation. More pharmaceutical companies use the injection device as a way to differentiate their drug in the market. In a fiercely fought market space with a lot of competition, such as generic drugs; this method of differentiation could mean the success or the failure of a drug. Also, the injection molding process of a polymer syringe inherently offers a broad range of customization possibilities.” 

	Polymer syringes offer advantages beyond customization and differentiation. The material maintains glass-like transparency, resists breakage, and offers excellent barrier properties to keep the medication stable throughout its shelf life. Schott polymer syringes are available in 1–50-mL sizes and delivered ready-to-fill in a nest-and-tub configuration. For more sensitive applications, Schott TopPac SD syringes feature a reduced extractable and leachable profile that ensures high drug stability (2). 

	Glass ampoules remain widely used to package injectable drugs, and demand is actually growing in emerging markets. Although typically used for high-volume, mainly small-molecule drugs, ampoules “could be interesting for biopharma products as well,” notes Neus Ferré, global product manager, Ampoules at Schott. 

	Schott’s glass ampoules combine dimensional stability with 100% inspection to suit either end of the spectrum: long runs at high speeds or flexible fill/finish systems for small batches. “At Schott, we are following a zero defect philosophy, resulting in ampoules of high and stable dimensional quality,” reports Ferré. She explains, “On the one hand, this is achieved by an excellent raw material-Fiolax Type I borosilicate glass-combined with a precise manufacturing process. On the other hand, we have invested in intelligent camera inspection systems that help to improve both cosmetic and dimensional quality even further.” 

	The DualFusion vial from Wheaton, now DWK Life Sciences, combines the best properties of both plastic and glass into one container. Using plasma-enhanced chemical vapour deposition, an organosilicate protective layer is fused with a silicon dioxide barrier layer that is fused to a cyclic olefin polymer (COP) shell to form a robust, covalently bonded material. The outer COP shell provides mechanical strength, protects against breakage, and can withstand temperatures from -196 °C to 121 °C without cracking. The inner barrier layer prevents permeation of oxygen, water vapour, and other gases, protects against delamination, and eliminates concerns over leaching of metal ions, which can compromise the integrity of vial contents (3). 

	Each ready-to-use, ready-to-sterilize DualFusion vial has a unique barcode for traceability and authentication. Applications include highly toxic drugs and biologics (4). More recently, there’s been interest for freeze-drying applications. The vial has a completely flat bottom that allows efficient temperature transfer from the lyophilizer to the drug product, and the vial’s barrier layer allows extended storage time, says Jeffrey Reid, strategic markets manager, DWK Life Sciences. 

	The increase in personalized medicine is driving growth in small batch fills. “Therefore,” says Reid, “pharmaceutical companies require smaller packouts of ready-to-use (RTU) packaging components.” To address this need, DWK Life Sciences will begin supplying RTU packaging components such as vials, rubber stoppers, and seals grouped together in one box with an average packout of 200 pieces per component. “This will allow our customers to shift to smaller fill runs and not have to worry about a large scrap rate of packaging components,” concludes Reid. 

	1. Corning, “Merck and Pfizer Collaborate with Corning to Modernize Pharmaceutical Glass Packaging,” News Release, July 20, 2017.
	2. Schott, “In Light of Growing Demand, Schott Again Increases Its Polymer Syringe Production,” News Release, July 26, 2017. 
	3. Wheaton, “The New DualFusion Vial Is First Vial that Combines the Benefits of a Strong, Protective Plastic Outer Layer and the High-Performance Barrier Properties of an Inner Silica Layer, News Release, July 31, 2016. 
	4. H. Forcinio, 

	When referring to this article, please cite it as H. Forcinio, "Improved Materials Enhance Parenteral Packaging," 

Articles

Features

Manufacturers introduce innovations in glass and plastic packaging for injectables.

Improved Materials Enhance Parenteral Packaging

	Pharmaceutical manufacturing has long played a major role in the economy of Puerto Rico, representing 72.4% of its total exports in 2016, according to the US Bureau of Labor Statistics (1). In 2016, Puerto Rico-based facilities exported $14.5 billion in drug products, 25.5% of the US total and more than the amount of product exported by any US state.

	The US territory, which has struggled for years under a heavy debt burden, took another blow on Sept. 20, 2017 when Hurricane Maria knocked out all electrical power and nearly all phone service for the 3.4 million residents. One week after the storm, the power grid, communications, and transportation systems were in ruins. Food, water, medicines, and other living essentials were in short supply. While government agencies and relief organizations initiated humanitarian efforts, pharma companies with facilities on the island assessed the damage to their facilities and contributed to relief efforts (2).

	AbbVie and Amgen reported minimal damage to facilities and were working to restore normal operations. Eli Lilly and Company reported its two manufacturing sites in Puerto Rico had minimal damage, and that operations would not be hindered and there was no supply risk to patients. AstraZeneca reported it was receiving updates regarding the status of its plant in Canovanas and its employees, but believed that the facility fared well. Bristol-Myers Squibb said the company was evaluating the situation around its pharmaceutical operations, executing contingency plans to mitigate product supply risk, and working to bring operations back online. 

	As of Sept. 27, 2017, FDA identified more than 40 high-priority drugs where short-term disruptions could lead to shortages. The agency is working with at least five companies impacted by the hurricane to prevent critical shortages of medical products in Puerto Rico and across the United States, including coordinating transport of critical drugs from Puerto Rico.

	Previously, tax laws that enabled US drug manufacturers to send profits from the island’s manufacturing facilities to parent companies on the mainland without having to pay federal taxes encouraged companies to establish operations in Puerto Rico. Those incentives expired about 10 years ago, leading to the shutdown of some facilities.  Some worry that other facilities damaged by the storm may not reopen (3), hindering the island’s physical and financial recovery.

	FDA Commissioner Scott Gottlieb expressed similar concerns-in addition to worries about drug shortages-in a Sept. 25, 2017 statement (4). “The island is home to a substantial base of manufacturing for critical medical products that supply the entire world. This industrial base is an important source of jobs and economic vitality for the island. It is a key to Puerto Rico’s economic recovery. The manufacturing facilities are also a pivotal source of critical medical products for the entire United States. Helping to bring these resources back in operation is an important goal of ours and of Puerto Rico’s,” the statement read. Puerto Rico faces a long, difficult path to recovery. Will Pharma be part of the healing process?

	1. Bureau of Labor Statistics, Puerto Rico: Price Movements of Top Exports and Other Highlights, www.bls.gov/mxp/puertorico.pdf, accessed Oct. 2, 2017.
	2. 

Pharma Gives Update on Puerto Rico Manufacturing Operations

,” Sept. 28, 2017, accessed Oct. 2, 2017.
	3. M.I. Schwartz, “

Pharmaceutical Manufacturing in Puerto Rico after Maria-Where Does it go from Here

?” FDA Law Blog, Sept. 28, 2017, accessed Oct. 2, 2017.
	4. FDA, 

Statement from FDA Commissioner Scott Gottlieb


	Volume 30, Number 10
	October 2017
	Page: 6

	When referring to this article, please cite it as R. Peters, “Pharma’s Role in Puerto Rico’s Future," 

From the Editor

Reeling from financial and tropical storms, Puerto Rico needs stable industry to aid its recovery.

Pharma’s Role in Puerto Rico’s Future

Viruses replicate or grow within living organisms, from man to microbes. Therefore, any biological system used to generate biological or biopharmaceutical products could be contaminated with viruses. Viruses can cause serious or fatal illness. Even viruses not known to be highly pathogenic, or to cause significant disease in humans, could potentially do so if introduced into an immune-compromised host and/or by a non-natural route of infection (e.g., intravenous or intramuscular inoculation rather than respiratory or oral spread). Some viruses can result in chronic infections, or persist silently within cells for long periods. For example, retroviruses, a family of viruses known to cause serious disease in humans and animals, integrate into the host cell genome as part of their lifecycle, and can result in life-long infection or cellular change.

	There are several, well-documented historical instances of virus transmission to humans through contaminated vaccines. Some early batches of yellow fever vaccine, for example, produced in hens’ eggs were found to be contaminated with avian leucosis virus. In the late 1950s and early 1960s, batches of poliovirus and adenovirus vaccines were contaminated with Simian vacuolating virus 40 (SV40) from rhesus monkey kidney cells. Viruses have also been detected in cell culture-derived products without transmission to humans or animals. Examples are shown in 

					Epizootic haemorrhagic disease virus

	Virus contamination could arise due to the presence of virus in the original cell line or biological system used, or to the inadvertent introduction of virus into cell cultures during a manufacturing process. Raw materials of animal origin, a manufacturing process operator, or even materials contaminated by contact with animals or animal-derived material are possible contamination sources. Contamination of Chinese hamster ovary (CHO) cell banks with murine minute virus (MMV), a virus primarily found in the urine of rats and mice, could potentially have resulted from this latter route.

	Although there is significant effort to move away from the use of animal-derived materials such as bovine serum or porcine trypsin for cell culture, many cell lines have historically been exposed to these materials and could potentially be infected with a range of bovine and porcine viral contaminants. For example, the most likely source of contamination of live rotavirus vaccine with porcine circovirus, identified initially in 2010 via next generation sequencing, appears to have been non-irradiated porcine trypsin used in the 1990s to manufacture the Vero cell banks used for vaccine production (1-3). 

	Control of potential virus contamination in biologicals

	Three principal and complementary approaches are generally applied for controlling viral contaminants in biologics: the selection and control of starting materials; the testing of source materials and the products; and viral clearance. This article primarily focuses on testing of source materials and products. 

	Regulatory authorities require testing to be carried out at every stage of the manufacturing process of the product, including cell substrate banks, viral seed banks, raw materials of animal origin, bulk harvests, and batches of the final manufactured clinical product. The samples must be tested to recognized international guidelines, such as the International Council for Harmonization (ICH) guidelines, FDA Vaccine 2010 guidelines (4), and/or 

	There are many factors to be taken into consideration when planning a viral testing strategy, and these will include assessment of the risk of contamination from endogenous and adventitious viruses due to the starting materials and reagents used, as well as the nature and intended use of the final product. All potential contaminants may not be predicted. Novel infectious agents are being increasingly reported (e.g., novel coronaviruses, such as severe acute respiratory syndrome [SARS] and novel influenza virus variants), and no single assay method or approach will detect all viruses. A combination of approaches for virus detection, including general and specific assays, is therefore required. Potential test methods typically include adventitious agent tests, usually non-specific tests capable of detecting a broad range of viruses; species-specific assays, designed to detect the presence of identified potential contaminants (e.g., specific bovine or porcine viruses in serum or trypsin, respectively, or murine viruses in mouse cells); and tests for retroviruses.

	Viruses can be detected by using assays that look for evidence of infectivity in a living system (

 assays), or for viral markers including the presence of the virus genome (e.g., polymerase chain reaction [PCR]-based methods), viral proteins (e.g., enzyme assays for reverse transcriptase in retroviruses), or virus particles (e.g., by electron microscopy). 

	Electron microscopy (EM) is used widely in the industry as a generalized, non-specific screening method. It allows direct visualization of cells or samples, and can allow for the detection of a broad range of viruses as well as other micro-organisms, included bacteria, fungi, and mycoplasma. Although a useful screen, the sensitivity of the method is low. For example, virus present in a very small proportion of a cell bank (e.g., 1 in 1000 cells) may not be detected in a standard assay where 200-300 cell profiles may be examined. EM can also be a useful diagnostic and investigative tool if the presence of virus is suspected in cell cultures.

	Almost all cells contain retrovirus sequences. Some cell lines commonly used in the industry, such as murine hybridomas and CHO cells, are known to release retrovirus-like particles. Although the retrovirus particles released from CHO cells have not been shown to be infectious, murine cells can often release infectious virus. Regulations require the use of EM to look for the presence of retrovirus in cells and to quantify the load of retrovirus-like particles in bulk harvests when rodent cells such as CHO are used.

	Retroviruses express an enzyme known as reverse transcriptase (RT), which converts virus RNA to DNA and facilitates integration of the virus DNA into the host cell genome. It is virtually unique to retroviruses, so RT activity is an indication of potential retrovirus contamination. Regulations call for the use of PCR-based RT (PBRT) or product-enhanced RT (PERT) assays to detect retroviral RT enzyme activity (4-10). Although PERT assays are highly sensitive, they can sometimes give false positives from high background cellular DNA polymerase activity, so unexpected PERT positive results need to be confirmed by retroviral infectivity testing, using a relevant detector cell line(s) (11-14).

	Quantitative PCR-based assays (QPCR), such as TaqMan (Thermo Fisher) technology, or other nucleic acid tests (NAT), are widely used to look for species-specific contaminants by amplification of viral DNA or RNA. These methods are considered specific, and therefore it is only possible to detect what is looked for. The appropriate contaminants to analyze for are selected based on a risk assessment of what the material is, and what it is ultimately going to be used for, as well as relevant regulatory guidance.

	Not all viruses grow or are detectable in cell culture or 

 systems, and PCR-based assays are therefore useful for detection of such contaminants. However, a positive PCR result only indicates the presence of virus DNA or RNA, rather than reflecting the presence of infectious virus. Bovine polyoma virus, for example, is a well-known contaminant of serum, but a positive PCR result from serum cannot determine whether there is replicating virus present or merely DNA fragments. Therefore, positive results from PCR assays may require further investigation, and use of infectivity assays, if available, to determine if infectious virus is present.

	There are also practical considerations with respect to the use of these assays. For example, the PCR target must be highly conserved and the assay highly sensitive (<100-1000 copies per 200,000 non-infected cells for cell banks or <2000 copies per mL for vaccine seeds). Due to the high sensitivity, PCR is highly prone to contamination, so rigorous controls must be put in place to segregate the PCR reagents and test materials in different cleanrooms and to ensure that the workflow moves only in one direction.

	Industry interest in next generation sequencing (NGS), also known as massive parallel sequencing, deep sequencing, or metagenomics is strong. Using this method, a population of sequences in the sample can be surveyed, allowing the detection of unknown viruses, integrated retrovirus provirus, transcripts and endogenous sequences. 

	Assays that detect virus markers, including virus DNA or RNA, protein or particles, are an important component of a virus testing strategy. Interpretation of results can be difficult, however, as these assays may not distinguish between infectious and non-infectious virus. Many of these assays are also highly specific (e.g., PCR, enzyme assays). Therefore, additional approaches, including the use of assays capable of detecting a broad range of infectious viruses, are also required. 

	Infectivity assays are routinely used to screen for the presence of infectious virus contaminants. These may be non-specific, such as in-vitro and in-vivo assays for the detection of adventitious virus contaminants, or specific bovine or porcine virus assays or mouse antibody production tests (MAPs)/hamster antibody production tests (HAPs) for the detection of specific bovine, porcine, murine, or hamster viruses. 

) assays for the detection of adventitious virus contaminants involve inoculating selected indicator cells in culture with the test sample, maintaining the cells for a period of time to allow virus growth and spread, and looking for non-specific or general signs of infection common to many viruses, such as cell death or cytopathology, or hemadsorption (the ability of infected cells to bind red blood cells). This process is illustrated in 

 assays: Cell-culture assays for detection of adventitious virus contaminants. CHO is Chinese hamster ovary. BHK is baby hamster kidney cells.

	To be detected, a virus must be able to infect and grow within the indicator cell line(s) under the conditions used, and induce cytopathology or an alternative detectable effect (

). By using a range of cell lines capable of supporting the growth of different viruses, and appropriate end-points, 

 assays may allow the detection of a broad range of adventitious virus contaminants.

	The precise assay conditions selected will depend, for example, on the origin of the cell bank, the type of virus that may be present, the intended use of the product, and the requirements of the regulating authority. For example, ICH Q5A guidelines (6) advise that human and/or non-human primate cells susceptible to human viruses be used as indicator cell lines and end points for detection of cytopathic and hemadsorbing viruses. Likewise, the FDA Points to Consider (PTC) (1993, 1997) (8,9) recommend the use of at least three cell types (cells of the same species and tissue type as the production line, where possible; human diploid cells; and monkey kidney cells). 

	Vero cells are a commonly used monkey kidney cell line and can detect human adenoviruses, herpesviruses (HSV), arboviruses, picornaviruses (polio, enterovirus), SV40, vesicular stomatitis virus (VSV), paramyxoviruses (including mumps, measles, parainfluenza), and orthomyxoviruses. MRC-5 cells (a human dipoid cell line) can detect human herpesviruses, picornaviruses (polio, echo, rhino, coxsackie), VSV Indiana, paramyxoviruses (parainfluenza), and orthomyxoviruses. The use of MRC-5 and Vero cells, therefore, provides two indicator cell lines susceptible to a range of human viruses.

	Cell culture-based assays can also be specific, for example, by -including a specific end-point such as immunofluorescence with a specific antibody. This approach is used to detect specific viruses that may go undetected by other endpoint methods (e.g., non-cytopathic viruses) and this method is used routinely as part of 9 Code of Federal Regulations 113 for the detection of bovine and porcine viruses in fetal bovine serum, cell banks, and viral seeds. 

	Cell-culture assays are frequently performed for the detection of infectious retroviruses, either by infection of relevant cells in culture with a test sample or by co-cultivation with live test cells. Retrovirus infection is often non-cytopathic, and therefore relevant endpoints are typically included, such as the use of a PERT assay for detection of RT activity in culture supernatants, or a sarcoma-positive, leukemia-negative (S+L-) cell line, which results in transformed foci in response to infection with a relevant retrovirus. These assays include the XC, S+L- and Mus dunni assays used for rodent cell lines and their harvests, and co-cultivation assays using human cell lines for detection of human-tropic retrovirus.

	No amount of testing can ever definitively prove the absence of an infectious agent. Clearly, it is not possible to test all of a product, so if a contaminant is present at low level then there is a statistical chance that it will not be detected. Furthermore, not all viruses or all individual virus isolates will necessarily be detected in the assay systems used. 

	Virus safety testing therefore requires a risk-based approach involving a combination of methods, dependent on factors such as the production parameters, the viral risk assessment of raw materials, and the clinical application of the product.

Questions and Answers Relating to Finding of Porcine Circoviruses in Rotavirus Vaccines

 (June 3, 2010), accessed Sept. 19, 2017.
	3. WHO, “

Porcine Circoviruses and Rotavirus Vaccines

,” Extract from report of GACVS meeting of 16-17 June 2010 (July 23, 2010)  accessed Sept. 19, 2017.
	4. FDA, Guidance for industry

. Characterization and Qualification of Cell Substrates and Other Biological Materials Used in the Production of Viral Vaccines for Infectious Disease Indications

, General Chapter 5.2.3 Cell Substrates for the Production of Vaccines for Human Use (EDQM, Strasbourg, France).
	6. ICH, Q5A (R1), 

Quality of Biotechnological Products: Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin

, General Chapter 5.14 Gene Transfer Medicinal Products for Human Use (EDQM, Strasbourg, France).
	8. FDA, Point to Consider in the Manufacturing and Testing of Monoclonal Antibody Products for Human Use, Report (1997).
	9. FDA, Points to Consider (PTC) in the Characterization of Cell Lines Used to Produce Biologics, Report (1993).
	10. WHO, 

Recommendations for the Evaluation of Animal Cell Cultures as Substrates for the Manufacture of Biological Medicinal Products and for the Characterization of Cell Banks

, Technical Report Series No. 978, Annex 3 (2013).
	11. A. Lovatt, et al., 

, 82 (2) 185-200 (1999).
	12. Y. Xu and K Brorson. 

 (Basel), 113:89-98 (2003).
	13. B.A. Arnold, R.W. Hepler, and P.M. Keller, 

 25 (1) 98-106 (1998). 
	14. K. Brorson, et al., 


	Volume 30, Number 10
	October 2017
	Pages: 18–27

	When referring to this article, please cite it as R. Adair, “Control Viral Contaminants with Effective Testing," 

Detecting viral contaminants in biologic-based medicines-and identifying their source-requires a holistic testing approach.

Control Viral Contaminants with Effective Testing

The biologics market is projected to reach $399.5 billion by 2025, according to a report by Grand View Research (1). Growth is being driven by a number of factors including the superior efficacy and safety of biologics as a result of specific drug targeting, an aging population, and the shift toward personalized medicines. The drug development process for biologics, however, is not as straightforward as that for small-molecule drugs. Unlike small molecules that can be chemically synthesized, biologics are produced in genetically modified living cells using recombinant DNA technology. The complexity and size of these macromolecules not only present challenges in the manufacturing step, but also in formulation development. 

	“There is tremendous pressure to shorten the formulation development timeline to accelerate product development,” Jay Kang, director, Analytical & Formulation Development, Patheon, notes. “But the instability of a product because of poor formulation development can result in clinical hold and put the whole program at risk.” 

	Kang explains that the instability of a biologic can be caused by aggregation, deamination, isomerization, hydrolysis, oxidation, and denaturation. “The tendency of a biologic to exhibit these structural modifications depends on the properties of the protein and environmental factors including temperature, pH, and the ionic strength of the surrounding environment,” he says. “Several excipients have been tested to increase the stability of biologics, including the use of disaccharides and non-ionic surfactants. Although many of these agents are effective stabilizers, their use requires careful consideration in terms of local toxicity and potential immunogenicity. Understanding the mechanism of inactivation of biopharmaceutical drugs is crucial and can enable a rational approach to determine what excipients should be used for stabilization.” 

	Enrico Corona, director of Pharmaceutics & Process Technology, Patheon, highlights that because formulation development often occurs in parallel with process development, scientists not only have a limited supply of material, but they are also using materials that might not be representative to the final process. “Critical quality attributes (CQAs) are not clearly defined for novel biologics,” he says. “A lot of CQAs are based on similar molecules initially, which might not be the case. This poses challenges in making effective formulation decisions.”

	Moreover, because of their high molecular mass, biopharmaceuticals have lower permeability across biological barriers such as the skin, mucosal membranes, and cell membranes, Corona points out. “For this reason, injection is the primary mode of administration for most biopharmaceuticals,” he adds. Injections are not ideal, especially for chronic conditions. The pain and inconvenience caused by this invasive route can have a negative impact on patient compliance and quality of life. 

	Oral delivery offers advantages to both patients and manufacturers, but for biopharmaceuticals, success has been limited. “Both industry and academia have spent significant amount of resources on this effort,” Kang observes. “However, avoiding degradation in the harsh gastrointestinal environment as well as transporting large and hydrophilic biologic molecules into the blood stream remains a challenge. Until we see a breakthrough in both areas, oral delivery of biologics will remain an elusive goal for formulation scientists.” 

	David Lyon, head of biotherapeutics, Capsugel, now a Lonza company, notes that oral delivery of biologic APIs-mainly peptides and proteins-has been the “holy grail” of pharmaceutical drug delivery for the past several decades. “The delivery of biologic APIs is challenged by both physical-chemical properties of the molecules as well as the biology of the gut,” he explains. “Specifically, the challenges include hydrolytic sensitivities of the molecules to the acidic media in the stomach as well as the enzymatic activity of the intestine.” 

	Lyon adds that peptides and proteins have high molecular weights and are highly hydrophilic. Such properties are opposite to those required for passive permeation of molecules across the gut epithelium. “The stability of peptides and proteins to temperature, pH, and in some cases, light can also have an important impact on manufacturing,” he says. “And in such cases, a delicate balance between the formulation process and process conditions and the stability of the biologic API will be required.”

	Ryan Klein, senior director of R&D at Tergus Pharma, notes that the limited success of delivering biologics via the oral route has led to the exploration of other delivery sites such as the lungs and the skin. The inhaled or nasal route, for example, has attracted a great deal of interest, not only because of its potential for direct delivery of the drug locally to the respiratory system, but also as an alternative systemic delivery route. 

	“As a systemic dosing route, inhaled and nasal delivery presents a more patient-friendly alternative to parenteral delivery. It also has potential advantages in pharmacokinetic profiles compared to other options such as subcutaneous injection,” says Mark Parry, technical director, Intertek Melbourn (2). “Topical delivery, on the other hand, allows targeting of the drug to the site of action with a potentially lower dose than would be needed for systemic intravenous (IV) dosing-for example, in the treatment of a lung infection or delivery of a gene therapy to the lungs of a cystic fibrosis sufferer.” 

	According to Lyon, nasal delivery can be limited by surface area and rapid mucous turnover. “But the lung has a large surface area and a relatively porous membrane that it offers a good non-invasive target for the delivery of peptides and proteins,” he says, citing Alfrezza, an inhaled insulin product developed by MannKind Corporation, as an example. 

	A number of devices are used to deliver drugs via the inhaled or nasal route, from nebulizers and nasal sprays to dry powder inhalers (DPI) and pressurized metered-dose inhalers (pMDI). Ashleigh Wake, director of Biological Services, Intertek Manchester, highlights that device selection should take into account factors relating to both the properties of the compound being developed as well as the intended usage model of the product. “There are also related commercial considerations to be factored in,” she says (2). 

	“Some compounds may need to be present as a solid material because they lack long-term stability in solution; DPI products are advantageous in such cases, besides the additional benefit of patient convenience. However, engineering a DPI formulation requires the development of a suitable spray-drying process (or other suitable particle-engineering technique), which adds complexity and cost to the product and its development,” Parry explains (2). 

	“At Capsugel, we have developed a spray-drying/particle-engineering technology that allows the gentle processing of biologic APIs into room temperature-stable formulations that can then be inhaled using specially designed DPI capsules (for optimized clearance of the drug) and readily available DPI devices,” Lyon says. “Capsugel has progressed more than 10 inhaled peptides and proteins that are now in various stages of development.”

	Despite some of the advantages of a DPI formulation, nebulized and nasal solution and reconstituted solution products tend to dominate current developments, according to Parry. Lyon points out that nebulizers and pMDIs require the biologic to be presented as a solution. “While many proteins can be stabilized in solution, this often requires cold-chain storage (2–8 °C) to keep the protein in its correct three-dimensional structure,” he says. “Also, nebulization and pMDIs are generally considered less convenient for the patient and more challenging from a patient compliance perspective.” 

	According to Lyon, dry powder formulations offer the advantage of better patient compliance as well as being room temperature stable when properly formulated. Parry also agrees that the advantages of a simpler, shorter inhaled dosing process as well as improved shelf lives make DPI products more commercially desirable.

	“In terms of device compatibility, one of the early parts of development is to look at the compatibility of the product with the materials and methods of operation of the chosen devices,” says Wake. “For example, the aerosolization of solutions for nebulization can impart significant shear forces as well as increased exposure to oxygen in the air, which must be assessed in order to select an appropriate delivery device.” She explains that biologics can suffer from changes in activity and structure when exposed to extreme conditions, as typical of a nebulized or nasal system. It is, therefore, important to ascertain if the delivery mechanism has adversely affected such parameters (2). 

	Besides the typical quality control criteria of assay, purity, and impurities, inhaled and nasal products requires specific testing to look at the product performance, Parry points out. “These tests include measuring the delivered dose (i.e., the actual amount delivered by the device to the patient) and the particle or droplet size, which affects where the product will deposit,” he says (2). “These parameters are critical for inhaled and nasal product performance as they ensure that the right amount of drug is delivered to the right part of the nose or lungs, and are key stability indicating tests for development and routine testing of these product types.”

	The potential of delivering biologics through the skin is also being explored. “Biologics as topical treatments are playing an increasing role in treating a variety of skin conditions,” says Klein. He highlights, however, that there are unique challenges in delivering such large molecules across the skin given its function as a protective barrier. “The compact structure and hydrophobic nature of the stratum corneum is the primary barrier,” he says. “As a result, the cutaneous delivery of biologics typically requires the use of penetration enhancers or some other physical or chemical disruption of this skin layer.”

	Despite these challenges, Klein sees great opportunities for delivering biologics via the topical route, particularly for the treatment of skin conditions. “The advantages of topical delivery of biologics include direct treatment at the site of the disease, the avoidance of hepatic first pass metabolism, extended delivery times that can prolong the pharmacodynamic effect at the site of action in the skin, and the flexibility to remove the delivery system to discontinue administration of the drug,” he explains.

	From a formulation perspective, Klein stresses that it is important to select excipients and penetration enhancers that allow the drug to maintain its efficacy and reach the target site in sufficient quantities. “The tertiary structure of large molecules is crucial to their efficacy, and this conformation can be highly sensitive to certain excipients and processes used to formulate the final product,” he says. He adds that chemical degradation, aggregation, and conformational denaturation can lead to a significant decrease in efficacy. “Factors such as pH, salt content, shear, and heat that typically have minimal impact on conventional small molecules can have a significant impact on a biologic,” he says. “Thus, appropriate solvents and excipients should be carefully selected to ensure they are fully compatible with the drug substance in the final dosage form (i.e., cream, lotion, gel, ointment). The final process should be thoroughly evaluated and the design space fully characterized to establish the impact of manufacturing process on the final product.”

	According to Klein, most alcohols are incompatible with peptides and proteins and should, therefore, be avoided as solvents in favor of aqueous buffer systems that provide a more stable environment for biologics. “To optimize product shelf life, preservatives and stabilizers may also be necessary and should be added to maintain pH and prevent oxidation. Typical stabilizers include methionine, glutathione, and trehalose,” he says. 

	Klein notes that penetration enhancers are often required to enhance the delivery of large molecules, but must be selected carefully to ensure compatibility. “Many conventional penetration enhancers exert their effect due to their ability to disrupt the biological environment of the skin, and therefore, are not compatible with large molecules in the formulation,” he explains. “Specific enhancers that are amenable to most biologics include isopropyl myristate, propylene glycol, and N-methylpyrrolidone.” 

	Another alternative to injections, for biologics, is the transdermal route, which offers the possibility of a faster onset of action compared to subcutaneous administration, according to Lisa Dick, microstructured transdermal system (MTS) new technology and product development manager, 3M Drug Delivery Systems. “Microneedle delivery provides an alternative to standard syringes and needles or autoinjectors,” she says. “For needle-phobic patients, microneedles are less threatening than standard injection needles.” 

	For transdermal products, the drug molecule needs to be relatively small (i.e., several hundred atomic mass units) and permeable through the stratum corneum, observes Mark Tomai, head of Toll-Like Receptor (TLR) and MTS Business Development, 3M Drug Delivery Systems. “Most biologic drugs are too large for passive intradermal delivery,” he says, “that’s why microneedle-based delivery systems have been developed.” 3M has developed hollow and solid microneedle systems, which use biocompatible polymeric microneedles to bypass the barrier properties of the stratum corneum.

	The hollow microneedle technology by 3M is a single-use delivery system designed for self-administration. Liquid formulations are contained in a reservoir and delivered into the skin via a 1-cm

 microneedle array. The microneedles can accommodate a range of molecules and drug volumes of up to 2 mL, as long as stability in the liquid form is maintained (3). 

	“For liquid formulations delivered through hollow microneedles, skin tolerability and viscosity are key considerations during formulation development,” says Tomai. “Non-viscous formulations flow readily through the narrow flow paths in the microneedle-based devices, but viscous formulations are more likely to require a long delivery time due to back pressure from the skin toward the volume being delivered.” According to Tomai, it is possible to deliver more viscous solutions of up to approximately 25 centipoise (cp) with the 3M hollow microstructured transdermal system (hMTS), and there are options for delivery of up to 80 cp solutions in the future (2).

	Dick stresses the importance of ensuring that the drug product formulation is chemically compatible with the microneedle array and device, including storage over time. “Drug molecules in a liquid formulation that are delivered using a hollow microneedle injector must be physically able to withstand shear forces when flowing through the device. Such physical compatibility considerations are especially important for biological drugs, which can denature or become inactive,” she explains (2). 

	3M’s solid microneedle technology is based on tiny needles mounted on a wearable patch, which has been designed to deliver proteins, vaccines, or other solid formulations up to 300 mcg (4). “In this case, the drug is coated on the microneedle patch and these systems have the advantages of having many short microneedles, being easy for a patient to self-administer, and potentially being stable at room temperature,” says Dick. There are, however, several formulation considerations that need to be taken into account, for example, the balance between chemical stability, the ability to coat onto solid microneedles, and the ability of the formulation to release into the skin, Tomai highlights. “Chemical stability considerations are similar to those of other dosage forms. The ability to coat a formulation onto solid microneedles is drug dependent and relies on solubility, target dose, and viscosity. For the ability of a formulation to release into the skin, it needs to be released from the microneedle surface through its inherent solubility in the dermal interstitial fluid,” he says. There may be more than one acceptable formulation composition for a drug molecule, Tomai points out, therefore, it is a matter of testing several formulations for manufacturability and the eventual outcome for effective treatment (2).

	The impending patent expirations of biologic blockbusters continue to fuel the development of biosimilars. There is a lot of pressure for faster formulation development as companies strive to quickly file an investigational new drug application, according to Kang and Corona. “Most companies are using high throughput methods to screen large amounts of buffer/excipients more quickly and efficiently. There is also the development of kinetic models to predict drug product expiration dates based on stressed or accelerated stability results,” they say. “In addition, we see increasing emphasis by regulators on efforts to measure, characterize, and control subvisible particles in biologics.”

	There is, at the same time, a shift toward the development of formulations that are more convenient for patients. With key biologics coming off patents, there are opportunities for product differentiation, such as delivering biologics via non-invasive routes. Lyon believes that in the near future oral delivery of biologic APIs will be fairly common for APIs treating local gut disease states, such as Crohn’s and irritable bowel syndrome. “This delivery modality will require protection from acid-based hydrolysis using enteric-coated multiparticulates or an intrinsically enteric capsule technology (e.g., Capsugel’s enTRinsic drug-delivery technology).” However, he highlights that significant breakthroughs will have to be made to translate currently marketed biologic APIs from IV delivery to drug products delivered orally.

	1. Grand View Research, “Biologics Market Size Worth $399.5 Billion by 2025,” Press Release, March 29, 2017.
	2. A Siew, 

Drug Delivery Systems-Hollow Microneedle Technology

Drug Delivery Systems-Solid Microneedle Technology


	Volume 30, Number 10
	October 2017
	Pages: 12–17

	When referring to this article, please cite it as A. Siew, “Formulation of Biologics for Non-Invasive Delivery,” 

Cover Story

There is a lot of interest in delivering biologics via non-invasive routes in attempt to improve patient compliance and convenience. 


Formulation of Biologics for Non-Invasive Delivery

 in early August 2017 reauthorizing critical five-year user fee programs that fund FDA oversight of medical products, just in time to avoid major agency disruptions (1). The vote was delayed by contentious debate on Capitol Hill over revising the Affordable Care Act. But once the wrangling over Obamacare fizzled out, the Senate quickly enacted the FDA Reauthorization Act (FDARA). It mirrored the bill approved by the House in early July and was signed by President Trump on August 18. 

	By enacting new fee programs for drugs, biologics, generic drugs, medical devices, and biosimilars before they expired on Sept. 30, 2017, Congress avoided massive FDA layoffs. Equally important for agency staffers charged with implementing new fee policies, this user fee bill is relatively “clean,” benefitting from enactment of the extensive 21st Century Cures Act last December, which tackled many of the more controversial proposals for accelerating and streamlining the development, testing, and review of medical products.

	Key provisions added to FDARA seek to spur development of pediatric cancer therapies and innovative medical devices and to deter import of illegal or counterfeit medicines. The bill reauthorizes the orphan drug grants program, while limiting orphan drug exclusivity awards to products that demonstrate a clear superiority over existing therapies, and it requires sponsors to conduct studies on new tropical disease treatments to qualify for priority review vouchers. Several provisions aim to speed up field inspections of manufacturing facilities and to assess whether delays in resolving deficiencies found in preapproval inspections block new product approvals. The legislation seeks expedited review of responses to inspection observations for priority applications and for those related to drug shortages. 

	Efforts to lower prescription drug prices ended up with largely symbolic language backing patient access to therapies, plus provisions for speeding the development and marketing of generic drugs to enhance market competition. FDARA establishes a priority review track for competitive generic therapies and an accelerated development initiative for high-demand products; brand manufacturers have to update information on products withdrawn from the market to help clarify which drugs have limited competition. 

 (PDUFA VI) aims to make revenues more predictable for FDA by relying more on a new product fee paid by manufacturers that is based on number of approved products. At the same time, PDUFA reduces application fees and discontinues levies for manufacturing establishments and supplements (2). 

	The overall increase in funding will help improve FDA’s electronic submission process and IT initiatives and expand programs for hiring and retaining review staff. Because PDUFA already has reduced review times for new drug applications (NDAs) by achieving more first-cycle approvals, the new PDUFA agreement focuses more on managing the mushrooming demand for development-phase meetings, boosting resources for the breakthrough drug program, advancing the review process for rare disease treatments, and bolstering support for combination products. There’s continued emphasis on advancing model-informed drug development, biomarker qualification, the use of real-world evidence, and incorporating the “patient’s voice” into regulatory decision-making. 

	Manufacturers of drugs, biologics, and generic drugs face added pressure to ensure that all facilities involved in product development and future production are fully identified in applications. Omitting this information in a submission can delay needed facility inspections, says FDA. Under PDUFA, applications that lack full facility information face a three-month approval delay for an NDA or efficacy supplement and two months extra for approving a manufacturing supplement. FDA states that it aims to complete all inspections of clinical and manufacturing sites within six months of accepting a priority application and within 10 months for standard submissions, leaving two months at the end of the review process to address deficiencies found during site visits. 

 (BSUFA II) is revised to collect $45 million in revenues through program and application fees to support product development and review (3). BSUFA also wants manufacturers to identify all planned production facilities in applications and supplements to avoid inspection delays that could add two months to a review timetable. FDA specifies that mid-cycle and late-cycle meetings will discuss chemistry, manufacturing, and controls (CMC) issues, and that it aims to complete all facility inspections within 10 months of application receipt. 

	The BSUFA program will advance through publication of guidance on key regulatory issues, including statistical methods for demonstrating similarity and a final policy for developing interchangeable biosimilars. FDA published 

 on CMC postapproval changes for biological products in August 2017 (4), and a similar document for biosimilars is scheduled for early 2019, along with final advisories on biosimilar naming, labeling, and clinical pharmacology data development. 

(GDUFA II) also increases fees overall, to reflect a greater volume of abbreviated new drug applications (ANDAs) submitted to FDA than originally anticipated. More revenues will come from a new program fee based on approved products and facilities, with large generic-drug makers (more than 20 approved products) paying the full $1.5-million fee in 2018, medium companies (5-19 products) paying about half, and firms with less than five approved generics paying one-tenth the amount, or $160,000 in 2018 (5). Fees for filing an ANDA rise from approximately $70,000 in 2017 to $172,000 in 2018; facility fees for finished drugs and active ingredients remain fairly even, with the exception of a sizeable reduction for contract manufacturing organizations (CMOs). In announcing the 

 (6), FDA notes that it will assess facility fees based on information submitted in applications, rather than relying on company self-identification. 

	A number of key issues failed to make it into FDARA, largely to avoid legislative delay, but they may linger, as Congress is under pressure to deal with the federal budget and tax reform proposals by year-end. One topic that could surface is a proposal for establishing user fees to support expedited review and 

 (7). FDA and manufacturers have negotiated an agreement for accelerating development of OTC monographs, but too late to include it in FDARA. Congress recently held hearings on the program, and it could be included in other health policy legislation this year.

	Another high-profile topic is the right-to-try (RTT) 

approved by the Senate, which promotes access to certain experimental therapies that have completed Phase I testing for individuals with terminal illnesses and no other treatment options (8). Under the Senate bill, patients would not have to apply for FDA approval to access these drugs, and it limits liability of pharma companies, prescribers, and dispensers for problems arising from early use of such products. This aims to encourage manufacturers to provide a test therapy when requested, but still does not require sponsors to agree to such action. House RTT advocates have proposed their own reform bill, and it may take some time to reach agreement on a measure that satisfies all parties. 

PDUFA Reauthorization Performance Goals and Procedures Fiscal Years 2018 Through 2022

Biosimilar Biological Product Reauthorization Performance Goals and Procedures Fiscal Years 2018 Through 2022

CMC Postapproval Manufacturing Changes for Specified Biological Products to be Documented in Annual Reports, Guidance for Industry, Draft Guidance

GDUFA Reauthorization Performance Goals and Program Enhancements Fiscal Years 2018-2022

. 
	6. FDA, “Generic Drug User Fee Rates for Fiscal Year 2018,” 

Potential Over-the-Counter Monograph User Fees

Volume 30, Number 10
	October 2017
	Pages: 8–9

	When referring to this article, please cite it as J. Wechsler, “FDA User Fees Promote Manufacturing Readiness," 

Regulatory Beat

Industry and FDA face new fee structures and new challenges in implementing fee initiatives.

FDA User Fees Promote Manufacturing Readiness

	Mergers and acquisitions (M&A) are a central feature of the contract development and manufacturing (CDMO) industry today. Several new deals are being announced every month, some of them quite substantial, and these deals are reshaping the industry. 

	CDMOs are in great demand by both strategic buyers (i.e., companies in the CDMO business or a related business) and financial buyers (i.e., private equity firms). Valuations of companies acquired in M&A deals are reaching high levels as buyers compete to win the prize. While private equity investors typically use a “rule of thumb” to value businesses at 10 times earnings before interest, taxes, depreciation, and amortization (EBITDA), some deals have gone as high as 20x EBITDA. One small CDMO that recently went through a process reported that they had received nearly 10 offers from potential investors.

	The interest in CDMOs as acquisition targets is driven in large part by the demand for contract development and manufacturing services from emerging bio/pharmaceutical companies. Those companies generally lack internal development capabilities and are highly dependent on CDMOs and contract research organizations (CROs). Emerging bio/pharma companies themselves have attracted large amounts of investor capital as they have become a major source of new product candidates for global bio/pharma companies. Thanks to growing demand from emerging bio/pharma companies, CDMOs have enjoyed high double-digit growth rates in recent years, and investors in CDMOs are betting that those rates of growth will continue into the next five years at least.

	Therein lies the rub: today’s high valuations are based on current market conditions, but history tells us that extrapolating today’s market well into the future is dangerous. External financing for emerging bio/pharma companies is notoriously cyclical: a boom in the late 1990s collapsed along with the bursting of the dotcom bubble in 2000. After several poor years, the market rekindled again in 2004 but collapsed with the global financial crisis in 2008. Public financial markets did not really open again for emerging bio/pharma companies until 2012-2013, and the industry is now four years into the current financing rebound. While an imminent collapse in bio/pharma funding is not predicted, history suggests that caution is warranted. The challenge for the industry is illustrated in 

Figure 1: R&D spending and cash on hand for emerging bio/pharma companies. (Courtesy of the author)

	R&D spending by publicly-traded emerging bio/pharma companies has risen rapidly since the beginning of 2015, although it has been flat in the first few quarters (blue columns). However, most of those companies have cash on hand equivalent to just over four quarters’ of R&D spending (red line). If external financing becomes more difficult to raise, as it did in 2016, companies will slow their rate of spending in order to conserve their cash until they can raise more. With just four quarters’ of cash on hand, spending could slow quickly if conditions worsen.

	The implications of making acquisitions in an overheated market will differ depending on the motivations of the buyer, and the way the buyer finances the deal. Strategic buyers have a long-term perspective, and measure success in terms of market share, revenue growth, and enterprise value. The motivations of financial buyers, however, are often more complicated. They typically make acquisitions with defined investment horizons of about five years, and their focus is on how to optimize their cash return on investment over that period. While concerned with enterprise value at the end of the holding period, private equity investors may also seek a faster return by using the company’s cash flow and debt capacity to finance dividends. Their take on what makes an acquisition attractive is often different from that of the strategic buyer.

	The conflict between near-term cash returns and long-term investments can be particularly severe in the case of pharmaceutical manufacturing and development. A substantial capacity investment can take two-to-three years to design, construct, and validate, and ramping up utilization of that capacity increment will take several more years after that. For a financial investor with a five-year horizon, an investment that is cash-negative for most of that period may not be attractive, even if it enhances the long-term value of the business.

	This is not to suggest that private equity firms are not welcome buyers of CDMOs. Often the businesses private equity buyers invest in are short on the capital, know-how, financial discipline, and executive skills necessary to take their businesses to the next level. The best private equity firms are very good at providing the resources to enable business growth and maturation. In an environment of frothy valuations, however, investors in debt-financed acquisitions may be challenged to feed businesses all the resources they need to grow.

	But using a lot of debt to buy a business at the top of a cycle can be dangerous. As revenues flatten out or fall on the downside of the cycle, debt-laden businesses will struggle to make the necessary investments as well as service their debt. A number of CDMOs experienced financial challenges in the wake of the downturn in the late 2000s and were forced to restructure or close down altogether. Bio/pharma companies should do careful financial due diligence when qualifying CDMOs, especially for commercial requirements.

	Another concern is the impact that M&A activity has on customer perceptions, especially global bio/pharma companies. On the one hand, M&A creates companies with broader capabilities and scope, which enables bio/pharma companies of all sizes to simplify their supply chains. 

	However, the M&A activity also creates uncertainty around the supply chain. Given the current rate of activity, there is no assurance that the CDMO a biopharma company contracts with today will be the same company that is fulfilling its order two years from now. The business model, objectives, culture, and operating skills of a new owner may be different from the owner the CDMO originally contracted with. 

	Global bio/pharma companies may be particularly concerned about changes in ownership. Already reluctant to outsource and keenly attuned to supply chain security issues, too much churn in the supply base can make those companies wary about working with CDMOs.

	Overall M&A is a positive for the CDMO industry. The current activity attests to the industry’s robustness and long-term prospects, and rewards the entrepreneurs who have built admirable businesses. But buyers and sellers need to be wary of the downsides of the overheated market. 

Volume 30, Number 10
	October 2017
	Pages: 10–11

	When referring to this article, please cite it as J. Miller, “Up and Away, M&A," 

Perspectives on Outsourcing

Mergers and acquisitions are positive for the CDMO industry, but there is a downside.

Up and Away, M&A

Q.: I am a quality assurance professional in a manufacturing plant. I still struggle with the concept of risk-based decision making. Can you provide me some advice on how I can make appropriate risk-based decisions?

	A.: The pharmaceutical industry continues to change rapidly. Over the past 10-15 years, there have been a number of developments that have impacted how companies approach various aspects of their business including the emergence of the generic industry, biosimilars, virtual companies, contract service organizations, compounding pharmacies and 503B outsourcing facilities, mergers and acquisitions, and more sophisticated information technology platforms. The complexity of the industry today makes risk-based decision making seem convoluted at best.

	Risk-based decision making is difficult no matter what position or department you are in at a company or how many years you have been in your position. Most employees are comfortable when the answer seems to be yes or no. It is much harder to make a decision when the answer lies somewhere in-between the yes and no. So, how do we go about making an appropriate risk-based decision? There isn’t any magical formula or calculation to guide you. To make an appropriate risk-based decision, we need to understand the interrelationship of the product, process, and any associated deviations and investigations that occurred during manufacturing. 

	Let’s take a look at a situation that might help clarify the risk-based decision process. You are the vice-president of quality for a manufacturing organization. One of your products for treatment of cancer is on the drug shortage list because the current API supplier has decided they will no longer provide the API. You were trying to secure a new API manufacturer but could not find one that could reliably provide the API that met the expected quality attributes, so the company has decided to cease providing the drug to the market. 

	You have the last three available lots of the API and have manufactured the associated final product lots. The product is aseptically filled and then lyophilized. During the inspection of the second product lot, the quality inspectors inform you that they have detected a defect and the lot has failed its second acceptable quality limit (AQL) for the defect. The defect detected is defined as product between the vial and the stopper and it displays as a white dot the size of the head of a pin. The standard operating procedure (SOP) defines this defect as ‘cosmetic’. The inspectors also inform you that they expect the product lot will fail the third AQL inspection and that the product will need to be rejected per standard operating procedure requirements. They also inform you that the product has passed all other quality attributes including those determined by chemical analysis and that there were no deviations associated with the manufacturing. You ask your inspectors to halt the inspection for this particular defect while you look into the matter. The question you need to ask is: what further information do I need in order to be sure I make an appropriate decision? 
	The easy decision is to perform the third AQL inspection, fail the lot if it doesn’t pass, and document the reason for the failure. The harder decision is to make a risk-based decision to release the lot. Let’s take a look at some additional information available to help you make your decision. The first thing to determine is the medical indication for the product. In this case, the product is a cancer treatment drug. The second piece of information to determine is if the cosmetic defect has any impact on the potency of the product. In this case, through laboratory analysis, it is determined that the potency or stability of the product is not affected by this particular defect. Based on this information, you document a material review of the situation and recommend ceasing inspection of the cosmetic defect and releasing the product. 

	What information made you comfortable in making this decision? Because this is a life-saving drug that is in short supply, you realize that doctors will potentially need all of this product to be able to safely transition patients to an equivalent treatment because it could take more than one treatment cycle for the doctors to find an appropriate drug substitution. You were also able to determine through chemical analysis the potency was unaffected by the defect and would not pose a threat to patient safety. You will still need to investigate the defect and try and determine its root cause, but based on the data available you should be confident that the product is safe for the patient. If there is any magic formula to risk-based decision making, it is to keep patient safety in mind and focus on whether the product meets its defined quality attributes. If you keep these points in mind you should be able to make reasonable, documentable, and defendable risk-based decisions. 

Volume 30, Number 10
	October 2017
	Pages: 58

	When referring to this article, please cite it as S. Schniepp, “Making Decisions Based on Risk," 

Ask the Expert

Focusing on whether the product meets its defined quality attributes should help one make reasonable, documentable, and defendable risk-based decisions, according to Susan Schniepp, distinguished fellow at Regulatory Compliance Associates.


Making Decisions Based on Risk

One of the challenges with biopharmaceutical production is the need for enhanced process analytical testing techniques. Manufacturing biologics, such as monoclonal antibodies and therapeutic proteins, inherently relies on complex and sophisticated cell-based processes that require close monitoring, particularly during scale-up for commercial production. Sensitive testing and sophisticated data analysis are important for ensuring product quality.

	The launch in 2004 of FDA’s guidance on process analytical technology (PAT) set the regulatory framework for biopharmaceutical processes (1). The objectives include increasing process robustness and process understanding and improving yields by way of less rejections and reprocessing to enable batch release in real-time (2).

	When a biomanufacturing process has been developed, process characterization studies are typically conducted to define the ranges for various control parameters. These studies involve a number of small-scale bioreactor cultivations.

	Of the data generated during these studies, only that which is needed to deï¬ne the acceptable ranges for the control parameters are processed in more detail. Evaluating specific sets of performance data (e.g., metabolite profiles) with a toolbox of advanced statistical methods can be used to forecast the product quality and quantity of mammalian cell culture processes (2).

	Though described as a “holistic” approach, the PAT concept is often reduced to the specific aspects of real-time monitoring and multivariate modeling. The many new applications of sophisticated on-line analyzers have since been evaluated, targeting the enhancement of bioprocess monitoring capabilities (2).

	Some monitoring techniques typically involve infrared spectroscopy, dielectric spectroscopy, and 2D ï¬uorescence. Other exotic analyzers, such as proton transfer reaction mass spectrometry or electronic noses, have also found their way into bioprocessing.

	To correlate the complex signals of most on-line analyzers with meaningful parameters for cultivation, such as viable cell density or metabolite concentrations, the signals of these analyzers must be modeled by multivariate statistics, according to the authors of a study (2).

	One way to innovate bioprocesses is to use new analyzers that can thus generate new data sets, but using data sets of routine at-line or off-line analytics by applying more sophisticated data analysis methods is an aspect of PAT that is often neglected, the authors said.

	In that study (2), the use of performance-based modeling (PBM) allowed for the prediction in daily intervals of the ï¬nal product concentration and 12 quality attributes (QAs). This approach gave the best forecast for product concentration in an early phase of the process. Some glycan isoforms were also predicted--with accuracy--several days before the bioreactor was harvested.

	PBM thus demonstrated its capability to predict the endpoint of the manufacturing process early on by only using commonly available data, even though it was not possible to predict all QAs with the desired accuracy.

Process analytical testing for biopharmaceuticals requires enhanced methods due to complex bioprocesses.

BioPharm International-10-01-2017

Improved Materials Enhance Parenteral Packaging

Pharma’s Role in Puerto Rico’s Future

Control Viral Contaminants with Effective Testing

Formulation of Biologics for Non-Invasive Delivery

FDA User Fees Promote Manufacturing Readiness

Up and Away, M&A

Making Decisions Based on Risk

The Challenges of PAT in the Scale-Up of Biologics Production

Optimizing Protein Aggregate Analysis by SEC

Development of Purification for Challenging Fc-Fusion Proteins

Molecular Cloning, Expression, and Purification of a Recombinant Fusion Protein (rNT-gp96-NT300)

BioPharm International, October 2017 Issue (PDF)