Susan Haigney is lead editor of Pharmaceutical Technology and Pharmaceutical Technology Europe.

Susan Haigney

The first half of 2020 will be remembered for the rapid spread of the SARS-CoV-2 novel coronavirus. As the bio/pharmaceutical industry raced to develop vaccines and treatments, drug companies looked for ways to balance the demands for pandemic-related research and development, while maintaining ongoing development projects for diseases and conditions.

	The urgency of new research programs, combined with altered work environments due to social distancing requirements, made contract service providers a viable option for many bio/pharma companies. These contract research organizations (CROs), contract development and manufacturing organizations (CDMOs), and contract manufacturing organizations (CMOs) also faced the challenge of managing existing workloads, changing needs of clients, as well as rapid turnaround to address pandemic concerns. Impacts of the pandemic on the contract services industry-as well as the response-has been varied.

	While the long-term impact of the pandemic is too early to understand or predict, says Cindy Reiss-Clark, senior vice president, commercial marketing and customer solutions at West Pharmaceutical Services, some trends have been observed, including delays in clinical trials themselves, development pipeline reprioritization, and finding new ways to connect to patients.

	Wilbert Frieling, corporate senior vice president, global discovery services at Charles River, has seen the shift in focus to COVID-19 treatments push work to contract research organizations. “This boost of directly COVID-related work has been absorbed by the flexibility and capacity inherent to CROs. As volume in the market fluctuates, CROs are able [to] easily accommodate increases of work in a short time frame. Also, of course, during this time, other work hasn’t stopped. So, we’ve made a concerted effort to accommodate new projects while maintaining existing programs for other indications,” says Frieling.

	Some non-essential clinical study visits stopped or were delayed during the pandemic because of patient reluctance to travel and local restrictions, says Michael Brooks, president, Covance Clinical Development and Commercialization Solutions. “The business has experienced customer-initiated trial delays, limitations and access to certain trial sites, and interruptions to the supply chain,” says Brooks.

	But Brooks also sees a healthy biopharma drug development market. “In fact, COVID-19 is likely to strengthen the fundamentals of drug development operations to enable more effective use of data insights, digital solutions, and better patient engagement,” Brooks states. “As countries and regions begin to reopen, we expect impacted non-COVID-19 clinical trials to resume, potentially with more focus on decentralized trial solutions, which can include digital capabilities and mobile nurses/phlebotomists. These trials reduce the need for patients to travel, which for many is a burden to trial participation.”

	Contract manufacturers are also seeing an impact. CDMO Recipharm has seen an increase in demand for the production of antibiotics to treat secondary infections in COVID-19 patients, says Erik Haeffler, vice-president, manufacturing services and head of sustainability. “To meet this demand, we are working hard to ensure our facilities can continue to operate while at the same time protecting the safety of our employees,” he says. The company is manufacturing antibiotics in four facilities, taking steps to increase the safety stock of API and raw materials, evaluating shift patterns for existing team members, and recruiting more personnel where needed. “Our safety protocols have also undergone enhancement, with additional risk assessment undertaken and the introduction of workflow adjustments to maximize social distancing,” says Haeffler.

	He expects the demand has reached its peak, however, and hasn’t seen an impact on the company’s normal operations because their manufacturing of beta-lactams and cephalosporins occurs in dedicated plants.  “While there have been necessary changes to how our business is operating in terms of safety and distancing, our broader business plans continue as normal,” he says.

	Inhalation specialist, Vectura, has seen an increase in formulation and analytical services during the pandemic, according to Mark Bridgewater, chief commercial officer, Vectura, including an increase in demand for dry powder inhaler and pressurized metered-dose inhaler expertise and technology platforms, he says.

	The pandemic’s impact on the company’s overall business has not been as great as anticipated, however, Bridgewater explains. “Recruitment to clinical trials was initially impacted, but we are seeing a move back towards normality. Priorities have, of course, changed to meet the immediate needs of patients, but it is amazing how robust our society has proven in dealing with the COVID-19 impact. The industry’s resilience has been truly outstanding.”

	Catalent, which has facilities in China, Italy, and other areas affected by the pandemic, took steps to track the pandemic and interpret how it may affect the company’s business by setting up a dedicated management team. “We have also had to respond quickly, innovating and adjusting our processes and ways of working to help vaccine innovators around the world to move their COVID-19 projects forward with greater speed, enabling the ingenuity, technology, and manufacturing expertise and passion of our people to come through,” says Elliott Berger, vice president and chief marketing officer, Catalent. Proactive investments made by the company have helped to mitigate the impact of the pandemic on their customers’ products. “For example, well before the COVID-19 outbreak, Catalent announced that it was to spend $200 million to expand capacity for biologics drug substance in Madison, WI, and fill/finish capabilities in Bloomington, IN. Such investments are now helping to accelerate availability of manufacturing capacity,” he says.

	The pandemic has changed the way many companies in the pharmaceutical industry conduct business. Contract organizations and suppliers have been adjusting their practices as they also protect their employees, with many implementing remote processes.

	“We have been impacted in our ability to support our customers with traditional face-to-face meetings, so we have embraced technology to stay connected virtually. Because West is a global organization, our manufacturing operations and supply chain efforts are aligned with local government guidelines,” says Reiss-Clark. “We continue to work closely with our customers to mitigate any impacts to our ability to deliver goods and services. To date, we have had minimal disruption due to the pandemic.”

	Catalent has restricted visitor access to the company’s facilities, limited employee travel, and implemented remote working. “But the pandemic has proven again that ‘necessity is the mother of invention’, and we are trying new things every day,” says Berger. “For example, we have rolled out new wearable camera technology to over 30 facilities in just weeks, enabling our customers to do virtual plant visits and audits, collaborating with us in a very innovative, secure, and interactive manner, as well as allowing our sites to bring together expertise and support from the global network.”

	Charles River has moved to a virtual model when working with clients. “Before the pandemic, there was still a lot of personal contact, in-person project discussions, and on-site audits. Now, we are leveraging all types of virtual connections for meetings, as well as virtual site audits. By these means, we have stayed close to our clients and continued to fulfill their needs,” says Frieling. The company is also examining their processes for working with suppliers. “Our procurement team has been monitoring any changes very closely and helped significantly in sourcing the required supplies to keep the business going. This combination of staying close to our clients and managing our supplies allowed us to continue to deliver for our clients,” he says.

	Recipharm is also using a virtual model, providing virtual access to its facilities so customers can audit and inspect their services. “This initiative will allow our customers to virtually experience our facilities and capabilities, while simultaneously satisfying their need to review the robustness of our processes. While we are continuously monitoring the impact of COVID-19 on all our worldwide operations, we are also working hard to maintain our number one priority, which is to uphold our responsibilities to all our customers,” says Haeffler.

	“Clearly, there has been no physical interaction,” says Bridgewater. “Due diligence and audits have been virtual or paper based. There has been a level of innovative resilience that people and companies have adopted to continue to drive business forward.”

	With the health crisis creating an all-hands-on-deck situation, a collaborative approach between health authorities, regulators, pharmaceutical companies, and contractors will be necessary to develop and manufacture effective and safe treatments. “I believe it will take strong partnerships and a holistic approach to expertise and resources in order to develop, manufacture, and fill the vaccines for distribution around the globe,” says Reiss-Clark. “Planning is key. We have to think about the total supply chain and capacity to make the doses required for herd immunity. Everyone will be needed.”

	According to Brooks, the pandemic has created a stronger relationship for Covance and its clients, finding common ground with the goals of patient safety and data integrity. “This has also been true of regulators, and we have seen remarkably productive collaborations,” he says. “In addition, we are collaborating with sites on critical patient safety considerations, evaluating the use of Covance and third-party technology to help research sites more effectively manage trial activities, and have deployed enhanced solutions for clinical trials and research sites to lessen the burden on patients, investigational sites, and healthcare providers.”

	Frieling believes that outsourcing companies can play a key role in battling the pandemic. “By beginning to outsource research programs, the industry reduces their necessity for constant on-site support, and places that requirement on outsourcing partners, who are equipped and capable to carry out those activities anyway, with expertise across drug development. An increased reliance on outsourcing with a geographic spread will allow the biopharma industry to better continue research under extreme circumstances like we’ve experienced with COVID-19,” he says.

	“We think the industry has now realized that we have to realistically assess capabilities and gaps and work closely together to move projects forward,” says Berger. “Catalent has gone to the extent of risking starting work before contracts were finalized and signed, we have repurposed capacity and equipment between programs, we moved to purchase equipment available on the secondary market for the new programs outside the usual budgeting and procurement cycle. We have also created innovate contracting models to account for those ‘at risk’, and if approved, we will need millions of doses in a few months. This flexibility and willingness to work in new and collaborative ways makes a big difference,” he says. 

	Catalent is helping pharma and biopharma partners prepare for anticipated demand by offering outsourced capacity to complement in-house capabilities, Berger says.  “To illustrate this, we are currently helping a customer to prepare for large-scale commercial manufacturing of a vaccine candidate for COVID-19 in Bloomington, and we are partnering with a leading clinical-stage messenger RNA (mRNA) medicines and vaccines company in Madison to support the expected manufacture of an mRNA vaccine candidate against the SARS-CoV-2 coronavirus,” Berger says.

	The pandemic will drive an increase in the outsourcing of biologics development, at least in the short-term, says Haeffler, noting that “as vaccine production increases, considerable manufacturing capacity is going to be required to meet the ambitious annual capacity targets for 2021 that are in the region of 1 billion doses.”

	Short-term growth created by the pandemic will increase as the development, testing, and manufacturing of these products ramps up, Haeffler says. He also believes there will be a future impact to the industry. “Spurred by the current crisis, the bio/pharmaceutical industry is also likely to see long-term adjustments that will result in increased measures being put in place to handle the threat of future pandemics,” he explains. “I would expect to see greater focus on the development of more collaborative relationships, as well as an increase in pharmaceutical companies looking for partners that can offer the rapid and flexible end-to-end development and production processes necessary to speed products to market in crisis situations."


	Vol. 44, No. 7
	July 2020
	Pages: 60–63

	When referring to this article, please cite it as S. Haigney, “Contractors Balance Increased Demand During COVID-19,” 

Articles

The COVID-19 pandemic has created a rise in demand for R&D and a shift in focus for some contract organizations.

Contractors Balance Increased Demand During COVID-19

 spoke with Richard Denk, senior consultant aseptic processing and containment, SKAN AG, about the risks of contamination in biopharmaceutical manufacturing and how this risk can be mitigated.

Pharmaceutical Technology Biologics and Sterile Drug Manufacturing


	eBook: Biologics and Sterile Drug Manufacturing, May 2020
	May 2020
	Pages: 38–42

	When referring to this article, please cite it as S. Haigney, “Considerations in Contamination Control,"

 Pharmaceutical Technology Biologics and Sterile Drug Manufacturing eBook 

A contamination control strategy can prevent contamination in sterile product manufacturing. The right system, equipment, and personnel training are also essential to mitigate risk.

Considerations in Contamination Control

spoke with John Harmer, director, technical sales at Vanrx Pharmasystems about considerations in choosing the best system and equipment for contamination control in pharmaceutical manufacturing.


	eBook: Biologics and Sterile Drug Manufacturing, May 2020
	May 2020
	Page: 41

Pharmaceutical Technology spoke with John Harmer, director, technical sales at Vanrx Pharmasystems about considerations in choosing the best system and equipment for contamination control in pharmaceutical manufacturing.

Best systems and equipment for contamination control

spoke with Jens Andersson, purchasing director at Cambrex Karlskoga, about the best way to ensure the security of the bio/pharmaceutical materials supply chain.

What is the contract manufacturing organization’s (CMOs) responsibility in ensuring the quality of materials they use in the production of APIs?

 Cambrex prefers to take full responsibility for ensuring the quality of the raw materials that are used in our manufacturing processes. Ultimately, we are responsible for the quality of the final API produced at our sites and ensuring that it meets customers’ specifications. Therefore in our opinion, it makes sense that we take the responsibility to source raw materials of the correct quality to undertake the campaign or product. We also find this process to be quicker and more cost-effective than if the end customer undertakes the sourcing and sends material to us, as we can use our own supplier network and can use suppliers with which we have a well-established relationship without having to necessarily qualify new suppliers.

What are the steps and/or best practices for qualifying suppliers?

 There are several steps that are undertaken when we qualify suppliers, with the first being to evaluate the quality of raw materials against the specifications to ensure that they meet both the stated purity and the demands of the project we intend to use the materials for. Then we send questionnaires to the suppliers that cover a wide range of topics, from quality to health and safety practices, as well as environmental policies and responsibilities, and ethical guidance of the company. If needed, audits are carried out on-site by our QA [quality assurance] specialists for suppliers of raw materials with critical impact on the final product quality, such as the main building blocks of the final API.

 For critical raw materials and services we re-evaluate suppliers every two years. We carry out on-site audits every two to three years depending on how critical the raw material or service is; however, audits can also be initiated outside of the regular schedule for other reasons, such as quality or supply issues.

What additional challenges do high-risk materials pose? Does the oversight of these suppliers intensify?

 The main challenge is that for suppliers of critical raw materials we need to make a much more thorough initial qualification and risk assessment. This can be time consuming and, at times, it can be difficult to get the data and information needed. At Cambrex, we do have a robust supplier network where we have been able to establish strong relationships over a number of years that mitigates this risk.

 When there have been reports of suppliers falsifying certificates of analysis (CoAs), how can a pharma company or contractor be sure the information they are receiving from a supplier is correct? Is this why testing of materials is important?

 For critical raw materials, we will always carry out our own analyses to confirm the vendor’s CoA and ensure the quality of the material. For less critical raw materials such as common solvents or regularly used bulk acids and alkalis from reliable and trustworthy vendors, goods can be received only on CoA, but we will undertake random tests to ensure the CoAs.

What should a pharma company or contractor do when FDA puts a supplier on import ban? Should companies have a backup plan to prevent product shortages?

A company needs to be proactive and should always aim for dual sourcing capabilities for critical raw materials, so that any risk of supply is minimized. A risk assessment should always be carried out to evaluate the danger of interrupted deliveries.

 What has the recent NDMA impurity issue taught the industry about materials quality and the importance of testing materials?

 Given that the situation with the NDMA is still ongoing, it is too early to say what lessons need to be learned from it. However, in 6–12 months the situation will hopefully be clearer, allowing for a detailed review to take place and evaluation of any future risks to be made. It is paramount that patient safety is the highest priority so the industry as a whole has a duty to ensure that decisions are made that do not compromise this in any way, and that any oversights that have been made previously do not happen again.

	When referring to this article, please cite it as S. Haigney, "Manufacturing APIs and the Supply Chain," 

Pharmaceutical Technology spoke with Jens Andersson, purchasing director at Cambrex Karlskoga, about the best way to ensure the security of the bio/pharmaceutical materials supply chain. 

Manufacturing APIs and the Supply Chain

The bio/pharmaceutical industry is a global network that ties together an array of developers, manufacturers, and suppliers. Bio/pharmaceutical companies, therefore, may source APIs and excipients from companies thousands of miles away. This global aspect of the industry, naturally, creates a complex supply chain that could leave patients vulnerable if not properly overseen. The discovery of nitrosamine impurities, including N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA), found in angiotensin II receptor blocker (ARB) medicines (1) in 2018 is an example of how ingredient issues can affect patients and the supply chain and the importance of testing ingredients. Now, the global COVID-19 coronavirus pandemic has the potential to disrupt supply chains, site inspections, and other activities associated with supplier qualification and oversight.

	Sponsor companies and manufacturers are responsible for ensuring the components they use are safe and effective. FDA has cited companies for failing to test their incoming API and raw materials “to determine their identity, purity, strength, and other appropriate quality attributes” (2). According to a spokesperson for IPEC-Americas, sponsor companies must verify the quality of materials, which includes qualification of the supplier through on-site good manufacturing practice (GMP) audits and/or a third-party GMP certification. Incoming materials should have their identification verified and the quality department should give its approval to release the materials for use. This includes performing-at a minimum-an identification test, and may include other tests necessary to ensure the quality for the intended use as per 21 

	Risk assessments of both suppliers and materials should also be performed, according to IPEC-Americas, with a specific focus on the intended use of the material. The risk assessment should also evaluate possible concerns with efficacy, variability, safety, and quality. And this evaluation should not end with the risk assessment. The sponsor should “[establish] a process for continued monitoring of the supplier and the quality of incoming materials,” according to IPEC-Americas.

	How do sponsor companies choose and monitor material suppliers to ensure the ingredients they are purchasing are fit for purpose? Linda Evans O’Connor, vice president and chief of staff at Lachman Consultant Services, Inc., suggests that sponsors start by obtaining information from the supplier about its capabilities and compliance history through a questionnaire. Material samples should also be obtained to determine if they are fit for their intended purpose. Site audits should be performed, and quality agreements should be put in place, she says. Finished product trials should be performed if the materials meet the requirements. Batches should then be tested for stability. Periodic monitoring of the supplier should be performed with data reviewed on a predefined basis in addition to performing surveillance audits, according to O’Connor. IPEC-Americas stresses, however, that an appropriate risk assessment cannot be performed without onsite audit information. 

	Susan J. Schniepp, executive vice-president of post-approval pharma and distinguished fellow, Regulatory Compliance Associates, says that companies should begin the qualification with an onsite audit. “Once the audit is performed and any identified concerns resolved, the two parties, purchaser and supplier, can enter into a quality agreement. After the quality agreement is approved, the purchasing company can start the process of ‘qualifying’ the supplier. This qualification usually involves testing of the material to confirm the supplier’s certificate of analysis (CoA) is accurate and develop a history that demonstrates the ability of the supplier to continually provide a suitable product,” says Schniepp.

	The supplier should then be placed on an approved supplier list, according to Schniepp. “The initial qualification for a supplier to be considered an approved supplier usually involves complete confirmatory testing on the first 10 lots of material received and then a periodic check and confirmation by the purchaser of the entire testing regimen listed on the CoA received from the supplier.”

	Performing audits of material suppliers is key for ensuring the quality of materials, but how often should these audits be performed? O’Connor suggests that a risk-based approach should be used to determine when and how often a supplier is audited. “Many factors can go into the risk model, such as type of material (e.g., API, excipient, sterile, non-sterile, complex dosage form, etc.), location, past regulatory or audit history, recalls, quality of incoming goods, complaint history, importance to the business of the materials (i.e., Is this an API for your blockbuster drug and lack of supply would have a material impact on the business?). A minimum frequency per material type should be defined (i.e., for an API, every two years),” O’Connor says.

	IPEC-Americas agrees. “Whether the supplier is an excipient manufacturer, contract manufacturer, distributor, or service provider (e.g., a contract testing lab), the initial audit frequency should be based on results from the initial supplier/excipient risk assessment along with any additional mitigation measures identified. Based on on-going monitoring, a sponsor company should determine whether to adjust the audit frequency.”

	A quality risk management plan is key, agrees Schniepp. Frequency of audits should be based on the criticality of the material and the past performance of the supplier. “This plan should identify supplier vulnerability (i.e., single source, secondary supplier, etc.), which should help determine audit frequency. The quality agreement should reflect the risk plan but there should always be a contingency to allow for-cause audits as needed. Laboratories used by either the supplier or the purchaser should be audited and included as an element of the risk plan,” says Schniepp.

	Auditing under difficult circumstances. Having a consistent and properly executed audit program is paramount to maintaining the timeliness and integrity of the supply chain, says Schniepp. Audits, and the information obtained during them, allow one to assess a supplier’s risk, especially during crises such as the COVID-19 pandemic. “Having the baseline knowledge of your suppliers’ operations will help assess where critical resources need to be allocated during a crisis period. While not ideal, audits can still be performed on suppliers through the use of questionnaires and video conferencing. If visuals are required for the supplier assessment, the use of an electronic device or video streaming options could be employed. Bottom line, to keep the supply chain viable during crisis mode we need to think outside of our normal operating procedures and experiences,” says Schniepp.

	If travel is limited due to global situations such as the COVID-19 epidemic, O’Connor suggests getting creative. “For example, performing a virtual audit, while not ideal, is a possibility, and would require cooperation of the sponsor and the manufacturer. Document review and interviews can be performed remotely. Companies could even look at virtual facility tours using appropriate technology. However, these types of audits are not ideal, and shouldn’t replace on-site audits. Another solution is to partner with a local company that has the local resources to perform the on-site portion of the audit. This will allow on-site audits to occur even when international travel bans are in effect,” says O’Connor.

	CoAs provide manufacturers with detailed information about materials including material manufacturer, quality testing information, specifications, batch numbers, and other information (3). FDA has been known to cite companies for incomplete or incorrect information on CoAs (4). So, how reliable are these documents and how much emphasis should sponsors put on them when it comes to ensuring material quality?

	O’Connor suggests that sponsor companies create a library of CoAs or labels so they can verify that the information is correct. “Also, maintaining a relationship with suppliers is key. Anything unusual needs to be flagged,” says O’Connor.

	Building trust between the sponsor and supplier is important, agrees IPEC-Americas. “A robust supplier qualification program, including an onsite GMP assessment of a supplier, by either the sponsor or a qualified third party, and development of a partnership with the excipient supplier are necessary to establish and build trust in the validity of their CoA.”

	Annual confirmation testing of CoA results is also necessary, says IPEC-Americas (5). “Full testing of an excipient is required until a robust supplier study has been completed and a reduced testing program has been approved. Only once trust has been established can the sponsor move to a reduced testing program. However, identification testing is always required to ensure the identity of incoming materials.”

	To establish that the quality testing information included in the CoA is accurate, incoming materials must be tested against the requirements in the CoA, Schniepp insists. “The best way to ensure the CoA is accurate is through complete testing. In cases of falsification of the CoA, results testing is mandatory to make sure the material is suitable for use; however, it must be coupled with a review of the supplier’s overall quality system. Even if the material meets the testing qualifications listed on the CoA, it may not be suitable for use due to other potential GMP violations that might be present at the supplier facility,” she says.

	“In the case of falsification, the purchaser should be concerned with data integrity issues that lead to the falsification in the first place. If a purchaser suspects a supplier is falsifying the results on a CoA they need to initiate a for-cause audit and quarantine the suspect material until they can confirm it was satisfactorily manufactured following cGMP expectations. Passing test results does not confirm compliance to cGMPs,” Schniepp explains.

	Many drug sponsors engage contract manufacturing organizations (CMOs) to conduct drug production steps. So, what is the CMO’s responsibility in ensuring that materials are safe and effective?

	O’Connor says that while both sponsors and CMOs share responsibilities, the sponsor has the “ultimate” responsibility of its supply chain. “Sponsors and CMOs share responsibilities, but the selection, qualification, and oversight of suppliers is the sponsor’s responsibility, whereas day-to-day testing is generally the CMOs/CDMOs, although sometimes that goes to the sponsor as well. The sponsor has ultimate responsibility for the entire supply chain, so even if it delegates part of that responsibility to the CMO/CDMO, it is ultimately responsible.”

	Sponsors must ensure that they have signed agreements in place with any CMOs and/or CDMOs they are using that identifies the responsibilities of each party when it comes to ensure the quality of materials, according to a spokesperson for IPEC-Americas.

	Both sponsors and CMOs/CDMOs must have an active role, according to Schniepp. “The specific level of involvement of the sponsor may depend on the confidence they have in the CMO/CDMO organization. The CMO/CDMO should make sure they involve the sponsor in decisions involving material quality, so the sponsor is aware of the impact on their product,” says Schniepp.

	Maintaining a safe supply chain is crucial in the bio/pharmaceutical industry. The efficacy and safety of the materials used in drug products is of utmost importance. And it is the sponsor’s responsibility to ensure the quality of all materials used in their products. Sponsors must not rely on others to ensure quality, says O’Connor. Also, not all suppliers should be treated the same. “Clearly, some suppliers have greater risk than others, either based on the product type, location, etc. These suppliers should receive more scrutiny,” she says. Sponsors also must not cut corners or do what is convenient, says O’Connor. For example, she notes, it is inconvenient, but necessary to audit suppliers in China and India. In addition, sponsors should also not make supplier decisions based on price or availability instead of quality and safety, says IPEC-Americas.

	Communication is key to supplier oversight, says Schniepp. “Both parties need to be willing to talk as frequently as needed to address issues before they manifest into a disruption in the supply chain. The frequency of these conversations are not necessarily defined in a quality agreement. They are important in establishing an open relationship between the supplier and the purchaser so issues can be solved before supply chain disruption occurs. Not all problems can be solved through the terms included in the quality agreement and both parties must be willing to work outside the defined ‘communication schedule’ of the quality agreement to avoid unnecessary supply-chain interruptions.”

	1. FDA, “FDA Statement on the FDA’s Ongoing Investigation into Valsartan and ARB Class Impurities and the Agency’s Steps to Address the Root Causes of the Safety Issues,” Press Release, Jan. 25, 2019.
	2. FDA, 

Warning Letter to Henan Kangdi Medical Devices Co. Ltd, MARCS-CMS 587699

Warning Letter to Spectrum Laboratory Products, Inc.,

 MARCS-CMS 579958, July 31, 2019. 
	5. FDA, 21 

 211.84(d),  Title 21–Food And Drugs, Chapter I–Food And Drug Administration, Department Of Health And Human Services, Subchapter C–Drugs: General, April 1, 2019. 


	Vol. 44, No. 4
	April 2020
	Pages: 72–76, 83

	When referring to this article, please cite it as S. Haigney, "Being Vigilant in Supplier Oversight," 

Risk assessments, audits, and good communication between sponsor and supplier are key elements of supplier oversight.


Being Vigilant in Supplier Oversight

Biologics, including cell and gene therapies, have continued their upward trend in the pharmaceutical industry in the past few years. Pharma companies are investing in these therapies, and FDA has been encouraging the development of generic versions of already established biologics (1). Biologics, however, are costly to develop and manufacture, causing a variety of pharmaceutical companies to turn to contract development and manufacturing organizations (CDMOs). In response to this demand, CDMOs are continuing to invest in biopharmaceutical services and manufacturing facilities.

	“The industry is investing in an increasing number of API biologics (cell, gene, vaccine, and virus therapies), although this still accounts for a low proportion of CapEx [capital expenditure] projects in the period 2019–2025 (7%). The use of cell and gene therapies in the market is not well established, and the required manufacturing costs and level of expertise are high. CapEx projects involving API chemical or commercial solid-dose manufacturing as a percentage of total CapEx has decreased between the period 2016–2018 and 2019–2025,” says GlobalData Analyst Adam Bradbury.

	Shiva Khalafpour, vice-president, head of Commercial Mammalian and Microbial Development and Manufacturing at Lonza, agrees. “The biotechnology sector is projected to grow faster than the conventional pharma sector (9% vs. 6% CAGR [compound annual growth rate] 2019–2024). The strong venture capital funding for biotech companies will continue to support a healthy growth that positively impacts the outsourcing sector.”

Gene Therapy Market Opportunity for CMOs–2019 Edition

, shows an investment by CDMOs in greater capacity for anticipated gene therapy pipeline products, either through acquisitions or building facilities (2). “Some pharma companies including Pfizer and bluebird bio are also investing in gene therapy manufacturing facilities for excess capacity contracts or for in-house manufacturing of proprietary therapies. Cobra Biologics Ltd, Symbiosis Pharmaceutical Services Ltd, Novasep, LakePharma, Oxford BioMedica Plc, and Sanofi have also made recent major investments in gene therapy manufacturing, especially in viral vector manufacturing for gene transfection,” says Fiona Barry, editor, PharmSource, a GlobalData product.

	According to Eric Langer, president of BioPlan Associates, CDMOs offer expertise, cell and gene therapy processes, personnel, and capacity that pharmaceutical companies may not have. “In our research on the make-vs-buy decision process, we have found that many companies decide early in their development that they intend to become a fully integrated bio/pharma company, including seeing manufacturing as a core competency.  Others see manufacturing as potentially outsource-able and not part of their core competency. Still others need the flexibility to decide their manufacturing strategy as their pipeline develops and as their investment situation unfolds.  Nearly a third of biologics are produced using CMOs [contract manufacturing organizations] and CDMOs, and these organizations are now an integral and indispensable part of the industry,” says Langer.

	How has the push toward biologics changed or added to the processes pharmaceutical companies are outsourcing and CDMOs and CMOs are offering? According to Bernie Clark, vice-president, Marketing and Strategy, at Catalent Biologics, the contract industry will continue to evolve to meet the needs of the developing biologics market and to support the trend of personalized medicine.

	“Next-generation biologics, such as ADCs [antibody-drug conjugates], bi-/multi-specifics, gene therapy, and cell therapy, are growing sectors of the biologics industry, and providers are adding capabilities to support the unique needs of these novel modalities. For example, new analytical techniques are being developed to support these new therapies, and providers are evaluating whether it makes sense to adopt them as part of their offerings. Other capabilities being evaluated include potential process improvements, such as continuous manufacturing and automation, and providers are conducting cost-benefit analyses for adopting these technologies into their platforms. One driver to adopt continuous manufacturing, but also a more general industry trend, is the shift toward biologics that treat smaller patient populations, such as therapies that address orphan indications. This shift has resulted in a movement towards manufacturing smaller batch sizes, which has led to more investment in smaller bioreactors, with a heavy emphasis on single-use technology,” says Clark.

	Catalent has been evaluating possible new capabilities, says Clark, and acquired Paragon Bioservices as part of their expansion into the gene therapy market. “On the technology front, we adopted the Beacon system from Berkeley Lights to expedite clonal selection and improve titers for monoclonal antibodies and Fc fusion proteins. However, it is not enough to just acquire the right equipment or technology; contract organizations also need experts who are knowledgeable and experienced in the challenges that need to be addressed. We are focused not only on adopting new technologies for our customers but also on hiring or building the right expertise to support them across our global network,” says Clark.

	“Cell and gene therapy manufacturing is, of course, relatively new to the biopharma industry, and these will be seeing significant increases, especially as the cell and gene therapy innovators move their pipeline toward commercialization. As demand for clinical capacity increases, there will be a potential capacity crunch for CDMOs capable of meeting these needs.  But doing so will require having the skilled staff capable of work in this segment. And hiring of these experts is becoming increasingly challenging,” says Langer.

	According to Langer, the next two years will see more analytical testing being outsourced. “From our annual report (3), we find that analytical testing, including bioassays, leads the list with 32.8% indicating they will be doing more.  Following is cell line development (24.1%) and cell and gene therapy production (23.4%). Fill/finish operations appear to be contracting slightly over the past five years, from a high of 27.8%, indicating an decrease in outsourcing, to 19.7% this year who plan more fill/finish outsourcing over the next two years. Downstream process development is on the rise in terms of outsourcing trends. Validation services, on the other hand, have declined somewhat over the past nine years.”

	Khalafpour sees strong growth in mammalian-derived molecules, which may require the services CDMOs can provide. “Based on market assessment, mammalian appears to remain the preferred production technology with the highest growth potential due to pipeline increase and improvements in manufacturing technology,” says Khalafpour. Small and virtual biotech companies are expected to own these molecules, according to Khalafpour, and these companies may not have the expertise or services needed to produce these products. “In addition, the development and manufacturing of biopharmaceuticals is getting more complex in terms of production processes and regulatory environment while forecasting remains uncertain,” says Khalafpour.

	Lonza has announced the acquisition of a sterile manufacturing facility in Stein, Switzerland for clinical production and commercial launch of parenteral drugs, according to Khalafpour. The company is also building a development and manufacturing facility in Gaungzhou, China.

	Development of new and more complex molecules are in store for the industry, according to Khalafpour. Clark sees biosimilars as the next trend in outsourcing because of the amount of innovator products coming off patent and the unique needs associated with analytical testing. The promise of next-generation biologics is also becoming evident, according to Clark. “Mid/large pharma companies are taking notice and acquiring companies and molecules to expand their pipelines. The shift in focus to these new therapeutic classes may impact the types of programs that a sponsor company outsources. For example, they may choose to outsource the manufacturing of monoclonal antibodies or recombinant proteins that they had previously manufactured in-house to free up internal resources to focus on their next-generation therapies,” says Clark.

	Khalafpour agrees. “As far as drug manufacturing is concerned, we see smaller production volumes driven by personalized medicines, highly active compounds, [and] higher titers as well as continuous manufacturing and process intensification.”

Statement on Efforts to Help Make Development of Biosimilar and Interchangeable Insulin Products More Efficient

PharmSource–Gene Therapy Market Opportunity for CMOs–2019 Edition

, December 2019.
	3. BioPlan Associates, 

16th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production


	Supplement: Partnering for Bio/Pharma Success
	February 2020
	Pages: s4–s8

	When referring to this article, please cite it as S. Haigney, “Growth in Biologics Market Inspires Outsourcing," 

Pharmaceutical Technology Partnering for Bio/Pharma Success 

CDMOs and CMOs will continue to invest in biopharmaceutical services and facilities as the bio/pharmaceutical industry looks to biosimilars and personalized medicine.