Susan Haigney is managing editor of BioPharm International, susan.haigney@ubm.com.

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. 33, No. 7
	July 2020
	Pages: 43–47

	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 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. 33, No. 4
	April 2020
	Pages: 34-37, 56

	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

	The burgeoning cell therapy and gene therapy market segments continue to spur new partnerships and business expansions for contract manufacturing organizations (CMOs) and contract development and manufacturing organizations (CDMOs) in the second half of 2019.

	CombiGene, a gene therapy company located in Sweden, announced it signed an agreement with Cobra Biologics-a CDMO that provides DNA, viral vectors, and microbiota for preclinical, clinical, and commercial supply-for the production of the epilepsy gene therapy candidate drug CG01 (1).

	The agreement includes a Master Service Agreement that details the terms under which the two companies will collaborate. There will be three separate contracts: quality, production of plasmids, and production of CG01. The agreement includes manufacturing of CG01 by Cobra for clinical studies and future commercial production, according to a October 14, 2019 press release.

	“I am very pleased that we have selected Cobra as our manufacturing partner,” said Karin Agerman, chief research and development officer at CombiGene, in the press release. “The choice of a CDMO marks a significant milestone in the CG01 project and an important step towards clinical studies. Our collaboration will now begin in earnest and we see potential for it to continue for many years to come.”

	“For almost 20 years, Cobra has been manufacturing DNA and viral vectors for its gene therapy customers and we are pleased to be involved in bringing CG01 closer to market,” added Peter Coleman, CEO at Cobra Biologics, in the press release. “CombiGene has recognized our expertise and track record, and this project fits perfectly into our newly expanded viral-vector manufacturing facility, which will soon be capable of commercial scale supply.”

	Also on October 14, 2019, Lonza announced an extension to its partnership with Genmab, a Denmark-based biotechnology company specializing in antibody therapeutics for cancer, which covers preclinical and clinical development and manufacturing for part of Genmab’s pipeline (2). Lonza’s Ibex Solutions in Visp, Switzerland is designed to provide Genmab with the flexibility and speed needed to take candidates toward investigational new drug application (IND) filing and commercialization, Lonza reported.

	Lonza’s Ibex Design enables Genmab to take their candidates from gene to IND in 12 months and move to reserved manufacturing capacity in Ibex Develop for clinical manufacturing and biologics license application submission. The agreement aims to provide Genmab with security of supply and the ability to move rapidly into clinical manufacturing.

	The new agreement will cover development and clinical manufacturing of drug substance and drug product for certain programs in Genmab’s pre-clinical and clinical pipeline. These include more complex molecular formats developed using Genmab’s DuoBody technology.

	Lonza also announced it is entering into a manufacturing service agreement with Cellectis, a clinical-stage biopharmaceutical company that specializes in developing immunotherapies based on allogeneic gene-edited chimeric antigen receptor (CAR) T cells (UCART), for the clinical manufacturing of Cellectis’ allogeneic UCART product candidates targeting hematological malignancies (3).

	Manufacturing of the cell line will take place at Lonza’s GMP facility in Geleen, Netherlands where the frozen, off-the-shelf, non-alloreactive engineered CAR T cells will be industrialized with defined pharmaceutical release criteria for the patient population, according to a October 1, 2019 press release.

	“This agreement not only bolsters our product supply for clinical trials, but it ensures that we are producing first-rate product candidates so that we can potentially deliver new hope to patients living with certain blood cancers,” said William Monteith, executive president, technical operations, Cellectis, in the press release.

	“We will draw on the experience at our cell and gene therapy center of excellence in the Netherlands, ideally equipped to support Cellectis in bringing their promising pipeline of allogeneic CAR-T therapies to people around the world in need of life-saving products,” added Alberto Santagostino, senior vice-president, head of cell and gene technologies, Lonza, in the press release.

	Clinical and commercial contract agreements

	Rentschler Biopharma announced in a October 4, 2019 press statement that it will further enhance and develop an existing collaboration in Japan with Summit Pharmaceuticals International Corporation (SPI), a wholly owned subsidiary of Sumitomo Corporation (4). Through its collaboration with SPI, Rentschler Biopharma has secured new contracts with Japanese pharmaceutical companies. SPI and Rentschler Biopharma are working together with Japanese clients to outline projects from early clinical stage up to commercial launch.

	“Our relationship with SPI has been highly productive and fruitful, and we have been impressed by their strong network and extensive experience in contract manufacturing and supply. Japanese pharmaceutical companies are playing an important and expanding role in the global healthcare market, and we are delighted to be continuing this productive collaboration as we grow our client base in Japan,” said Frank Mathias, CEO of Rentschler Biopharma, in a company press release.

	Catalent announced it has entered into a long-term commercial supply agreement with Minerva Neurosciences, a Waltham, MA, USA-based biopharmaceutical company focused on the development of therapies to treat central nervous system disorders (5). The companies will focus on roluperidone (MIN-101), an investigational compound under development by Minerva, for the treatment of negative symptoms of schizophrenia.

	A Phase III clinical trial of the drug is currently being conducted in Europe and the United States, according to a Sept. 24, 2019 press release. If successful, roluperidone (MIN-101) will be the first treatment approved to treat symptoms of schizophrenia in the US, according to the companies.

	“Launching any new drug with a partner marks the culmination of many years of hard work and having to overcome challenges, and is a milestone for a project,” said Aris Gennadios, president, Catalent Softgel & Oral Technologies, in the press release.

	“We are pleased to be working closely with our partner, Catalent, under a long-term supply agreement for a compound with the potential to treat negative symptoms, one of the leading unmet needs in schizophrenia,” added Rick Russell, president of Minerva Neurosciences, in the press release.

	Novasep revealed on October 1, 2019 that is has launched a dedicated unit in Seneffe, Belgium that offers fill/finish clinical and commercial services for biological products (6). The unit, Senefill, forms part of Novasep’s flagship for the manufacturing of commercial viral vectors, Senrise-IV, and will provide standalone fill/finish services in addition to integrated drug product manufacturing, ranging from formulation to packaging. Operations undertaken at Senefill will support Novasep’s key biopharmaceutical markets.

	“Senefill is a major step for Novasep to achieve its growth strategy, Rise-2,” said Michel Spagnol, chairman and CEO of Novasep, in a press release. “This unit strongly distinguishes Novasep from its competitors in the market for viral-vector drug product manufacturing services. It was crucial for us to be able to meet the growing needs of our clients for targeted and innovative therapies and address patients’ needs.”

	1. Cobra Biologics, “CombiGene Signs Agreement with Cobra Biologics for Production of Candidate Drug CG01,” Press Release, October 14, 2019.
	2. Lonza, “Lonza’s Ibex™ Solutions to Support Genmab’s Growing Clinical Portfolio,” Press Release, October 14, 2019.
	3. Lonza, “Cellectis and Lonza Enter cGMP Manufacturing Service Agreement for Cellectis’ Allogeneic UCART Product Candidates,” Press Release, October 1, 2019.
	4. Rentschler Biopharma, “Rentschler Biopharma Announces Enhanced Collaboration with Summit Pharmaceuticals International Corporation to Expand Japanese Operation-Base,” Press Release, October 4, 2019.
	5. Catalent, “Catalent and Minerva Neurosciences Enter Commercial Supply Agreement for Schizophrenia Drug Roluperidone,” Press Release, Sept. 24, 2019.
	6. Novasep, “Senefill, Novasep’s Commercial Facility for Aseptic Filling and Finishing Operations, Is Now Ready to Operate,” Press Release, October 1, 2019.


	Vol. 32, No. 11
	November 2019
	Pages: 10-12

	When referring to this article, please cite it as S. Haigney, "Developments in the Biopharmaceutical Outsourcing Industry," 

Contract manufacturers are making strategic partnerships and expanding services in the last quarter of 2019.

Author | Susan Haigney

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