October 17, 2023
In our current financial climate, biotechnology companies are facing significant funding difficulties that necessitate careful decision-making when it comes to outsourcing biomanufacturing processes and balancing budgets. Reliable, high-quality bioproduction is paramount to success. Considering the complex nature of biomanufacturing and the intricate requirements involved, biotechnology companies should choose contract manufacturing organizations (CMOs) that operate within current financial constraints and that possess the expertise, regulatory compliance, and technological capabilities necessary to ensure seamless technology transfer and high product quality. Therefore, CMO selection is important to preventing manufacturing delays, supply-chain disruptions, and setbacks with clinical programs, development timelines, and critical milestones. By exploring the complex landscape of CMO selection, process sponsors can make strategic decisions and develop effective partnerships, helping to mitigate risks and increase the likelihood of manufacturing success.
Manufacturing Expertise
A CMO’s track record is important, especially regarding whether a manufacturer has worked with products that are similar to what a sponsor needs to produce. An experienced CMO can offer valuable insights, specifically with process analytics and troubleshooting. Equally important is whether a CMO has a history of successful technology transfers. A CMO with a team of experienced scientists, engineers, and manufacturing specialists can help sponsors to mitigate risks associated with scale-up to commercial production.
The Transition from Process Development to Commercial Production: Typically, CMOs performing good manufacturing practice (GMP) production do not need to use bioprocess equipment from the same vendor that sponsors used during small-scale development activities. Many equipment suppliers even provide predictive models for evaluating scale-dependent parameters, such as conditions for production-scale bioreactors. However, it is critical for sponsors to investigate potential equipment-related scale-up issues, which could result in extended timelines and increased costs. Moreover, equipment suppliers are likely to provide scale-up support for programs that use their technologies for both small-scale development and commercial manufacturing. Although downstream processes generally are considered to be less scale-dependent than are cell-culture processes, a sponsor still should determine whether a given CMO has successfully transferred small-scale downstream processes developed using specific equipment. Doing so can minimize risks of equipment issues.
A sponsor also should consider its long-term manufacturing strategy and how that aligns with available production scales at a prospective service provider. Although many CMOs for clinical activities offer batch sizes up to 2000 L using disposable bioreactors, such capacities may be unsuitable for future commercial manufacturing needs. Moreover, small batch sizes might be required for GMP clinical campaigns, potentially necessitating use of smaller bioprocess equipment or partly filled bioreactors. Although most bioreactors have a specified minimum fill volume, sponsors should evaluate a CMO’s experience with manufacturing at different scales based on specific needs for clinical and production scales.
Technology-transfer experience and success are key aspects to consider when evaluating contract manufacturers. An experienced CMO will assign to each sponsor a dedicated project manager who possesses the necessary expertise to ensure a smooth technology-transfer process. An effective contract partner also will have a well-established transfer process. That typically entails comprehensive assessment of process and facility compatibility, evaluation of equipment requirements, and identification and mitigation of potential risks. By gaining technology-transfer experience, CMO personnel learn how to integrate a client’s technology seamlessly into their operations, ultimately contributing to the success of future projects.
Many CMOs specialize in drug-substance production and can make final bulk drug substance efficiently. However, some such companies do not have the facilities needed to undertake drug-product manufacturing, specifically capabilities for automated fill–finish activities. In such cases, it becomes necessary to engage another service provider that specializes in fill–finish operations. It could be advantageous to work with a CMO that offers only drug-substance services if a sponsor has an existing partnership with an established drug-product manufacturer. Leveraging such connections can reduce time and minimize potential delays.
The success rate of batches manufactured is a metric that holds particular importance. Typically, CMOs maintain a batch-failure or -rejection rate below 10%. However, that figure can vary depending on the complexity of the manufacturing processes involved. Batch failures can stem from process-related issues encountered with early stage projects. Thus, a lower-than-average success rate is not necessarily indicative of CMO performance.
New and Small CMOs: Working with a recently established or less-experienced contract manufacturer should not be ruled out because such partnerships can lead to long-term opportunities that result in mutual growth and success. A new CMO might be more flexible and open to tailoring its services to meet specific requirements than an established manufacturer might be. New contract partners sometimes offer competitive pricing to attract clients, and they can be more willing to negotiate pricing terms and offer cost-saving solutions. Because a new CMO is building a reputation and client base, it also might be able to give a project more attention than would a larger contract manufacturer. That said, drug developers should conduct thorough due diligence when evaluating a new service provider’s capabilities and experience and when assessing risks for delays and problems.
Analytical Experience
One crucial criterion is whether a CMO has an established quality control (QC) group with expertise in verifying standardized analytical methods and procedures that have been established by recognized pharmacopoeial organizations, such as the United States Pharmacopeia and the European Pharmacopoeia. Experience with in-house method qualification and validation is valuable, too. Although it is common for some specific analytical tests to be outsourced, sponsors must determine whether a CMO’s QC group can provide necessary support for in-process testing and product release.
A related consideration is a CMO’s ability to perform stability studies, which involve long-term, GMP-compliant experiments that assess a product’s stability over time under different conditions. Such studies provide crucial information about product shelf life, storage requirements, and recommended storage durations. Sponsors should determine the number of ongoing stability programs that a prospective CMO is performing on behalf of customers. That information can indicate a contract partner’s experience with and capacity for coordinating and executing complex studies effectively, helping the sponsor to ensure accurate performance of analytical testing and reliable generation of data.
Although a CMO’s analytical instrumentation need not be identical to what a sponsor has used during small-scale process development, there are certain situations in which using the same instrumentation is preferable. Simple laboratory instruments (e.g., for measurement of pH, conductivity, and absorbance levels) are unlikely to result in significant differences despite being from different suppliers. However, when measuring specific quality attributes (aggregate and particle levels) or product characteristics in a final drug substance or product, it can be advantageous to use the same vendor’s equipment during process development and subsequent manufacturing activities. During contract negotiations, CMOs sometimes offer to provide specific analytical systems to support a project.
Regulatory and GMP Compliance
When evaluating CMOs, ensuring compliance with regulatory standards is of the utmost importance. A sponsor should determine whether a prospective partner consistently adheres to relevant regulations, such as GMPs and specific requirements set by health authorities such as the US Food and Drug Administration (FDA) and European Medicines Agency (EMA). Reputable CMOs maintain comprehensive quality management systems to support ongoing adherence to standards.
Evaluating a CMO’s history of regulatory inspections represents a key component of a sponsor’s vendor assessment. Results from routine GMP inspections provide insights into a manufacturer’s compliance and identify areas for improvement. Audits conducted by other customers serve as an additional layer of scrutiny, offering valuable information about a contract organization’s manufacturing processes, QC systems, and overall compliance. Requesting information about a CMO’s audit schedule and the outcomes of regulatory inspections can provide a sense of the company’s track record in meeting customer and regulatory expectations. International Organization for Standardization (ISO) certifications such as ISO 9001 (quality management) and 13485 (medical devices) further validate a CMO’s commitment to quality management principles.
During vendor selection and auditing, customers should communicate openly about their specific needs and expectations regarding regulatory compliance. Detailed audit observations and responses typically are treated as confidential information, but CMOs should be able to provide high-level summaries and discuss actions taken to address findings without breaching confidentiality. Willingness to provide high-level information demonstrates a CMO’s transparency and dedication to addressing regulatory concerns while respecting the privacy of clients. Open communication and alignment of expectations are key to a successful partnership with a compliant and reliable CMO.
Location
Process sponsors would do well to consider location when shortlisting potential CMOs. Sponsor-company representatives should conduct site visits as part of contract discussions so that they can meet CMO project teams in person. Frequently, a member from the drug developer’s quality assurance (QA) team also participates in a vendor audit as part of a supplier-qualification program. Therefore, sponsors should account for travel distance and logistics.
As a drug program progresses, someone from the client company might need to be present at the manufacturing facility to observe operations and provide input on manufacturing events and deviations. Time-zone differences across locations can pose challenges, especially when client input is urgently needed but representatives are unavailable because of differing time zones. As part of an overall CMO-selection process, sponsors should consider location, resource availability, needs for travel visas (if applicable), and local restrictions, such as those imposed during the COVID-19 pandemic.
Supply-Chain Management
Sponsors should ensure that their manufacturing partners can demonstrate efficient inventory management. Delays in obtaining raw materials and consumables, such as virus filters and chromatography resins, can influence project timelines significantly. It is an advantage if a prospective CMO has established relationships with key vendors to maintain a stock of chemicals and consumables that are identical to or comparable with the materials that a sponsor used during process development; such arrangements help to ensure smooth transfers between customer and CMO processes. Evaluating a CMO’s inventory-control practices — e.g., for forecasting, demand planning, and inventory management — also helps to maintain a seamless supply chain. Large CMOs leverage economies of scale and often hold preferred-customer status with vendors, providing advantages such as reduced risk of material delays when ordering supplies.
Logistics and distribution capabilities are equally important to assess because such factors have bearing on timely delivery of finished products. Timing is especially important when bulk drug substance needs to be shipped from one contract manufacturer to another. Related considerations include a CMO’s experience with cold-chain logistics, temperature-controlled storage, and complex export and import requirements during international distribution.
Cost Considerations
Cost is a crucial CMO-selection factor for most biotechnology and pharmaceutical developers. Sponsor companies need to adhere to budget constraints, particularly in the current financial climate. Therefore, selecting a CMO that offers competitive pricing within a sponsor’s available budget is essential. But sponsors must strike a balance among cost, quality, and reliability. Relying on cost as the single factor when choosing a CMO can increase risks for manufacturing delays and supply-chain issues, potentially causing setbacks in clinical programs, development timelines, and other milestones.
Several local factors influence the overall cost of CMO services. For instance, employment costs and taxes in different regions can affect a CMO’s overall cost structure significantly.
It is worth considering CMOs that offer additional services such as research and development support. Even if such services come at a high cost, they can bring significant value to sponsor organizations.
Sponsors should give serious consideration to the availability of manufacturing slots. Some CMOs have limited capacity or high demand for services, both of which can increase costs and timelines. Such manufacturers might offer favorable payment terms or negotiate upfront payments. Flexibility in financial arrangements might make a CMO seem more attractive, especially for preclinical-stage biotechnology companies with budget and cash-flow constraints. However, cost should be weighed against other considerations such as quality, reliability, and potential for long-term partnership.
Responsiveness to Questions
Sponsors should not underestimate a CMO’s responsiveness (or lack thereof) to questions posed throughout the selection process. The time taken for legal review of a confidentiality agreement (CDA), the speed at which a proposal is provided, and the promptness with which technical questions are answered all serve as indicators of a CMO’s commitment to effective communication during technology transfer.
The same goes for attention to detail. If a CMO representative includes previous client names in a proposal, then that should raise concerns about the manufacturer’s review process and overall attentiveness. Such errors can undermine confidence in a CMO’s ability to handle sensitive information accurately and securely.
After receiving a proposal, a CMO is expected to respond promptly to client technical questions and to be proactive in scheduling a call with its technical team. Lengthy delays in issuing replies do not make good impressions, nor do discussions that are led primarily by sales representatives, who might have limited technical expertise. At such early stages, meaningful technical input from a CMO’s team not only provides valuable insights, but also fosters effective collaboration.
Based on responsiveness to questions and attention to detail during the selection process, biotechnology companies can gauge a CMO’s commitment to open communication, ability to meet project timelines, and professionalism. Prompt and thorough responses, along with meaningful technical engagement, contribute to building successful partnerships and technology transfers.
Partnership Development
Biotechnology companies are facing funding challenges that require careful decision-making when outsourcing manufacturing processes. Balancing budgets with the need for reliable, high-quality production is paramount. CMO selection plays a significant role in preventing manufacturing delays, supply-chain disruptions, and setbacks in clinical programs and development timelines. Key considerations include manufacturing expertise, analytical experience, regulatory compliance, location, supply-chain capabilities, cost, and responsiveness to questions.
Choosing a CMO that aligns with current cost constraints, possesses the necessary expertise, and demonstrates consistent regulatory compliance helps to ensure seamless production and high product quality. By considering such factors, biotechnology companies can navigate the complex landscape of CMO selection, mitigate risks, and ultimately achieve manufacturing success through strategic decision-making and effective partnership development.
Anthony Newcombe, PhD, is owner and managing director of Applied Biopharm Consulting Ltd., Clonakilty, Cork, Ireland; 353-87-3634486;
[email protected]; https://www.appliedbiopharm.com.
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