Whether you are developing a new monoclonal antibody (mAb), cell therapy, gene therapy, or large molecule biologic drug, the decision to tackle GMP manufacturing in house or work with a contract development and manufacturing organization (CDMO) represents a pivotal crossroads in your product’s journey to market. Below, we discuss key considerations to help you determine which strategy best suits your process, product, and team.
Getting GMP ready for in-house manufacturing
In-house manufacturing offers the appeal of having complete control over your product and can provide long-term cost benefits. But are you and your team ready to take on the demands of GMP compliance and regulatory approval? Here, we map out some general considerations and tips for succeeding in GMP manufacturing.
Learn the ABCs of GMP
What is GMP? GMP stands for Good Manufacturing Practices and refers to the specific manufacturing procedures required by countries and international organizations. The FDA oversees GMP certification for drug development in the US by enforcing current GMP (cGMP) guidelines. GMP, including cGMP, provides a regulatory framework that ensures the quality of manufactured human drug and biological products as well as the proper design, control, and monitoring of manufacturing processes and GMP facilities. A manufacturing transition mandates compliance with GMP standards to ensure treatments are safe and meet quality specifications.
“Compliance with governmental regulations is not something you choose to do. It is something you must do if you plan to produce cellular therapies or other biologics approved for human use. Although challenging, the process is not difficult. If a laboratory has even an inkling that manufacturing may occur, they should start to plan and organize their body of work in a compliant manner,” explains Helen Huls, PhD, independent consultant.
“It is never too early to start, as regulatory approval is needed before a product can be infused into a patient. All relevant requirements must be met and a safe-to-proceed letter received from the appropriate government authority.”
GMP guidelines, although seemingly complex to understand and execute, represent the minimal requirements for compliance. Regulations are purposefully flexible in order to allow manufacturers latitude on how to best implement necessary controls and continually improve upon them.
“The framework is not specific to any one type of biologic or cellular therapy; it is a way of doing manufacturing. Processes need to be under control and perform as expected,” says Steven Keizer, director of quality and GMP program manager, Centre for Commercialization of Regenerative Medicine (CCRM) in Toronto.
“You need to say what you want to do before you do it, do exactly what you said you were going to do, be able to prove it, and also be able to improve on the system. Manufacturing under GMP should be very boring and repetitive. When it is exciting, it typically means something is wrong.”
Build a team with an understanding of GMP manufacturing
The development of a new production line will typically require a tremendous investment into infrastructure, capacity, and resources. Compliance with GMP requirements needs to be a primary focus from early on and throughout process development and manufacturing. All employees must understand the importance of GMP regulations and commit to consistently upholding them.
When building a production line from lab-based processes, keep in mind that staff primarily familiar with research might not know the specifics of regulations relating to late-stage drug production. Hiring manufacturing, quality assurance, and quality control teams experienced in GMP principles can ensure your organization is incorporating regulations appropriately across the board. If limited budget or timing does not allow for building proficient internal groups, consultants can help navigate complex compliance requirements.
Focus on quality from the start
Your team must build quality into design and manufacturing at every step to avoid unnecessary problems and delays. Dr. Huls suggests incorporating a strong quality management system (QMS) that captures written procedures to manage manufacturing oversight. Proper reviews and approval processes should be in place, and the group should review and understand the testing criteria for meaningful measures of sterility, identity, purity, and potency. Quality systems are expensive and require time and resources, but they are invaluable in preventing and addressing problems.
“The amount of documentation can be intimidating initially. A well-structured data and implementation plan will help to move the process forward smoothly. Expect new items to emerge that will need resolution,” says Dr. Huls.
A QMS is comprised of the entire set of documents, systems, and facilities involved in helping make a product. Documentation must be in place to back up label claims, and procedures that meet GMP guidelines must be followed the same exact way every time. The QMS, along with associated QMS software, serves as the umbrella that covers quality, manufacturing, and marketing personnel to make sure all are performing to the established standards.
The field of biotherapeutic production is still learning the ins and outs of manufacturing, so a QMS needs the ability to evolve. Additionally, the amount of product needed for Phase I and II clinical trials is low, limiting learning in early stages of development. A complex manufacturing process might be hard to reproduce at scale, so a program that emphasizes the importance of continual optimization to guide system direction encompasses a good strategy.
Steven Keizer uses the recently issued European Commission GMP guideline for advanced therapy medicinal products (ATMPs) to develop the CCRM framework. The regulations are entirely risk based and take a broad understanding of the complexities and real changes that are needed in traditional small molecule regulation to ensure that cellular therapies can get off the ground. Dr. Huls shares the following related example pertaining to the FDA: “The FDA requires assurances about access to GMP-grade raw materials and reagents. With the appropriate validation procedures and prior discussions with the FDA, instances may be approved where ‘for research use only’ (RUO) products can be used if GMP-grade is not available. The decision is data driven; the FDA has the final say.”
“If you want people to walk a certain path, you have to provide ways for them to stay on that path. To change behavior is challenging and GMP includes a lot of behavior management. You have to choose between new procedures, new training, or new engineered solutions. Then you must monitor to ensure the change has the desired effect,” inserts Keizer.
“You want to make things easily manageable, do not want your system to be cumbersome so people just push paper around all day, and you want the system highly visible so you or an outsider immediately know when something is out of control. It is an art and a science.”
Another hurdle is onsite audits, a standard business practice required by relevant health authorities.
“You prepare all the time for the inspections. To make a facility auditable, the system must be transparent to easily reveal the level of compliance. Expect some human and minor documentation issues. But if an audit uncovers an issue with data integrity, that is a signal that the implemented system is not strong enough to handle the manufacturing processes,” says Keizer.
“Data must be readable, easily retrievable, and permanent. Automated testing and manufacturing systems controls have to be properly in place to assure data integrity.”
Automate and close manufacturing for biotherapies
In transitioning from lab bench processes to manufacturing, underestimating scalability is common. Research scientists might not be familiar with manufacturing equipment. Or they might not have considered the logistics of preserving biological integrity over time, safe product transport, controlled documentation, and maintaining chain of custody. These are critical factors in demonstrating product control.
“Autologous cell therapy is a very tough product. Consider the variability of the starting material of each patient; one size does not fit all. You have to prove that operating procedures for manufacturing processes are reproducible, that you are able to detect and investigate product quality and deviations, and to maintain a reliable testing laboratory,” advises Dr. Huls.
To minimize contamination in biotherapeutic production, regulatory bodies will want to see a functionally-closed manufacturing process. Automation also eliminates the variable human factor of manual processes. Automated instruments promote process and product standardization because they are programmed to operate with consistency. With added digital capabilities, you can monitor, measure, track, and promptly address deviations to ensure product quality is maintained. See Figure 1 for an example of data that can be generated from a comprehensive cell therapy automation platform.
Fig 1. Chronicle automation software provides a unified digital platform to monitor cell therapy facility manufacturing operations and supply chain logistics.
Dr. Huls adds, “Scientists are invariably problem solvers, and, often, in manual processes will fix problems without documenting properly. That is great for R&D but for manufacturing you need continual improvement. An automated system provides the data traceability to let you perform true root cause analysis.”
Outsourcing with a CDMO
Rigorous regulations are in place for biotherapeutic production to ensure only safe and effective treatments are tested in clinical trials. Achieving compliance can require more expertise and resources than you have available, making outsourcing an appealing option to quickly generate critical data or materials relevant to your next milestone. Here, we outline some of the many key factors to consider and challenges to overcome when choosing to work with a CDMO.
Consider a CDMO if you find the right fit
Finding a services provider that has both the expertise and open capacity to develop and manufacture your product might be more challenging than you think. Capacity is continuously increasing to meet demand, but CDMO wait times can be 12 to 24 months (1). This length of time might be prohibitive to bringing therapies to patients in need and could require creative workarounds to keep your process moving forward. You could find yourself paying large sums to secure capacity slots, far in advance of when you will require support and with the added pressure and risk that you might not be ready once the CDMO’s services become available.
If you can wait for capacity to become available or if your strategy is based on unpredictable demand, leveraging CDMO support externally can lessen the risks associated with building infrastructure. Utilizing a CDMO can also help tighten cash flow internally prior to having a commitment that a drug product will meet approval in the market space. However, when speed to clinical trial is most important, recent advancements in modular facility designs can halve the time to market.
Lay a strong project foundation
From the initiation of a CDMO partnership, your organizations must work together to define project goals, clearly outline how the CDMO can help execute your business strategy, and specify how information will be transferred between teams. Establishing a documented project plan and standard operating procedures encourages effective collaboration, sets individual roles and responsibilities, and facilitates an efficient handover process.
For milestones and deliverables, your organization and the CDMO should set and agree upon timelines so you can track the project’s pace and ensure it is consistent with expectations. Change orders and contingencies are typical. Be prepared to revise and re-plan, as the biology of the process can impact the pace of development. Create trust and drive teamwork by being adaptable and willing to negotiate in this process.
Collaborate for success
When working with a CDMO, it is important that both sides operate as one team. Effective communication eliminates delays and misunderstandings that can create frustration and errors (Fig 2). When vetting CDMOs for your project, inquire about communication structure. If the CDMO does not outline a plan for effective communication, it can have a lasting effect on the strength and cohesiveness of your partnership.
Fig 2. Chronicle automation software provides a unified digital platform to monitor cell therapy facility manufacturing operations and supply chain logistics.
Mutual respect occurs by working side by side to understand how the services of a CDMO are supplementing the expertise within your organization, rather than replacing it. You and your CDMO will work together to foster process improvement and facilitate knowledge transfer. Build training into your plans so it occurs throughout the project and less time is spent doing so in the end. This transparency gives you the ability to work autonomously when you return to your facility.
Reaping the benefits of an experienced CDMO that values transparency and open lines of communication can provide a path to market for high-risk, difficult-to-manufacture biotherapeutics. These organizations offer expertise in developing safe and compliant production processes that can provide security and longevity to achieve commercial success.
Outline how to protect your intellectual property (IP)
Working with a CDMO means sharing valuable knowledge and data about your product and process. Ownership of the biotherapeutic IP almost always resides with the customer, but you should establish upfront whether there will be co-ownership or exclusive ownership of the techniques, process, and platform technologies.
You might want some information blinded in a black-box approach to protect the critical quality attributes (CQAs) of your product. A CDMO using this method receives samples from the customer to test and has an open relationship about the CQAs without knowing what they are. Some cell therapy CDMOs will not want to work this way because it makes process development more difficult. They could also be seeking a long-term relationship where, in the end, they manufacture your commercial product. If you are seeking this approach and a CDMO lacks the internal capability or willingness to execute, it could indicate a poor fit for your project.
Choosing your drug’s best path forward
The promise of recent scientific discoveries and medical breakthroughs will reach a dead-end without compliant, efficient manufacturing processes to deliver these therapies to the masses. Taking time to critically evaluate the best arena for developing and executing your production plan is a pivotal part of the biotherapeutic approval process. Whether in-house or with a CDMO, find the development strategy that fits your business and fosters the success of your product’s journey to the clinic. The patients waiting there will thank you.
Download the Business of Biotech podcast series to hear from guests who turned biotherapy ideas into clinical realities.
References
1. Reh, G. and Allen, S. 2019 Global life sciences and health care outlooks. Accessed 17 January 2020.
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