Patients in early phase clinical trials deserve the best quality product we can give them. This is particularly true for trials of products like vaccines, which are given to healthy people.
Yet the manufacturing of clinical trial supplies, especially for biologicals, poses some challenges which are different to those associated with preparing licensed products. For example, clinical materials for early phase trials (Phase I & II) are not usually made in dedicated facilities with dedicated equipment. Whether they are manufactured in-house or by a contract manufacturing organization (CMO), it is not feasible to build a new facility for a Phase I product – given that only a fairly small proportion of Phase I products make it to licensure.
So let's assume then, that you need to make your clinical products by campaigning within a multi-use GMP facility. This can be especially tricky when you are campaigning different live organisms. How do you ensure that you are maintaining sufficient control to assure patient safety, even as the product and process are constantly changing? And what if you need to do some test or scale-up runs to ensure that your new processes will perform as expected – can you use the clinical GMP manufacturing facility and equipment for non-GMP development work too?
Large companies and CMOs may have specific GMP facilities used to make clinical lots, while smaller ones may use the same facility for both process development and clinical manufacturing. Wherever your clinical materials are prepared, it is essential to ensure that the facility and equipment are maintained in a state of control, while also recognizing the need for flexibility. Pilot scale manufacturing facilities may also have periods of down time between campaigns, so controls should also address management of the facility during these periods. Whether it is standing idle between product campaigns, or whether it is in use for non-GMP process development and scale-up activities, you need to be confident that the activities of today will not have an impact on the clinical products of tomorrow.
It is indeed possible to maintain compliance while using a GMP facility for new products, or for non-GMP development work. You can even use a dedicated, licensed facility for development if you have the right systems in place. The key is to define a clear risk-based strategy which provides an appropriate balance of these priorities:
Priority #1: Maintain Compliance
- It is essential to protect your facility and equipment. You may be bringing in new, unreleased materials. If you work with biologicals, you may be exposing the facility to new organisms. You may want to use equipment outside of its validated parameters. All of these can be done if you have the right plan in place to mitigate the potential impact
Priority #2: Manage Use of Facilities for Multiple Products and Activities
- When multiple products are handled in a single facility, the risk of cross-contamination and mixups is heightened. Perhaps there will also be different personnel coming in to support different projects, some of whommay have limited GMP experience. How will you ensure that nothing goes wrong?
Priority #3: Allow Flexibility
- Recognize the need to allow development and non-GMP work, without compromisingthe safety and quality of your clinical batches
Whether you manufacture your own clinical lots, or whether you work with a CMO, it is important to make sure that the multi-use facility is well managed to ensure your patients are protected. Start with an assessment of the potential risks associated to the way you use, or intend to use, the area. What could go wrong, and what measures could you take to prevent it?
For any multi-use or campaigned facility, there should be procedures in place to protect the facility itself, the utilities, and equipment. Proposals to use novel and/or unreleased raw materials and consumables, or to introduce new organisms must be carefully reviewed before allowing work to proceed. This is essential even when campaigning only GMP products and processes, to protect the facility, the equipment and the productitself from accidental mix-ups or contamination. Does your CMO require you to provide this type of information before they take on your manufacturing? If they're not asking you, then they are not asking their other clients either.
There should be plans in place to deal with unexpected events. What happens if you are performing some non-GMP work in your facility and you have a deviation? Do you need to report it? If you use equipment outside of its validated parameters but it's only for non-GMP work, does it matter?
Time spent to ensure that you have a robust system for managing multi-use facilities will allow you to demonstrate to auditors and regulatory authorities that you are compliant and that you have patient safety always in mind. If you work with a CMO, make sure that you understand how they campaign their facilities and what other products they are making in them. None of us wants to have anything less than complete confidence in the quality of our clinical products.
*Chrysta Mayhew is the Deputy Director, Clinical Manufacturing Platform at Sanofi Pasteur in Canada