Authored By: Mo Heidaran, Mark Levi, Kimberley Buytaert-Hoefen and Robert Iser
The state of and design of facilities where the drug products for clinical trials are manufactured often determines the quality of the final drug product. In the US, unlike Europe, facilities are not necessarily inspected for compliance with CGMPs during the Phase I trial but are verified at the time of pre-license inspection. For business reasons, companies often start by manufacturing their products in less than ideal environments. For example, sometimes they may use a regular research laboratory with a BSL-2 biological cabinet or a room not originally intended as a manufacturing suite for clinical grade products (Stage I). As the product shows some promise, some sponsors move their manufacturing to a more suitable environment which is more controlled and classified (Stage II). Finally, if product is a success in Phase III, the third stage of facility upgrade may involve building a new manufacturing facility or contracting with a CGMP-licensed manufacturer.
It is important to note that facility and clean-room environmental controls and monitoring are critical aspects of manufacturing a quality product under CGMPs. This is particularly true since many cell and gene therapy products are not terminally sterilized and/or sterile filtered and quality tests could potentially be performed with samples which are not necessarily representative of the final drug product and/or adequate. Accordingly, quality cannot be tested into the product, and the facility environment remains to be the major source of contaminants in the final drug product. In such a situation, it is particularly important to manufacture clinical grade products in an environment which is deemed to be suitable for the product type based on the analysis of critical manufacturing and processing steps which could potentially place such product in direct contact with the environment.
We recognize that manufacturers often scramble during late stages of clinical trials to get ready for commercial manufacturing by dedicating huge amount of resources to building a new state of the art manufacturing facility. Planning for success early on allows for streamlining the process of finding an appropriate manufacturing environment which is flexible enough to accommodate further expansion in view of intended scale of commercial manufacturing which is achieved through either scale up or scale out. While scale up strategy may not require a large footprint expansion, a scale out of manufacturing involving replication of manufacturing unit operations definitely will. In view of the challenges which are an inevitable part of the product development cycle, developing a CGMP facility strategy early on to address manufacturing facility requirements is advisable.
As you plan for success you may want to consider the following when designing or selecting a facility for biologic product manufacturing:
What is the appropriate and flexible environment for manufacturing of your product based on your current state of manufacturing?
Can you move to manufacturing platforms earlier which are less open to the environment and more amenable to aseptic sampling?
If not, what are the available manufacturing platforms that are suitable for automation of your process? Are there any existing, functionally-closed platforms that allow you to manufacture products requiring less environmental control and monitoring?
Can you use isolators as part of your manufacturing?
What is you plan for commercial manufacturing scale out or scale up considerations?
Will you be using a CMO and if so, do you have an appropriate quality agreement in place to ensure robust manufacture of your product?
Have you discussed your plan about commercial scale manufacturing with the regulatory agency?
We at PAREXEL can provide you with early, strategic guidance about your overall manufacturing plan from Phase I to Commercialization for biologic products.