About eleven years ago, when I was dropping my son off at school before going to work, I was taking a sip from my coffee mug. From the back seat, my son shouted, “Daddy, don’t drink and drive!” I was surprised – did he learn that in school? He had started kindergarten barely a month earlier! I’m not sure whether it was in school or from an advertisement on TV or on some poster describing the consequences of “drunk driving” where he learned this valuable lesson so early (albeit a little too literally).
In the pharmaceutical industry, particularly when products under development are eligible for Expedited Programs for Serious Conditions – Drugs and Biologics, which is often the case for certain cell and gene therapies used for rare diseases, this concept is particularly important. In cases where promising phase I/II clinical results are observed, the program can move quickly to BLA filing and commercialization. Hence, in such cases, ideally, companies should plan for CGMP readiness starting from phase I clinical studies or even in preclinical development. What are the regulatory requirements for CGMP adherence in clinical phases? When you read “These drugs, which include biological drugs, are exempt from complying with 21 CFR part 211 under 21 CFR 210.2(c) (referred to as phase 1 investigational drugs),” you may assume that GMP requirements as set forth in 21 CFR Part 211 are not required for early clinical phase. However, this Guidance for Industry from the FDA outlines the CGMP requirements for phase I investigational drugs only.
Although the above-referenced guidance talks about expectations for phase I clinical trials, there is no specific guidance available for phase II products. Per 21 CFR 210.2(c), “However, this exemption does not apply to an investigational drug for use in a phase 1 study once the investigational drug has been made available for use by or for the sponsor in a phase 2 or phase 3 study…” Hence, full compliance with 21 CFR 210/211 is expected beginning with phase II clinical manufacturing.
So, how does your firm prepare yourself to be GMP compliant if you are at phase I stage and intend to continue subsequent clinical studies supporting BLA submission at the same facility? Here are some thoughts (and by no means is this an all-inclusive list):
1. Robust Facility Design
One of the major investments for manufacturing sterile drugs is designing a facility that can produce drugs that are safe for the patients. Once manufacturing begins, changing or modifying the design is time consuming and expensive. Cleanrooms should be designed so that a unidirectional flow of people and material is maintained to minimize contamination and cross-contamination. If multiple cleanrooms are used simultaneously for different products (for autologous therapies, even for the same product), adequate segregation of workflow and airflow of the rooms should be maintained.
2. A CMC Policy for Applying Phase-Appropriate CGMP
It is important to develop a CMC policy at early clinical phase manufacturing so that it can be adapted as the therapy progresses toward commercialization. While it is not necessary to validate all analytical methods and processes at phase I, it is prudent to have a defined policy for phase-appropriate measures. For example, in the Guidance for Industry Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs), the FDA recommends, for all analytical procedures, “that you evaluate assay performance throughout product development, have a validation plan in place prior to initiating later phase clinical studies, and complete validation before BLA submission.”
3. A Data Integrity and Governance Program
One important aspect of CGMP compliance is integrity of data. The concept of data integrity does not begin and end at the laboratory. It starts with the patient! It is important to establish a robust process to ensure that chain of identity and chain of custody are maintained. Regardless of the medium of the data (such as electronic, hybrid, or completely paper-based), the expectations are the same. Very often, equipment and associated software used during preclinical and early clinical studies do not meet the level of compliance required to meet all criteria defined in 21 CFR Part 11. However, prior to moving into later phase clinical studies, it is important to evaluate the applicability of such systems. It is recommended that investment is made based on future capabilities to avoid costly upgrades. For example, if there are options to buy systems that are “Investigational Use Only” or “Research Only” versus equipment that can be used with different versions of software with both “Research” and “21 CFR compliant” versions, choosing the second may be a wiser option. Although it may cost a little more at the beginning, there will be much less switching cost. Also, please remember that “GMP Ready” does not always mean fully GMP compliant.
4. A Robust Quality Culture
An area of the Quality System that is often overlooked is setting up a good quality culture. Having a robust culture can drive an organization from pre-clinical to commercial launch without major hiccups. For this, the presence of leadership is paramount. You can find more about Quality culture in a previous Lachman blog post here.
5. An Agile Quality System
Finally, combining all the points mentioned above, it is necessary to build a Quality System that is flexible, phase appropriate, and relevant at the time of use. While phase-appropriate CMC policy will define the level of compliance at each stage, it is also important to understand the expectations of the regulatory agencies. While the CFR is not often revised, guidance documents in which the FDA describes its current thinking and how the CFR is relevant in different areas are published routinely by the Agency.
As you can see, it is never too early to talk and think about GMP when it comes to producing pharmaceuticals. If you are at an early clinical stage and want to progress to the next stages or if you are thinking about submitting a BLA, feel free to contact us at lcs@lachmanconsultants.com for an evaluation or assistance.
