
Before the stage is set and the curtain rises for a debut performance, the time-consuming process of putting together a Broadway show is the perfect analogy used by Jim Mencel, Senior Drug Substance Consultant at Design Space InPharmatics, to describe process validation for Active Pharmaceutical Ingredients (APIs) when preparing for filing with the FDA. The pathway by which API manufacturing processes are readied for commercial use comes to its apex with a series of integrative process evaluations at near commercial scale, which aid in ensuring that the process is robust, reproducible, and ready for “opening night” – process validation, and “prime time” – continuous manufacturing of commercial supply. As for a Broadway troop preparing for a stage play on opening night and continuing performances, the chemical development team must always think about preparing for process validation and eventual commercial manufacturing. Later phase API manufacturing should look and feel increasingly like the anticipated commercial process. This includes determining where key materials will come from and what their quality must be, much like ensuring that a certain piano will always be there and in tune for each performance.
From Dress Rehearsal…
The three common process evaluation events toward getting the API manufacturing process ready for commercial launch are the campaigns to prepare registration, engineering, and validation batches. API process validation takes place in the late phase of clinical development, where all eyes are on the performance of the manufacturing process and on the quality of each intermediate and of the final API. Regulatory approval of the registration filings is impacted by the success of this endeavor. A first formal scale up evaluation of the intended manufacturing process may be the “registration batches” program. This segment of process evaluation generates material for formal stability testing required for the registration filing, by what must be considered as the intended commercial process. This is likened to an informal “dress rehearsal” in Mencel’s analogy. This evaluation is ideally performed at or near anticipated commercial scale, in the intended commercial equipment at the site where commercial manufacturing will occur.
In the Broadway analogy, this is when the positioning of the cast and props, appropriateness, effectiveness, practicality and safety of costumes and special effects, the sound, lighting, balance between the performers and the orchestra, and the general flow of the production are evaluated and adjusted “behind closed doors” at the actual performance venue. This would be a full live production of the intended stage play. Hic-ups are allowed but must be rooted out going forward. There is never “behind closed doors” for FDA in GMP manufacturing; however, they accept the need for necessary adjustments to the process during the registration batches while expecting them to be representative of the intended commercial process.
After the registration batch experience, the team will usually convene a “post-action review” to discuss how things went and identify aspects of the process that may need better understanding or definition. Separately, quality process risk assessments and lab evaluations will have been underway to identify process parameters for each chemical step that impact quality, and to determine limits within which to operate. Sources and critical quality requirements for materials will be confirmed.
In most environments, the adjustments made in the plant during the registration batches, any follow-up revisions arising from the post-action review, any final safety adjustments, as well as the fully defined processing parameters will be evaluated one last time in a set of “engineering batches”. These batches should represent not the intended but the actual commercial process. If they have been run according to the final, formalized chemical process as described in the registration filing, they may be eventually used commercially. In a stage play analogy, this is the formal dress rehearsal, perhaps in front of a friendly test audience, with all adjustments to the performance in place, now anticipating this form of the production to be the opening night version. All ques, props, music, effects and movement must be coordinated and work together flawlessly. “As in practice, so in performance”. For the chemical process, all materials controls, physical controls, process parameters, analytical controls, and all elements of batch execution must work together to render acceptable API with minimal “hic-ups”. The regulatory affairs group, quality unit, and commercial group are the “test audience”. Was the production run as agreed and intended? Did the production work? Were there too many hic-ups? Are we ready for opening night?
…To Opening Night
The registration and engineering batches should instill confidence that the process is understood, parameters are correctly defined, analytical controls are reliable and effective, the process is safe, equipment and chemistry are well matched, and key outcomes are predictable. Here, the dress rehearsal phase is concluded and the production moves to opening night in front of a live audience of “critics”. This final process evaluation is “process validation”, also called “process performance qualification”. At this point, the process needs to be “frozen”, with no further major adjustments necessary. While FDA may choose to review any GMP manufacturing that occurs during the program, there is an understood, open invitation – and expectation – for them to intensively review the validation program. Dr. Mencel states, “Validation is very formal. Validation really, in a stage analogy, is Opening Night. This is where the critics are all present, everybody’s breathing on you, you’re going to be in the headlines the next day, and everything needs to go…”
For validation batches, the team writes a general validation protocol, as a sort of performance program, and separate protocols for every step of the process that indicate how each will be run and predict key outcomes. This can be daunting, as it is almost as if you need to predict the future. Even more daunting, the protocol is made available to the “critics” to review along with performance and the team is saying, “Here is the play and our lines – did we get it all exactly right?” This is where the confidence needs to come in from running the registration and engineering batches and practicing the lessons from the dress rehearsals. Opening night for a chemical process being debuted in validation generally involves multiple successive runs of each step of the process. Each run must be a success, and critics’ reviews of the production will entail every batch run as part of the validation. There are two key groups of “critics” in this analogy. The quality unit will intensively monitor every aspect of the production in real-time against the protocol and regulatory quality requirements. Unlike a stage performance, one key body of critics, the FDA, and other regional regulatory authorities generally review the production after the fact using the protocols and written manufacturing records and reports to verify that the process was run as designed, that all controls were implemented, effective and satisfied, and that final product met all quality requirements for all batches prepared in the validation. Validation is when all the facets of production come together, from suppliers, process, controls, equipment, and final product. Finally, all the hard work forms the masterpiece when opening night debuts for a Broadway show.
Stepping Into The Spotlight: Early Filing
For promising new drugs that meet specific criteria, the FDA has programs that allow for registration filings based on a more limited clinical data set. This subject is its own topic, but pertinent to the current topic, CMC groups can be required to undertake process validation far earlier than usual.
The CMC group cannot skip steps but rather needs to reach stages of readiness more quickly than normal. For the CMC group, this can feel like being pushed under the spotlight before everything has been perfected or before the performers have fully memorized their lines. Quality expectations for the CMC component of the filing are not reduced in such programs. What may often be compromised as development time is prioritized toward process control and ensuring safety and quality is process efficiency. There may likely be far fewer plant batches of each stage by the intended commercial process than would be preferred to gain experience and comfort. Nonetheless, an alert CMC team must glean all that can be learned from every production batch to develop confidence in the process as it is readied for the required scale of operation.
Dr. Mencel explains that expedited filing is a relatively recent thing in the United States and that it will be interesting to see how this will play out. For such rapid programs, communication is key within the CMC team, and as needed, with the regulatory agencies who will review the registration filing. It helps to identify issues and needed changes as far in advance as possible. Whether a corporation decides on early filing or not, multi-discipline support and interaction are integral to the readiness to undertake process validation and commercial API manufacturing. When an early filing is the intention, some ad-libbing may be needed and allowed to close the intended plan and script as the production is honed in real-time, but for CMC, “the show must go on”.