The time-consuming process of a Broadway show’s production can serve as a useful analogy for process validation for Active Pharmaceutical Ingredients (APIs) when making preparations for filing with the Food and Drug Administration (FDA), says Jim Mencel, Senior Drug Substance Consultant at Design Space InPharmatics.
Image Credit: DSI, a PLG Company
The track by which API manufacturing processes are prepared for commercial use is comparable to overlapping integrative process evaluations at commercial scale. This ensures the process is reproducible, robust and ready for process validation and the manufacturing of commercial supply.
Like a Broadway cast preparing for opening night, chemical development teams should consider preparing for process validation and commercial manufacturing. Late-phase API manufacturing should be similar to and feel like the final commercial process. This includes establishing the sourcing of critical materials and what their quality must be.
Preparing the API Manufacturing Process for Launch
API process validation occurs in the late phases of clinical development, where the focus is on the performance of the manufacturing process and the quality of each intermediate and final API. Three frequently employed process evaluation events that prepare the API manufacturing process for commercial launch include the campaigns to prepare registration, engineering and validation batches.
An initial formal scale-up evaluation of the planned manufacturing process may be considered the registration batches program. This portion of process evaluation creates material for the necessary formal stability testing needed for the registration filing, which will eventually be considered the intended commercial process. This evaluation is ideally conducted close to commercial scale using the requisite commercial equipment at a site where commercial manufacturing will take place.
The FDA makes allowances for necessary adjustments to the process during the GMP manufacturing production of registration batches while expecting them to be wholly representative of the final commercial process. After the registration batch experience, the team will usually conduct a post-action review to determine how the process ran and identify specific aspects that may need to be further defined.
Quality process risk assessments and lab evaluations will have been underway separately to determine process parameters for each chemical step influencing the final quality and to set limits within which to operate. Sources and critical quality requirements for materials will be confirmed.
In the majority of environments, there will be a final evaluation of any adjustments implemented in the plant during the registration batches, follow-up revisions arising from the post-action review, and final safety adjustments as well as the fully defined processing parameters. These final evaluations are known as “engineering batches."
These batches should be fully representative of the commercial process. If they have been conducted in line with the final, formalized chemical process as detailed in the registration filing, they may eventually be used commercially. This is the formal dress rehearsal that takes place in front of a test audience. Regarding the chemical process, all physical controls, controls of materials, process parameters, analytical controls, and elements of batch execution must work synchronously to ensure acceptable API with minimal errors. The regulatory affairs group, quality unit, and commercial group can be considered the test audience.
Process Validation
The registration and engineering batches should instill the confidence that the process is safe and understood, parameters are defined correctly, analytical controls are effective and reliable, equipment and chemistry are well matched, and key outcomes can be easily predicted.
The final evaluation of the process is known as “process validation," also called “process performance qualification." While the FDA may review any GMP manufacturing that takes place throughout the program, there is an understanding and expectation that an open invitation is in place for them to review the validation program intensively.
For validation batches, the team determines a validation protocol as a general performance program and individual protocols for each step of the process that signifies how each will run and predict any key outcomes. This can be intimidating, as you need enough foresight to predict the future.
The protocol made available to the critics to review along with performance and the team can also be intimidating. Confidence in the process should be drawn from running the registration and engineering batches and reviewing the lessons learned during dress rehearsals. There are generally multiple successive runs of each step of the process involved when it comes to “opening night" for a chemical process showcased in validation. Each run must be successful, and the critics’ reviews of the product will cover every batch run as part of the validation. There are two primary groups of critics in this analogy.
The quality unit will track and assess every aspect of the production intensively in real-time against the protocol and regulatory quality requirements. The FDA, and any additional regional regulatory authorities typically review the production retroactively using the protocols and written manufacturing records and reports to validate that the process was run as intended, that all appropriate controls were implemented, effective, and satisfied, and that final product fell in line with all the quality requirements for all batches prepared during validation.
Validation occurs when each component of the production process comes together as planned, from suppliers, equipment, process, controls, and final product.
Step Into the Spotlight: Early Filing with the FDA
The FDA has programs that faciliate registration filings based on a limited clinical data set for promising new drugs that meet a series of distinct criteria. Relative to the topic in hand, CMC groups may be necessary to conduct process validation earlier than usual. The CMC group cannot skip steps but instead needs to reach stages of readiness at a rate faster than normal.
Quality expectations for the CMC component remain just as stringent in such programs. Therefore, development time may be handed over and prioritized toward process control to ensure safety and quality. There may likely be a reduced number of plant batches of each stage by the commercial process as would be preferably intended to gain experience and comfort. Alert CMC teams must be ready to adapt to learnings from each production batch to instill confidence in preparation for scaling the operation.
Expedited filing is a relatively recent occurence in the United States and how this will play out in the future has yet to be determined. For such rapid programs, the most important factor is communication across the CMC team and with the regulatory agencies who will review the registration filing as necessary. Whether a corporation decides on early filing, multi-discipline support and interaction are vital to the preparedness to engage with process validation and commercial API manufacturing.
When the intention is to submit an early filing, some ad-libbing may be required to close the intended plan and script, but for CMC, “the show must go on."
About DS InPharmatics 
DS InPharmatics (DSI) provides regulatory, technical, and project management consulting services to healthcare product companies that manufacture and/or market pharmaceuticals, biopharmaceuticals, and cellular and gene therapy products.
Since 2007 we have provided our clients with innovative strategies and exceptional quality work products intended to enhance product development, approval, and marketing presence. Whether advocating CMC strategy, directing CMC operations or developing CMC submission content that represent the best interests of emerging biotech, we focus on the critical CMC issues and build programs that enhance development.
In April 2021 we were thrilled to announce that DSI has just become part of ProductLife Group.
French-headquartered ProductLife Group (PLG) is well-known in the Life Sciences market. It has a track record of successfully managing global outsourcing programs and insourcing services for its international client base. The company is on a mission to help transform human health outcomes by optimizing regulatory affairs, safety & vigilance, and quality compliance for life sciences organizations worldwide.
The fit between our two organizations could not be more perfect. We will complement PLG's growing biotech services portfolio. US biotech sponsors recognize DSI as a leader in consulting for go-to-market strategies and RA pre-market consulting. At the same time, PLG has a strong reputation for managing end-to-end outsourcing of regulatory affairs and pharmacovigilance activities worldwide.
Our merger with PLG will harness our combined strengths, offering our clients on both sides of the Atlantic support with their developed drugs approvals and post-approvals compliance, plus advisory services on the best market strategies to deliver a rapid ROI on their development. Together we will offer our clients increased pharmacovigilance capabilities - including a QPPV; pharmacovigilance consulting; and a fully validated safety database - as well as complementary toxicology-related services; RIM/electronic document management services; and support for medical device regulatory requirements.
We see enormous potential in this new chapter for DSI and you, our clients. As a PLG company, we have the opportunity to become part of a global force in life sciences regulatory and compliance solutions and services, and we're incredibly excited to add our momentum to that effort.
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