Process performance qualification pitfalls, and how to avoid them
For just a moment, let’s imagine we remove our pharma engineering hats and slip into running shoes. Let’s swap out our dedication to drug development and manufacturing and replace it for weeks, months and even years of physical training all for one goal: completing a marathon.
To say you’ve put in the work is an understatement. Long hours in the gym, longer hours on the track. Trading pizza for protein shakes and carrot cake for, well, carrots. Running through pain, rain and strains to gain that extra advantage on the lengthy, 26.2-mile road to a remarkable physical feat. Rounding the final corner, the checkered banner of the finish line comes into view. What a welcome sight.
So welcome that you stare into the distance long enough to veer off the roadway and headfirst into a lamppost. Goodbye marathon, hello hospital. OK, pharma development hats back on. In our neck of the woods, such snatching of defeat from the jaws of victory closely resembles a drug development journey that travels great distances before stalling out in the process performance qualification (PPQ) stage.
Up to that point, the drug project has passed several key milestones. For new small molecules and biologics, rigorous multi-phase clinical trials are wrapping up. For abbreviated new drug applications (ANDAs), a complex reverse engineering process has led to a generic product that stands up to its brand name big brother. Everything seems ready for the final push to commercialization, the crossed T’s and dotted I’s of a resource-rich project years in the making.
And then it isn’t. And worse, the reasons were, like that lamppost, entirely avoidable. Let’s explore a few case studies where the path to commercialization took unfortunate detours at the least tenable time: the final runup to approval and launch. In the process, we’ll discuss best practices that can help keep drug approvals on course for the winner’s circle.
Case study #1: Too generic
Our first example is a hard lesson in being hyper-selective and detail-oriented when it comes to both vendors and processes. Specifics matter, and a lack of them can lead to a formulation recipe for disaster.
In this case, the project originated several years ago and involves the ANDA regulatory pathway. This segment typically comprises generic drug development, and carries inherent benefits and drawbacks. On the plus side, ANDAs almost always have a pre-approved predecessor: a brand name drug whose safety and efficacy have already passed regulatory muster. However, since these original brand name drugs often involve exclusive APIs and other substances, at least some degree of reverse engineering is typically required to develop an optimized formulation and process.
With ANDAs, then, it stands to reason that among the most crucial aspects of formulation development is drug substance sourcing. In this case, as in most, the brand name manufacturer had an exclusive relationship with its API supplier, so an alternate source was required. Ultimately, the vendor chosen by the generics company underwhelmed — to put it kindly — and these shortcomings didn’t come to light until well after the process had moved forward along the pre-commercialization pipeline.
Highlighters out, because this scenario showcases a pre-commercialization must: proper, thorough supply chain and raw material risk assessments. Part and parcel to a comprehensive drug development process is designing a robust validation strategy that considers a product’s critical quality attributes (CQAs) — those properties that must be controlled within a certain range to ensure a product meets a set of predetermined standards.
Unfortunately, the issues with this project stretched well beyond the drug substance supply chain. Indeed, neither the product properties nor the production process was well-defined, two factors that sit atop a “problem tree” and can branch out to cause any number of unforeseen, unwanted issues.
Simply put, in pharma development and manufacturing a dearth of adequate critical process parameters (CPPs) is a fatal dose of failure. Without a thorough checklist of attributes that must be known, honed and reliably repeatable, something is bound to go awry. Take, for example, a drug produced in liquid form and subsequently lyophilized for its distribution journey. If a manufacturer doesn’t have a clear idea of optimal mixing times, the liquid product is likely to suffer; from there, without a knowledge base about hold time limitations (the critical period between the product’s production and its filling, sealing and lyophilization) then the product’s efficacy or even safety may be adversely affected.
Any number of these shortcomings can lead to a drug submission not meeting contemporary regulatory requirements, including those pertaining to the Manual of Policies and Procedures (MAPP), a collection of directives and internal procedures insisted upon by the FDA’s Center for Drug Evaluation and Research (CDER). To stay in the lyophilized lane, one issue can revolve around conformity to concentration requirements, since such drugs are typically diluted prior to the freeze-drying process. In this case, the result was predictable: the initial drug submission was confronted with numerous information requests and complete response letters (CRLs), chiefly due to concerns about overall product quality. The time and resources lost were considerable — and avoidable.
Case study #2: Details matter
Our second scenario involves a Biologics License Application (BLA) that was initiated several years ago. As with the ANDA project, unforced errors led to CRLs along with several questions from regulatory authorities about drug product manufacturing.
Developing and manufacturing any pharmaceutical product is a delicate, multistep dance, but producing biologics medicines is especially exacting. Some of the pitfalls in this project mirrored those in the first example, including a lack of sufficient mixing studies to satisfy regulatory requirements.
Others were specific to the next-level challenges posed by sterile injectables; in this category, the project’s setbacks included incomplete filter validation, a reporting gap that can call into question a biologic’s mission-critical sterility. For understandable reasons, a biologic product’s sterility must be both assured and provable, and any inadequacies concerning filter validation process will not be overlooked by the discerning eyes of regulatory officials.
Again, the process starts crashing through branches on the “problem tree.” As with the ANDA example, the BLA project suffered from ill-defined in-process controls (IPCs), with CPPs that were not understood in sufficient depth to satisfactorily produce the formulation in a consistently predictable fashion. A shortage of so-called micro-validations — including reinforcing the drug’s fine print attributes, such as endotoxin methods — completed the incomplete picture.
The simple truth was that the process hadn’t been completely thought through. And the truth hurt far more than feelings: the litany of issues wasn’t discovered until after the initial PPQ batches, leading to sunk costs for both precious API and valuable partner engagement time and infrastructure usage.
These case histories highlight just a few of the disheartening detours that can occur along a drug’s pathway to commercialization during the PPQ stages. Depending on the regulatory category, these stages may comprise activities occurring after Phase III clinical trials but before full market readiness. Other PPQ pitfalls can arise stemming from insufficient or incomplete communications with regulatory agencies regarding a product’s expectations, or not conducting detailed risk assessments and corresponding remediation plans. And of course, none of the above matters unless both the pharma company and its selected CDMO are fully prepared to handle one of drug approval’s final hurdles: on-site inspections.
Adhering to a tried-and-true set best practices during the PPQ stage can prevent a drug approval from stalling out on the final lap. For starters, you should seek to establish an ironclad protocol for commercial supply agreements that sets clear parameters for drug substance continuity and, most importantly, quality. Only with the proper product ingredients in hand can a manufacturer make informed decisions on the next step: finalizing CQAs and, relatedly, a buttoned-up process failure mode and effects analysis (PFMEA).
Next, stick the landing on a final process validation campaign. Such a systematic procedure is crucial to ensure a manufacturing process can consistently produce quality products. Subsets of this step include drug product stability registration, continuous process verification and, furthest downstream, packaging and shipping validation.
Collaboration is key
The final item in our best practices collection should be bolded, capped and scrawled across the top of the checklist for any pharma company engaging a contract development and manufacturing organization: COLLABORATE WITH YOUR CDMO.
In the end, what your CDMO doesn’t know can hurt you even more than a faceplant into a lamppost. The due diligence that you undertake when selecting the right CDMO takes outsized effort; the process should, at least, consider prior experience with similar formulations, the ability to support both short- and long-term needs, depth of development capabilities and, per our purview here, process for onboarding new products and assisting with regulatory submissions. Now, put that sound decision to hard work.
Above all, this means bringing that CDMO as fully into the process as possible. Details matter. In the marathon that is drug development, approval and commercialization, there’s no ribbon for a second-place finish.
