By Louis Garguilo, Chief Editor, Outsourced Pharma
Our industry is science-driven and technical, and we are overall a society of specialists. No one can understand in detail all that makes up the development, manufacturing, and commercialization of a specific drug.
At the same time, possessing the inquisitive qualities of the scientist and engineer, most of us also have an interest, to the extent possible and time permitting, in learning more about segments outside our expertise. In a sense, this is a self-validation of who we are as individuals that collectively make up the pharmaceutical industry.
In terms of individual careers — and despite a continuing trend overall toward specialization — I’d suggest that those most inquisitive about both their internal and external realms climb the highest. When we do venture into the science and technology, business strategies, tactics, and various challenges beyond our expertise and throughout the industry, we often find similarities with our own fields.
One of these (rather amusing) similarities is that the “experts” aren’t all that confident about the details of their own field. This can be experienced when wandering into another realm of validation, that of drug development processes, drug substance, and product. Here we encounter a field full of debate, some moving pieces, and comments such as, “It’s up for interpretation.” Perhaps the first thing we encounter is a realization that the FDA has simultaneously laid both a heavy and light hand on the shoulder of the validation professional. In other words, it’s “follow the guidelines” but elucidate case-by-case. Let’s try to validate how it’s working out.
GUIDANCE FOR THE JOURNEY OF DISCOVERY
Even if we who know little about process and product validation, if put in a room with such experts, we’d expect to hear (mind-bending) quality statistics, experience table-thumping analytical fortitude, and see charts, graphs, and schema of exacting science and statement. And indeed often within their meetings, you do get all of that. But we’d also get an earful of comments like “It’s up to interpretation,” “That depends,” and my favorite, “Do we need to follow the guidance?”
With no malicious intent — it all stems from a lack of knowledge on my part — but these experts of expected exactitude can sound more like weathermen predicting the veracity of the prevailing winds. The forecasts are currently centered around a piece of FDA advice entitled, “Guidance for Industry/ Process Validation: General Principles and Practices.” Like the larger world of cGMP, documents drive discussion that leads to actual implementation. What adds to the “popularity” of this current document — first published in January 2011 — is the fact it’s an updated version of the original guidance on the subject … issued in May of 1987. (For the record, I was still in Mt. Carmel Elementary School.)
The document states: “Since then [May 1987], we’ve obtained additional experience through our regulatory oversight that allows us to update our recommendations to industry on this topic.” That’s just shy of 30 years of accrued knowledge to update! Now multiply that by hundreds of drug manufacturers working with hundreds of CMOs to make sure we’re all up to speed. Add that the guidance “aligns process validation activities with a product life cycle concept and with existing FDA guidance, including the FDA/International Conference on Harmonisation (ICH) guidances for industry, Q8(R2) Pharmaceutical Development, Q9 Quality Risk Management, and Q10 Pharmaceutical Quality System,” and we’ve entered into an interesting warp of pharmaceutical space and time.
A VALID VALIDATION INTERPRETATION?
Continuing our “travel” into this new realm, we can capture (with validated equipment, of course) discussions such as these (which take place at locations such as Outsourced Pharma Conferences).
Q: Interwoven within the guidelines from the FDA on process validation — now five years old — and the progression from Phase 1 to Phase 2 are concepts and approaches for technology transfer. How do these process validation guidelines apply and how often are they incorporated into a tech transfer to a CMO?
A: It very much depends on who the customer is. If it’s a virtual customer, with one person tasked with this activity, such as what I’m currently doing at my company, there aren’t subject matter experts. You’re relying on the CMO to be doing most of the work on implementing the proper validation protocols. For this type of sponsor, it helps substantially to maintain the same CMO, as long as they have a proven track record, when moving your compound from Phase 1 to 2, and even more so from Phase 2 to 3.
"The FDA has simultaneously laid both a heavy and light hand on the shoulder of the validation professional."
A: Conversely, if you’re a large pharma with strong technical support and subject matter experts, it’ll probably work much differently. You’ll be prescriptive about what you want and drive protocols. So from a validation perspective, there will be less of an issue if the decision is to change CMOs between stages.
Q: If I understand your answers correctly, it depends upon the customer and it depends upon the company size when deciding process validation. Is that to say that throughout the industry we’re not uniformly implementing the FDA guidelines for validation?
A: Well, you could ask the same question about GMPs. There’s not a checklist saying, “This is exactly what I need to do.” It’s following the intent of what’s being asked for. You should be able to prove that intent to the FDA. For example, there are four or five different ways you could do a careful, low-risk and high-work maintenance validation, with strong documentation and an intensive experimental scale-down/ scale-up process for a compound … or you can do the bare minimum to conserve early funds as interpreted within FDA guidelines, as long as you are in discussions with the FDA as to what you are doing and your objectives.
A: If it’s a product expected to progress very quickly, perhaps meeting unmet medical needs, from the side of the FDA, it would probably move faster through process validation than if it’s a follow-on biologic. Although the standards for validation aren’t relaxed by inspectors, the extent of testing and monitoring may be reduced. If a company has a fast track, and they’re willing to take higher risk, they’re probably going to minimize the work versus a company with a low-risk tolerance that needs everything to happen right the first time. Yes, to answer your question, there is a high level of variability on how process validation is done and can be approved by the regulatory bodies.
A: Agreed. You’ll get six different answers, if you ask that question of six different people. Obviously we all know this, but particularly nowadays, you should start your interactions with the regulators as early as possible. Chances are they will have requested some additional characterization of your product and process at some stage during the development of your molecule anyway. And you definitely should have your CMOs involved in all of this.
A: I think many find that this type of coordination and interaction actually leads to pleasant surprises. There are some flexibilities that the agency will provide. They’re not going to be very liberal, so to speak, but on some points, depending on the data that you have and can generate, you could propose certain strategies, which include a very high level of product characterization, to make the agency comfortable.
A: We just went through that. We were actually very happy in terms of the discussions we had with the regulators. We were trying to utilize two different sites as part of the commercialization process. One was at a CMO where we had done all the clinical fills, and then the other was an internal site for full commercialization production. The discussions with the agency on the strategies for validation actually ended up being very good.
THE VALIDITY OF IT ALL
To bring us back from this journey of validation, and in case you are looking for some firmer ground to again stand on, we can end with a more direct interpretation of the state of this field.
A: Validation guidances are near and dear to me. I practically sleep with this FDA document under my pillow. It’s five years old now, and in many meetings and discussions with the FDA, I’ve learned the agency indeed takes it for granted that the industry has already fully adopted at least this new validation paradigm.
A: So much so, that a lot of the FDA’s focus has already moved on to the quality metrics side of the equation. I’ve been in quite a few discussions with sponsors, CMOs, and the FDA, and the question often comes up, “Is this process validation really required or is this just a recommendation?”
A: Well, if you just read the opening pages of the new quality metrics draft guidance, the authors make it quite clear that they view the process validation paradigm as a requirement. It’s an aspect of GMP. I’ve been surprised by what a strong stand they’ve taken. Frankly, I like seeing that. I think it makes good business sense that sponsors and CMOs look at it as more than just a compliance requirement. I do not think it’s optional to adopt the new validation guidance.
So there. Perhaps it is a more “settled science.” Now it’s back to the actual document for more interpretation. At least for some of us. Best wishes.