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A guest editorial from Emil Ciurczak, Contributing Editor, PharmaManufacturing.com

While reading a trade magazine recently, I was struck with the detailed information on how to design and implement a Corrective and Preventive Action (CAPA) system. ISO 9001:200, Clause 8.5.2 states, “…the organization shall take action to eliminate the cause of nonconformities encountered…” For medical devices, 21 CFR Part 820.100 states, “…each manufacturer shall establish and maintain procedures for implementing corrective and preventive action…” Similar wording appears in 21 CFR Part 211 for drug companies. Do we really need all these regulations to ensure we make the product as we are “supposed to” be making it?

Now, it strikes me as interesting that we still consider (under cGMP, of course) the NDA (New Drug Application) as “perfect” after all our trial, production-sized batches. What did you say? We only make three batches? But surely, numerous hours of physical and chemical design went into designing the product. And don’t forget how smoothly we went from pilot-size to production-size. What? A full-time staff of troubleshooters, you say? That many people are needed?

So, based on that information, we submit our “perfect” formulation and a plan of what to do when it fails to work. Hmmm…what’s wrong with this picture? An online source says, “Implementing corrective action and preventive action systems for FDA-regulated manufacturers is a necessity to guarantee quality and ensure compliance with Current Good Manufacturing Practices of the Quality System (QS) Regulations.” [1] Well, I’m just a humble country chemist, but (already with the “but”) if we did our homework and actually knew what we were doing, why do we need a corrective action plan?

I remember saying something recently about GMPs stating that relevant measurements should be taken during the process to ensure good product (back in the 1970s, even). I must have missed the part that said to run blindly until we go out of spec then do an investigation to find out why. From speaking with associates who routinely do OOS (Out Of Specification) investigations, there seem to be two categories of findings: the obvious (error in the lab, error in weighing in the plant) and the “como sabe (who knows?)” type, which leads to never knowing.

It is a fact that many, many lots of products simply go out of expiry in the warehouse, waiting for a cause of failure to be found. The problem with current production (under cGMP) is that if we do not know what the critical steps are, how can we find where the product made a wrong turn? We’re not even sure when the product makes a correct turn! We approach the production of pharmaceutical products much like using directions from MapQuest.com. Whether or not a bridge is out, we proceed down a road. Why? Because we went down that road for the first three NDA batches, that’s why.

PAT is the moral equivalent to using common sense: if we see that a bridge is out, we take a detour. In cGMP, we don’t look for the bridges; we simply say, “It worked last year, so let’s keep driving…we’re covered by cGMPs (read: SOPs).” Check the particle size of the raw materials? Wasn’t in the filing; forget about it. What about polymorphism? Nope, wasn’t in the document specifications 10 years ago. How about flowability, compactability, pore size or density? Nope, nope, nope and nope. I guess it’s much easier to conduct several (dozen?) OOS investigations each year than understand the process. [I have a button that states, "Several months in the lab can save an hour in the library." Not exactly the same, but close.]

Now, please don’t misconstrue what I am saying. There is no reason not to have a plan, should some disaster strike a production run. Not having such a plan would be akin to leaving your house without insurance. However, to stretch a comparison, that doesn’t mean you can leave a pot on the stove and go to the store. Having a “disaster drill” and “evacuation plan” doesn’t mean not taking all precautions to prevent the disaster.

Assuming that because a product ran smoothly three times in a row (possibly years ago), it is not necessary to keep a vigilant watch on all current incoming materials and process parameters is the ultimate fantasy (yes, even including that website). Under the “traditional” way of manufacturing, using the “three strikes, er, uh, batches and you’re out” approach, it is impossible to do business without a well-thought-out CAPA in place.

What I am saying is that the idea of a CAPA has to morph into something new under the QbD and PAT manufacturing paradigms. In lieu of a change-control based approach, designed to find the problem with a single batch (“Round up the usual suspects”), we will have an ongoing CAPA, using “design space” mini-adjustments throughout the process. Since I already used a driving analogy, I’ll try another: current CAPA documents wait until we go up a curb, then we try to find where we hit a pothole to make us lose control. Using a PAT set-up, we monitor the road constantly and avoid the potholes before we hit the curb.

All we are saying is give PAT a chance… (apologies to John Lennon). We can’t do it sort of, part way, keeping some elements of the process static and changing others. That’s like being “partially pregnant.” DO IT!


Reference

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Guest content from John Avellanet, managing director of Cerulean Associates:

As professionals affiliated with the biotechnology industry, we often forget that many of the struggles faced today have been solved before by other fields and industries. As Ambrose Bierce wrote, “There is nothing new under the sun, but there are lots of old things we don’t know.” The question is, where to look for inspiration?

In the 1970’s, the global automobile industry faced a huge push by consumers and regulators to improve quality and safety. Manufacturing costs skyrocketed. At the same time, up went oil prices, adding a third dimension to the problem: how to improve the fuel efficiency of cars while also improving safety and quality?

There were many strategies to tackle this complex problem (Total Quality Management, for instance), but Toyota found, and was the first to capitalize on, a simple, effective answer: following the Japanese principle of kaizen, continuous improvement, to its logical beginnings, Toyota management and engineers found that the sooner quality and safety were built into the process, the more costs declined. In fact, building quality, safety and efficacy into the product at the early concept, design stage was the most cost-efficient (here I use “efficacy” to capture the concept of fuel efficiency, but also features, passenger room and so forth). This then freed them to play with and innovate on the remaining elements such as style, handling and so on.

Admittedly, the days of the Corolla were numbered, but those early attempts provided Toyota the funding and marketplace stature to build today’s Lexus. In fact, the items that most executives at the time argued were massive hurdles for the industry – quality, safety, efficacy – are now bandied about as competitive qualities. Volvo does not make the most beautiful of cars, but surveys of Volvo owners repeatedly point out the top three answers for why they purchased the Volvo over all other options: safety, followed by efficacy and quality.

In my work helping executives at biotechnology, pharmaceutical and life science firms, I often hear attempts to rationalize away such a comparison with “Yes, but we are talking about hundreds of potential compounds in the early preclinical stage, so that’s not really applicable.” Yet automakers today routinely develop hundreds of concept cars and frequently go on to build many more prototype cars for road testing than any biotech or pharmaceutical firm has new treatments in clinical trials. In fact, the cars you and I will be able to buy seven to ten years from now are currently being tested (along with others that won’t make it) on raceways and simulated town streets and rainstorms right now in Michigan, North Carolina, Japan, Germany and so forth.

Lessons and analogies from other fields and industries can help us reframe the compliance challenges we face and point to ways to reduce costs, boost innovation and improve market success. Ultimately, the biotechnology and pharmaceutical firms that take the most advantage of these will be the ones dominating the industry 25 years from now.

If you’d like to read further examples and applications that might be more suited to the situation you face, I’ve made a number of my published articles available as PDF downloads in the Resource Library of Cerulean Associates.

I welcome your comments, suggestions or questions. Please feel free to contact me at any of the points either on the Cerulean Associates website or within my articles.

I look forward to talking with you.

john