Note: The views expressed in this article are those of the author and do not necessarily represent those of his/her employer, GxP Lifeline, its editor or MasterControl, Inc.
At last count, there have been approximately 35 submissions to FDA's CDER with full Quality by Design QbD packages covering all manufacturing operations. To date a few have been approved, notably Pfizer's own Chantix and Selzentry. In one case, the pre-approval inspection was waived and in the other, the inspection occurred but, as the company noted, there were no observations related to the QbD component of the submission. In both cases the concept of the design space was accepted, allowing the company to operate anywhere within this area without further regulatory approvals. Of course, the internal change control system would be used to assess and judge the change before the change could be implemented. So it appears that drug makers of small molecular weight drugs are off to a strong start, although it has taken quite a number of years to accomplish this.
Biologics or biotechnology drug manufacturers are clearly running behind with approximately six or so submissions of full QbD packages. To date, I am not aware of any full package having been approved. Why?
On analysis, there are two things that immediately surface. First, small molecular weight compounds have been more successful than larger molecular weight drugs. This is probably a reflection of the complexity of the manufacturing process for most biotech products where the number of unit operations is substantially larger than for most small molecular weight drugs. Thus, the development and data packages will be much more comprehensive and will take more effort to assemble and even to generate.
However, there is a second point to see in the data and that is that all the submissions and approvals, that I am aware of, have come from Big Pharma or Big Biotech. And why is this? There are two reasons that come to mind immediately.
The first is that the smaller companies (either biotech or drug) do not want to lead the initial charge. Any new endeavor is fraught with stops, starts, and restarts, so smaller companies, often short of cash and resources, do not want to be the pioneers. Their strategy might be to let the "big boys work out the pathways and we will follow along afterwards when the path is clear and less risky." They neither want to be on the cutting edge nor the bleeding edge. This suggestion appears quite logical and may explain the absence of the smaller companies in the initial sets of submissions. Clearly, if we wait a few years this hypothesis will be shown correct. Or perhaps wrong.
But is there another reason or answer?
The second reason is that perhaps QbD is not possible for the smaller companies. This has been suggested on several LinkedIn group discussions and has led to vigorous debate. And the logic goes:
To develop a full QbD package for submission requires a sophisticated development organization with infrastructure, including battalions of scientists with laboratory and pilot plant facilities and coffers of money to invest in understanding their products and processes at precisely the time when you do not even know if they work yet. This work must be completed at about time the Phase 3 process is being developed and that usually happens when you are in Phase 2 trials. Thus this investment is at a very risky time in development. Start too early and the product fails and you have thrown away a large investment. Leave it until you are sure and you will delay your submission. Even a delicate balance between these two competing factors will result in a huge investment prior to knowing the success of your drug candidate. This may be justifiable for Big Pharma and Biotech, with their large bottomless coffers (if they still exist). But what about the smaller companies?
Smaller companies are varied but are characterized by having very shallow coffers, often just enough to take that molecule through clinic. They also do not have huge development departments of process scientists and in some cases, rely on outsourced development. They also often do not have large pilot plants, if they have them at all, and often rely on contract manufacturers even for clinical manufacturing, let alone commercial operations. Some, in fact, are essentially virtual. Therefore it appears that they just do not have the resources, in their varied forms, to do the work.
So does this mean that smaller companies are being discriminated against and that they will not be able to compete against the Big Boys? The answer is, not necessarily.
While they do not have the same level of infrastructure, resources and money as their Big Brothers, some of the mid-sized ones do have pilot plants, labs and process scientists that should not be dismissed. These companies have two very valuable things that Big Pharma does not have.
The first is agility. I have worked at both large and small companies and have also consulted at these same types. The common element I see at smaller companies is the ability to make decisions rapidly and adjust to the changing environment. The counterparts at the larger companies tend to be restricted in the ingrained bureaucracy with multi-level decision-making necessary to operate. This agility allows these smaller companies to put a plan in place, begin execution and rapidly adjust as the conditions change—something their big counterparts are not able to do.
The second is risk appetite. In addition to my experience working and consulting at both types of companies, I have also worked on jointly-run projects where a small and a large company team up to bring a product to market. While I am sure the larger companies are bewildered at the apparent recklessness of small companies as they plan their trials, the smaller companies are often impatient at the slowness and lack of appetite for risk borne out by the larger. While I do not advocate reckless behaviour, even our regulators embrace Quality Risk Management (ICH Q9), so why not include it in your design for a QbD submission and even your development strategy?
Thus I contend that while the lack of resources, infrastructure, money and staff may be a challenge for the mid-sized development companies, it is offset by their agility and risk appetite. So all is not lost for them. They will have to carefully monitor their trials, continuously looking for signals that indicate the likelihood of failure for their prime candidate. That could be a safety signal that begins to show in Phase 2, exactly when mid-sized companies are beginning their full court press in development of the commercial process and QbD. In a similar fashion, they will have to be diligent to simultaneously look for efficacy signals. These sometimes are misleading or even absent, giving false senses of hope and despair. Agility and risk taking will aid them and counter balance the resources they do not possess.
What about the small or virtual companies? Is there any hope? Or are they doomed? Will this be too much of a burden?
Well obviously, I believe that all is not lost.
The larger of the small biotech companies described above have a business model that indicates they want to be the next Amgen or Genentech, so they plan to take their molecule to commercialization, and through various strategies and alliances, reap the rewards of the research endeavors. They want to be fully-integrated drug companies. For them, QbD is the wave of the future. I have several clients who are doing precisely this in their development programs and QbD implementation. However, they are being cautious.
For some, they may choose to not go the "whole hog" and do the "soup to nuts" QbD like Big Pharma. Small companies may pick certain unit operations that are more risky or that have more likelihood for post-approval improvements. For instance, the production reactor in a cell-based biotech product may be chosen to allow more flexibility to improve yield and hence plant productivity. They might also choose the first step in the purification chain to help deal with the increased productivity of the reactor. Small molecular weight drug developers may focus on the attributes of the active pharmaceutical ingredient needed for drug product formulations for problematic tabletting or coating operations for prolonged release formulations. There is nothing the regulatory guidance that indicates you have to do everything before approval. Once launched and revenues come pouring in, then you might backfill other steps as you determine their values. The product may never even reach completion.
What about the others? There is more than one business model out there. There are some companies that are truly research boutiques and there are others that want to get a little more from their research labors. Let's examine each with respect to QbD.
Model One - I am a research boutique. I develop research ideas, gather lab-based data and perhaps do some animal work to show efficacy and safety. I now sell my research to a bigger company for development. The company takes the research, develop it further, go to clinical trials and eventually commercialize it. The purchaser becomes the company that does the QbD. Clearly the product is purchased very early on before any process is developed for clinical research, so the research boutique need not worry about QbD. I have had several of these companies approach me to start QbD and I have persuaded them to think again. They are astonished that a consultant is recommending not to be hired.
Model Two - I am a developer of products that actually go into human research and then I sell them. I might even sell my company at this point and start over again. My business model calls for me to develop candidates, develop the preclinical data and submit an investigational new drug (IND) application. Then I start Phase 1 and even Phase 2. To do that I need to be able to make the product under GMP but I recognize that the process I use is not a commercial process or even one that can lead to a commercial process. It is a process to get into humans quickly. Even Big Pharma and Biotech use this strategy. So should I do a full-bore QbD development? Obviously not. Even if I think my process is good and able to be commercialized, any effort I put into QbD might not be value added.
Remember the purchaser is a conservative Big Biotech or Pharma that wants to do its own development work, including QbD. Even if I present the drug candidate with a process development and QbD package, we all know big companies will want to do it in-house. So they will likely pay for the development, IND, and initial clinical research in their valuation of the product. They will definitely undervalue the process development and QbD activity. For the best ROI, simply discover the molecular structure and indication, perform the preclinical to get into clinical and do the Phase 1 and 2 studies. Do not invest in advanced process work and QbD. In a similar fashion, I have advised these companies of this strategy and to perform the ROI calculations.
How do I determine the proper approach for prospective clients? Before I give them any answer, I do some research. I determine whether it is a Big Pharma or a smaller company. I ask what type of business model they are using. If it is to get research candidates and sell, I say don't worry about QbD. If they plan to get into trials and sell the product or company, I also say do not bother. For companies that want to become the next Amgen, I say use your agility and risk appetite to plan QbD. Don't do it all at once. Start by defining your tentative processes and then define your critical quality attributes (CQA's) at each unit operation. Some will be clear and others less clear. As the process gels, solidify these CQA's. Begin to define raw material requirements and then critical control points and control strategies. Choose which process steps you will do first and proceed. This will take you well into the development phase when you begin to create the interplay between these three elements. At that point, you are well on your way to developing your QbD package, full or abbreviated. Always keep your eyes on the clinical trial (Phase 2 - mostly unblinded) for the negative safety and efficacy signals to stop working and to save money.
Remember as a mid-sized company, you may not have the horsepower but you definitely have the maneuverability to challenge the Big Boys. For smaller companies, think before you act and do what makes sense for your business model. For the Big Boys, you are already off to a good start.
Peter Calcott, Ph.D., is president and CEO of Calcott Consulting, which is focused on delivering solutions to pharmaceutical and biotechnology companies in the areas of corporate strategy, supply chain, quality, clinical development, regulatory affairs, corporate compliance, and enterprise e-solutions. He is also an academic program developer for the University of California-Berkeley’s Biotechnology and Pharmaceutics Postgraduate Programs. Prior to this he was VP at PDL BioPharma where he was responsible for development and implementation of quality and compliance strategy across the corporation. Previous to that he was chief quality officer and led the quality and compliance function at Chiron and Immunex Corporations and was director of quality assurance for SmithKline Beecham and for Bayer for their biotechnology and biologics businesses. He has also held positions in research and development, regulatory affairs, process development, and manufacturing at other major pharmaceutical companies. He has successfully licensed products in the biologics, drugs, and device sectors on all six continents. Dr. Calcott holds a doctorate degree in microbial physiology and biochemistry from the University of Sussex in England and completed his post-doctoral work at McGill University in Montreal, Canada. Recently, he was chair of the regulatory affairs committee of BIO and presently serves on the board of BayBio, a biotechnology industry association in San Francisco. He has been a consultant for 17+ years to various governments, industries, and academic institutions during his career. Dr. Calcott has authored more than 80 original research papers, reviews, and books.