Good Advice: The Value of Outside Expertise

While high-profile CROs, CMOs, and CDMOs consolidate and grow, a cadre of individual consultants soldier on. Tablets & Capsules spoke with several of them about their work. They are Anthony Grenier, Ben Locwin, John McCarty, Chris Moreton, and Michael Tousey.

Many pharma companies have a good amount of in-house expertise, as do many CROs/CMOs/CDMOs. Where does your work fit in?

Grenier: My clients are experts in developing new molecules and making some promising early-stage clinical trials. But when it comes to scaling up and working in a full cGMP environment, they need strong guidance and to be put in the right hands. They need additional expertise to move to the next clinical stage, which is always crucial, but especially for one-product companies. 

In other cases, a virtual pharma company acquires latestage or legacy products from Big Pharma and are managed by executives in business development or finance. Even if they negotiated a great deal to acquire the assets, when it comes to finding the right partner to transfer their product they often end up dealing with a partner that is not a good fit for their market size or they’re not flexible enough to address their needs. Because I own my own business, I can respond quickly to clients and it’s easier to get on the same page so I can help with their project. 

Locwin: It helps to shake up the status quo, and we’re always prepared to confront the “sacred cows” of an organization. There are a great number of misconceptions about how business processes should look during research and development of candidate drug molecules, and about how development and trials must be performed. You don’t want to do things just because “We’ve always done it that way.” 

McCarty: IntraTAB is not a CRO/CMO. We’re a specialty pharma company with a drug delivery technology. I still do some consulting, but only on projects that will develop drug products for truly unmet clinical needs and that involve products that are a challenge to formulate. For example, currently I am consulting for a company in Israel that has a drug to treat mild cognitive impairment, for which there is currently no approved product. 

Moreton: My experience is as a formulation scientist. I’ve worked on projects at every stage from preclinical formulation, to transfer, to commercial manufacture, and not just with tablets and capsules. The ultimate objective is to launch a successful product, and I can see the bigger picture. I then translate that understanding into how I advise my clients. For example, there may be several ways of resolving an issue, and you have to know the best way forward to achieve an efficient development pathway. 

I work directly for my clients, and they can share information with me that they would not think to share with a CDMO. I also know what questions to ask. I’ve worked with CDMOs for a number of years, and their motivations don’t always align with the customer’s. I can act as a bridge between my client and the CDMO and reduce misunderstandings and missteps—lack of bioavailability, for example—that lead to failure and delay. It may take up to 2 years to get back on track, and return to clinical Phase 1 studies after an initial bioavailability failure. Most small pharma companies cannot survive such a setback because their financial backers will pull out.

Tousey: I was in sales and service and when I’d go to service a tablet press, the formula wouldn’t work. So I started understanding more about how products perform. Now I help people to improve all across the manufacturing process, not just at the machine. The companies that supply machines are spires of genius, but we cover a full range of equipment. We can put the puzzle pieces together. Otherwise, if you’re a manufacturing company, you’re really relying on islands of expertise from equipment suppliers. Customers have these great machines but the performance between them—the process—isn’t working as well as it could. Who is making the connection between all those operations? That’s a lot of what I’m doing. 

What type of work and projects are most rewarding? 

Grenier: The most rewarding projects are the ones where you apply your expertise to help a customer in a field you had never explored before. For example, I have a customer, a biopharmaceutical company, that is developing a bioprocess to produce a lyophilized product as the active ingredient. They have great bioprocessing engineers and can produce the active ingredient up to the early clinical stage. But when it came to making some capsules, they had no clue how. I assisted them by identifying the right equipment and partner to do the R&D, and then the transition to clinical. While I have a good background in solid dosage forms from working in the traditional pharmaceutical industry, I would never have dealt with the biotech world if I weren’t consulting. The beauty is that I learned a lot about how this live product is made and the way in which their process could impact the powder’s physical properties downstream. 

In another case, a customer turned to me after months of looking for a solution or a manufacturing partner, and I was able to help them. That made a difference; it actually resolved their sourcing issue. 

Locwin: It’s gratifying any time my work impacts how a healthcare or pharma company approaches their strategic offerings, how a brand reaches the market, its success with the public, and the numbers of effectively treated patients. Those are the important things. I do enjoy innovating behavioral marketing approaches in pharma and healthcare, where we can dramatically influence the public’s perception of healthcare treatments by how we approach the messaging and how we manage the data analysis of social media. 

McCarty: The most rewarding are projects that solve truly unmet medical needs, smoking cessation therapy, for example. Our sublingual nicotine tablet delivers nicotine rapidly, similar to cigarette smoking and vaping, with a time to maximum plasma concentration—Tmax—in the range of 5 to 14 minutes. About 443,000 people die prematurely every year from smoking or exposure to secondhand smoke, and another 8.6 million have serious illnesses caused by smoking. We spend almost $100 billion annually in the US on medical treatment of smoking-associated diseases and about the same—these are estimates— on lost productivity due to smoking. There is a lot of room for improvement with smoking cessation and healthier nicotine alternatives. Gums and lozenges have a Tmax in the range of 40 to 90 minutes, which does not satisfy nicotine cravings. Yet very few new NRTs—nicotine replacement therapies—have been introduced. We need a faster-acting NRT that resembles the nicotine pharmacokinetics that people get from smoking a cigarette, which our product does and is available for licensing worldwide. 

Moreton: I enjoy all formulation projects and formulation development work; problem solving, working with my clients to achieve a successful formulation, be it for clinical use or commercial use. From a professional development perspective, often the more rewarding projects are the more challenging ones because one learns so much more. For example, working through the interplay between formulation variables and analytical discrepancies can be very challenging. Other challenges include the development of dissolution tests for poorly water-soluble drug formulations. 

Tousey: I love seeing the lights go on. It’s one of the greatest things about doing training. I’ve had people stand up and ask “Why did I have to wait 10 years for someone to put all these pieces together for me? I get it now!” I also love solving a problem and solving it quickly. I don’t want to camp out at somebody’s manufacturing site. It’s very unusual for me not to have something wrapped up in a few days.

If you were king for a day, what changes would you like to see in how your clients operate?

Grenier: My role as a consultant is to adapt to my client’s reality and recommend a path forward. But it would help if companies—before outsourcing the development or manufacture of their product either commercially or clinically—would have the end in mind. Risk assessments should be performed diligently. Why offshore production for an immediate gain in the cost of goods if it results in a need to hire more people for quality or technical oversight? If that infrastructure is already in place that might work, but small pharma companies will face challenges with that model. 

Similarly, don’t allow a contractor to develop a nonviable process for your clinical needs, because that will have a severe impact later. It’s better to take a bit more time with the right CMO so your Phase 1 work can become a commercially viable process. You won’t need to change it after successful clinical trials. 

Locwin: I’d suggest W.E. Deming’s advice: “It’s not enough to do your best. You first need to learn what to do and then do your best.” 

McCarty: That’s a big topic. My pet peeve with CROs/CMOs is a data dump that includes no interpretation. As a client hiring a CRO/CMO, you should expect to receive experimental and/or processing data that shows they made at least some effort to provide an interpretation. 

Moreton: Understand the big picture. Typically, startups focus on first-in-human studies but they need to remember that they have to go on to a clinical Phase 2, etc., and without too much delay. Making decisions based on short-term expediency has led many companies to suffer delays because they have not planned adequately for the continuation of the project. 

We should also look at the rules governing how companies operate financially. The current rules mean that companies are too focused on the short term, whereas new drug development is a multi-year undertaking. Even generic drug development takes a couple of years. 

Tousey: What our industry needs most is tablet-grade ingredients. There are very few ingredients that are truly tablet-grade, and most manufacturers of tablets don’t understand what they need, so they’re not asking for the right thing. Another big misunderstanding is about the nature of tablet ingredients. Some people think if you’re only adding a half percent of this or a little bit of that, it shouldn’t really make a difference, but it does. That little extra colorant or a little different flavor alters the performance. 

People should also understand there is no such thing as a perfect blend. There are just too many variables. We can get within a certain range, yes, but that’s it, because we’re only using a volume and time approach. 

Anything else? 

Grenier: Companies must move products to market more efficiently in order to reduce their development and tech-transfer costs, not necessarily by offshoring but by working better. My clients are making more requests for cost reduction and efficient manufacturing processes. This will be achieved by doing things right, and if it’s not done right the first time, then at least minimize the waste of time and resources with better product and process understanding. QbD is one of the great ways to achieve it from early product development stages. 

Moreton: I believe we’re going to see progress in the oral delivery of peptide drugs. Nothing has moved beyond clinical phase 2 so far, and I think this will change. Doing so, however, will require independent approval of new chemical excipients by the FDA, i.e., the approval of the excipient would not be solely part of the drug product NDA approval. Progress has been slow.