Four Keys to Optimizing Process Research

Posted: September 8, 2020

API Manufacturing and Pharmaceutical Manufacturing

Developing new chemistry for tomorrow’s drugs, nutraceuticals or combination products can be far more efficient and lighter on the budget if your CDMO has the following important attributes:

  1. A top-notch R&D team
  2. A well-equipped facility
  3. Relationships that can be leveraged
  4. A commitment to continuous optimization

This article will elaborate on the role each of these plays in choosing and working with a CDMO for your API development and manufacturing programs.

TECH TRANSFER
  1. A top-notch R&D team can make or break a project
    A CDMO’s R&D team is its most valuable asset—and the most important differentiator among CDMOs.  There is no question that having access to a strong team saves sponsors a great deal of time and money.  It can make the difference between a project’s success and failure. Here’s why. 

    As sponsors know, developing new chemistry to create a novel API is a challenging, complex undertaking.  Problems can and often do crop up every step of the way.  Moving a project forward requires that any and all problems—an unanticipated impurity or a lower than expected yield, for example—be resolved before advancing to the next step.  Resolving such issues with minimum delay to a project’s timeline requires the strong problem-solving skills of an experienced, knowledgeable team.  It’s akin to the difference between having an amateur or novice cook preparing a meal vs. a chef at a Michelin 3-star restaurant.  The amateur will be easily confounded by something as simple as a missing ingredient or not knowing how to adjust for the impact of high humidity, whereas the seasoned chef will have a bag of tricks to create a meal that pleases even the most discerning diner, no matter what obstacle presents itself during food preparation. 

    What constitutes a strong team? It’s one that’s experienced, creative, motivated and accustomed to dealing with challenges that arise, whether from a chemical or physical chemistry standpoint.  I would also venture to say that our team is one of the strongest in the business for another reason:  they have worked closely together for many years, some for decades, and, like a well-honed Michelin restaurant, get the job done no matter how highly technical or difficult.  Our extremely low staff turnover rate is another good sign that our cross-functional teams enjoy their work—and working together.

    For sponsors, it’s comforting to know that the same team will see the project through, minimizing delays.
  2. Why a broad range of in-house equipment matters
    An integrated CDMO should be well equipped to perform both its CRO and CMO functions, and to do so as efficiently as possible.  Although a well-equipped CDMO’s investment in plant and equipment might increase the billing rate somewhat, it’s likely the total project cost will be lower, since processes will not need to be validated again and again, as happens when technology transfer is required should different organizations be involved in a project.

    A variety of equipment is important because you want to ensure that the manufacturing plant will be able to handle whatever process emerges from the development phase of the project.  It may be difficult to predict at the onset of a project what might be needed as it progresses.  Consequently, having many different options is essential. 

    The CDMO should also be equipped to manufacture the range of quantities needed, from Phase 1 clinical trials to the increased material required for Phase 3 trials and commercialization.

    As important as the quantity of equipment is having a good mix of equipment, including reactors of different sizes and some constructed of different materials.  Various types of equipment to filter and dry the product are also necessary.

    It’s not necessary for a CDMO to have every piece of equipment.  We play primarily to our core expertise in process chemistry and chromatographyOther functions we leave to the experts, outsourcing operations such as microbiological Nuclear Magnetic Resonance (NMR) and metals testing to those who have that very specific equipment and can perform those tests most expeditiously.
  3. Relationships that can save money with no impact on quality
    Although the quality of work we have seen that was done in Asia, then brought to us, is not always  up to our high standards, we—and our sponsors—are fortunate to have found a trusted lab in India with which we have formed a strong relationship over the past 10 years.  Our sponsors can leverage this relationship to their advantage. When we have projects with multiple steps, the early steps can be performed at lower cost at the overseas lab.

    As well, it provides us the opportunity for the labs to work in parallel to speed projects, especially in rush situations.
  4. What are the major benefits of continuous optimization?
    At Seqens North America, we have developed an addiction of sorts—to optimization.  Whether it’s after initial process development or after confirming synthetic routes or during and after scale-up, we are compelled to see if we can, for example, squeeze out more yield at each step or tweak the viscosity.

The bulk of optimization typically occurs when we’ve made the jump from small amounts of materials to 100 grams. That’s a big jump.  We look to see how the chemistry behaves, spending more time on the physical end of it than on the chemical end.  We then start to look at such factors as how the material handles, the particle size, and whether impurities increased due to scale-up. 

How to best separate, the material’s viscosity, stirring, agitation—they’re all subject to optimization.  We check to see if we can move the material appropriately and whether we can manipulate the process so it’s conducive to manufacturing—not too viscous or too thick.    

How has this constant tweaking benefitted sponsors? Our classic example is the company that came to us to make two 20 kg batches, at a cost of $400,000-$500,000 per batch. We and the sponsor’s team worked closely together.  We jointly decided the projected merited additional investment and set to work.  We knew the process we developed would yield the 20 kg.  However, with some process changes and continuous optimization, the first batch yielded 38 kg.  There was no need for a second batch, saving the customer hundreds of thousands of dollars. 

We have many articles about optimization and keeping down costs. Check out: “Sound Process Optimization Never Really Ends On the road to drug substance supply and commercialization, one of the most critical stages is Process Optimization since it lays the groundwork for scale-up, when you move into GMP,” “How to Keep CMO Costs Down During the Process Optimization Stage of Drug Development,” and “Four Ways the Kilo Lab Development Phase of Drug Manufacturing Can Save Time and Money.” Or if you’d like to talk more with us about optimization, call us at (978) 462-5555 or email us at info@pcisynthesis.com. 

About the Author

Ed Price CEO of PCI Synthesis
Ed is President & CEO of SEQENS North America (formerly PCI Synthesis). He serves as a co-chair of the New England CRO/CMO Council and sits on the Industrial Advisory Board for the Department of Chemical Engineering at UMass, Amherst. Ed is also a long standing member of the American Chemical Society and advises the Bulk Pharmaceutical Task Force of the Society of Chemical Manufacturer’s and Affiliates (SOCMA)...

Do you have questions? Talk to Ed.