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Contract service organizations can offer biopharma companies early insight into dangers that may hinder a drug’s later development.
The “fail fast” approach to drug discovery and development works on the premise that the sooner you know a molecule will not have the desired efficacy, safety, or performance, the faster you can move on to another candidate, saving time and money. While a molecule may look promising in early development studies, are drug developers confident that formulation or manufacturing challenges won’t create a “fail later” situation?
In the traditional approach to drug development, companies race to get molecules to clinic, postponing questions about formulation and manufacturability until formulation steps later in the clinical phases. This traditional approach may work for easy-to-formulate APIs that can be delivered via an oral dosage form. For more complex biologic drugs, the task is not that simple. Formulation and development experts from contract development and manufacturing organizations (CDMOs) note that the race to clinic and beyond may tempt drug companies to take shortcuts that end up costing more along the path to commercialization.
Formulation studies require time, money, and expertise-resources that may not be available for smaller drug companies in early research phases. Development-phase companies anxious to get to clinic may seek to gain an advantage by postponing early stage formulation development. Formulation groundwork, however, can identify the best drug candidates, allow for optimization of the molecule, and reveal potential roadblocks in the manufacturing process.
“Companies desiring to sell early stage assets should consider that buyers expect to see formulation and manufacturing process development results that demonstrate the product can be commercialized,” says Eugene McNally, vice president, consulting, PPD.
For small-molecule drugs, detailed preformulation studies can help drug developers understand a molecule’s physicochemical characteristics, solid-state characteristics, and dissolution rate, says Robert W. Lee, president of Lubrizol Life Science Health’s CDMO division. Biologics are more complex with aggregation and degradation of special concern, as they are much more sensitive to stresses from manufacturing and environmental conditions; typically, biologics require extensive pre-formulation studies, says Stuart Madden, vice-president, drug development and consulting, ICON.
“For large molecules, it’s not just the sequence of the monomers (i.e., amino acids or nucleotides) that is a concern but also the three-dimensional structure,” says Lee. “During formulation development, it’s important to track this 3-D structure as this may be key to its biological activity, and this may very well be impacted by the formulation.” An indication of solution stability, and whether a lyophilized, or dried, formulation will be needed to maintain stability, is typically the starting point for development of large molecules, adds McNally.
In addition to analytic studies, a range of predictive modeling programs can help determine dose frequency, formulation, and route of administration for clinical trials, assess stability, bioavailability, and genotoxicity, and pharmacokinetics and pharmacodynamics.
The decision to divert limited resources from early formulation studies can come back to haunt many drug developers. For example, poorly soluble compounds can add up to an extra year on the development timeline, notes Darren Matthews, research leader, pharmaceutical sciences, Charles River.
“It is critical for companies to understand that investing in formulation and process development during the early phases can yield dividends in the long run,” says Sanjay Konagurthu, senior director, Thermo Fisher Scientific–Pharma Services Group. “The company should obtain a mechanistic understanding of the formulation and process.”
Whether due to oversight, lack of knowledge, or lack of resources, failure to fully understand the molecule in development and how it will be manufactured are common mistakes small biopharma companies make. “Even seemingly straightforward projects can reveal issues at a later stage,” says Lee. “The more information you have about molecules early on, the decisions you make can be better informed to further your probability of success.”
Not performing the testing, to either save money, secure funding, or compress the timeline, is the most common mistake observed by Matthews. “As a result, the formulation scientist must solve these challenges through formulation strategies, with no guarantee of success, as opposed to fixing the chemistry early on, which would have been an option pre-candidate nomination. The net result is significantly more cost and time added to a project.”
“Falling into the ‘sunk cost’ trap can be one of the biggest mistakes for a small company, especially if it is their only asset. Not every molecule that performs well in early in-vitro testing will have the appropriate characteristics to be a drug,” explains Lisa Caralli, director of science and technology, pharmaceutics, Catalent Pharma Solutions, San Diego. “Engaging formulators in discussions with medicinal chemists earlier in discovery/asset acquisition will help select the right molecules for development.”
“Companies need to consider performance, stability, and manufacturability from the get-go and throughout formulation and process development,” says Konagurthu. “While product development scientists commonly work on formulations and stability in the early development phases, manufacturability is not always a priority. Scale-up is not always trivial or predictable unless process knowledge is developed that is scale-independent. This knowledge should guide equipment selection, link the critical process parameters to critical quality attributes, and establish the design space.”
Two errors small companies make, identified by Madden, are not having a clear understanding of the target product profile; and going into the clinic with poorly formulated or poorly characterized drugs that can lead to erroneous or misleading data sets. “CMC [chemistry, manufacturing, and controls] is an area that can often be neglected by small companies, particularly where an asset has been acquired from a larger pharma partner,” Madden says. “Additionally, small companies sometimes fail to understand scale-up and tech transfer requirements, particularly where they plan to commercialize a product.”
“Prioritizing thoughtful protocol development from the outset can lead to much more efficient studies that not only ensure the drug exhibits the characteristics desired in the target product profile, but also save time and money,” explains Scott Dove, vice president, early development, PPD.
With resources-inhouse expertise, instruments, equipment, time, and funding-at a premium, small bio/pharma companies face difficult decisions about what functions to conduct internally and which ones to outsource.
Small companies should consider possible limitations to their resources, says Dove, and assess the knowledge and expertise of internal staff to handle challenges that may occur. “Early development requires an investment in lab space, instrumentation, and manpower, which can be costly,” he says. “Small companies often have limited capital. Strategic investment analysis should be done to determine which investment will best help them achieve their long-term goals.”
“If the small company has specific, specialized, internal capabilities with respect to aspects of its development program, it is likely to be cost effective to keep these in-house, especially if these activities are not germane to the drug product’s quality assessment and the data are not required to be developed under [current good manufacturing practices] CGMPs, which would carry a heavy overhead,” says Madden. “Routine GMP activities can be outsourced. There is a healthy CDMO market for choices.”
If a company’s internal team lacks first-hand experience, it should consider outsourcing to subject matter experts, recommends Caralli. “A few people are asked to wear many hats in lean companies, and recognizing the knowledge gaps is essential.”
Outsourcing can be a way to fill gaps in an organization’s skill base. “If you’re working with an unfamiliar route of administration or with compounds that possess challenging physicochemical characteristics, engaging a partner with the relevant expertise and experience can help you avoid many pitfalls and speed up your programs,” says Matthews.
The business objectives and capabilities of a small company play a key role in the decision to outsource. “For completely virtual companies, every task has to be outsourced as they do not have any internal capabilities,” says Konagurthu. “For companies that have some internal capabilities, considerations such as R&D vs. GMP equipment and capabilities, experience in CMC, clinical phase of development, formulation and process development experience, manufacturing scale requirements, timelines, and other business objectives govern decision making.”
In addition to questions about what tasks to outsource is the matter of when to seek external assistance. “As a CDMO, our preference is to get involved as early as possible in the development process as sometimes clients spend a long time heading down the wrong path and come up with suboptimal formulations that need fixing,” says Lee. “Transferring these suboptimal formulations over to us and asking us to fix them can cost more money and time than if they had just come to us earlier on in the process.”
For small companies that have in-house expertise in preclinical formulation development, it makes sense to start work internally; those companies that lack this skill should outsource as soon as possible, says Lee. “It’s also more cost effective to outsource to an established development partner rather than building missing infrastructure in-house, particularly for smaller companies.”
Using a CDMO that offers multiple contract service functions including drug substance manufacturing, drug product development, commercialization, clinical packaging, and distribution offers the convenience of all functions-and responsibility-with one vendor. A lower burden of supplier oversight and technology transfer can be beneficial for small companies.
“Some [contract research organizations] CROs have broad offerings that mean you can place many, or all, of the various studies you require with the same supplier, cutting down on the administrative burden of coordinating work and sample transfer between multiple partners,” suggests Matthews.
In the competitive drug development environment, what can small bio/pharma companies do to ensure their molecule is getting the attention it deserves from a contract service provider? The answer involves both processes and people.
Madden suggests taking a three-pronged approach. First, have a well-defined contract with specific activities, deliverables, and timelines. Second, he says, “ensure a CMO project manager is assigned to the project and there is a regular project meeting timetable with agenda, action items, and minutes, etc. It is incumbent on the biotech to also have a project manager to ensure the continuity of the project for the biotech. Finally, there should be a senior-level relationship for resolution of any issues that can’t be resolved by the team.”
Meredith Perry, director of pharmaceutics, Catalent Pharma Solutions, San Diego, recommends asking the contract laboratory how they schedule work and assign resources, both for R&D and for manufacturing, so that there is transparency up front. “Ask for a main point of contact such as a scientist or project manager, so that you always have someone at the CDMO who will advocate for your project’s needs,” she says.
A strategy for a small biopharma company to ensure that it is not overshadowed by big project at a CDMO is to “do your due diligence,” stresses Lee. “Ensure that you evaluate an array of CDMOs and speak to peers who have worked with them,” he says.
“It’s true that certain CDMOs prioritize large-volume projects but it’s not the case across the board,” Lee continues. “If you are a smaller company, you will want to work with a CDMO that understands the criticality of your program. In some cases, companies only have one compound, which makes choosing a CDMO perhaps one of the most critical tasks in the development program.”
“Focus on relationship building,” recommends Caralli. “People want to work with others who appreciate each other’s contributions and with whom they feel part of a team. Do not use a CDMO as solely an extra pair of hands. People will bend over backwards when they have a personal connection, so the size of a company or their financial resources matter less.”
Vol. 33, No. 3
When referring to this article, please cite it as: R. Peters, “Seeking Early Answers to Formulation Questions” BioPharm International, 33 (3) 2020.