October 23, 2023 PAO-10-23-CL-02
Drug development is a complex and lengthy process that must be pursued in a manner that ensures that the ultimate result is a safe and effective therapeutic — which can be manufactured with consistent quality using sustainable processes with attractive economics. Ultimately, 90% of new chemical entities never advance past the preclinical testing phase.
Despite the complexity of the drug development process, rapid development and approval of COVID-19 vaccines has created growing expectations that all new candidates should advance through the drug development cycle much more quickly than has been considered realistic in the past. Simultaneously, insurers and governments are placing increasing pressure on drug developers to only bring to market drugs that offer real advantages over existing products in terms of efficacy, cost, and/or attributes that increase medication adherence.
Complicating the picture for small and emerging pharma companies is their need to expend significant effort raising the funding needed to support discovery, preclinical, and chemistry, manufacturing, and controls (CMC) activities that generate Investigational New Drug application (IND)-enabling data, all with the hope of entering first-in-human clinical trials. Securing and maintaining that funding has become more difficult over the last two years as funding availability has decreased. Small and emerging pharma firms are thus driven to shrink development timelines and generate valuable data as quickly as possible.
Additional challenges facing all drug developers include, according to PricewaterhouseCoopers, “high inflation, talent shortages, rising capital costs, challenging foreign exchange impacts, pressures on consumer spending and ongoing Federal Trade Commission (FTC) scrutiny of transactions,” as well as “blockbuster patent expiries, rising competition across most therapeutic areas and the impact of the Inflation Reduction Act (IRA) of 2022.”1 All of these trends are additional drivers for drug development cost and timeline reductions, but those much of course be achieved without any decrease in quality, safety, and efficacy.
In addition to limited funding, startup pharma companies face the challenge of needing to generate CMC data with access to limited amounts of very expensive drug substances (active pharmaceutical ingredients (APIs)). Accelerated process and product development requires deep process and product understanding, which in turns requires completion of multiple in vitro, in vivo, toxicity, stability, and other assessments as early in the development cycle as possible. All of these tests are expensive and require API material.
A carefully designed approach to very-early-phase development that includes rapid generation of accurate, high-quality data supporting relevant candidate evaluation allows elimination of those not likely to succeed. By failing fast, or more specifically sufficiently early, the cost, resources and effort involved in advancing these molecules to later stages can be redirected to candidates with a much higher likelihood of success.2,3.4 (It should also be noted that R&D costs increase dramatically as a candidate moves through later development phases).
The overall result is reduced time to market and more cost-effective drug development while still ensuring product safety, quality, and efficacy.
One of the biggest hurdles to failing fast for many emerging pharmaceutical companies, many of which are founded and run by scientists, is the fundamental drive to develop as much data as possible before making important decisions. Often, these companies have only one candidates, so it is much more difficult to make the hard decision to halt a program very early in the development cycle. Those companies driven by the goal of selling their technology to big pharma are, in addition, less likely to carefully scrutinize their molecule — particularly with respect to aspects that might not matter until later in the development cycle, such as manufacturability.
In fact, manufacturability is one of two key aspects — therapeutic efficacy being the obvious second attribute — that should be evaluated as early as possible in the development process, ideally before preclinical studies if possible. Formulation of the API to provide sufficient bioavailability is necessary to evaluate efficacy and is an increasing necessity, given that three quarters of candidate APIs in the pipeline are poorly soluble or insoluble. While this work is being completed, the sustainability and scalability of the overall manufacturing process must be evaluated, a step that most companies do not complete.
Notable problems occur when projects are rushed into the clinic without careful consideration of formulation and manufacturing aspects. Indeed, lack of appropriate formulation development can derail a program. Optimizing a dosage form may be necessary but must be accomplished without impacting product performance. Use of excipients that are no longer on the market or that do not meet regulatory requirements creates significant issues as well. Qualification of alternative excipients is very expensive and time-consuming.
Scalability is as important a consideration as efficacy. If a candidate advances from phase I to phase II trials, and sufficient material cannot be produced, making process changes is a challenge. This involves conducting bridging studies to demonstrate that the material produced using the new process is the same as that obtained using the original one — a lengthy, time-consuming, and costly endeavor that generally extends the timeline.
Mikart is a CDMO offering support for formulation development and manufacturing of patient-centric drug products that address swallowing, taste, and palatability concerns with expertise in liquid solutions and suspensions, multiparticulates, minitablets, sprinkle formats, ODTs, and chewable and sublingual tablets, among other dosage forms, as well as aqueous-based coating and other taste-masking and controlled-release technologies. Mikart also offers packaging solutions ranging from high-density polyethylene and glass bottles, unit dose cups, and cold form and thermoform blisters, including child-resistant packaging that can still be opened by elderly patients.
The onboarding process for clients ensures alignment of expectations and establishment of goals and milestones, which is essential for any sponsor–CDMO relationship to avoid surprises and misunderstandings. Indeed, with Mikart, clients are able to view their project timelines in real time without needing to speak to a project manager.
This close interaction is possible because Mikart is a mid-sized CDMO serving small to mid-sized pharmaceutical companies. A combination of flexibility, transparency, open communication, and responsiveness allows for the development of true, two-way partnerships in which both Mikart and our customers benefit equally.
Commonly, small and emerging pharma companies are established with a molecule that a clinician or academic scientists believes has the characteristics to make it efficacious against a particular disease. However, they typically lack a formulation and process experts that can convert their idea into reality.
In a standalone R&D lab, Mikart supports customers with early formulation and process development. The non-GMP, small-volume formulation area allows exploration of different excipient combinations and drug formats. With this equipment, it is possible to produce a single tablet or capsule for evaluation. It is also worth noting that — by the end of 2023 — Mikart will be acquiring an instrument from Nanopharma Solutions that enables sublimation of powdered API followed by deposition on sugar spheres or other matrices to for solid dispersions without the use of solvents.
Indeed, the ability to develop many different dosage forms (e.g., capsules, tablets, powders in bottles or sachets, liquids,) provides greater opportunities to determine optimum delivery solutions. In addition, having worked on countless projects involving many different types of APIs for more than 50 years, Mikart’s SMEs also have access to a deep knowledge base and the expertise to make those hard decisions about halting programs unlikely to be successful, even with minimal data.
The instruments in the dedicated R&D analytical lab are calibrated and GMP-compliant, which gives Mikart the flexibility to quickly develop methods that can be readily transferred to production. As a lab dedicated to R&D, it is also possible to quickly complete a full complement of analytical techniques to comprehensively characterize drug substances and drug products, affording a better understanding of both. Furthermore, the analytical, formulation, and process development groups work very closely together, which also allows acceleration of early preclinical efforts in support of early go/no-go decision making.
Most small and emerging pharmaceutical companies have just one chance to prove that their drug candidate and technology will successfully reach the market. Even those with multiple candidates have limited resources and cannot afford to carry the costs of development of candidates with little likelihood of success. It is therefore essential to determine at the earliest possible point whether a new molecule should be dropped or further investigated.
Mikart is positioned with its decades of experience in small molecule formulation, method, and process development to help pharma companies make that decision. Moreover, this expertise is supplemented by extensive lab-scale capabilities for gathering large quantities of data with limited amounts of API and limited customer investment. Consequently, clients of Mikart can be confident in the evaluation of their drug candidates at the earliest development stages. Those determined to be promising will have a high likelihood of demonstrated good therapeutic efficacy and be manufacturable. Meanwhile, companies can redirect their resources away from those deemed to be unlikely to succeed to other opportunities.
Dr. Elkarim has over 21 years of extensive global experience in drug development, contract manufacturing, and project and portfolio management. Prior to Mikart, Nazar was the senior director of product design and development at Pfizer Consumer Health, leading the development of several brands such as Nexium®, PREPARATION H, Dimetapp®, and Robitussin®. He also held several positions at Patheon Pharmaceuticals including head of project management and the site head for Patheon’s softgel development services. Nazar has also managed Johnson & Johnson suppliers of pharmaceutical products and research contractors around the world. Dr. Elkarim has extensive experience in process excellence with high proficiency in Six Sigma methodology. He earned his Ph.D. in analytical chemistry from Texas Tech University and his M.S. in organic chemistry from West Texas A&M University.