Strategies for Entering Phase 1 Clinical Development with Limited API

Discovery and development of new medicines to extend or improve the life of patients is a challenging and expensive endeavor. The cost of developing a new drug is estimated to be between $800 million and $2 billion and often requires 10 or more years of development with the FDA only approving, on average, 30 new chemical entities per year.

As posted on Contract Pharma
Issue: June 2021

Removing API supply as a criterion in the “Go/No-Go” decision tree and enhancing the opportunity to successfully navigate the pharmaceutical “Valley of Death.”

Discovery and development of new medicines to extend or improve the life of patients is a challenging and expensive endeavor. The cost of developing a new drug is estimated to be between $800 million and $2 billion and often requires 10 or more years of development with the FDA only approving, on average, 30 new chemical entities per year.

Attrition rates in pharmaceutical development are astronomically high by any standards, with seemingly promising drugs often failing in the earliest stages of development. In fact, the transition from research and preclinical development to the clinic is so perilous that it is frequently referred to as the “Valley of Death.” In addition to the primary challenge of demonstrating a drug to be safe and efficacious, pharmaceutical companies, especially those small in size, must overcome a litany of obstacles to complete the preclinical development testing required to file an IND, including access to capital, lack of proper research facilities, inadequate clinical expertise, and limited drug supply.

Because of the high attrition rate of compounds moving through early development, rapid “Go/No Go” decisions in drug development increasingly control the degree of subsequent investment in either a compound or a molecular mechanism for one or more indications. “Go/No Go” decisions are critical to determine the balance between depth and breadth of investment in any single compound or mechanism. A correct go decision is important so that resources are not wasted on inferior compounds and diverted from the development of medicines of value to patients. Conversely, a correct no-go is also important so that a valuable medicine is not terminated prematurely.

Pre-clinical Development & Manufacturing Challenges
Once a lead candidate is identified, a typical preclinical development program consists of six major efforts: manufacture of the drug substance or active pharmaceutical ingredient (API); pre-formulation and formulation or dosage design; analytical and bioanalytical methods development and validation; metabolism and pharmacokinetics; toxicology, both safety and genetic toxicology and possibly safety pharmacology; and good manufacturing practice (GMP) manufacture and documentation of drug product for use in clinical trials.

Importantly, before a pharmaceutical company subjects the drug candidate to costly pre-clinical and clinical trials, the drug must be deemed feasible from a chemical synthesis and manufacturing standpoint. The drug candidate should also be safe and feasible during scale-up because while the initial route of synthesis uses small-scale techniques in a laboratory, in order for a drug to be viable, it needs to be suitable for large-scale manufacturing.

When a molecular entity is selected, pre-formulation activities commence to determine its physical and chemical properties, including counter ion salt or polymorphic form, solubility, and stability. The outcome of this stage is a recommended form, and the API portion of the project transitions to issues surrounding reaction efficiency, cost of goods, purity and control of impurities, and batch-to-batch consistency. In most cases the original medicinal chemistry reaction must be refined to improve availability of common starting materials and reaction reproducibility and scalability to maximize both product consistency and yield for each batch.

Ultimately, all preclinical drug development programs require an adequate drug supply. As development progresses, increasing quantities of higher quality APIs are required for small non-good laboratory practice (non-GLP) efficacy studies, early formulation activities, in vivo dose range-finding studies, and finally rigorous IND-enabling GLP toxicology studies.

In addition, API stability and degradation, including identity of major degradation products, are evaluated for a variety of storage conditions and documented in the CMC section. These latter steps fall under GMP guidance and are beyond the capabilities of most investigative research laboratories. At some point in the process, the investigator may opt to transfer the synthetic process (along with appropriate legal intellectual property documentation) to a specialized contract development and manufacturing organization (CDMO) that will produce required batches along with a Certificate of Analysis or GMP release for each batch. Once an API batch is released, it is ready to be used in GLP safety toxicology studies or prepared/formulated for clinical use.

At this juncture, the API must be well characterized in terms of structure identity (crystalline or polymorphic), counter ions (salts) and co-crystals, impurities, stability, chirality and enantiomer(s), appearance, solubility, and other chemical and physical properties. These properties will continue to be referenced throughout API scale-up process chemistry and GMP manufacturing.

In short, manufacturing and process development activities must be designed to meet the need of the clinical trials. In order to produce the products efficiently and at the required quality, the developer must, through a series of process development activities, establish the manufacturing process and optimize it to meet regulatory requirements while ensuring that it is cost-effective and reproducible.

Looking at the many challenges for pharmaceutical developers, particularly those small in size with limited resources, successfully navigating the early manufacturing and production process can determine whether a drug will succumb to the “Valley of Death” or continue on its journey towards potential approval and commercialization. The ability for a pharmaceutical company to fully account for the manufacturing needs and challenges of its API and develop a sound strategy for producing the drug efficiency, consistently and cost-effectively is critical to success.

However, this process is often overshadowed in the drug development hierarchy as greater attention is naturally directed towards evaluating the safety and efficacy of the compound and whether the drug could translate into a commercially viable product. Undoubtedly these traits are what ultimately decide a drug’s future, yet a drug that cannot be manufactured at scale will never be a viable product, no matter the benefits it provides.

Further complicating matters, many resource-constrained companies are often forced to contend with API supply limitations. This can be due to the complex nature of the chemical product, which makes reproducing the asset at scale challenging. Or it could simply be the case that the company is cash strapped and cannot afford large-scale production. Either way, limitations with API can be a serious barrier to product advancement and can, in fact, be a key influencer as to whether a company proceeds with or ends its drug development effort. “Go” or “No Go”.

Making such a critical decision based on API supply rather than safety and efficacy is not a position that any company would want to be. For a CEO, a dilemma like this can lead to a place of desperation where the “least worst” option is the only viable path forward, whether that be a death-spiral financing, a leave-the-cupboard-bare licensing agreement or a sale of the asset at a fraction of its potential value.

Thankfully, there are alternatives that marry tried-and-true manufacturing QbD principles with creative, risk-based approaches that can allow a drug developer to attain the same levels of excellence as a resource-rich company while utilizing a fraction of the API normally required. Though each pharmaceutical product is unique and will demand certain processes unto itself, at Enteris BioPharma, we have found success with several techniques that can be applied across a large swath of APIs to enable advancement to the next stage of development. Doing so, we have been able to guide our clients through key pre-clinical assessments that allowed for the development of the optimal drug formulation while conserving valuable API.

Peptides represent one of the fastest growing therapeutic categories with more than 200 approved therapeutic proteins and over 100 peptides on the market, accounting for approximately 10% of the pharmaceutical market at a value of $40 billion per year. Thus, peptides offer a good backdrop for detailing techniques that can allow companies to get the most bang from their API buck. However, these same “tips and tricks” can be utilized with other APIs, such as small molecules, another large and rapidly growing therapeutic class.

The first step in formulating a drug product is conducting a developability assessment, which entails the developer evaluating the API against a set of pre-specified questions designed to get a baseline of the drug and the development challenges it may face. There are three main categories of questions that should be weighed—Characteristics of the API, Project Status and Feasibility for Oral Delivery. Of note, the last category—Feasibility for Oral Delivery—is not a necessity if there is no plan to develop the drug orally, but given the attractiveness of orally delivered drugs it is a recommended assessment to undertake.

Of the three categories, understanding the Characteristics of the API is crucial to determining a manufacturing strategy. In the case of a peptide, questions to be considered include: What is the peptide sequence? Are there chemical modifications to the peptide? What is the total molecular weight? Is the peptide soluble in pure water, buffers or salt solutions, or an acidic pH? Does it aggregate? Is it susceptible to proteolysis? These questions can be easily modified for other drug categories, such as small molecules.

Once the developability assessment is complete, the process shifts quickly to pre-formulation development. It is at this stage where limited API quantities can present the first of many hurdles for developers. This is particularly the case with peptides, which tend to be flocculant, electrostatic powders that make weighing operations a challenge.

An approach that can make working with peptides more efficient is re-lyophilizing the API directly into an HPLC injection vial. This technique takes advantage of the peptide’s amorphous state and lends to improved precision and reproducibility, while eliminating repeated sample weighing, which can lead to variability and the loss of valuable drug substance. Importantly, employing this approach can reduce the API required in pre-formulation to just 75 to 100 mg, which can help to significantly conserve drug quantities.

Additionally, during the pre-formulation stage, developers will want to assess the solubility of the API. This is a particularly important undertaking given that approximately 70% of current new chemical entities are in the BCS Class IV category. As a result, developers will need to identify excipients to improve the absorption of the API and determine the manufacture of those as well.

Typically, excipient compatibility studies are a pressure point for developers with limited API due to the demands of the experiments involved. However, there are techniques that can be applied that result in a rich and dense data set from a small amount of API. One such methodology—binary mixture studies—entails the API being tested individually against multiple excipients, which are then stressed under a predetermined set of conditions, including temperature, time, or water content. Such studies are beneficial in comparing the impact of various enhancers on stability and also for the selection of various non-enhancing tableting excipients. Importantly this research can be completed with approximately 40 mg of API.

Resulting data can serve to identify and exclude incompatible enhancing excipients and other tableting excipients for formulation development, while also characterizing the impact of API/excipient ratios. Moreover, the research can inform real-time stability degradation product identification for future applications and aid in stability study investigations.

The pre-formulation and formulation studies provide the building blocks for the next critical step – small scale manufacturing for animal studies. Initially, one to two prototype tablets are typically hand-pressed based on the formulation designs from which IPC testing is conducted to measure compression curves, hardness, DT and friability, as well as additional, API-specific data points. From there, an additional 50-60 hand-pressed prototypes are developed, which undergo more refinement before being subjected to the animal PK study.

Identifying the reference standard is key juncture in the advancement of an API. There are techniques in this stage that can be employed to drastically reduce the amount of API needed. In short, the reference standard is prepared from a few hundred milligrams (100 mg is enough for more than 200 tests) of a well-characterized lot of API. It is then formulated as a liquid to a target concentration of 0.5-1.0 mg/mL and filled into cryo-tubes with screw-on caps, 1.0 mL/tube, and stored frozen until use. From these samples, the reference standard is characterized and qualified. Potency is determined and homogeneity is tested from beginning, middle and end of fill and effect of freeze/thaw cycling.

The final chapter in readying an API for the transition from pre-clinical to clinical is GMP manufacturing of Phase 1 trial supplies. Here, all of the prior developmental work can be applied to scale the API for production. Critical at this juncture is, unsurprisingly, the ability to accurately determine how many tablets are required for Phase 1, recognizing the need to include enough tablets for release testing, clinical retains, non-clinical testing and most importantly for stability studies. Stability studies should not, under any circumstances, be shortchanged because there is no resetting the clock if the data are inadequate.

In conclusion, by applying the above-described methodologies companies can stretch a minimal supply of API during pre-clinical formulation and product development to yield robust data and enable the efficient transition to clinical-scale manufacturing. Pre-formulation studies can be completed with as little as 125 mg of API and a high-quality reference standard can be prepared with as little as 100 mg of API. Moreover, tablet manufacturing for small scale animal studies and cGMP CTM manufacturing can be done rapidly and efficiently, while a minimum stability study that covers the duration of the clinical study at the long-term condition can be completed with about 100 tablets.

Collectively, the results from these studies are suitable for the beginning of the development lifecycle and beyond, providing a gateway to the clinic and removing API supply as a factor in whether a drug product is a “Go” for in-human studies.

Thomas Daggs

Thomas Daggs, MBA, is Senior Director Product Development and Quality Control at Enteris and is responsible for the Analytical and Quality Control groups as well as CMC project management for the company. With more than 15 years of pharma, biotech and diagnostics experience, Mr. Daggs possesses broad knowledge of all aspects of pharmaceutical development with technical strengths in analytical methodology/controls.

Angelo Consalvo

Angelo Consalvo is Director of Manufacturing at Enteris and is responsible for cGMP manufacturing and pre-formulation characterization studies for the company. Mr. Consalvo has more than 34 years of biopharma experience in process development and manufacturing. Throughout his career, he has led the successful development and transfer of numerous commercial manufacturing processes and built an expertise in working with small molecule and peptide/protein APIs, both recombinant and synthetic.