Tips and tools from Syntagon

How to eliminate risks on the road to Phase I clinical trials

When it comes to developing a new API, why take unnecessary risks? Syntagon has identified five critical issues that are often overlooked when developing material for Phase I clinical trials:

• Improve solubility, stability and bioavailability: establish solid-state form for your compound at an early stage
• Take control and track changes: plan ahead for purity profile, safety and toxicological studies
• Maintain a consistent analytical method for purity and assay
• Carefully consider an appropriate level of quality and scale: define specifications to avoid backtracking
• Allow ample time for critical activities

Introduction
Imagine you are Director of CMC (or equivalent) in an emerging pharmaceutical company, assigned with the task of getting the newly selected candidate drug into Phase I clinical trials. The compound is a small molecule and rough timelines for the start of clinical trials are communicated to the shareholders and sponsors. Any delays can be extremely costly and in-house experience is limited. With a medicinal chemist's gram-scale description in hand, what issues will determine your success in producing a clinical API formulated for use, including the approved regulatory documentation?

At first, the risks and checkpoints may seem endless. For this reason, we have compiled a list of key factors that will help you gain control of the process. While this list is by no means exhaustive, it does reflect the most critical issues that we have identified from our experience over the past two decades.


Solid-state form
Do you have the capability to produce a salt (acid or base) of the final compound? If the answer is yes, then you have excellent possibilities to improve solubility, stability, and bioavailability as well as to fulfill a broader patent protection. Evaluation of salts and polymorphs is of paramount importance, and we recommend proper screening for alternatives that meet your requirements and long-term needs at an early stage. To go back and reinvent compound forms will almost certainly be costly and time-consuming.

A stable, crystalline material may be less soluble than an amorphous material. However, bringing an amorphous compound forward in development exposes the project to the risk of crystallization at a later stage (e.g. when the purity of the API increases).


Tox/Clinical batch
Will you prepare one or two batches for tox/safety and Phase I clinical trials? The material used for initial safety and toxicological studies will set the stage for impurities allowed in the API for clinical use. Preparation of one cGMP batch for use in both tox and clinical studies (Phase I) minimizes the risk for deviating impurity profiles. The drawback is an extended timeline, during which less process information will be generated. Whichever strategy you choose, be sure to retain batch samples for future comparison of impurity profiles between batches and always evaluate changes in analytical methods. Ultimately, the risks and benefits of either approach need to be evaluated on a case-by-case basis.


Analytical method
Invest in an accurate and robust analytical method for purity and assay at the start of the project. By maintaining the same analytical method throughout all development stages, it will then be easier to keep track of the impurity profile. During the development stages, several analytical laboratories will analyze the material for different purposes (e.g. API manufacturer, final dosage form manufacturer, bioanalytical laboratories, etc.). A robust analytical method will eliminate unwelcome surprises during this process and deliver more consistent results.

A pure and well-defined material, known as the Analytical Reference Standard, will serve as a reference for identity, purity and assay of future batches and will also indicate differences between analytical laboratories.

Be aware of the difference between purity and assay. Purity gives a percentage of related impurities detected (normally through UV-detection), but does not fully depict the total strength/potency/content of the API in a sample of 100 mg. Assay gives the full picture including solvents, inorganics and related impurities. In early stages, assay by ¹H-NMR can be very useful. Eventually, however, a chromatographic method for assay, using the analytical standard as a reference, is strongly recommended. To summarize: Be certain that you have a true picture of the purity and assay of your material.


Impurity profile
The impurity profile of the API is to a large extent determined by the starting materials, the process and the stability of the compound. As mentioned above, later changes from the impurity profile of the material used for initial tox and safety studies may cause extra activities such as bridging tox studies. Changes in process, analytical methods and starting materials (supplier or quality) may cause a change in the compound's impurity profile. Related impurities will typically be the main focus for impurity profile investigation and you may consider identifying the structure of you major related impurities at an early stage. To summarize: Keep close track of your impurity profile.


Specification
The specification for the API needs to be carefully set. ICH guidelines define the requirements for a commercial stage API at doses up to 10 grams/day. When developing a commercial drug we recommend a gradual, step-by-step increase of requirements. Typically, the specification for related impurities will be loosely set for early development batches and tightened at a later stage when the process is well established. The first draft specification will be based on the performance of the process at that time as well as on the level of impurities present in early tox material.

Additional emphasis should be placed on potential genotoxic compounds/PGIs (European requirement). Reagents and process intermediates with structural similarities to known genotoxic compounds need to be controlled in the API.


Manufacturing/process
The process needs to be robust and safe for its intended use and scale. At an early stage of development, a non-optimized process can be tolerated as long as the quantity and quality can be met. However, it may be worthwhile to focus additional efforts on the later stages of the process. The last chemical step and final purification are very likely to strongly affect the impurity profile. Further emphasis should be placed on the rationale for the GMP starting point and nomination of API starting materials. To summarize: The chemistry and process may be further developed at a later stage, but it is important to maintain full control of the impurity profile.


Timeline & project planning
Allow time for evaluation of critical items such as solid-state form, analytical method, process safety and raw material supply. If critical raw materials are not available from stock, it could easily take two months or more before they are prepared and received. Shortcuts on key items will most likely come back to haunt you. Solid-state evaluation must be timely and should be finalized before the final steps of the process can be developed. To summarize: Typically, a scale-up from gram scale synthesis to first cGMP material takes 4-6 months.


Scale of material required
How much material, in grams or kilos, is required for the intended study or studies? When low doses are planned, and when the intended indication is for a limited population, it may appear that less than 100 grams of material is needed. However, when considering material for QC-testing (10-20 grams), retained sample (20-30 grams), stability studies according to guidelines (approx. 30 grams, depending on the program) and losses during manufacturing of the dosage form, it may be worthwhile to aim for 500 grams. For a three- to five-step synthesis, the extra cost is generally limited to raw materials at this scale and stage of development. To summarize: Make all plans and calculations with an appropriate margin of error. You are likely to be surprised at how useful or necessary the excess material may be.

Time to move onto Phase I clinical trials. Good luck!