Life Science Leader Magazine Supplements

CMO 2017

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Page 33 of 81

By S. Naganathan STRATEGY FOR EARLY-PHASE API DEVELOPMENT LIFESCIENCELEADER.COM THE CMO LEADERSHIP AWARDS 2017 32 MATERIALS PLANNING Manufacturing SALT SELECTION AND POLYMORPHISM A form (polymorph) screen should be embarked upon as early as the drug candidate is identified. As most drug candidates have basic or acidic functions, a salt is appropriate for control of both a robust solid-state form and also as a control point for achieving impurity rejection. Having said that, one should not dismiss pro- ceeding with a freebase (or free-acid) as the final form being developed. There have been many instances where a salt really does not add much to the bioavail- ability or stability compared to the freebase. However, the formation and breaking of the salt provide an important stage for purification. Quite often there may be more than one viable salt or polymorph, and the final form for development may not reveal itself well into the development process. So, the toxicological studies will have to be initiated with one salt (form) and then a different salt (form) may be preferred for human trials. This switch requires a bridging toxicol- ogy/pharmacokinetic study. STABILITY & ANALYTICAL METHOD DEVELOPMENT Development of analytical methods and controls to assess impurities, forms, and stability (degradation) of the drug substance must be undertaken early in the development. This is especially true for the develop- ment of stability-indicating methods and obtaining early indication of the stability of the selected form of the drug substance. This is one aspect of development that cannot be mitigated by throwing more resources at it! A six-month stability study takes six months no matter how hard one tries to shorten that duration. CDMO SELECTION Working with a compressed timeline means that sev- eral activities are happening simultaneously, and judi- cious selection of a CDMO becomes very important — including one-stop vs. several specialty experts. While a one-stop provider may understand the contexts and timelines better, it may not have the insight and exper- tise into specialized problems (e.g. polymorph-related issues). The most important characteristics are adapt- ability to rapidly changing conditions, technical exper- tise, and ability to communicate clearly in a timely manner. L typically three to six months from nomination of the candidate. In the six months it takes to conduct the toxicology studies, the process is refined sufficiently to enable the cGMP manufacture of the batch to be used in Phase 1 trials (commonly referred to as GMP-1), just in time for the IND application to become effective. In this approach, the clinical trials start nine to 12 months from candidate nomination. In our experience, the two-batch strategy has been employed successfully in over 20 programs, resulting in a median time of 11 months from candidate nomination to being ready to dose humans. THE CHALLENGES The cornerstone of chemical development is ensuring that results obtained in clinical and nonclinical studies using every batch of drug substance can be connected to a past and a future batch — it is not as important to have the highest purity levels from the outset as it is to have progressively lower levels of the same set of impurities in every successive batch, or to have elimi- nated most of them altogether. Every impurity above a certain level must be qualified in toxicological studies. The appearance of a yet-unseen impurity would be a significant problem, and potentially cause delays to clinical studies. The majority of challenges during early process devel- opment and synthesis fall into the following areas: IMPURITY CONTROL It is difficult to manage the impurities resulting from starting materials early in development, especially when the route of synthesis is still under development. In fact, the starting materials may themselves be under development, let alone the process for their manufac- ture. The most common way to ensure that starting materials do not contribute to different impurity pro- files in the two-batch strategy is to employ the same batch of key starting materials for the toxicology and the clinical batches. Better yet, if a route of synthesis can be established early, the manufacture of advanced intermediates can be undertaken at a CDMO while process development is ongoing. In some cases, we have utilized the synthesis of an advanced intermediate by a CDMO to evaluate its suitability for the manufacture of the drug substance, especially if it possesses capability to operate under cGMP. Ultimately, avoiding impurities cropping up unex- pectedly depends on the quality of the analytical method (see below). As the chemical process gets refined and the side reactions brought under control, once-insignificant, or even once-invisible, impurities become prominent. SRIRAM NAGANATHAN is senior director of chemical development at Dermira, a biopharma- ceutical company focused on bringing innovative and differentiated products to dermatologists and their patients.

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