Issue link: https://www.e-digitaleditions.com/i/276262
Tablets & Capsules March 2014 19 Beyond API-in-capsule Instead of relying solely on API-in-capsule, sponsors should evaluate another strategy—one that incorporates co-processed excipients—for developing oral dosage forms, particularly for first-in-human studies. From a sci- entific perspective, using excipients makes sense because conducting Phase I trials with a clinically relevant dosage form—whose manufacture and performance can be reproduced at a commercial scale—can add significant value to early clinical trial data. It can also reduce the risk of later-stage complications. After all, when researchers are forced to change the dosage form during the clinical-development phase, risks increase significantly, and years may be added to devel- opment as the product's clinical performance changes. Often, such changes occur between the toxicology stage and Phase I and Phase II trials, complicating researchers' attempts to bridge early-stage data to later-stage clinical data. For example, if first-in-human studies are conducted using neat API in a capsule, complications could arise in Phase II studies that are con- ducted using a formulated dosage form if the clinical data aren't comparable. That could force researchers to perform another Phase II study or even another Phase I study. At the very least, it would require a crossover study. Given the competitive nature of the pharmaceutical industry, having to repeat Phase I or Phase II studies could jeopardize the development of a product and/or the success of the sponsoring company itself. Too often those of us working in product development discover that a second Phase I or II formulation is required, usually because we didn't completely understand how the dosage form performed or how formulation changes made ahead of clinical trials could affect that performance. The appeal of QbD To avoid or mitigate these risks, consider adopting a systematic approach to dosage form development using Quality by Design (QbD). It's an approach that continues to gain acceptance in the pharmaceutical industry, espe- cially for developing new dosage forms and filing abbre- viated new drug applications (ANDAs). Indeed, as of January 2013, all ANDAs for products to be marketed in the USA must include QbD elements. For new drug applications (NDAs), both the FDA and the European Medicines Agency (EMA) are operating pilot QbD pro- grams. While little data is available about the success of the FDA's pilot program, it's likely that one or more regu- latory agencies will implement some form of QbD requirement for NDAs once the programs conclude. (Through September 2011, four of the 32 total NDAs the FDA received for new chemical entities (NCEs) con- tained some QbD elements. Data for 2012 and 2013 aren't yet available.) It is also likely that NCEs now enter- ing the clinical phases of development will have to meet some form of QbD requirement when the sponsors file NDAs. The guidances on QbD are available from the Inter - national Conference on Harmonization (ICH) in docu- ments Q8, Q9, and Q10, which have been adopted by the EMA, the FDA, and Japanese authorities. The QbD elements that pertain to pharmaceutical development are the quality target product profile (QTPP), critical quality attributes (CQAs), risk assessment, design space, control strategy, and product lifecycle management. Definitions of each element and details about them are presented in clear detail in the ICH guidances. The elements most relevant to the early stages of product development are QTPP, CQAs, and risk assess- ment. The design space, control strategy, and product lifecycle management are more applicable to later phases of product development (phases II and III and marketing applications). Establishing a QTPP provides a very clear and com- prehensive framework from which you can initiate prod- uct development. Establishing the QTPP and understanding the CQAs will, in turn, enable you to perform a risk assessment. The assessment should evaluate all factors involved in drug product manufacture and the potential for those factors to affect the QTPP and the product's CQAs. That means assessing the API, excipients, and all the steps in the manufacturing process. For an API-in-capsule formulation, this would include the API, the capsule, the capsule filling process, and the packaging process. For a for- mulated dosage form, many more factors would be involved, including excipients and the additional processing steps (i.e., granulation, blending, and tablet compression). These additional factors produce a more complicated risk assessment and, as a result, a more time-consuming development program, which would seem to favor an API-in-capsule approach. After all, the simpler the dosage form, the lower the risk of developing problems that could prevent the start of clinical trials. But performing clinical trials using a dosage form that is not commer- cially viable also entails risk. In fact, it puts the product's overall development at risk. Plus, since you need to con- duct compatibility studies of the API and the capsule shell anyway, it makes sense to study excipient compati- bilities as early as possible. That can be done with a well- designed excipient-compatibility matrix, which should take no more time on stability than the compatibility studies of the API and the capsule. Naturally, the addi- tional analytical time devoted to the excipients would add cost. Yet both cash and timelines are tight, and many of us cannot afford to place product and process development The API-in-capsule approach only defers the development work needed to supply later-phase clinical materials and commercial products. d-Lambertart_18-21_Masters 3/5/14 10:06 AM Page 19