Three Things to Know About API Development for Phase 2 Clinical Trials

When preparing for Phase 2 clinical trial programs, one of the biggest challenges is scaling up to produce significantly more Active Pharmaceutical Ingredient (API) material than the amount needed for Phase 1. Because Phase 2 clinical trials are larger, with more participants, material needs to be scaled.

Those outside our industry would think this is a linear progression: do the R&D, develop the API, test it, make enough for Phase 1 trials and when Phase 2 rolls around just make more of the same API.  Sure, making additional product would be that simple – if we were cranking out products such as wine corks or chocolate bars.  APIs, however, are far more complicated.

This article will focus on three things to know about producing APIs for Phase 2 clinical trials.

  1. Why the chemistry needs to be reviewed and scaled before proceeding

    It’s at Phase 2 that sponsors come to the realization that they have to make a significant additional investment in R&D.  As a CDMO, we find that we need to do more process R&D in order to scale up significantly.  Until we know the API we have developed for Phase 1 is safe for human use, a significant investment in process chemistry isn’t necessary. But once the drug candidate moves into Phase 2 trials, it makes sense for sponsors to invest in R&D that will do two essential things:  assure the product can be scaled up and processes are optimized to improve yield.

    This Process Research identifies the most efficient route to developing and manufacturing drug candidates for Phase 2 clinical trials. Based on more than 20 years of synthesizing a broad range of compounds for numerous sponsors, we deem process research vital for keeping projects on track.

    Taking the time to scale up for Phase 2 in the non-GMP kilo lab ultimately saves time and money, and we highly recommend it at this stage.  It’s less costly to prove the substance can scale in conditions that mimic but don’t incur the cost of the GMP manufacturing suites.   Another reason to scale up in the kilo lab is to assure that the desired polymorph of the API is obtained.   If problems are going to surface, it’s best to find them here, before going directly into the GMP facility.  We want to avoid having to idle the plant while issues are being resolved, causing a series of delays.  That would be a costly mistake. You can chew up considerable financial resources if you learn during cGMP that the process does not scale up.

    To assure the chemistry works, we run the process in the kilo lab, usually three times, collecting the appropriate information.  The kilo lab phase is an important foundational phase that can save tremendous costs in the long run. It helps the sponsor and our team to be sure we understand the steps involved, the parameters, and deal with any impurities should they be produced as we scale up to get ready for GMP manufacturing. Conducted the right way, the kilo lab phase ensures that manufacturing is a smoother, more efficient process.

    Even when everything goes smoothly, sometimes we can tweak processes for greater yield.  If process changes are going to made, this is the time to do it.  Why is that so important? Because this is the start of the documentation that will be included in any potential regulatory filings, including the Drug Master Files (DMFs) and any Investigational New Drug Applications (INDs).
  2. Make small engineering batches before starting manufacture

    Before going into the manufacturing plant for the first time, we recommend making small engineering batches.  It’s new chemistry and we don’t want to be surprised.  Engineering batches are useful for Phase 2 supply planning.  We review the equipment to be used and scale down to the smallest batch possible in that vessel.

    In making those engineering batches we learn a great deal more about the process than we knew in Phase 1, about how the chemistry behaves, and about how it will scale up.  Usually two batches are needed, other times three. Sometimes we get lucky and the first engineering batch works well–there are not many deviations or change controls, which is what we’re looking for.  Oftentimes we use the first batch as a learning and as part of development of the compound.  That allows the second and third batches to go more smoothly.
  3. Step up analyticals for Phase 2

    For Phase 1 API supply methods are qualified. Phase 2 requires validation.  Some sponsors want validation to begin at Phase 1, but the danger is that if we make changes, analyticals have to start all over again.  If we change reagents, we have to do new analyticals. If we change a raw material, it requires new analyticals. If we change a solvent or a process that would change the profile, the analyticals change with it.

    It’s difficult to predict what will happen as the API develops. Therefore, we recommend to our clients that they not waste time and money on validation in Phase 1, but step it up in Phase 2. 


Going from manufacturing APIs for Phase 1 to Phase 2 supply involves the largest transition in preparing material for clinical trials.  It involves scaling up new chemistry that can surprise at larger scale.  Process research, kilo lab scaleup and analytical development are key to smooth transitions from Phase 1 to Phase 2, and for preparation for Phase 3 trials.  Sponsors would do well to work with a reputable company that does good work, can advise where and when to deploy financial resources, and has the ability and resources to be flexible as scenarios change, which they often do.