Biotech firms often have tight timelines to prove the concept of their NCE. As a result, modern clinical development pathway requires rapid manufacturing of the “first Kilo”.

The procedures typically available to CMOs for early phase manufacturing are laboratory-based processes, which are designed to manufacture a few grams. The goal at this stage is not to generate a long term economically feasible process, but to deliver high quality material in a safe and efficient manner. Key to this is responsiveness and adaptability in the Process Development laboratory. However, by necessity, little attention has been paid to analytical methods, isolation procedures or process safety upon scale-up.

The recommended approach with these types of projects is to try and initiate as many concurrent activities as possible. Process chemistry, analytical methods, process safety and regulatory requirements  have to be in place when the process is scaled under cGMP.  Typically, first run through of the chemistry is used to generate both data and samples in the following areas.

• Preliminary safety and scalability assessment of the chemistry.
• Screening the chemistry through a pre-defined set of analytical methods (with particular focus on UPLC to speed up analysis) to enable the analytical development group to gain a head-start on method development.
• Preliminary attempts to identify impurities using in-house LC-MS and kinetic data
• Subjecting the initial sample prepared by familiarization chemistry to analytical method development, initial process safety screening (DSC, etc.), and isolation system development (solvent screening for crystallizations).

During the process, a variety of activities need to be executed within a short timeframe and require close and frequent communication between the teams involved (R&D, Analytical and Production). The activities include addition of new analytical methods, tracking impurities and volatiles and designing strategies to control them, as well as identifying and addressing process safety concerns.

The culmination of all these activities are the “typicals” or process representative reactions. These are mock production runs, carried out in R&D laboratories or R&D kilo labs, which are similar to cGMP production, but with analytical involvement.  Data generated from these runs forms the basis of R&D development report, which is in turn used to generate MBR for GMP manufacturing in the plant. Further,  analytical methods are used to generate material specifications which are transferred to the QC team with guidance from the QA team. Finally, the close interaction and support from all teams is the key to ensure successful manufacturing of this ‘first kilo” in a timely manner.