Case Studies

Case Study One_

Objectives:

A multi-stage process development and manufacturing program required in order to develop and deliver quantities of an advanced intermediate and the API to support toxicology and early formulation studies and further supply to meet initial clinical trial requirements. Issues:

  • Timelines to meet both toxicology and FTIH requirements were both extremely tight
  • However, the chemical route to both the KI and API had not been identified
  • The physical form of API had not yet been identified - an oil

Outcomes:

Stage One:

  • In order to avoid timelines slipping various methodologies were tried in order to partially optimise the client’s lab process [3 chemical steps from a key intermediate].
  • Salt screening and polymorph investigations were undertaken as soon as API became available and yielded the first crystalline form the API.
  • Result: Under extreme time pressure 200 grams API was furnished to enable studies to begin at the CRO.

Stage Two:

  • FTE PRD program to develop a new economic route very shortly after stage 1 initiated
  • The route to the API was disconnected
  • A novel new route devised which utilised an alternative intermediate which had better physical characteristics
  • Route scaled-up successfully and tech transferred to a large scale CMO for FTIH manufacture
  • Result: the better reproducibility and higher yields meant that the novel route was patented by the client.
  • Client was able to benefit from an accelerated progress of the project from stages 1 and 2 due to the early PRD [formulation and salt forms of the API fixed as well as the impurity profile]

Stage Three:

  • Process development of the key intermediate needed due to irreproducibility and low yields
  • R&D observed that finer grade of reagents required in order for the reaction to proceed smoothly. Buying specs for the reagents amended to meet this
  • Multi-kilo batches prepared successfully

Case Study Two: Benefits of Early PRD_

Objectives:

Ubichem was asked to prepare and optimise a critical intermediate

Issues:

  • Med Chem route was expensive and low yielding due to poor stereoselectivity
  • Ubichem recommended an FTE program to explore this reaction further

Outcomes:

Stage One:

  • After understanding the reaction kinetics in detail discovered that the optimum conditions lay with using a sufficiently strong base to increase the reaction rate in order to avoid substantial material loss due to formation of undesired by-products
  • Various process improvements enabled Ubichem to supply material for both the FTIH and Phase I batches

Stage Two:

  • However the optimised route still required the use of an expensive custom made reagent - therefore having a significant impact on COG
  • Used our technology tool box in order to suggest and develop an economically viable alternative route
  • Ubichem prepared material for impurity profile comparisons and proof of concept batches for API derived from material made via the alternative route

Stage Three:

  • Secured medium-long term supply of critical raw materials - using Ubichem’s expert knowledge of the marketplace.
  • It is important to get new suppliers qualified and planning for long term supply to be in place

Case study 3: Route development_

Objectives:

Ubichem was asked to prepare an cGMP advanced intermediate.

Issues:

  • Ubichem received a tech package for an advanced GMP intermediate
  • Ubichem was concerned about the long term viability of the route provided (Toxicity of reagents used and overall COG)
  • Keen to avoid using a highly carcinogenic starting material

Outcomes:

Stage One:

  • Process derived from the client’s tech package was successfully implemented
  • Ubichem independently developed a totally new route utilising safe starting materials and crystalline intermediates for all the stages
  • Research at our risk yielded a representative sample

Stage Two:

  • Ubichem was then tasked to prepare a 10kg scale up batch using the new route
  • This was followed by 600kg manufacture to support Phase II trials

Case study 4

Objectives:

Ubichem asked to prepare a complex heterocyclic API for toxicology and clinical trials based client’s tech package within a tight timeframe.

Issues:

  • Assessment of project concluded that the existing multi-step route was not a commercially feasible option
  • Linear MedChem route
  • Very expensive reagents and starting materials currently only available from small scale lab suppliers with very limited scope for future bulk availability
  • Key building block: no suppliers or even a viable synthetic route

Proposal:

After a disconnection evaluation of the target API Ubichem proposed a development program in parallel to scaling up the MedChem route.

Outcomes:

Stage One:

  • Due to time constraints the initial research focussed on two areas (in descending order of priority):
  • (i) supplying multigram quantities for tox based on the MedChem route as originally requested which was successfully implemented
  • (ii) research into preparing the key building block via a scaleable route
  • R&D program performed in parallel determined the future manufacturing route with a representative sample

Stage Two:

  • New route was taken forward with an intermediate scale-up batch for further toxicology and cGMP manufacture for Phase 1 supply is planned for 2008.
  • Process was optimised further and scale-up issues ironed out.
  • Client has filed the new route.
  • Ubichem has prepared a selection of analogues now accessible by the new route.
Ubichem Research