I. Process development

How a multi-stage process development and manufacturing program designed by our company led to a totally novel route that was patented by the client and delivered accelerated multi-kilo batch production.

 

Client: Mid-sized Biotech company

 

Objectives: A multi-stage process development and manufacturing programme required to develop and deliver quantities of an advanced intermediate and the API to support toxicology and early formulation studies, plus further supply to meet initial clinical trial supplies

 

Issues

  • Timelines to meet toxicology and Phase I requirements were both extremely tight
  • The chemical route to both the key intermediate and the API had not been identified
  • The physical form of the API (an oil) had not yet been identified

 

Outcomes

 

Stage one

  • To prevent timelines slipping various approaches were tried to 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 of the AP

 

Result

Under extreme time pressure 200g API was prepared to enable studies to begin

 

Stage two

  • FTE PRD program to develop a new economic route started soon after stage one initiated
  • Disconnection approaches to determine a new route to the API were evaluated
  • A novel route was devised utilising an alternative intermediate which had better physical characteristics
  • Route scaled up successfully and tech transferred to a large scale CMO for manufacture

Result

  • Improved reproducibility and higher yields meant that the new route was patented by the client
  • The client benefitted from accelerated progress of the project 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 due to irreproducibility and low yields
  • R&D observed that finer grade of reagents required in order for the reaction to proceed smoothly
  • Buying specifications for the reagents amended accordingly

Result

Multi-kilo batches prepared successfully

We demonstrated the ability to develop a process rapidly in order to ensure supply of material to tight timelines, thus keeping the client’s project on track.

 

II. Effective Scale Up

Using our knowledge, understanding and experience, we identified and scaled up an alternative, commercially viable route for the client which avoided the use of a highly carcinogenic starting material.

 

Client: Major global pharma company

 

Objectives: We were asked to prepare a cGMP advanced intermediate based on the client’s tech package, because we had particular expertise in the synthesis of similar molecules

 

Issues

  • We were concerned about the long term viabilility 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
  • We independently developed a totally new route utilising safe starting materials and with crystalline intermediates at all stages

Result

Research at our risk yielded a representative sample

 

Stage two

  • Our company was asked to prepare a 10kg scale-up batch using the new route
  • This was followed by 600kg manufacture to support phase II trials

Result

Successful scale-up and manufacture of 600kg of the key intermediate using a new, commercially viable, route

Our company utilised its knowledge of sourcing raw materials and ability to design, develop and scale-up commercially viable routes to supply hundreds of kilos of material to support the client’s clinical trial programme.

 

III. Route Design and API Synthesis

How we developed a new route for a complex heterocyclic API in an extremely short timescale when the clients’ multi-step route was not commercially feasible.

Client: European Biotech company

 

Objectives: Our company was asked to prepare a complex heterocyclic API for toxicology and clinical trials based on the clients tech package within a tight timeframe

 

Issues

  • The existing multi-step route was not a commercially feasible option
  • Linear medicinal chemistry 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 our company proposed a development programme in parallel to scaling up the medchem route

 

Outcomes

Stage one

  • Due to time constraints, initial research focussed on two areas
  • Supplying multigram quantities for tox based on the medchem route as originally requested, which was successfully implemented
  • Research into preparing the key building block via a scaleable route
  • R&D programme carried out in parallel determined the future manufacturing route and produced a representative sample

 

Result

Both areas were successfully delivered, enabling timely progress to stage two

 

Stage two

  • The new route was taken forward with an intermediate scale-up batch for further toxicology. cGMP manufacture for phase I supply to follow
  • The process was optimised further and scale-up issues ironed out

 

Result

The client filed the new route and our company prepared a number of analogues now accessible by the new route

Our company undertook development activities in parallel to ensure timelines were met. A scaleable route to the clients API was developed, allowing previously inaccessible analogues to be synthesised, and larger quantities of material to be made at a commercially viable price.

Case Studies

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