Development of batch processes in the pharmaceutical industry

Sven Wagner

Traditional development from an engineering prospective

Chemistry is fixed Detailed analysis of the process or chem. rxn Generate process understanding, i.e. rate

laws with the kinetic parameters Derive the best process parameters with respect to the given frame work Utilisation of the best suitable reactor type Design unit operations based on physical properties

The path to a new medicine

Years 1

10

11

12

13

14

15

16

Drug Discovery Target and lead Lead identification optimisation

Drug Development Development Concept testing for launch Clinical Development Phase I Phase II Phase III 50-150 100-200 500-5,000 people people people

Product life Launch cycle support

Phase IV studies continue

Toxicology and pharmacokinetic studies (absorption, distribution, metabolism, excretion) Pharmaceutical and analytical development Process chemistry and manufacturing Registration and regulatory affairs Sales and marketing (preparation, promotion, advertising and selling) No. of compounds Up to 1,000,000 10-15

1-8

1-3

Development constraints
Projected peak volumes Environmental impact Robustness (incl. by-products) Complex and changing chemistry API delivery for clinical trials during development Attrition risk Process Safety Patents Lead times Costs (chemicals & manufacture)

API quality

Process

Regulatory requirements

Flexibility, i.e. using of batch/semi-batch processing

Availability and versatility (rxn, separations etc) Not process specific design Relatively easy scaled from lab experiments Batch/Semi-batch more robust to inaccurate knowledge about the process, i.e. allowing shorter lead times easy cleaning
Risk minimisation for launch of product

Development challenges
Development of the chemistry typically

iterative Regulatory issues narrows possible changes to the process in later phases of development Cost-benefit management Balance potentially conflicting targets for several interest groups (e.g. regulatory vs. safety) Increased pressure to reduce costs

Engineering approach
Work in close collaboration with chemistry Working in parallel Strengthen background in physical organic chemistry,

reaction engineering and synthetic chemistry to maximise contribution to process design Awareness training for chemists regarding mass transfer, mixing, process safety etc. Chemical Operational Hazards Hazards Utilising specialists and generalists

Process Preparative Reaction Development ChromatoEngineering Engineers graphy PAT Crystallisation

Engineering issues
Ensuring an efficient communication with other functions Chemical Reaction Engineering

How to achieve best CRE impact during the process development? How to gather high quality data in a short period of time? Balance between specialists and generalists critical mass Preparative chromatography, CRE for batch process and Process Safety difficult to recruit in Sweden Cost-benefit management of activities Introduction of new technologies