Block 1: Lecture 12: Scale up chemistry - API from mg to kg

What are the characteristics of the scale-up and process development of an API?

• Differences from small scale synthesis

• Synthesis planning

• Working with outsourcing partner

• GMP

• Safety

What are the process (R&D) requirments?

What do we need to know about the process of an API?

1. Reproducible process on scale

2. Available starting materials at an acceptable cost

3. Patent or other regulations

4. Identification of critical reaction parameters

• Understanding their effect on yield and quality

5. Process safety

• Is a change of synthetic route required for safety reasons?

6. Unit operations suitable for pilot plant

What are 7 differences between lab and pilot plant?

1. Working on scale takes time

• 1 hour in the lab = several hours in the pilot plant

2. Some unit operations are more difficult on scale and/or are not commonly used.

• Rotary evaporation/ distillation to dryness

• Purification by chromatography

• Rapid transfers

• Keeping temperature very low

• Drying with Na2SO4

3. Filtration

• Mud takes time to filtrate

• Alternative solutions to ordinary suction filtration: pressure filter, filter dryer, centrifuge

4. Keep dilution low

5. You can’t see what is in the reactor

• How do the crystals grow?

• If you can’t see the phase separation in a separating funnel, it’s even harder through a sight glass.

6. Safety

• A small exotherm on lab-scale can be magnified to a large exotherm in the plant.

• It is dangerous to make additions in one, quick shot.

• Flammable solvents

• Static electricity

7. Impact on environment

How do you select a synthetic route?

• Few steps

• Minimize protecting groups

• Order of synthetic steps

• Convergent synthesis

• Telescoping

• Available starting materials

• Suitable solvents (avoid diethyl ether, hexane, chlorinated solvents)

• Keep waste streams low

Which critical process parameters should be identified in optimisation?

Temperature, pH, stoichiometric ratio, addition rate, mixing efficiency, reaction time, concentration, crystallisation conditions…

What happens when optimisation is done at a too early stage?

It will just lead to waste

What are the differences between an initial sythetic route and a pilot plant route?

What are common scale-up challenges?

• Poor mixing

• Heat transfer limitations

• Difficult filtration

• Different crystal morphology

• Unexpected impurity formation

• Equipment limitations

• Longer cycle times

What are the 4 steps in selecting an outsourcing partner?

1. Should be appropriate for the phase of development

• Early development: innovative and strong technical capability

• Later development: optimization, routine manufacturing

2. Specific processing and equipment capabilities?

3. One- stop-shop: minimise the number of technical transfers in the future?

4. Location

How do you work with an outsourcing partner?

• Frequent meetings (face to face, Teams)

• Written updates

• Reports

• Go and visit!

• Start in time!

What is an API?

An “API Starting Material” is a raw material or intermediate that is used in the production of an API and that is incorporated as a significant structural fragment into the structure of the API.

What should be applied after API?

From this point on, appropriate GMP should be applied:

• Number of synthetic steps

• Good control strategy (specifications, IPC)

Good manufacturinbg practice (GMP)

• Suitable manufacturing facilities

• Written instructions (SOP standard operation procedures)

• Written batch protocol

• Records are made during manufacture: demonstrate that all steps have been performed

• Trained staff

• Controlled raw materials

• Traceability

• Cross contamination should be prevented

GMP is not only documentation. It is a system that ensures product quality, patient safety and process consistency.

Who is responsible for the API/GMP?

• You as a sponsor is responsible for the quality

• Contract manufacturers (including laboratories) should be evaluated by the contract giver to ensure GMP compliance of the specific operations occurring at the contract sites.

• Audits, questionnaire

• Regardless of where the active pharmaceutical ingredient is made, companies must adhere to strict safety and quality standards set by the country where it will be used.

What are 3 characteristics of cleaning an API?

• In pilot plant production cleaning and control of cleanliness is time consuming.

• Cleaning may sometimes need as much documentation as the chemical process.

• Extremely important that the cleaning is done and verified properly as cross contamination between different API’s is a disaster.

How is safety monitored in a pilot plant?

Reagents

• Stability and toxicity

Process

• Stability and toxicity of intermediates

• Control of exotherms

• Control of gas formation

• Concern and control of static discharge

• Flammable materials (If exotherms are in a gaseous environment they can be under pressure.)

DSC

Differential Scanning Calorimeter

What are 4 possible safety evaluations?

1. Lab scale observations

2. Literature and calculations

3. DSC (Differential Scanning Calorimeter):  when you start to raise the temperature, there is no going back.

• Peak = mountain energy that is removed in order to keep the temperature constant

4. Reaction calorimeter