TOPIC 2.0: API Synthesis (Reaction)

GMP Requirement when Designing an API Reactor

“Equipment used in the manufacturing, processing, packing, or holding of a drug product shall be of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance”

Design Considerations for API Reactor

• Suitable Charging System

• Good Mixing

• Complete Discharge (of batch contents at the end of a reaction)

• Contamination Prevention

Design Considerations for API Reactor — Suitable Charging System

• Refers to charging or transferring of reactant or catalyst into the batch reactor

• To prevent cross contamination of holding/storage tanks

• For safety reasons

DIP PIPES

• Used for liquid reactants charging

• Prevents the formation of electrically charged fine droplet mists

  • Hazardous if tank atmosphere is flammable

ADEQUATE NUMBER OF HEADER TANKS

• Used especially when there are multiple reactants

  • Having only 1 header tank can lead to cross contamination in the event of reserve or misdirect flow

• Header tanks are connected to the reactor via manifolds

DEDICATED REACTOR DOSING SYSTEMS

• Install metering pumps to pump reactants directly from drums/tanks

  • Adds reactants into the tank in a controlled flow rate or in accurate quantities

Design Considerations for API Reactor — Good Mixing

• Necessary to promote contact between reactants

• Contact of reactants is crucial to achieve a complete reaction → higher percentage production yield and minimises unreacted reactants

BAFFLES IN A MIXING TANK

• Reactors are equipped with variable speed agitators and baffles → stops the swirling of reactants

• Without baffles, the tangential velocities coming from any impellers causes the entire fluid mass to spin → creating a vortex

  • Particles just spin around in a laminar flow and different layers of fluid just slide past each other with minimal mixing between them

• Baffles reduce the vortex, stagnant zones, sedimentation and circular circulation

Design Considerations for API Reactor — Complete Discharge (of batch content at the end of a reactor)

• To minimize carry over into the next batch

NO DEAD LEGS

• At valves or along pipelines

• Absences of dead legs are denoted by “MIN” (ie. minimum distance) on P&IDs (ie. Piping & Instrumentation Diagrams)

• Dead legs are areas of a piping system that rarely see flow, yet are still exposed to process

  • They are to be avoided as they are prone to hold ups of material → contaminates next batch and can cause corrosion if not cleaned properly

SLOPING OF PIPING

• Intentionally built in to facilitate draining towards low points in the piping systems

BOTTOM DISH DISCHARGE

• Bottom of the reactor is often designed in a shape of concave dish → to enable complete discharge of the contents in the reactor to the next vessel

• Ensures complete product removal to minimize contamination or carry over into next batch

Design Considerations for API Reactor — Contamination Prevention

“Equipment shall be constructed so that surfaces that contact components, in-process materials, or drug products shall not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements.”

• Prevents shedding of materials from the equipment into the product

• Easy to clean for complete removal of product before using equipment for a different product

• Common reactor construction materials are carbon steel or stainless steel (316L)

  • Glass lined → when reactants are reactive to metal

  • Internal mirror finish → more polished surface = easier to clean

• Seals for fittings, instruments, flange gaskets, O-Rings should be made of inert materials

  • They are temperature resistant and compatible with the chemical it makes contact with

• Jacketed vessel minimises the use of coils for temperature control

  • Coils are difficult to clean and risk contamination if the coil is corroding

• Nozzles or spray balls are often built into the reactor to facilitate cleaning-inplace (CIP)

  • dangerous and difficult for one to climb into the reactor to clean it