API Flashcards
Describe typical chemical API process
Receipt raw materials/solvents
Dispense quantities required
Initiate reaction sequences
Purify/isolate intermediates/ final substance
Final substance isolation
Dry/Filter
Micronize if required
What are control parameters in typical API manufacture?
Weight, Temp, Time (rate of reaction), Pressure, filter size, drying time, drying temperature.
What are typical API specifications?
Description
Assay
ID
Impurities (Rel sub, Res solvent, Elemental, E/L)
Physicochemical properties
Particle size
Polymorphic form
Chiral purity
Water content
Microbial limits
What are the QP legal issues with changing API supplier?
Need API QP declaration (Audit)
Need MA update
Need to have national competent authority approval for each batch if 3rd country
What are the different API Purification methods?
Recrystalisation, Isolation, distillation, evaporation, Solvent extraction, Chromatography, Freeze drying.
What water grades are required for API? What if sterile API?
Potable, if sterile then need to be controlled for endotoxin and bacterial bioburden. Final processing step needs to be WFI. EMA guidance document.
Describe a typical virus/Cell based biologics/Biotech API process.
Receipt of raw materials- Natural in origin. Eggs or cells
Eggs/ Cells incubated to optimum growth state
Virus/ Cell DNA contains required material to illicit required immune response/ Create protein of interest
Virus/DNA inoculated into eggs/ cells
Cells/ Eggs act as bioreactor and multiply required virus or target protein under incubation
Cells/Eggs cooled to stop growth
Harvesting steps include clarification, Tangential flow filtration, centrifugation for purification
Dilute with buffer and sterile filtration for bulk material.
Subsequent steps to insert into final containers
What are typical specifications for Biologics active substance?
Drug products?
Substance;
Appearance
ID
Impurities/Purity
Quantity
Potency
Product;
Appearance/Description
ID
Impurities/Purity
Quantity
Potency
Ph
Osmolality
What are typical purification methods for biotech/biologic products
Clarification (course filtration)
Tangential flow filtration- separation method using Ultrafiltration.
Centrifugation- with sucrose gradient to allow extraction at specific RF value
Chromatography- separation
Where does GMP begin for different API manufacturing?
Chemical- Introduction of API starting material
Animal API- Introduction of API starting material
Plant API- Introduction of API starting material
Herbal extract- Further extraction
Powdered Herbs- Physical process/ packaging
Biotech fermentation- Maintenance of working cell bank
Classical fermentation- Introduction of cells into fermentation
What are the rules around API solvent recovery?
Allowed if;
-Approved procedure
-Recovery method approved
-Recovered solvent meets specification
-Allowable within MA
What are API requirements for IMPs?
No guidance legally, section 19 of part 2 gives some guidance.
How do you control incoming materials for API manufacture?
Supplier assurance
Audits
Initial review of receipted goods- tampering/ labelling
Cleaning status and certification of transport
Loading vessels used and perform incoming ID test prior to process discharge.
When can you blend materials?
When can’t you blend materials?
Blending of materials of same specification is acceptable, combining fractions of a production process.
It is not acceptable to blend OOS API with in specification API to average out result.
What is re-processing?
What is re-working?
Re-processing is introducing unreacted material back through the routine process stream (IPT shows incomplete reaction)- if done repeatedly, indicated non robust CPPs and consider revalidation.
Re-working is performed where material does not meet specification and is subject to deviation evaluation. Increased (Equivalency) testing and stability considerations are required as well as MA/CTA impact. May also require additional method validation due to ‘new’ outputs from new process steps.
