What testing would you expect for an API?
Appearance - Visual
Identification - HPLC / UV
Assay - HPLC
Related Substances - HPLC
Particle Size - Sieving / X-Ray Diffraction.
Water Content / Loss on Drying- Karl Fisher
Residual Solvents - GC
Residual Catalysts
Polymorphism
Isomer
During API manufacture what methods are there for purification?
Distillation
Crystallisation
Extraction
Washing
Centrifuge
API’s must be manufactured in accordance with ?
Part II EU GMP, ICH Q7, 1252 /2014, Distributed to 2015/C95/01
What is a CEP vs DMF?
Certificate of Conformance to the European Pharmacopeia - demonstrates equivalence.
DMF - Drug Master File
Typical Manufacturing Controls for an API
ICH Q7 GMP Part II
Temperature
Pressure
Agitator Speed / Time
Rate of Addition
API Powder - Drying Conditions
What are the key Manufacturing Steps in API Production?
Dispensing
Mixing
Chemical Reactions
Extraction
Purification
Drying
Particle Size / Micronisation
Filling
Packing
What are the main risk factors when assessing Nitrosamines?
Synthesis Routes
Use / Re-Use of Solvents
Starting Materials
Packaging Materials
What are the contents of a CEP?
Name of Manufacturer
Intermediates
Sterilisation details (If Applicable)
Impurities
Max Daily Dose Values
Residual Solvents
Container Closure
Water Quality
Micro Quality
Does Part II of EU GMP apply to:
a) Vet
b) IMP
a) Yes
b) Section 19 states that it’s the manufacturer responsibility to ensure the IMP is of appropriate quality but there is no requirement to comply with Part II
Where does GMP start for a chemical vs a biological API?
Part II - has table
Chemical is during the introduction of the API starting materials
Biotech - maintenance of working cell bank
How is micronisation of API done?
Jet milling using compressed air or nitrogen
Particles collide with each other at high velocity fracturing into smaller sizes
Advantages over milling is that no heat is generated for heat sensitive materials and the particle size is a lot finer
What are the typical sources of impurities?
Organic- degradation products, by products, starting materials, intermediates
Inorganic- catalysts, heavy metals, residual salts, reagents
Residual solvents
What are the different classes of solvents?
Give examples
Class 1 - avoid - benzene
Class 2 - limit - acetonitrile, methanol
Class 3 - use - acetone, ethanol
What are the reporting, identification and quantification thresholds for impurities of APIs?
ICHQ3
Max daily dose <2g/day - 0.05%, 0.10% , 0.15%
Max daily dose >2gday - 0.03%, 0.05%, 0.05%
What is the definition of the following in relation to API manufacturing?
a) Reprocessing
b) Reworking
a) Were API that is OOS is reintroduced to the manufacturing process such as repetition of recrystallisation / filtration / milling step to bring it within specification. This is part of an established process that is typically registered.
b) The root cause of the OOS is understood. Reworking will require appropriate testing and evaluation. Concurrent validation may be appropriate. Reworked batches impurity profiles should be compared to established process
What is a polymorph? How do we test for these?
Is a distinct crystalline form
Tested using IR and microscopy
What is an isomer and how do we test for this?
Same chemical formula but different arrangement of atoms (stereoisomers are mirror images)
HPLC / GC / MS
What is a gringard reagent?
Used in production of complex molecules to produce carbon- carbon bonds
What is seeding?
Seeds are used to control the crystallisation process in order to produce a desired size/ shape/ polymorphic form
What would you expect in a PQR for APIs?
Critical IPCs and test methods
Batches failing specification
Deviations
Complaints / returns/ recalls
CAPA
Changes
Stability
What would you cover in audit of API?
ICHQ7 Part II PICs
Supplier Management / Outsourcing
CPPs for API - Rework / Reprocessing / Blending
Contamination Control Strategies
Cleaning Validation
Solvent Use
QC - polymorphism / isomers / impurities
Stability
What is telescoping in relation to API Manufacturing?
Where processing steps within an API process are combined to run multiple steps in sequence often without isolation or purification of intermediates
Increases impurity risk
Impact particle size
Polymorphic form
Increase risk of isomer formation
What is an ASMF?
Active Substance Master File
Submitted to keep information relating to API manufacture confidential
Applicants Section and Restricted Part which is submitted for MA approval
