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.
What are the different impurity sources in Chemical API manufacture?
Biotech/Biologic manufacture?
Chemical;
ICH Q3 A,B, C, D,E
Chemical contamination;
Organics, Inorganics, Solvents
Related substances
Residual solvents
Elemental impurities- catalysts
E/L from filters
CROSS CONTAMINATION
Nitrosamine risks (Amine, recovered solvents, cross contamination, degredation)
Physical contamination;
Man
Material
Equipment
Environment - inadequate cleaning
Utility
Microbial;
Water sources, people
Biologic manufacture
Endogenous/exogenous contaminants
Biological;
Host cell material
Fermentation cell material
Virus
Prions
Protein sources
Blood impurities
Endotoxins
Chemical;
E/L- Filters
Physical;
As above
Microbial;
Water, Cellular material, people.
What are the reporting requirements for impurities? Where is the guidance found?
ICHQ3B
MDD <2g/day, Report 0.05%, ID 0.1% (or 1mg/day), Qualify (Safety profile) 0.15%
MDD >2g/day, Report 0.03%, ID 0.05%, Qualify 0.05%.
What are the different classes of solvent?
Where is guidance on this?
ICHQ3C- Residual solvents
Class 1- Avoid (Benzene, Carbon Tetrachloride)
Class 2- Limit 50-5000PPM (ACN, Methanol, Toluene)
Class 3- Low toxicity >5000PPM (Acetic acid, Acetone)
What are the different classes of elemental impurity?
Where is guidance?
ICH Q3D- Elemental impurities
Commercial drug product
Risk assessment to any potential element that could be present
PDE limits defined
Class 1- Human Toxicants (Arsenic, Mercury, Lead)
Class 2a- High probability of presence in DP. Cobalt, Nickel, Vanadium.
Class 2b- Reduced probability- Gold, Silver.
Class 3- Low toxicity, Barium, Chromium 500ug day.
Other elements- Low inherent toxicity. Al, B Ca, Fe.
What are common risk factors for Nitrosamine presence?
Amine group
Recovered solvents
Process degradants
Certain Packaging materials
Cross contamination
What are the 3 steps of EMA guidance for Nitrosamines?
What actions are to be taken in the event of nitrosamine identification?
- Risk assess and evaluate possibility of nitrosamine presence in marketed products
- Test products at risk (report isolated nitrosamines to HA)
- Apply for MA changes to reduce risk
Actions in the event of identification- Utilise guidance in ICH M7- Mutagenic impurities. Consider lifetime exposure risk.
What testing is required for Nitrosamines?
What guidance is there on specifications/tests?
Specialist technology- GC/HPLC- Mass spec detector. Validated methods
PhEur general chapter- 30PPB limit tests, Quantitative methods. Covers 7 known Nitrosamines and EDQM also provide reference standards.
What are the legal documents associated with API manufacture?
2004/27/EC- EU
2012:1916- UK HMR
2015/c95/01- Distribution
What is an API QP declaration?
What does an API site require?
What are the MHRA certificates issued to API manufacturers?
What are importation controls over APIs?
Any exceptions?
QP declaration for MA and variations to confirm audit performed and meets UK GMP requirements- Contracted out or done themselves. EMA guidance template.
API site requires certificate from NCA- inspection from NCA
MHRA registration and certificates issued are Importation, Manufacture, distribution- Guidance in flowchart for Ni and GB.
Importation controls under 2011/62/EC
- If not on approved country list for AS, NCA written confirmation needed for each batch.
- Must follow GMP for APIs (Part 2)
- Must follow distribution guidance (2015/C95/01)
Exception for NCA written confirmations would be if EU/UK has audited that site (positive outcome) and only to ensure availability of product.
What is the impact on a variable potency or purity within API batches?
What is expected purity of APIs?
Lack of effect
Toxic doses - Side effects, ADRs
Impurity issues- ADRs, side reactions, Nitrosamines, isomerism.
Purity value >98%
What factors can impact bioavailability?
Particle size of API
Homogeneity
Administration method
PKA/PH gradient / solubility
Absorption site condition
Polymorphic crystal structure of API
What microbial control would you expect for non sterile APIs?
API process is hostile (solvents, temps)
Water as final purification step and final packaging are sources.
Biologics- many sources of exogenous contamination.
Non sterile- 100cfu/g TYMC, 1000Cfu/g TAMC
What would you expect to be in a VMP for your API facility?
Overall policy for site
CPPs from development
Process;
CQAs for API
Impurity control
Purity control
Related CPPs for manufacturing
Equipment/Premises;
Annex 15
Calibration
Facility/ Utility
Prospective vs concurrent validation
Revalidation requirements
Cleaning;
Validated methods
Detailed protocol and report
Worst case, HBEL, PDE, Solubility
Visual examination
Recovery efficiency (swabs/rinse)
Clean/dirty hold times
Across manufacturing stream
Defined cleaning approach and documented procedure.
What are the considerations for sterile APIs? Does API always have to be sterile for parenteral?
If final dosage form is sterile, API should also be sterile unless;
- Terminal sterilisation
- Sterile filtration step
Must still comply with endotoxin specifications and controlled bioburden.
If must be sterile API, then Annex 1 applies and annex 2 for biologics.
Media fill requirements for all steps.
What are water quality requirements for APIs?
EMA guidance document- specific cases given.
Sterile- WFI for final purification
Non sterile API going into Parenteral- Purified water
All else- Potable water.
What contamination control measures are in place for API manufacture? Where is guidance found?
EMA guidance on PDEs
GMP part 2
ISPE (air quality and handling)
Dedicating facilities
Segregating activities within the facility
Dedicated equipment
Pressure regimes (negative pressure to prevent product contamination)
Recirculation (No extract re-circulation and graded filters based on activity)
Dust extraction controls
Process design (LAFs, Isolators, Cabinets)
Single use systems
Campaign manufacture
Cleaning validation
Clothing control
Waste control
Supervision
What are the different kinds of Biologic/Biotech Purification process?
Protein A affinity Chromatography (Biologic MABs)
Ion exchange Chromatography
Size exclusion Chromatography
Tangential Flow Chromatography
Viral Inactivation (Ph4, Solvent/detergent, Formaldehyde)
Viral Filtration- 15-35Nm nanofiltration
Sterilising filter
What would typically be monitored in a fermentation vessel?
Time, Temperature, Stirring speed, Ph, Dissolved oxygen,
What is the difference between Biologic and biotech processes?
Biologic- Recovery of biological entity from naturally occurring starting material
Biotech- Protein grown by simulated growth of cells (CHO/Bacteria/Virus)
What are the GMP concerns with Biologic/Biotech manufacture? Where is GMP guidance?
GMP Guidance Eudralex volume 4 Annex 2
- Starting material contamination and variability (cells, viruses, eggs)
- Scale up and adventitious contamination
- Variability in biological assays
What control and declarations need to be made by a manufacturer of a raw material with TSE risk?
CEP covering the control through general monograph
Declaration regarding manufacture to GMP (ISO9000)
Willingness to be inspected
Use of agents- Letter of authorisation and their willingness to be inspected.
