API Basics Flashcards
Atypical API
API used in a product that is not usually considered as an API but has an active effect. E.g. Calcium Carbonate, Glucose, Glycerol
Tend to be manu. as excipients, not APIs, therefore equipment & controls not usually up to std of ICH Q7/EU GMP part 2.
Typically have physical effects rather than pharmacological, but still seen as APIs by the regulators.
MA holder must assess and document to which extent GMP is complied with and provide a risk-based justification for acceptance of any derogation. The QP declaration for the material should set out in detail the basis for declaring that the standards applied provide the same level of assurance as GMP. (From EMA Q&A)
Key factors: Conduct RA, Supplier assurance key, on site audits, TAs with suppliers. Must have understanding of supply chain. Expect full testing of material to ensure meet standards for use as API.
Typical Biological / Biotech API Synthesis
Biological: Recovering bio-entity from natural starting material, e.g. blood plasma
Biotech: Stimulate growth, through multiple growing steps, of the desired biological entity in cells
Product typically formed in one step, most of process is growing (cultivation - fermentation), recovery & purification (chromatography and filtration (0.2um filters))
Purify recovered product to allow IV injection
Common purification method: ion exchange chromatography
Dedicated air handling units, change areas/air locks for processing area & dedicated people for cultivation bioburden reduction & prevent cross cont.
Master cell banks: Starting material for biotech API synthesis
Used as starting material for years
QP oversight required
Slight changes can have big impact!!
Typical Chemical API Synthesis
Multiple reaction steps, followed by purification and isolation steps
Typically low yields due to process loss
Long lead times
Strong chemicals, high temps and pressures – utilities must be able to withstand these
Chemical API Purification:
Recrystallisation
Filtration
Decolourisation (carbon)
Solvent extraction
Chromatography
Precipitation/Distillation/Evaporation
Chemical API Isolation:
Centrifugation
Filtration
Decanting
Drying req’d after isolatio
QP API Declaration (2004/27/EU)
Confirm API manu in accordance with GMP
Verify supply chain
API site audited (2/3 yr)
Required with every MAA or variation
Recrystallisation
Most common method used to purify APIs.
Crude product (API & impurities) dissolved in appropriate solvent. Either the desired compound / impurities can be removed from the solution, leaving the other behind.
Typically, mixture of “compound A” and “impurity B” dissolved in small amount of hot solvent to fully dissolve mixture, making a saturated solution. Solution then allowed to cool. As solution cools the solubility of compounds in solution drops. This results in the desired compound dropping out (recrystallizing) from solution and impurities remaining in solution.
The slower the rate of cooling, the bigger the crystals form. Critical to control rate of crystallisation.
Purity checked after each recrystallization step by measuring the melting point, since impurities lower the melting point. NMR spectroscopy can also be used to check the level of impurity. Repeated recrystallization results in some loss of material because of the non-zero solubility of compound A.
QP concerns regarding changes to Recrystallisation:
Change control with risk assessment. Patient safety impact.
Must consider 7 key points!!
1. Residual solvents limits (Q3C)
2. Elemental impurities (Q3D)
3. Impact of particle size of finished API bioavailability
4. Potential polymorphism/stereoisomers - adopts crystalline form, can be inactive, have different physical properties (solubility differences, or different effects on storage) or have patient safety impact
5. Overall effect on bioavailability of product (comparative dissolution)
6. Impact to moisture / volatile matter contact of API
7. Update to CEP / ASMF / MA - Likely to be Type II variation.
8. Nitrosamines QRA impact
Centrifugation
Most common method of isolation. Separation of the desired material from the mother liquor.
Difference Between Chemical/Biological API:
Manufacturing Process: Chemical API typically has multiple reaction steps and contaminants/impurities removed through purification steps and there is more freedom to rework/reprocess material. For biologics the API is typically formed in one step and the rest of the process focuses on recovery, cultivation and purification. Simpler to define CPPs and measure impact of change for chemical APIs. Biologics tend to be for sterile products therefore aseptic processes must be built into manufacturing process design. More process variability for biological APIs.
Premises: Chemical API synthesis produces very potent product therefore focus is on preventing cross contamination and operators from the product. Focus in biologics is on protecting the product from people therefore bioburden control throughout the process is NB. Both processes tend to use closed systems. Chemical API sites ‘dirty’ and Bio sites ‘clean’.
Batch Size: Chemical APIs batch size normally much larger than for biologics.
Lead Time: Biologics take much longer to manufacture than Chemical APIs (months vs. days) due to longer and more complex recovery and purification steps.
Personnel: Greater reliance on technology and operator skill to maintain CPPs for biologics.
Terminology
Testing: Simpler to characterise and develop appropriate methods for chemical APIs than biologics.
GMP: Level of GMP applied based on type of manufacture. In practice ‘full’ GMP is applied to biologics for the whole manufacturing process due to nature of the product. For chemical APIs level of GMP increases as you move through manufacturing process.
Registration of APIs in Europe – 4 options
EU – Control Through Registration
Certificate of Suitability (CEP) of PhEur monograph (preferred option)
API manufacturer demonstrates PhEur monograph controls API quality
EDQM issue certificate; valid 5 years
Full details of manufacture and QC of drug substance from the API manufacturer in MAA
European DMF (ASMF)
Way of presenting data to the NCA when API data ‘owner’ is not the MAA.
API manu submits ASMF directly to NCA and cross references MAA. Any questions related to API sent directly to the API manu.
Contains ‘Open’ and ‘Closed’ part. ‘Open’ part contains info to allow MAA to assure the quality of the API. ‘Closed’ part contains details on synthesis of API and is only available to the NCA.
Other evidence of suitability
API Importation (2011/62/EU – FMD):
API manu. in accordance with GMP
FMD: White list country / third country
FMD: Third country - Statement from NCA of GMP compliance. If not provided EU NCA may inspect & issue GMP cert
FMD: API dist. in accordance with GDP
FMD: API importers/distributors registered
FMD: Excipient GMP QRA (PQG/IPEC GMP Gdl on Excipients – based on ISO 9000)
Sterile APIs:
APIs for sterile products should be sterile unless product is:
Terminally sterilised
Produced by process which includes sterilising filtration
ICH Q7 applies up to point where sterile processing begins
APIs may be QP cert if DS is essentially DP - not legal req.
Reprocessing
Repeating a processing step. Re-introducing an intermediate/API, (not met spec/unreacted material), back into the process.
If routinely performed should be part of manufacturing process.
Rework
Subjecting an intermediate/API, including one that has not met specification, to processing steps different to the established manufacturing process e.g. recrystalising with a different solvent.
Requires protocol, must demonstrate material is of the appropriate quality after reworking.
Solvent Recovery/Recycling
Recovery of material from solvents allowed approved procedures used and recovered materials meet specification before being re-used. Must be documented.
Solvent recycling allowed follow approved procedure, recycled solvents meet spec and process is documented. Cross contam risk.
May have limit on how many times this is allowed, and this limit may be registered.
Can be cause of differences seen in impurity profiles if typically use fresh solvent and move to recovered/recycled solvent.
Key Items in Changing API Supplier:
Change Control
Location of API site: EU/non-EU (API importation considerations).
Site audit (compliance with E/Lex Vol 4 Part II/ICH Q7)
Variation to add API supplier to MA
Technology Transfer
Method Transfer
Demonstrate material equivalence (physical properties and MA specification tests). Particle Size, Crystal shape and Size NB.
Trials and Process Validation
API batches placed on stability
Bulk batches placed on stability
New API QP Declaration
QTA in place
API importer/distributor must be approved & registered within EU
EU – no NCA inspection! Onus on user to ensure suitability
API Supplier: Audit scope - ICH Q7 / EudraLex vol 4, part 2
PIC/S Aide Memoires for auditing API & Cross Contamination control
Pre-audit:
Vendor questionnaire
Previous Audit
Review complaints/deviations/changes/KPIs/PQRs
Ask for SMF up front
Gives an idea of Reg inspection history, QMS, out sourced activities
Can follow items up during audit
QRA for areas of focus during audit
Audit:
Items from SMF
QMS, Quality vision & mission, Senior Management review, KPI’s, Self -Inspections
Deviations
Change Controls
Customer complaints / Recall / Returns
Training systems
Documentation control
Production controls
Rework / reprocessing, recovery of solvents, recovery from mother liquor, solvent recycling, rejection of materials
Cross contamination strategy
Cleaning Validation / Verification
Laboratory system, DI, OOS procedure & OOS investigation
Maintenance, qualification & validation systems
Buildings and facilities (design and maintenance)
Outsourced activities and supplier management
Brokers / distributors and associated controls as per FMD
Facility Tour, reviewing cross contam. risks & control strategies, particularly in a multi-product facility, storage and management of materials, quarantine areas, temp / humidity control and monitoring, HVAC, GMP facility conditions and EM at final stages of production, controls around recrystallisation, packaging and labelling controls, release processes.
