APIs Flashcards
You are auditing a raw material supplier. What specifics would you look at while on site?
According to Part 2 of Vol4 of the Rules governing medicinal products there are GMP guidelines that API manufacturers of to adhere to. This is in line with ICH Q7. Audit and evaluate their: Documents and record keeping Understand the manufacturing process and the point at which GMP commences in chemical synthesis. QMS: CC, Dev, Complaints, Recall, Training, Equipment (Validation, Maintenance and Cleaning) Material Management Packaging and labelling Storage and distribution Lab Controls Agents, Brokers, Traders and distributors Relabelling Technical Agreements Area and Facility Dedicated vs Multi purpose Validation Policy Storage and QC
Is it acceptable to reuse solvents in the API manufacturing process?
If testing of the solvents confirms that they are suitable then it is acceptable, How this occurs must be documented and controlled. This is as per Section 14.4 in Part 2 of Vol4.
What is the regulatory basis of GMP in API manufacturing?
The rules governing Medicinal Products in the European community: Vol4 Part II. This is legislated in the EU under EU Directive 2003/94/EC as amended. and is legisalted in UK law under sect 32 of SI 2012 No.1916.
What is a CEP and how would you get one?
CEP is a Certificate of Suitability for Substances. A company can get on…
API Arrives on site and paperwork details a different site of manufacture from that approved. The had moved sites due to a shut down period. THis is the second batch receipt on site. The previous batch of API has been used and is not on the market. As the on site QP what woudl be your course of action?
We have 2 situations:
1. New API
2. Previous receipt
for each one we will consider GMP, Reg and Patient Safety.
To ensure a suitable investigation is carried out for each I would open up Deviations.
For 1. until I understand and gather more information I would like to keep the product in quarantine. Initial actions would include:
Still continue to perform release testing however perform test on each carton and if reduce sampling exists return to normal sampling.
Also would request to review the TA and the MA to check what sites are authorised and which ones are not. Both from a Quality agreement perspective and legal licence. Is the site outside EU (Did we provide a QP declaration? If so which site(s)?)
WRT the second batch this is a bigger concern if the product used was not from an authorised site of manufacture as this means we have released product to the market not in compliance to its MA and the root cause as to how the previous receipt error was not picked up at relase needs further evaluation.
Why the site did not notify our company of such a change would need to be established- is this not covered in the TA.
When is a QP API declaration is required?
QP’s declaration concerning GMP compliance of the Active substance used as starting materials and verification of its supply chain
New MA application
Variation on existing MA: Change or add API maufacturer
per: Art 46(f) 2001.83.EC
What is the format of the QP API declaration?
5 parts
Part A (MFG sites): Include all sites - API, finished products, importation, batch drt
Part B (GMP compliance): QP of MIA use starting materials + importation/batch cert QP
Part C (Basis of the declaration): Audit or Third Party or no audit(Atypical / travel advice)
Part D (Supply chain traceablity): Supply chain established + documented / Rx Ax for all sites in the chain / documents ready for inspection
Part E attestation of the responsible QP): Needs to be EU QP
What is Therapeutic Window? Examples?
Therapeutic window is the range within which a drug performs its function. It is the ideal level that is both effective and safe. for some drugs this range is very small eg. Digoxin some have wide range: Penicillin and one with med is: Diphenhydramine
How would you risk assess excipients?
Route of adminstration Impact on quality of dosage form History of adultery i.e. heparin, propylene glycol, glycerol, Micro risk: endotoxin, pyrogens TSE risk Natural source
What are the important physical characteristics of APIs?
Particle size: powder flow + dissolution + DPI
Morphysm: dissolution
Moisture content
What are the potential sources of microbiological contamination of APIs?
Water used in final crystallisation + rinsing step + packaged into API
Starting material: biological or terrestrial origin
Premises: cleanroom design principles
During storage or distribution
What are the main microbial contamination related to plant source APIs?
Erwinia spp + Pseudomonas spp + Bacillus spp+ Cladosporium spp + Alternaria spp + Rusarium spp
Ecoli + Salmonella spp - if use sewage as fertiliser
What is bioequivalence and how would you demonstrate bioequivalence?
Comparison of 2 products: in vivo extent and rate of absorption equivalent
Durgs with bioequivalence problems: Warfarin + levothyroxine + Digoxin
In vivo animal studies - if correlation model exists
In vitro testing - if correlation model exists
In vivo bioavailability study in humans - 75/75 rule: 75% of subjects within 75-125% of the ref product chosen
Should not be more than 20% difference between products at 95% CI
What is a drug master file?
means of presenting chemistry data to the regulatory authorities for MAH
Preserve confidentiatlity of API MFG
Simplify submission
MAH have access to open part(US: no access at all)
Only cover API in EU (US: cover durg product, packaging materials, excipients and other ingredients in drug products)
Covers: New API + Exisitng APIs + Pharmacopoeial APIs
What are the options of registering an API in europe?
4 options
Certificate of suitability of Ph Eur monograph (Preferred)
Full details of MFG and QC of the drug substances from the MFG
European DMF (for non-pharmacopoeial substances only)
MA applicant cannot cross ref DMF without consent of the ownder of the file
What are the main considerations of API processes?
Synthetic routes: documented process + related substances/impurities
Chemical transformations: Linear or covergent - clean up/purification process
Time: days? Weeks? Months?
Yield:
Scale: larger scale than dosage form MFG
Validation:
R&D - CPA (critical product attributes), CPP (Critical process parameters) and proven accpetable ranges (PAR) established from lab
Production phase: Key stages validation needed
What does reprocessing mean?
Introduce an intermediate or API back to the process and repeating a crystallisation step or other process
Part of established process
What does reworking mean?
Put intermediate / API through process step that are different from established MFG process
How would you apply pharmacopoeial standards?
If pharmacopoeias std exists, then need to comply with.
Does not mean have to use routinely - provided justificaiton of superior method
If a general monograph of a dosage form exisits, must comply even if API not included in EP
What are the links between EDQM and EP?
Technical Secretariat and publishes EP
Co-ordinate CEP
Co-ordinate official medicines control labs (OMCL) - marketed product surveillance
What are the QP considerations on pharmacopoeias?
Must comply if monograph exists
Must comply throughout shelf life
Must also comply general monographs
If Pharmacopoeial grade - must comply all criteria
Alternative methods can be used for routine testing - if in doubt - EP method
Pharmacopoeial compliance - comply to standard only - separate to GMP
Pharmacopoeial standard - minimum standard - may need additional tests
Secondary Ref std can be used for routine analysis - if calibrated with primary ref
System to evaluate impact of pharmacopoeial updates
Aware of new monographs updates
OMCL may test your product
What are the contents of BP?
6 volumes Vol 1+2: Medicinal substances Vol 3: Formulated prep: General monographs Formulated prep: Specific monographs Vol 4: Herbal drugs, prep and medicinal products Materials used in homeopathic preparations Blood related products Immunological products Radiopharmaceutical prep Surgical materials Vol 5: Appendices IR ref spectra Index Vol 6: BP vet
