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Flashcards in APIs Deck (55):

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
Technical Agreements
Area and Facility
Dedicated vs Multi purpose
Validation Policy
Storage and


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?
Scale: larger scale than dosage form MFG
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:
IR ref spectra
Vol 6:
BP vet


What are the basic principles applied to any chem R&D activity?

All R&D activities should be subject to a QMS
All experimental work should be repeatable
Good scientific recording essential
Req of QA increases as development activites progress: API to CT to Tech transfer


What are the objectives in API process development?

Determine structure of API (proof of structure)
Develop synthetic route suitable for commercial scale MFG + validation
Develop IPC
ID and quality impurities
ID polymorphs
Develop test methods and specifications
Investigate chem stability
ID degradation products + detection method of all impurities
Transfer process into production


How do you set API specification?

Impurity profile: >0.1% ID and >0.15% qualified
Qualification: determine risk to pts
?toxicity profile: if known literature will suffice
otherwise some study
specify physicochemical properties of the API: crystalline form, polymorphishm and particle size distribution


Where does technology transfer apply in the development of API processes?

Transfer of scientific info from researhc to the development group
Transfer of technical info to the production group


What is a tech transfer plan used for?

Executed using formal TT protocols
Clear phases, objectives and defined roles/responsibilities
Review of TT in a form of TT report is needed


What should be included in a Tech Transfer Report?

Research report
Development history report
Process development report
API product description
Stability data report for API and intermediates
Development batches campaign reports
Analytical development/validation studies report
API packaging requirement
API labelling requirement
Materials management
Regulatory info


What is a provisional specification?

It forms the basis for discussion between supplier and customer in agreeing on the type and quality of RM
Need to strike a balance of capability and formulation need


What does a typical API pharmacopeial specification include?

Characteristics: appearance + colour + solubilities + colour of solution
Chemical properties: Tests for ions + moisture content + loss on drying
Physicochemical properties: UV spectrum + pH + Melting point + optical rotation + test for polymorphism
ID tests: UV + IR + Specific colour reactions + Chromatography + melting point
Purity tests: process (heavy metals / specific metallic impurities / residual solvents / Catalysts) + Decomposition (Related substances)


What is the scope of GMP guide part II?

Human drug API from all sources: chem, fermentation, biotech, natural sources
API from blood or plasma
API for CT
Later chem isolation from biological, botech or fermentation
Applies to the MFG of API after the introduction of "API Starting Material"
NOT sterile API after point of sterilisation
NOT Vaccines, whole cells, whole blood, plasma
NOT medical gases, bulk drug products
NOT radiopharmaceuticals


What should an API PQR include?

IPC and final product test results
Process deviations and specificaiton failures
Changes carried out to processes or test methods
Stability studies
Complaints, recalls
Adequacy of corrective actions


What is APIC? What do they do?

APIC: Active Pharmaceutical Ingredients Committee
Sector group with Cefic (the european Chemical Industry Council)
Consists of chemical and pharmaceutical companies MFG APIs or ealier stages
Ensure pt safety by API compliant
Issue best practice documents


What are the strategies to control cross contamination in API MFG?

Separation of critical activiteis and certain product categories
Layout designed to give sutiable: material flow + personnel access + maintenance access
Finishes to allow adequate cleaning and attainment of req EM standard
Ventiation system to provide product protection


What are the product types that require clear separation?

highly toxic herbicides and pesticides
Steroids and hormones
Other potent or sensitising drugs


What are range of filter efficiency under EU classification?

EU 3 - prefilter
Couple with EU 6 or 7
EU10 - 14 range: HEPA


What are the two main ways of which impurities are generated?

Related substances: by-products + degradation products + structurally realted to the API
Process contaminant: Process specific (reagnets / solvents / catalysts) + process independent (foreign matter, residues from dirty equipment EM)


How would you control level of related substances in the API?

Good comunication between R&D and MFG staff
Process validation and control in routine MFG: limits + reproducible
Confirm impurity profile over the range of working limits
Control of RM


What are the Part II guidance on reporting, ID and characterisation of impurities?

Report if: 0.05% (2g daily dose)
Structure characterisation: >0.1% (0.05% if (>2g)
ID degradation product: >0.1%
ID 2g 0.05%


What are the likely sources of chem contamination?

From MFG process: by-products, degradation products, residual reagents, solvents or catalysts
Cross contmaination: ingress of lubricant, seal fluids or heat transfer fluids
Separation of activities
Poor ventilation - powder
Poor segregation, packagin and labelling or materials
Lack of equipment control


What are the main sources of physical contamination?

1. RM + reagents + solvents: sieving + filtration before use
2. MFG EM: ventilation + building fabric + pest control + plant housekeeping
3. Equipment: Disintegrating gaskets + o rings + screens + rust + nuts bolts + swarf rubbing and wearing
4. Personnel: pens + screwdrivers _ personal items + clothing + packaging


What are the techniques used in processing and purifying API?

Filtration, crystallisation and isolation
Filtration: purify solid products + dissolve crude product + low solubility for impurities
Crystallisation: Critical to final physical form - bioavailability
Crystallisation: Natural cooling + Controlled crystalisation (agitation + temp) + Seeding
Isolation: follows crystallisation + mother liqior (impurities)
Decolourisation: combine with filtration and crystallisation - followed by isolation + activated carbon - absorbs impurities + colour
Precipitation: replace crystalisation - acid/alkaline add to solution or distillation
Drying:after isolation + homogenised after drying
Evaporation: used instead of distillation of high boiling point liquids - thermal stable
Solvent extraction: different polarity
Resolution of optical isomers: L dopa + esomeprazole


What are the stages of chemical process validation?

Process Design:
R&D: ID critical process parameters/critical quality attributes - matrix experiement
R&D: Est impurity profiles + set product spec
R&D: Analytical method devised and provern
R&D: stability studies start
Process Qualification:
Point of which API starting materials are introduced
Essential structural element emerge
Pt where CQA is affected by the process
Pt where introduce/remove impurities
Stage where API molecules are formed
Stage after which no significant impurities will be removed
Purification sequences in the API process
All purifed API finishing stages


What are the three options of validation?

(note: Annex 15 for validation)
Prospective (preferred approach)
Not expected validation on the first MFG batch - but studies must be performed - results published before distribution of drug product
Validation should be carreid out as soon as production is estabilshed to commercial scale on a routine basis
Concurrent validation of API process
Alternative methods for old estabilshed APIs
At least 3 batches
Carried out as per prospective
No restriction of the API batches


What are the specific hold up points in equipment in API MFG?

Reactor dome
Nozzles on reactor domes
Dip-pipe on reactor domes
spray balls
sample points
Dead-legs in process pipes
Equipment wells (Bottom)
Difficult to clean, inaccessible points


What are the selection criteria of selecting a cleaning validation study candidate in a multi-purpose equipment?

Difficulty of cleaning
Worse case scenario


How should residue limits to be calculated?

Based on potency, toxicity and stability of the chemical studied


How to establish cleaning validation limits?

GMP guidelines do not state limits
Limit: practical, achievable and verifiable
Based on: product + processes used + equipment used
Biological activity known
Pharmacological active dose (PDD) or Min daily dose
Carry over - 1/1000 min daily dose
No defined daily doses
Based on LD50
10 ppm?


What are the major risks and challenges to product quality associated with biotech MFG?

Inherent instability + variability + pathogenic contamination
Potential for variability in the cultivation process - lack of control
Potential for variability of outcome of the cultivation stage to overstress the purificaont procedures = inadequate purity and variable potency
Potential - contamination - extraneous agent in MFG
Inability of in vitro analysis alone to confirm quality of final product
Relative insensitivity of bioassay - assess product quality


What are the relevant GMP guidance on MFG of bulk biopharmaceuticals?

Annex 2
Annex 5
Annex 14
Part II: Chapter 18: cell culture and fermentation


What is a classical fermentation product?

Synthesis takes place via fermentation processes - using fungi or bacteria
Resulting low molecular weight - purified by conventional chemical process
i.e. antibiotics and vitamins


What is a biotech product?

More complex
Larger (often by a factor of 1000 or more)
Proteins or nucleic acids
Susceptible to microbial degradation


What is a typical MFG process of a biotech process?

1. Combination of seed and starting materials
2. Small scale cell culture
3. Large scale cell culture
4. Inactivation
5. Harvest
6. Purification
7. Bulk product
8. Filtration
9. Storage


What is a seed lot/cell bank system?

Quantity of cells used to seed a cell substrate or growth medium, processed at one time and of uniform composition, adequately characterised etc
Definitive master seed lot/cell bank prep from a homogeneous suspension of viruses or microbial cells - aliquot to storage
MFG working seed lot:
prep from fixed finite passage of the master
Both master and working seed must be adequately characterised:
Freedom from contaminating microbes
Characterisation of relevant gene product
Stability beyond the highest passage level to be used for production


What are the general precautions in preparing seeds/cell banks?

Must be prepred in a GMP lab designed to minimise cross contamination and mix-ups
Materials used assessed against formal specifications and release for use
No other cell banks should be handled simultaneously in the same lab or by the same operator
Cell bank should be aliquot from a single culture - pooling of several cultures - variation in properties