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PR3145 (pharm law) > Lecture 2 Assessing Manufacturers Compliance > Flashcards

Lecture 2 Assessing Manufacturers Compliance Flashcards

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1
Q

limitations of conventional product testing

A
  1. can only test on a ‘representative’ sample size
  2. can only test if the analyte and test method is known
  3. can only test if test method is specific, accurate and reliable (aka validated)
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2
Q

types of QA of product moved upstreams

A
  1. product design/formulation of dosage form
  2. control of starting materials (APIs, excipients, and containers)
  3. GMP compliance by manufacturers of API and finished dosage forms
  4. contamination control, process validation and stability testing
  5. use of innovative technologies and approaches (process analytical tech PAT, parametric release)
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3
Q

limitations of sterility testing

A
  1. high stat probability of passing sterility test even when contamination level is relatively high
  2. sterility test is by no means cheap (both pos and neg test)
  3. two weeks of incubation period is needed for sterility test
  4. sterilised products cannot be released in real-time
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4
Q

parametric release of terminal sterilised LVPs

A

parametric release are release based on key parameters of a validated sterilisation process, instead of results of batch sterility test:

  1. temp
  2. pressure
  3. sterilisation time/cycle
  4. bioburden of pre-sterilised parental product
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5
Q

what is quality risk management

A

a systematic framework to manage quality risk in stepwise approach comprising risk identification, analysis, reduction and communication

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6
Q

objective of QRM

A

assess risk to product quality/patient, and then manage these risk to an acceptable level

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7
Q

steps in QRM

A
  1. risk idenfication
  2. risk analysis
  3. risk reduction
  4. risk communication
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8
Q

risk identification

A
  • quality of starting materials
  • production and packaging processess
  • premises and equipment
  • personnel (human) errors
  • warehouse and pest control
  • cleaning procedures and contamination
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9
Q

risk analysis

A
  • failure mode and effects analysis (FMEA)
  • fault tree analysis (FTA)
  • hazard analysis and critical control points (HACCP)
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10
Q

risk reduction

A
  • reliable suppliers
  • amend cleaning procedures
  • revalidate processes
  • training/ retraining
  • tighten pest control program
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11
Q

risk communication

A

communicate to internal staff and external stakeholders

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12
Q

who should be concern and business of quality of medicines

A
  1. manufacturer:
    - product and manufacturer licence holder
    - distributor and advertiser
    - research and development scientist
    - production/ QC experts
  2. regulator HSA
    - product quality reviewers
    - GMP inspectors
    - analytical scientists
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13
Q

hard skills and knowledge required by manufacturers and regulators

A
  1. pharmacology and pharmacotherapy
  2. medicinal chem
  3. pharmaceutics
  4. pharmaceutical microbiology
  5. pharmaceutical law
  6. GMP and quality standards
  7. statistics
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14
Q

soft skills required of regulator and manufacturer

A
  1. confidence
  2. assertiveness
  3. integrity and impartiality
  4. perseverance
  5. tact and diplomacy
  6. oral communication and negotiation skills
  7. report writing and written communication skills
  8. willing to travel overseas regularly for business
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15
Q

what is quality

A
  • fitness for use for treating patients
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16
Q

what does the quality of medicinal products includes

A
  1. identity of starting material
  2. potency of starting materials API
  3. purity (absence of contaminants)
  4. pharmaceutical quality attributes (of finished dosage form)
    - hardness, friability, size, dissolution profile
    - pH, clarity, color indexes, microbial limits, sedimentation
    - viscosity, sterility, endotoxin level
    - stability and homogeneity
17
Q

what is a contaminated medicinal product

A
  • contains undesirable foreign matters of chemical or microbiological nature
  • may be present in starting, intermediate or bulk product
  • introduced during manufacturing: procurement, sampling, processing, packaging, repackaging, storage, transportation
18
Q

classification of contaminants

A
  1. intrinsic:
    - present inherently in API, excipients, packaging materials used in formulating product
    - not removed completely from starting andpackaging material during manufacture
    - aka impurities often specific in nature
  2. extrinsic:
    - originate externally from production personnel, process equipment, packaging equipment, manufacturing premises
    - usually non-specific in nature
19
Q

why is there a need to control impurities

A
  • overall therapeutic effect of medicinal product is dependent not only on its pharmacological properties of API but also on toxicity of impurities present
  • need control of impurities in starting materials and finished products are an important part of drug development, manufacturing and GMP compliance, and regulatory assessment for marketing approval
20
Q

types of impurities in API

A
  1. process related:
    - un-reacted API starting material/ intermediates
    - residual reagents and catalyst
    - residual solvents
    - residual heavy/other metals
    - by-products
  2. drug-related impurities
    - degradation products (after API formed)
  3. polymorphs
    - eg. cimetidine, carbamazepine, ampicillin
  4. stereoisomers:
    - eg. dopamine, propranolol
  5. container-closure system and labels
    - primary containers: residual polymers.monomers, plasticisers, antioxidants, coating materials
    labels: adhesive, printing ink
21
Q

types of controls on intrinsic contaminants

A
  1. QC testing of materials and finished product (manufacturer)
  2. assessments of impurity profile (HSA product reviewer)
  3. GMP compliance (manufacturer)
  4. periodic GMP audits (HSA inspectors)
22
Q

types of control of extrinsic contaminants

A
  1. GMP compliance

2. periodic audits by GMP inspectors to verify compliance

23
Q

relation of operations to potential risk of contamination

A

increased operations within a given facility piece of equipment, increase risk for contamination

24
Q

factor influencing stability of medicinal product

A
  1. product-related factors:
    - formulation of the product
    - physico chemical properties of drug subs/ excipients
    - types of primary container and packaging material used
  2. environmental factors:
    - temp
    - moisture
    - light
    - oxygen
    - physical stress during transportation
    - in-use contamination during consumption
25
Q

product stability

A
  • demonstrated through stability testing program
  • take into consideration product related and environmental factors including:
    a. real time studies
    b. accelerated studfies
    c. continual stability studies
  • establish shelf life when stored, distributed and used under recommended temp, RH, and other envi conditions
26
Q

effect of elevated temperature during storage

A
  1. loss of potency (degradation)
    - loss in efficacy, patient’s life at stake
  2. loss of vehicle (evaporation)
    - increase concentration of API to >110% of labeled amt
    - toxic/harmful
  3. hardening of tablets (loss moisture)
    - change dissolution profile
    - alteration in bio-availability
    - change in rate and extent of systemic absorption
    - loss in efficacy or therapeutic failure
27
Q

effect of elevated RH/moisture content during storage

A
  1. formation of toxic degradation products (hydrolysis)
    - acetic acid from aspirin
    - epi-anhydrotetracycline from tetracycline (renal damage)
    - penicillenic acid from beta-lactam antibiotics (anaphylaxis)
  2. loss of package integrity and label clarity
    - reduction in label quality; critical if essential info is obliterated
  3. loss of adhesion of transdermal patch
    - may drop, no med administeration
28
Q

effect of increased agitation and vibration during transportation

A

ingress of micro-organisms into products:

  • poor container closure integrity/ hairline cracks
  • drop in microbiological quality of product
  • unsafe product (if intended to be sterile)
29
Q

effect of poor handling of product during in-use

A

contamination of product:

  • drop in microbiological quality of product
  • unsafe product
30
Q

what is process validation

A

ensuring and providing documentary evidence that manufacturing processes are capable of consistently producing a finished product of required quality

31
Q

major steps involving process validation

A
  1. establish tablet quality specifications
    - blend homogeneity, hardness, thickness, friability, particle size, dissolution profile
  2. identify critical processes
    - blending, milling compression
  3. design sampling plan
  4. design testing plan
    - blend uniformity and compression
  5. set acceptance criteria
    - within 90%-110% of labeled amount
  6. perform statistical analysis
    - intra and inter batch
32
Q

statistical analysis

A
  1. intra batch analysis:
    - demonstrarted consistency of all 3 validation batches
  2. inter batch analysis
    - demonstrate equivalency among the 3 validation batches and pilot batch (used for clinical trials studies)
33
Q

validation protocol essential elements include

A
  1. objectives
  2. scopr
  3. persons responsible
  4. critical processes
  5. list of raw materials and equipment used
  6. sampling plan
  7. testing plan
  8. frequency of sampling and testing
34
Q

validation report essential elements include

A
  1. validation rest results
  2. data analysis
  3. statistical analysis
  4. recommendations and conclusions
  5. attachments: batch records, manu flow chart, stats control charts, tablets and graphs
35
Q

traditional approach to process validation

A
  1. process validation: 3 consec successful production batch

2. revalidate: changes to critical process, equipment, materials

36
Q

new approach to process validation

A
  1. identify critical quality attributes
  2. extensive process design and process qualification
  3. monitoring of critical process parameter
  4. continued process verification beyond 3 production batches
    - assures process remain continually in a state of control and products manufactured are consistently of good quality

PR3145 (pharm law) (6 decks)

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