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PR3145 > Lecture 2 Assessing Manufacturer’s Compliance to Product Quality > Flashcards

Lecture 2 Assessing Manufacturer’s Compliance to Product Quality Flashcards

1
Q

What is the 1st phase of quality prior to 1880?

A

Quality by appearance based on Compounding Skills of Apothecary (Pharmacist)

  • Rounder Pills
  • Clearer/Tastier Elixirs
  • Smoother/Whiter Creams
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2
Q

What is the 2nd phase of quality from 1880 to 1960?

A

Quality by Testing

  • Product tested at the end of batch manufacturing process
  • If product passes test(s), it was deemed to be of good quality
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3
Q

What are the limitations of conventional product testing?

A
  • Only a representative size is tested (due to destructive nature of tests)
  • Need to know analyte and the respective test method to test
  • Can only test if test method is specific, accurate and reliable , i.e. if it is validated
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4
Q

What is the lesson learnt from the melamine milk scandal?

A

Test methods need to be specific, accurate and reliable to test for impurity

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5
Q

What is the 3rd phase of quality post 1960?

A

Quality by design

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6
Q

What does quality by design include? (QA of product moved upstream includes)

A
  • Product Design/Formulation of Dosage Form
  • Control of Starting Materials (APIs, Excipients and Containers)
  • GMP Compliance by Manufacturers
  • Contamination Control, Process Validation and Stability Testing
  • Use of Process Analytical Technology (PAT) and Parametric Release
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7
Q

What is Parametric Release?

A

Parametric Release is the release of a batch of injectable product which has been terminally sterilized, without the need to conduct batch sterility testing

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8
Q

What led to the development of Parametric Release?

A

Limitations of the Batch sterility testing

  • There is a high (statistical) probability of passing Sterility Test, even when contamination level is relatively high
  • Sterility testing is not cheap
  • 2 weeks of incubation period required for sterility testing
  • Sterilized product cannot be released in real time
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9
Q

What is the expected sterilization assurance level for parametric release? (NOT TESTED)

A

<= 10^-6

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10
Q

What are the critical process parameters (CPP) for parametric release for injectables?

A
  • Temperature
  • Pressure
  • Sterilization time/cycle
  • Bioburden of pre-sterilized parenteral product
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11
Q

What is Quality Risk Management (QRM)?

A

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

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12
Q

What is the objective of Quality Risk Management (QRM)?

A

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

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13
Q

What are the steps for Quality Risk Management (QRM)?

A
  1. Risk identification
  2. Risk Analysis
  3. Risk reduction
  4. Risk communication
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14
Q

Are clinicians able to assess quality of medicines?

A

No

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15
Q

Is the distributor and advertiser involved in quality?

A

Yes

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16
Q

How is quality defined?

A

Fit for purpose (for any product)

Fit for medicinal purpose (for a medicinal product)

fitness for use for treating patients (who are sick)

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17
Q

SUMMARY

What does quality of a medicinal product include?

A
  • Identity and Potency of ingredients
  • Purity (absence of contaminants, including impurities)
  • Pharmaceutical Quality Attributes of finished dosage form: stability and homogeneity of finished product
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18
Q

What are the Pharmaceutical quality attributes of finished dosage forms?

A
  • Viscosity, Sterility, Endo-toxin Levels
  • pH, Clarity, Color Index, Microbial Limits, Sedimentation Rate
  • Hardness, Friability, Particle Size, Dissolution Profile
  • Stability, Homogeneity

I think critical quality attributes would be: purity, stability, homogeneity

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19
Q

How is purity assessed?

A

Absence of impurities/contaminants from product

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20
Q

What are contaminants introduced during manufacturing also known as?

A

Cross-contaminants

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21
Q

SUMMARY

How are contaminants classified?

A

Intrinsic Contaminants, often SPECIFIC in nature (aka impurities)
Extrinsic Contaminants, often NON-SPECIFIC in nature (aka cross-contaminants)

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22
Q

What are the types of impurities in APIs? (intrinsic contaminants)

A
  1. Process-related (at the end of synthesis reactions)
  2. Drug related (degradation, after API formed)
  3. Polymorphs
  4. Stereoisomers
  5. Impurities from Container-Closure System (primary containers, the polymer or coating materials) and Labels - impurities may seep through containers and contaminate product
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23
Q

How can intrinsic contaminants (impurities) be controlled?

A
  • QC testing by manufacturer
  • Assessments of impurity profile by HSA product reviewers
  • GMP compliance by manufacturers
  • Periodic GMP audits by HSA inspectors
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24
Q

How can extrinsic contaminants (cross contamination) be introduced?

A
  • Personnel
  • Premises
  • Equipment
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25
Q

How can extrinsic contaminants (cross contamination) be controlled?

A
  • Manufacturer compliance to GMP

- Periodic audits by GMP inspectors to verify compliance is impt

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26
Q

How should the Premises be controlled to minimize cross contamination?

A
  • controlled environment

- effective partitioning (“closed system” with positive air pressurization)

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27
Q

How should the Personnel be controlled to minimize cross contamination?

A
  • Proper Gowning by Personnel Collecting Samples of Starting Materials
  • Observance of Personal Hygiene by Operator
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28
Q

How should the Equipment be controlled to minimize cross contamination?

A
  • Use of Clean Stainless Steel Sampling Rod to Collect Samples
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29
Q

SUMMARY

What is the general rule of thumb for assessing cross contamination risk?

A

Increased operations within a facility/piece of equipment = increased risk for contamination

single product –> product groups –> multiple products (sharing multi-purpose env, in manufacturing env lacking contamination control)

Pay greatest attention to generic drug manufacturers

30
Q

SUMMARY

Are contaminated products only found in manufacturers of developing countries?

A

No, it is a problem with both developing and developed manufacturers

31
Q

What are the Product quality documents submitted to regulators for market authorization?

A
  • Control of Drug Substances
  • Control of Excipients
  • Control of Container-Closure System
  • Control of Finished Product
  • Control of Manufacturing Processes
  • Product Development
  • Stability Testing
  • Process Validation
32
Q

What are some of the product related factors that can affect stability of a medicinal product?

A
  • Formulation
  • Physico-chemical properties of API/excipients
  • Type of container and packaging material
33
Q

What are some of the environmental factors that can affect stability of a medicinal product?

A
  • Temperature
  • Moisture
  • Light
  • Oxygen
  • Physical stress during transportation
  • In-use contamination during consumption
34
Q

How can a stability testing program be conducted?

A
  • real time studies
  • accelerated studies
  • continual stability studies
35
Q

What is the purpose of a stability testing program?

A

to establish shelf-life of product when stored, distributed under recommended temperature, pH and other environmental conditions

36
Q

What is the name of a study conducted under intended market conditions for 6months?

A

Real-time study

37
Q

A study was conducted using NaOH, 90% humidity, 45 degrees Celsius. What is the study type?

A

Accelerated study under elevated/stressed conditions

38
Q

A study spanning 2 years was conducted for a batch of product that claimed 1 year shelf life after market authorization was granted. What is the study type?

A

Continual stability study

39
Q

What is the effect of elevated temperature during storage?

A
  1. loss of potency via degradation
  2. loss of vehicle via evaporation
  3. hardening of tablet via loss of moisture
40
Q

What is the effect of elevated humidity/moisture during storage?

A
  1. formation of toxic degradation products via hydrolysis
  2. loss of package integrity and label clarity
  3. loss of adhesion for transdermal patch
41
Q

What is the effect of agitation and vibration during transportation?

A

ingress of microbe/MO into product –>

  • poor container-closure integrity/ hair-line cracks
  • drop in microbiological quality of product
  • unsafe product (if it is intended to be sterile)
42
Q

What does process validation mean?

A

Process valdiation is the means of ensuring and providing documentary evidence that the manufacturing processes are capable of consistently producing a finished product of required quality.
- carried out on at least 3 consecutive full scale batches

43
Q

What are the major steps involved in process validation?

A
  1. Establish Tablet Quality Specifications
  2. Identify Critical Processes: blending, milling, compression
  3. Design sampling plan
    - blending: 10 samples
    - milling: 1 representative sample
    - compression: ~6x20 tablets
  4. Design Testing plan
    blend uniformity
    compression
  5. Set acceptance Criteria
  6. Perform statistical analysis (inter and intra batch) for 3 batches
44
Q

How can the Process Capability (Cp) be calculated for intra-batch analysis?

A

Cp = (USL - LSL)/6SD

  • USL = upper specification limit
  • LSL = lower specification limit
  • SD = standard deivation
45
Q

What is the required Coefficient of Variation (CV aka SD) for inter-batch analysis?

A

CV (or RSD) among 3 validation batches and pilot batch <= 5%

46
Q

How is the required Process Capability (Cp) for intra-batch analysis?

A

Cp >= 1.3 (outliers <= 63ppm)

47
Q

What is the purpose of intra-batch analysis (part of statistical analysis)?

A

To demonstrate consistency within each of the 3 validation batches

  • performed on blend content uniformity tests results
48
Q

What is the purpose of inter-batch analysis (part of statistical analysis)?

A

To demonstrate equivalency among the 3 validation batches + pilot batch (used for clinical studies)

  • performed on dissolution test results
49
Q

What are the essential elements of the validation protocol?

A
  • objectives
  • scope
  • persons responsible
  • critical processes (with manufacturing flow chart)
  • list of raw materials and equipment used
  • sampling plan
  • testing plan
  • frequency of sampling/testing
50
Q

What are the essential elements of the validation report?

A
  • validation test results
  • data analysis
  • statistical analysis (SPC and Cp, ANOVA)
  • recommendations and conclusions
  • attachments (batch records, manufacturing flow chart, statistical control graphs, tables and graphs)
    SPC - statistical process control
    Cp - process capability
    ANOVA - analysis of variance
51
Q

What is the new approach to process validation (adopting quality by design)?

A
  • Extensive Process design and process qualification
  • identify critical quality attributes (CQA)
  • monitoring of critical process parameters (CPP)
  • continued process verification beyond 3 production batches
  • assures processes remain continually in a state of control and products manufactured are consistently of good quality
52
Q

Why is Purity an important quality attribute?

A

Contaminants and impurities in trace amounts can be highly toxic, rendering a product unsafe and harmful

53
Q

Why is Stability an important quality attribute?

A

A stable product maintains its quality, safety and efficacy throughout its shelf life

54
Q

Why is Homogeneity an important quality attribute?

A

A homogeneous product means that each and every unit of dosage form meets quality specification.

55
Q

How can Homogenity (consistency) be demonstrated?

A

Homogeneity is demonstrated through process validation.

56
Q

Whose business is it to assure quality medicines?

A
  • manufacturer: product and manufacturer’s licence holder; distributor and advertiser
  • the regulator (HSA): Product quality reviewers; GMP inspectors
57
Q

What are the hard skills and knowledge required for manufacturers/regulators in assessing quality of products?

A
  • pharmacology/ pharmacotherapy
  • medicinal chem
  • pharmaceutics
  • pharmaceutics microbiology
  • pharmaceutical laws
  • GMP and quality standards
  • Statistics
58
Q

What are the soft skills required of a regulator/ inspector?

A
  • confidence, assertiveness, integrity and impartiality, perserverance, tact and diplomacy, oral communication and negotiation skills, report wiritng and written communication skills; willing to travel overseas regularly
59
Q

What is a contaminated medicinal product?

A

Product that contains undesirable foreign matters

  • of chemical/microbiological nature (non-specific in nature)
  • may present in starting material, intermediate, bulk product
  • introduced during manufacturing
60
Q

What are intrinsic contaminants?

A

present inherently in APIs, Excipients (incl water) and packaging materials used in formulating product

not removed completely from starting and packaging materials during their manufacturing processes

61
Q

What are extrinsic contaminants?

A

Originate externally from

  • production personnel
  • processing equipment
  • packaging equipment
  • manufacturing premises (environment)
62
Q

Why is there a need to control impurities (intrinsic)?

A
  • overall therapeutic effect of medicinal product is dependent not only on its pharmacological properties of API (safety, efficacy and quality), but also on toxicity of impurities present
  • for MARKETING approval
63
Q

What are some polymorphs to take note of?

A

ampicillin, carbamazepine, cimetidine, mefenamic acid

64
Q

What are some stereo-isomers to take note of?

A

dopamine and propanolol

65
Q

What are some starting materials that could be an impurity?

A
  • closure: types of rubber, plastics
  • container: types of glass, plastics
  • active pharm ingredient
  • excipients
66
Q

What is the effect of poor handling of product during in-use?

A

contamination of product; drop in microbiological quality of product; unsafe product

67
Q

Under product stability, which of the following falls under ‘proper storage’?

A
  • elevated temp during storage

- elevated RH/moisture content during storage

68
Q

Under product stability, which of the following falls under ‘distribution’?

A
  • inc agitation and vibration during transportation

- poor handling of product during in-use

69
Q

SUMMARY

what is purity?

A

contaminants and impurities in small or trace amts can be highly toxic, rendering a product unsafe and harmful

70
Q

SUMMARY

what is stability?

A

a stable product maintains its quality, safety and efficacy throughout its shelf ife. Hence, a product needs to be properly formulated, stored, distributed and handled

71
Q

SUMMARY

what is homogeneity?

A

a homogeneous product means that each and every unit of dosage form meets quality specification. Homogeneity (consistency) is demonstrated through process validation

72
Q

SUMMARY

what are the 3 impt quality attributes of a medicinal product?

A

Purity, Stability, Homogeneity

PR3145 (10 decks)

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