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Regulation > Quality > Flashcards

Quality Flashcards

1
Q

What is QbT

A

Quality by testing. Product is tested at the end of manufacturing. If product passes the test, it is considered of good quality

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2
Q

Limitations of conventional product testing

A

1) Only a statistically representative sample size can be tested
2) Analyte (usually API/contaminant) must be known and there must be a suitable test method and reference standards available
3) Test method must be accurate, specific & reliable (i.e. validated)
4) Defects are only picked up at the end of manufacturing, thus defective products cannot be rectified/reworked
5) QC tests not conducted/released in real time, leading to expensive cost of storage of bulky products

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3
Q

What is QbD

A

Design & build quality into product. Quality assurance is moved upstream

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4
Q

What does QA involve

A

1) Product design/Formulation of dosage form
2) Control of starting materials
3) GMP compliance by manufacturers of APIs & finished dosage forms
4) Contamination control, process validation, stability testing
5) Use of innovative technologies and approaches e.g. process analytical technology (PAT), parametric release

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5
Q

What is the sample size for batch sterility testing

A

If batch size = 10,000 units, sample size = 20 units

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6
Q

What are the limitations of batch sterility testing

A

1) High statistical probability of passing batch sterility test, even when contamination level is relatively high
2) Costly
3) Sterilized products cannot be released real time (2 weeks incubation period needed to carry out batch sterility testing), hence leading to expensive storage costs during storage of bulky products (e.g. large volume parenterals)

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7
Q

What is parametric release

A

Release of a batch of injectable products (LVPs) which has been terminally sterilized, without the need for batch sterility testing

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8
Q

What are the requirements for parametric release

A

Release is based on critical process parameters (CPPs) of a sterilization process (e.g. autoclaving, moist heat sterilization) which has been rigorously validated (i.e. at end of sterilization process, should have SAL (sterilization assurance level) of ≤ 10^-6)

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9
Q

What are some CCPs that must be monitored during terminal sterilization to approve parametric release

A

Temperature
Pressure
Sterilization time/cycle
Bioburden of pre-sterilized product

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10
Q

What is quality risk management (QRM) & its objective

A

A systematic framework to manage quality risk in a stepwise manner
Objective: Assess risks to product quality/patient and manage these risks to an acceptable level

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11
Q

What are steps in QRM

A

1) Risk identification
2) Risk analysis
3) Risk reduction
4) Risk communication

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12
Q

Risk identification process

A

Identify risks in:

1) Quality of starting material
2) Premises & equipment
3) Personnel (human) error
4) Production & packaging process
5) Warehouse & pest control
6) Cleaning procedures & contamination

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13
Q

How is risk analyzed

A

Using analytical & quality control tools
Commonly used tools:
1) FMEA (failure mode & effects analysis)
2) FTA (fault tree analysis)
3) HACCP (hazard analysis & critical control points)

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14
Q

How is risk reduced

A

1) Reliable suppliers
2) Amend cleaning procedures
3) Training/Re-training
4) Revalidate training process
5) Tighten pest control

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15
Q

What is risk communication

A

Communicate QRM to internal staff and external stakeholders (to prevent repeat of mistakes)

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16
Q

Who should regulate quality & why

A

Manufacturers (product & manufacturer’s license holder, distributor & advisor, R&D scientists, production/QC experts)
Regulator (product quality reviewers, GMP compliance inspectors, analytical scientists)
Manufacturer & regulator both have hard skills, knowledge and equipment needed to assure good quality medicines

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17
Q

Hards skills required by manufacturer/regulator to ensure good quality medicines

A

1) Pharmacology/Pharmacotherapy
2) Medicinal chemistry
3) Pharmaceutics
4) Pharmaceutical microbiology
5) Pharmaceutical law
6) Statistics
7) GMP & quality standards

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18
Q

Soft skills required by regulator to ensure good quality medicines

A

1) Confidence
2) Assertiveness
3) Integrity & impartiality
4) Perseverance
5) Tact & diplomacy
6) Oral communication & negotiation skills
7) Report writing & written communication skills
8) Willing to travel overseas

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19
Q

Definition of quality

A

ISO definition:

1) Fit for purpose
2) Fit for medicinal purpose
3) Fit for use in treatment of patient

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20
Q

Quality depends on

A

1) Identity (of starting materials)
2) Potency
3) Purity
4) Critical quality attributes (CQA)
5) Cross-contamination control

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21
Q

What are CQA

A

Tablets: Hardness, friability, particle size, dissolution profile
Liquids: pH, clarity, colour index, microbial limits, sedimentation rate
Creams, ointments: Viscosity
Sterile products: Sterility, endotoxin levels
Overall: Stability, homogeneity

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22
Q

International product quality requirements for market authorization

A

Product quality documents to be submitted to regulator:

1) Product development
2) Control of drug substances, excipients, container-closure system, finished product, manufacturing process
3) Stability testing
4) Product validation

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23
Q

Purity is the

A

Absence of contaminants/undesirable foreign material

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24
Q

Contaminant may be

1) Nature
2) Present in
3) Introduced during

A

1) Microbiological / Chemical / Non-specific in nature
2) May be present in starting material / intermediate / bulk product
3) May be introduced during manufacturing process (cross-contamination)

25
Q

Importance of contamination control

A

Contaminant in small/trace amounts may be highly toxic –> renders product unsafe and harmful
Control of contaminants/impurities is an important part of drug development, manufacturing, GMP compliance, regulatory assessment for marketing approval

26
Q

Types of contaminants

A 
Intrinsic contaminants (impurities)
Extrinsic contaminants
27
Q

Source of intrinsic contaminants/impurities

A

Inherently present in APIs / excipients / packaging materials (not removed during manufacturing of these materials)

28
Q

Nature of impurities

A

Often specific (i.e. identity of these impurities known) –> can test for absence / levels of these impurities

29
Q

Impurities from API

A

Process related impurities
- Unreacted starting materials / intermediates
- Residual reagents / catalysts / solvents / heavy metals / other metals
- By-products
Drug-related impurities
- Degradation products
Polymorphs (e.g. Carbamazepine)
Stereoisomers
- E.g. Only L-isomer (levodopamine) of Dopamine has therapeutic effect
- E.g. Only D-isomer of Propranolol has therapeutic effect

30
Q

Impurities from primary container-closure system

A

Residual polymers/monomers (present after manufacturing of plastic containers)
- E.g. Polyethylene, polypropylene, polyvinyl chloride, vinyl chloride
Plasticizers, lubricants, antioxidants, stabilizers
Coating materials (resinous, polymeric)

31
Q

Impurities from label

A

Adhesives

Printing ink

32
Q

Control of impurities

A

1) QC testing of materials & finished product by manufacturers
2) Assessment of impurity profile by HSA product quality reviewers
3) GMP compliance by manufacturers
4) Periodic GMP audits by HSA inspectors

33
Q

External contaminants originate from

A

1) Production personnel
2) Processing & packaging equipment
3) Manufacturing premises

34
Q

Nature of external contaminants

A

Often non-specific

35
Q

Types of external contaminants

A

1) From personnel: Bacteria, fungi, particles, fiber, hair, saliva, sweat, dirt
2) From equipment: Rust, corroded material, product residual (from manufacture of other products), grease, lubricants, leached chemicals
3) From premises: Pests, cross-contamination, pollutants & extraneous matter

36
Q

Control of external contaminants

A

1) GMP compliance by manufacturers

2) Periodic GMP audits by regulators

37
Q

Contamination risk increases with

A

Increased operations within a given facility/piece of equipment

38
Q

Levels of contamination risk

A

Low risk of contamination:
Manufacture of single product (e.g. manufacture of certain API) - Dedicated & self-contained facility/building

Intermediate risk of contamination:
Manufacture of product groups (e.g. hormones, steroids) - Dedicated & self-contained areas/rooms

Highest risk of contamination
Manufacture of multiple products (usually generic drug manufacturers) - Non-dedicated facilities, multi-purpose equipment

39
Q

A stable product is able to

A

Maintain its safety, efficacy & quality throughout its shelf-life

40
Q

Ensure product remains stable by

A

Proper formulation, storage, distribution & handling

41
Q

Factors influencing stability

A

Product related factors

  • Formulation of product (interaction between components)
  • Type of container-closure system / packaging materials used
  • Physicochemical properties of drug substance(s) / excipients

Environmental factors

  • Temperature
  • Relative humidity / Moisture
  • Light
  • Oxygen
  • Physical stress during transportation
  • In-use contamination
42
Q

Elevated temperatures during storage can cause

A

1) Product degradation –> loss of potency
2) Evaporation of vehicle –> increase concentration of APIs (to&raquo_space; 110% of labelled amount)
3) Hardening of tablet due to loss of moisture content –> change dissolution profile

43
Q

Elevated moisture/relative humidity during storage can cause

A

1) Formulation of toxic degradation products via hydrolysis
2) Loss of label clarity & package integrity
3) Loss of adhesion of transdermal patch

44
Q

Increased agitation & vibration during transportation can cause

A

Loss of container-closure integrity / hair-line cracks –> ingress of microorganisms, leading to drop in microbiological quality and safety

45
Q

Stability testing involves

A

1) Real time studies
2) Accelerated studies
3) Continual stability studies

46
Q

Real time studies

A

Duration: Minimum 6 months
Conditions: Appropriate controlled storage conditions, depending on intended market / nature of product

47
Q

Accelerated studies

A

Conditions: Elevated/Stressed conditions
Objective: Project shelf-life beyond 6 months

48
Q

Continual stability studies

A

Retention samples kept for continual stability studies
Duration: Carried out after receiving MA/ product license; Shelf-life + further 6 months
Objective: Show that shelf-life predicted from accelerated studies is correct

49
Q

Example: Conducting stability testing for tropical market

A

Real time studies conditions: 30oC +/- 2; 75% RH +/- 5

Accelerated studies conditions: 45oC +/- 2; 90% RH +/- 5; Hydrolysis with NaOH

50
Q

What is homogeneity

A

Each and every unit of dosage form meets quality specifications

51
Q

Homogeneity is demonstrated via

A

Process validation

52
Q

Process validation is

A

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

53
Q

Minimum no. of batches needed for process validation

A

3 consecutive full scale batches

54
Q

Steps in process validation

A

1) Establish critical quality attributes (CQAs)
2) Identify critical process parameters (CPPs)
3) Design sampling plan
4) Design testing plan
5) Set acceptance criteria (set upper & lower specification limits)
6) Conduct statistical analysis for 3 batches (intra-batch analysis, inter-batch analysis)

55
Q

Example: Process validation of tablets

A

1) CQAs: Blend homogeneity, hardness, thickness, friability, particle size, dissolution profile
2) CPPs: Blending, milling, compression, equipment design, batch size, blending time, tablet compression speed

3) Sampling plan:
Blending - 10 samples each from top, middle, bottom of blender
Milling - 1 representative sample (~100g) drawn from mill
Compression - 120 (6 CQAs x 20 tabs/test) x 4 equal intervals x 3 compression speeds (low, target, high) = 1440 tabs

4) Testing plan:
Blend uniformity - Assay blend composition
Compression - Test for CQAs of tablet samples

5) Acceptance criteria:
E.g. 90-110% of labelled amounts

6) Statistical analysis
Intra-batch analysis - Conduct on blend content uniformity test
Inter-batch analysis - Conduct on dissolution test results

56
Q

Statistical analysis in process validation

A

Intra-batch analysis

  • Process capability index (Cp)
  • Demonstrate consistency of all 3 validation batches
  • Cp ≥ 1.3

Inter-batch analysis

  • Variance analysis - Coefficent of variance (CV)
  • Demonstrate equivalency of 3 validation batches & the pilot batch
  • CV / RSD ≤ 5%
57
Q

Documents needed to show manufacturer has conducted process validation

A

Must provide documents on:

1) Validation protocol
- Objectives
- Scope
- Personnel
- Critical processes (with manufacturing flow chart)
- List of raw materials & excipients used
- Sampling plan
- Testing plan
- Frequency of testing & sampling
2) Validation report
- Statistical analysis
- Validation test results
- Data analysis
- Recommendations & conclusions
- Attachments (batch reports, manufacturing flow chart, statistical control charts, tables & graphs)

58
Q

New approach to process validation

A

1) Identify CQAs
2) Extensive process design & process qualification
3) Monitoring CCPs
4) Continued process validation beyond 3 production batches

Regulation (6 decks)

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