Professional Documents
Culture Documents
Qualityassurance
Qualityassurance
HIV/AIDS Drugs
Training Module 4
Quality Assurance
Ben K Botwe
April 2005
1
Learning Objectives
Upon completion of this module, you will
be able to
• Explain the need for a systematic quality
assurance process for pharmaceutical products
• Describe key elements of the quality assurance
process for pharmaceuticals
• Discuss the procedures and standards for
prequalification of suppliers of pharmaceuticals
• Apply quality assurance and supplier selection
principles to case discussions
2
Rationale for this Module
• Quality medicines are safe, effective and
efficient tools for treatment of HIV/AIDS
• Poor quality (sub-standard) medicines may not
produce desired effects, may cause harm
• Errors in production can lead to sub-standard
medicines
• Quality Assurance principles can be used to
detect errors or problems in production and
ensure suppliers conform to standards and
expectations
• Battling HIV/AIDS: A decision maker’s guide
to the procurement of medicines and related
supplies provides framework for quality
assurance 3
Outline of the Presentation
• Introduction, Definitions and Quality
Assurance
• Good Manufacturing Practices
• Product Selection
• Suppliers and Manufacturers
• Selection and Sourcing
• Procedures for Prequalification of
Suppliers
• Stability and Equivalence
• Conclusion
4
• Case Study
Quality Assurance
• A process, not an end-point
• Must be independent of financial pressures
• Must ensure that quality policies are followed
• Must have final authority in product acceptance,
rejection and release to public
• Integral to production, not an add-on
• Responsible for day-to-day operations and for
longer term goal settings
• Quantitative discipline with specified parameters
5
DEFINITIONS
• QUALITY
• The totality of features and characteristics
of a medicinal product and its ability to
satisfy stated and/or implied needs
• QUALITY ASSURANCE
• The sum total of the organized
arrangements made with the object of
ensuring that medicinal products are of the
quality required for their intended use.
6
DEFINITIONS
7
Quality relationships
QA
GMP
QC
8
Quality relationships
Quality Management
Quality Assurance
GMP
Quality Control
9
FACTORS IN DRUG QUALITY ASSURANCE
LEGISLATIVE IMPORT
FRAMEWORK & EXPORT
-REGULATIONS CONTROL PACKAGING
DRUG
RAW PRODUCT
MATERIALS- QUALITY QC &
ACTIVE & ANALYSIS
INACTIVE
TRANSPORT
MANUFACURING DISTRIBUTION
PROCESSES DISPENSING
STORAGE & USE
& PROCEDURES
10
Quality Assurance
Primary Functions
• Quality Control
• Analytical testing of products
11
Quality Must Be Designed
Into A Product
• Quality is not an add-on: it begins with
research and development
• Product quality criteria must be established
• Detailed specifications provide quantitative
parameters for measurement
• Written procedures document how quality is
attained and maintained
• Continuous monitoring (sampling, testing) to
confirm quality is being built-into product
12
Quality Assurance: Essential
At All Stages
Quality Assurance Cycle
Research
Development
Raw Materials
Facilities
Documentation
Equipment
Personnel
13
Elements of the Quality
Assurance Cycle in
Pharmaceutical Manufacturing
• Research
• Development
• Prototyping
• Documentation
• Raw Materials
• Facilities
• Equipment
• Personnel and Supervision
• Monitoring, Feedback, Follow-up
14
Analytical Control Laboratory
Heart of Quality Management in
Pharmaceuticals
• Academically trained and certified staff
• Experienced supervision/management
• Capable of performing complex analyses
• Able to report honestly and in a timely manner
• Equipment and instrumentation must be suitable
for performing testing
• Access to reliable power, water and other stable
infrastructure
15
Quality Control & Analysis
• Qualification
• Design, Installation, Process and Operational
• Calibration
• Daily and periodic
• Validation
• Equipment, Method and process
• SOPs
• Authorized, used and updated
• Documentation
• Systematic and well kept
• Quality Manual
• Quality manager, staff trained and motivated to comply.
• Safety measures
16
Quality Assurance Throughout
the Manufacturing Process
• Monitoring environmental conditions
under which products are
manufactured/stored
• Monitoring of air and water systems to
prevent contamination– Air Handling
Units
• Monitoring of humidity
• Monitoring of personnel
• Feedback and follow-up 17
Manufacturing Process and
Procedures
• Dispensing / Weighing
• Mixing / Granulation / Preparation
• Compression / Encapsulation / Filling
• Equipment, Operational & Process
Qualification
• Validation & calibration
• Documentation and record keeping
• Yield Reconciliation
18
A Guiding Philosophy for Quality
Assurance in the Pharmaceutical
Industry
Poor Quality Medicines:
• Are a health hazard
• Waste money for governments and consumers
• May contain toxic substances that have
unpredictable, unintended consequences
• Will not have a desired therapeutic effect
• Does not save anyone any money in the long term
• Hurt everyone – patients, health care workers,
policy makers, regulators, manufacturers 19
CONSEQUENCES OF QA
BREACHES
Incorrect Amount
17%
No Active Ingredient
60%
23
Source: (WHO)
The Breadth of GMP
Covers all aspects of production including
26
WHO Technical Guide to GMP
General Consideration
“Licensed pharmaceutical products should
be manufactured only by licensed
manufacturers whose activities are
regularly inspected by competent national
authorities”
27
WHO Technical Guide to GMP
Key Concepts
• Validation
Action of proving (in accordance with
principles of GMP) that any procedure,
process, equipment, material, activity,
or system actually leads to expected
results
28
WHO Technical Guide to GMP
Key Concepts
• Qualification
Action of proving that any premises,
system, and items of equipment work
correctly and actually lead to expected
results
29
Associated Concepts
• Good Laboratory Practice (GLP)
• Good Clinical Practice (GCP)
• Clear language use
• Effective record keeping
• Design, installation, operational and
process qualification (DQ, IQ, OQ and
PQ)
• Self-inspection and self-regulation
• Good Distribution Practice (GDP)
30
Key Elements of GMP
(WHO Technical Guide)
• Sanitation and hygiene
• Qualification and validation
• Complaints
• Product recalls
• Contract Production and Analysis
• Self-Inspection and Quality Audits
31
Key Elements of GMP (WHO
Technical Guide)
Personnel
(Training, Hygiene)
Documentation Premises
(Equipment)
Materials
(Supplies, Ingredients)
32
Product Selection Issues
• Unique nature of medicines heightens
need for effective quality assurance
• All medicines used must be safe,
effective, and of consistent quality
• Failure to select proper products will
lead to treatment failure, drug
resistance, wasted resources and
human suffering
33
Product Selection Issues (Cont.)
4% 10%
6%
5%
8%
0-9 years old
10-19 years old
20-29 years old
30-39 years old
25% 40-49 years old
50-59 years old
>60 years old
42%
32%
Sexual Contact
Blood/Blood Products
54%
Not known/specified
14%
38
Combination Products
• More convenient, improve adherence,
reduce pill burden for patient
• E.g. Triomune (NRTI-NNRTI triple
combination therapy consisting of
stavudine, lamivudine, and nevirapine)
• Product formulations to allow twice daily
(or even once daily) dosing
39
Use of Medicines in Women
Who are Pregnant
40
Suppliers/Manufacturers
41
Sources of Pharmaceutical
Products
Multi-source
Well-established products, long history of use, no
longer subject to patent protection (e.g. Rifampin)
Single source
Newer products still subject to patent protection in
many countries (e.g. Saquinavir)
Limited source
More than single source/supply possible (e.g.
AZT); may be difficult to manufacture (e.g.
amphotericin); may be unprofitable drug with
limited market potential
42
Comparison of Sources
Multi-source Single/limited source
43
Identifying Product Suppliers
Systematic Approach
• Pre-qualification of suppliers and products
• Specifying supplier conditions in contract
• Monitoring quality of product and
processes
• Continuous evaluation of supplier
performance and product performance in
clinical practice
44
Identifying Product Suppliers
Specify Conditions
Evaluate Monitor
45
Selecting and Sourcing Multi-
Source Products
• Innovator vs. generic issues
• Prequalification systems
• Specific issues related to
interchangeability of products -
stability, bioavailability, bioequivalence,
etc.
46
Selecting and Sourcing Multi-
Source Products
• Innovator vs. generic issues
• Prequalification systems
• Specific issues related to
interchangeability of products -
stability, bioavailability, bioequivalence,
etc.
47
Procedures for Prequalification of
Suppliers
Rationale
More meaningful, effective, efficient and less
expensive to eliminate sub-standard
manufacturers and products at the opening
of bidding/tendering than during the process
Purpose
To ensure that products are manufactured in
compliance with GMP and products meet
established quality standards
48
Procedures for Prequalification
of Manufacturers
• Local Procurement Committee comprising
managerial, technical, and professional staff
54
Prequalification Verifications
Compliance with GMP
• Inspections and certification of facilities
or reliance on national regulatory
authorities
Compliance with good distribution practices
Issue
Guidelines
Receive
Submissions
Evaluate
Submissions
Perform
Inspections
Communicate
Decision
56
Summary of Prequalification
Processes: Manufacturer’s
Perspective
Submit
EOI
Submit
Product Dossier
Submit Site
Master File
Submit Additional
Data if needed
Submit Corrective
Action Plan if needed
57
Options for Prequalification
WHO Prequalification
Regional Prequalification
International Low-cost Suppliers
58
Pharmaceutical Stability
59
Stability Definitions (1)
• Capability of a particular formulation of
a pharmaceutical in a specified
container/closure system to remain
within specified physical, chemical,
microbiological, therapeutic and
toxicological specifications
60
Stability Definitions (2)
• The time from the date of manufacture
and packaging of the formulation until
its chemical or biological activity is not
less than a predetermined level
(generally, 90%) of labeled potency and
its physical characteristics have not
changed appreciably
61
Stability Issues
Time-related harmful events include
a) Deterioration of therapeutic activity
below specified threshold
b) Potentiation of therapeutic activity
above specified threshold
c) Appearance of toxic substance forming
as a degradation by-product
62
Factors Affecting Stability of a
Pharmaceutical Product
• Stability of active ingredient
• Interaction between active/inactive
ingredients
• Manufacturing process
• Dosage formulation
• Container/Liner/Closure System
• Environment during storage, handling
• Length of time between manufacturing
and usage
63
Evaluation of Therapeutic
Equivalence of Generic Products
Basic Assumption
Drug quality is a function of consistent
and optimal release, dissolution, and
absorption of active ingredient from a
dosage form: this impacts upon chemical
equivalence, lot-to-lot uniformity in
manufacturing, stability, etc.
64
Bioavailability
Measurement of both the rate of drug
absorption and total amount (extent) of
drug that reaches the general systemic
circulation from an administered
dosage form
65
Equivalence
More general, relative term indicating a
comparison of one drug with another
along a set of established
standards/criteria
•Bio-equivalence
•Clinical equivalence
•Therapeutic equivalence
•Pharmaceutical equivalence
66
Therapeutic Equivalence
Two different brands of a drug product
are expected to yield the same clinical
result
For therapeutic equivalence
• Pharmaceutical, chemical and bio-
equivalence must be demonstrated
• Product must be appropriately labeled
• Product must be manufactured in
compliance with GMP
67
Factors Affecting
Equivalences
68
Bio-Equivalence
• Indicates that a drug in two or more
similar dosage forms reaches the
general circulation at the same relative
rate and the same relative extent
• Does not necessarily demonstrate
clinical or therapeutic equivalence (but
does not necessarily rule it out either!)
69
Evaluation of Equivalence
70
Conclusions
GMP as a quality management system
• Ensure appropriate infrastructure
encompassing organizational structure,
procedures, processes, and resources
• Ensure systematic actions necessary to
provide adequate confidence that
product will meet quality standards and
expectations
71
Conclusions
Good Manufacturing Practices are
• Pivotal to quality assurance
• Everyone’s responsibility
(manufacturers, purchasers,
distributors, consumers)
• Clear, transparent, documented, readily
observable
• On-going, consistent, reproducible
72
Conclusions
• GMP are aimed at reducing risks
inherent in pharmaceutical production
• Qualification and validation provides
confidence in manufacturers’ processes
• Prequalification provides greatest
assurance regarding quality of
pharmaceutical products, based on GMP
and product dossier
73
Case Study
74
Case Discussion Question
How should the government of Fatakia
prioritize elements of Good
Manufacturing Practices, given the
unique situation it faces in procurement,
storage, and distribution of anti-
retrovirals? What if Fatakia does not
have the capacity to pre-qualify
suppliers?
75
Case Discussion Question
76
Case Discussion Question
In evaluating claims and documents made
by different manufacturers of the same
drug, what principles must be weighed to
ensure optimal health outcomes?
How would you advise the government of
Fatakia to develop an evaluation scheme
for multiple, competing providers of the
same medicine?
77
Case Study Summary
Key Issues
• Health System Infrastructure (e.g.
laboratory testing facilities, medics, etc.)
• Drug Distribution System (e.g.
transport/storage logistics, deterioration
in quality of products, drug diversion
issues)
• Financial Pressures (e.g. use of generic
products)
78
Case Study Summary
Prequalification of suppliers
In accordance with GMP
• Provision of dossier
• Random testing of samples (not pre-supply)
• Changes/variances must be
qualified/validated
• Demonstrated on-going commitment to
standards
• Options in case there is insufficient capacity
to pre-qualify suppliers
79
Case Study Summary
WHO Certification Scheme on the Quality
of Pharmaceutical Products Moving In
International Commerce
•Manufacturing authorizations
•Marketing authorizations
80
Case Study Summary
Equivalency Decisions
• Linked directly to GMP
• Additional burden of proof based on
pharmacopeial/compendial standards
• Differentiate bio-equivalence,
therapeutic equivalence, and clinical
equivalence
81
Case Study Summary
Stability Issues
• Drug specific issues
• Drug-formulation specific issues
• Container issues
• Storage/handling/transportation issues
• Drug Distribution System considerations
• Health Care System considerations
82