Drug and Therapeutics

Committee
Session 5.
Pharmaceutical Quality Assurance
Acknowledgment

Material for this session is adapted from Chapter 18,

“Quality Assurance for Drug Procurement,” of
Managing Drug Supply 2nd ed. Management
Sciences for Health and World Health
Organization, 1997.
Objectives
 Define medicine quality
 Understand how medicine quality is
assessed
 Understand how medicine quality is
ensured
 Describe the role of the DTC in
pharmaceutical quality assurance
Outline
 Key definitions
 Introduction
 Determinants of medicine quality
 How is quality assessed?
 How is quality assured?
 Important pharmaceutical quality issues
for the DTC
 Implications for the DTC
Key Definitions (1)
Pharmaceutical quality assurance (QA)—Sum of
all activities and responsibilities required to ensure that
the medicine that reaches the patient is safe, effective,
and acceptable to the patient

Pharmaceutical quality control—Process

concerned with medicine sampling, specifications, and
testing, and with the organization’s release procedures
that ensure that the necessary tests are carried out and
that the materials are not released for use, nor products
released for sale or supply, until their quality has been
judged satisfactory
Key Definitions (2)
Good Manufacturing Practices (GMP)—
Performance standards that WHO and many national
governments established for pharmaceutical
manufacturers covering, for example, personnel,
facilities, packaging, and quality control.

GMPs are part of the quality assurance activities that

ensure that products are consistently produced and
controlled to the quality standards appropriate to their
intended use and required by the drug regulatory
authorities.
Introduction: Goals of Medicine QA
Programs
 To make certain that each medicine reaching a
patient is safe, effective, and of standard
quality
 Obtaining quality products that are safe and
effective through structured selection and
procurement methods
 Maintaining quality products through the
appropriate storage, distribution, monitoring, and
use by prescribers, dispensers, and consumers
Characteristics of a Comprehensive
QA Program (1)
 Medicines are selected on the basis of safety and
efficacy, in an appropriate dosage form with the
longest shelf life

 Suppliers with acceptable quality standards are

selected

 Medicines received from suppliers and donors are

monitored to meet quality standards

 Medicine packaging meets contract specifications

Characteristics of a Comprehensive
QA Program (2)
 Repackaging activities and dispensing practices
maintain quality

 Adequate storage conditions in all pharmaceutical

areas are maintained

 Transportation conditions are adequate

 Product quality concerns are reported and

monitored
 Impacts of Low-Quality Medicines
 Manufacturing
process
 Packaging  Lack of therapeutic
 Transportation ? effect:
 Prolonged illness
 Storage MEDICINE  Death
condition QUALITY  Toxic and adverse
reaction
 Waste of limited
financial resources
 Loss of credibility
Determinants of Medicine Quality
 Identity: Active ingredient
 Purity: Not contaminated with potentially harmful
substances
 Potency: Usually 90–110% of the labeled amount
 Uniformity: Consistency of color, shape, size
 Bioavailability: Interchangeable products?
 Stability: Ensuring medicine activity for stated period

Identity, purity, potency, uniformity are defined in pharmacopoeias

and stated in certificate of analysis (COA)
Potential Bioavailability Problems
 Aminophylline
 Ampicillin  Levodopa
 Carbamazepine  Levothyroxine
 Chloroquine  Methyldopa
 Digoxin  Nitrofurantoin  Medicines with
 narrow therapeutic
Dihydroergotamine  Phenytoin
range
 Ergotamine  Prednisolone  Slow-release
 Erythromycin  Prednisone formulations
 Estrogens 
 Quinidine New formulations
 Furosemide (e.g., rectal
 Rifampicin
 Glibenclamide paracetamol)
 Spironolactone
 Glyceryl trinitrate
 Iron sulfate  Theophylline
 Isosorbide dinitrate  Warfarin
Standard Method for Bioavailability
Studies
 Subject: adult, healthy, nonsmoker, nondrinker
 Design: cross-over, 12–14 subjects
 Medicine administration: overnight fast, single dose
 Serial blood sampling: minimum 3 T1/2
 Medicine assay in plasma 100

 Parameters:
 Cmax 10

 Tmax 1
 AUC0- C T

 Judgment for bioequivalency: <20% difference

Rifampicin 450 mg Capsules:
> 100% Variation among Brand Names
Plasma RMP concentration (mcg/ml)
25

20

15

10
Originator

0
0 2 4 6 8 10 12 14 16 18 20 22 24

Source: Suryawati (1992) Time (hours)

Captopril 25 mg: Variation among
Brand Names
Plasma concentration (ng/ml)
300

250 N=12

200
Originator
150
Failed
100

50

0
0 1 2 3 4 5 6 7 8 9 10 11 12
N = number of studies Time (hours)
Source: Suryawati and Santoso (1994).
Nifedipine 20 mg: Generic vs. Brand Name

Plasma concentration (ng/ml)

180
Generic
160
Brandname
140
120
100
80
60
40
20
0

Source: Suryawati and Santoso (1995). Time (hours)

Slow-Release Diclofenac Tablet
Plasma concentration (ng/mL)

120

100 Imported
product
80

60

40
MEC = 20 ng/mL
20

0
0 1 2 3 4 5 6 7 8 9 10 11 12

Source: Suryawati (1989). Time (hours)

Medicines with a Stability Problem
 Tablets:  Oral liquids:
 Acetylsalicylic  Paracetamol
acid
 Amoxicillin  Injectable:
 Ampicillin  Ergometrine
 Penicillin V  Methylergometrine
 Retinol

 Select the most stable formulation with adequate packaging

How Is Quality Assessed?
 INSPECTION of products on
arrival
 Visual inspection
1
 Product specification review
(including expiration dates)

 LABORATORY TESTING for

compliance with pharmacopoeial
standards
 International Pharmacopoeia
 European Pharmacopoeia
 U. S. Pharmacopeia 3 2
COA
 British Pharmacopoeia
 National Pharmacopoeia

 BIOAVAILABILITY DATA
How Is Medicine Quality Assured? (1)
 Product selection
 Long shelf-life
 Acceptable stability
 Acceptable bioavailability
 Selection of appropriate suppliers
 Supplier pre-qualification
 Request samples from new suppliers
 Request specific reports and data for certain medicines
(e.g., bioavailability and stability studies)
 Collect and maintain information on supplier performance
 Product certification
 GMP certificate of manufacturer
 Product/batch certification (COA)
 Random local testing
How Is Medicine Quality Assured? (2)

 Contract and procurement specifications

 Pharmacopeia reference standard
 Local language for product label
 Standards for packaging to meet specific
storage and transport conditions
How Is Medicine Quality Assured? (3)
 Appropriate storage, transport, dispensing, and
use procedures
 Pharmaceutical distribution and inventory control
procedures
 Provision for appropriate storage and transport
including adequate temperature control, security,
and cleanliness
 Explicit enforcement of cold chain procedures
 Appropriate dispensing: containers, labeling,
counseling
 Avoidance of repacking unless quality control in
place
How Is Medicine Quality Assured? (4)

 Product monitoring system

 Problem reporting: who, how, where,

and to whom; what additional
measures; what follow-up information

 Product recalls: hospital or country level

Who Ensures Medicine Quality?
 Drug
regulatory
authority
 Drug and  Physicians
Therapeutics and other
Committee Medicine prescribers
Quality

 Hospital  Pharmacy
procurement (and dispensers)
office  Patients
Implications of Pharmaceutical QA for the DTC
 Providing technical advice on procurement of
pharmaceuticals
 Defining product specifications
 Generic medicines
 Bioavailability issues
 Stability issues
 Defining minimum laboratory testing
 Providing technical advice to hospital departments
 Medicine transportation and storage
 Dispensing

 Analyzing product problem reports

 Quality complaints
 Medicine recall system
Activity (30 minutes)
 Pharmaceutical quality assurance issues and
concerns on—
 Obtaining quality products
 Maintaining quality products at hospital level
 Examples of poor quality
 Discussion
 Are you satisfied with the quality of medicines you receive?
 Is quality maintained throughout your distribution network?
 Are there complaints of poor quality by patients or health
workers?
 Is there a formal mechanism for reporting and investigating
complaints?
 What role do you see for the DTC in improving and
maintaining quality in your health care system?
Summary (1)
 Ensuring quality of a product from selection to
use—
 Obtaining quality products that are safe and
effective through structured selection and
procurement methods
 Maintaining quality products through
appropriate storage, distribution, monitoring,
and use methods
Summary (2)

 Assessing quality includes—

 Inspection of medicines

 Laboratory testing when necessary

Summary (3)
 Assuring quality includes—
 Selection of medicines, dosage forms, and
packaging
 Use of prequalified suppliers
 Product certification
 Preparation and enforcement of quality-related
contract specification
 Appropriate storage, transport, dispensing, and
use
 Product monitoring systems