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 controlProcess

concerned with medicine sampling, specifications, and testing, and with the organizations 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 Transportation Storage condition

?
MEDICINE QUALITY

Lack of therapeutic effect:

Toxic and adverse reaction Waste of limited financial resources Loss of credibility
Prolonged illness Death

Determinants of Medicine Quality

Identity: Active ingredient
Purity: Not contaminated with potentially harmful substances

Potency: Usually 90110% 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 Carbamazepine Chloroquine Digoxin Dihydroergotamine Ergotamine Erythromycin Estrogens Furosemide Glibenclamide Glyceryl trinitrate Iron sulfate Isosorbide dinitrate

Levodopa Levothyroxine Methyldopa Nitrofurantoin Phenytoin Prednisolone Prednisone Quinidine Rifampicin Spironolactone Theophylline Warfarin

Medicines with narrow therapeutic range Slow-release formulations New formulations (e.g., rectal paracetamol)

Standard Method for Bioavailability Studies

Subject: adult, healthy, nonsmoker, nondrinker Design: cross-over, 1214 subjects Medicine administration: overnight fast, single dose Serial blood sampling: minimum 3 T1/2 Medicine assay in plasma 100 Parameters: 10 Cmax Tmax 1 AUC0- C

Judgment for bioequivalency: <20% difference

Rifampicin 450 mg Capsules: > 100% Variation among Brand Names

Plasma RMP concentration (mcg/ml)
25 20 15 10 5 0 0 2 4 6 8 10 12 14 16 18 20 22 24

Originator

Source: Suryawati (1992)

Time (hours)

Captopril 25 mg: Variation among Brand Names

300 250 200 150 100 50 0 0 1 2 3 4 5 6 7 8 9 10 11 12
N = number of studies
Source: Suryawati and Santoso (1994). Failed Originator

Plasma concentration (ng/ml)

N=12

Time (hours)

Nifedipine 20 mg: Generic vs. Brand Name

Plasma concentration (ng/ml)
180 160 140 120 100 80 60 40 20 0

Generic Brandname

Source: Suryawati and Santoso (1995).

Time (hours)

Slow-Release Diclofenac Tablet

Plasma concentration (ng/mL)
120
100

Imported product

80
60 40 20 0 0 1 2 3 4 5 6 7 8 9 10 11 12 MEC = 20 ng/mL

Source: Suryawati (1989).

Time (hours)

Medicines with a Stability Problem

Tablets:
Acetylsalicylic acid Amoxicillin Ampicillin Penicillin V Retinol

Oral liquids:
Paracetamol

Injectable:
Ergometrine Methylergometrine

Select the most stable formulation with adequate packaging

How Is Quality Assessed?

INSPECTION of products on arrival
Visual inspection Product specification review (including expiration dates)

LABORATORY TESTING for compliance with pharmacopoeial standards

International Pharmacopoeia European Pharmacopoeia 3 U. S. Pharmacopeia British Pharmacopoeia National Pharmacopoeia

COA

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 Therapeutics Committee Physicians and other prescribers

Medicine Quality

Hospital procurement office

Pharmacy
(and dispensers)

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 Examples of poor quality

at hospital level

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