Drug and Therapeutics CommitteeSession 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

? MEDICINE QUALITY

Manufacturing process

Packaging Transportation Storage

condition

Lack of therapeutic effect:Prolonged illnessDeath

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 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)

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 Parameters:

Cmax Tmax AUC0-

Judgment for bioequivalency: <20% difference

Standard Method for Bioavailability Studies

1

10

100

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

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

Source: Suryawati (1992)

0

5

10

15

20

25

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

Time (hours)

Originator

0

5

10

15

20

25

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

Plasma RMP concentration (mcg/ml)

Originator

Captopril 25 mg: Variation among Brand Names

N = number of studiesSource: Suryawati and Santoso (1994).

0

50

100

150

200

250

300

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

Plasma concentration (ng/ml)

Time (hours)

N=12

Originator

Failed

Source: Suryawati and Santoso (1994).

0

50

100

150

200

250

300

0

50

100

150

200

250

300

0 1 2 3 4 5 6 7 8 9 10 11 120 1 2 3 4 5 6 7 8 9 10 11 12

Plasma concentration (ng/ml)

Time (hours)

N=12

Originator

Failed

Plasma concentration (ng/ml)

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

Nifedipine 20 mg: Generic vs. Brand Name

020406080

100120140160180

0 1.5 3 4.5 6 7.5 910

.5 12 13.5 15 16

.5 18 19.5 21 22

.5 24

GenericBrandname

Slow-Release Diclofenac TabletPlasma concentration (ng/mL)

MEC = 20 ng/mL

Source: Suryawati (1989).

Importedproduct

Time (hours)

0

20

40

60

80

100

120

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

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 U. S. Pharmacopeia British Pharmacopoeia National Pharmacopoeia

BIOAVAILABILITY DATA COA

11

2233

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

MedicineQuality

Physicians and other prescribers

Drug and Therapeutics Committee

Hospital procurement office

Pharmacy (and dispensers)

Patients

MedicineQuality

Physicians and other prescribers

Drug and Therapeutics Committee

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

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?

at hospital level

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