Drug and Therapeutics Committee

1. Drug and Therapeutics Committee Session 5. Pharmaceutical Quality Assurance

2. 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. Acknowledgment

3. 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 Objectives

4. 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 Outline

5. 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—Processconcerned 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 (1)

6. 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. Key Definitions (2)

7. 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 Introduction: Goals of Medicine QA Programs

8. 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 (1)

9. 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 Characteristics of a Comprehensive QA Program (2)

10. ? MEDICINE QUALITY § Lack of therapeutic effect: Prolonged illness § Death § § Toxic and adverse reaction § Waste of limited financial resources § Loss of credibility Impacts of Low-Quality Medicines

11. 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 Determinants of Medicine Quality Identity, purity, potency, uniformity are defined in pharmacopoeias and stated in certificate of analysis (COA)

12. 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 Potential Bioavailability Problems • Medicines with narrow therapeutic range • Slow-release formulations • New formulations (e.g., rectal paracetamol)

13. 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 100 10 1 C T 0 2 4 6 8 10 12 14 16 18 20 22 24 Standard Method for Bioavailability Studies

14. Plasma RMP concentration (mcg/ml) 25 25 20 20 15 15 10 10 Originator Originator 5 5 0 0 0 0 2 2 4 4 6 6 8 8 10 10 12 12 14 14 16 16 18 18 20 20 22 22 24 24 Time (hours) Rifampicin 450 mg Capsules: > 100% Variation among Brand Names Source: Suryawati (1992)

15. Captopril 25 mg: Variation among Brand Names N = number of studies

16. Nifedipine 20 mg: Generic vs. Brand Name Plasma concentration (ng/ml) 180 Generic 160 Brandname 140 120 100 80 60 40 20 0 0 3 6 9 12 15 18 21 24 1.5 4.5 7.5 10.5 13.5 16.5 19.5 22.5 Time (hours) Source: Suryawati and Santoso (1995).

17. 120 100 80 60 40 20 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Slow-Release Diclofenac Tablet Plasma concentration (ng/mL) Imported product MEC = 20 ng/mL Time (hours) Source: Suryawati (1989).

18. Tablets: Acetylsalicylic acid Amoxicillin Ampicillin Penicillin V Retinol Medicines with a Stability Problem • Oral liquids: • Paracetamol • Injectable: • Ergometrine • Methylergometrine • Select the most stable formulation with adequate packaging

19. 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 1 3 2 COA How Is Quality Assessed?

20. 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? (1)

21. 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? (2)

22. 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? (3)

23. Product monitoring system Problem reporting: who, how, where, and to whom; what additional measures; what follow-up information Product recalls: hospital or country level How Is Medicine Quality Assured? (4)

24. Drug regulatory authority Who Ensures Medicine Quality?

25. 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 Implications of Pharmaceutical QA for the DTC

26. 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? Activity (30 minutes) at hospital level

27. 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 (1)

28. Assessing quality includes— Inspection of medicines Laboratory testing when necessary Summary (2)

29. 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