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

2. 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.

3. 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

4. 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

5. 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

6. 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.

7. 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

8. 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

9. 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

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

11. 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)

12. 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)

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 Standard Method for Bioavailability Studies 1 10 100 02468 1012141618202224 CT

14. Rifampicin 450 mg Capsules: > 100% Variation among Brand Names Source: Suryawati (1992 ) 0 5 10 15 20 25 024681012141618202224 Time (hours) Originator 0 5 10 15 20 25 024681012141618202224 Plasma RMP concentration (mcg/ml) Originator

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

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

17. Slow-Release Diclofenac Tablet Plasma concentration (ng/mL) MEC = 20 ng/mL Source: Suryawati (1989). Imported product Time (hours)

18. 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

19. 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 1 2 3

20. 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

21. 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

22. 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

23. 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

24. Who Ensures Medicine Quality?  Drug regulatory authority

25. 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

26. 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

27. 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

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

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