1. Drug Manufacture, Quality Assurance, and Regulation Tom Layloff Quality Assurance Advisor Supply Chain Management System – Providing Quality Medicines for People Living With and Affected by HIV and AIDS www.scms.pfscm.orgwww.scms.pfscm.org tlayloff@pfscm.orgtlayloff@pfscm.org The views expressed here are those of the author and may not be those of USAID, SCMS, FDA, or MSH. www.layloff.netwww.layloff.net tom@layloff.nettom@layloff.net

2. Objectives By the end of this session, you should be able to— Describe the difference between Active Pharmaceutical Ingredients and Dosage Forms Differentiate between brand vs. generic products and the conditions for interchange Be familiar with drug manufacturing requirements and Good Manufacturing Practices (GMP) Explain the concept of and issues relating to drug product quality assurance Identify risks associated with substandard and counterfeit drug products Understand the extent of the problem of substandard and counterfeit drug products in developing countries List and describe the components of a quality assurance system List criteria for quality testing Outline an approach for quality testing in resource-limited settings

3. The Drug Universe Begins with the Active Pharmaceutical Ingredient (API). APIs are chemicals that have been shown through clinical studies or long history of safe use to have desirable therapeutic properties when used appropriately. APIs are extracts from natural products or are chemically or biologically synthesized. The safety and efficacy (S&E) of APIs are established almost universally through the guidelines developed by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), www.ich.org.www.ich.org The ICH guidelines are adopted into the laws and regulations of the ICH countries (European Union, Japan, and USA) where essentially 100% of the drug research is conducted and which constitute over 85% of the world drug market. WHO has observer status and represents interests of other countries.

4. Global Pharmaceutical Sales by Region, 2005 World Audited Market 2005 Sales (US$B)% Global Sales % Growth Year-over-Year (Constant $) North America$265.747.0%5.2% Europe169.530.07.1 Japan60.310.76.8 Asia, Africa and Australia46.48.211.0 (China)(11.4)(20.4) Latin America24.04.218.5 Total IMS Audited*$565.9100%6.9% * Source: IMS MIDAS®, MAT Dec 2005. All information current as of February 27 Sales in ICH countries (No. America, Europe, Japan) totals 87.7%

5. More on APIs Chemically synthesized APIs (fine chemicals) are produced primarily in the China/India economic block, Korea, and Italy (near Milan). Biotechnologically derived APIs are almost all manufactured in the ICH regions. The clinical studies—Phase III—define the therapeutic window for a specific drug—too much may be toxic and too little may be ineffective. Summary: Clinical studies are used to define the safety and efficacy of a drug product containing the API and the therapeutic window in which the drug is effective.

6. The Nomenclature of APIs International Non-proprietary Names (INN) for APIs are assigned by the WHO or in the USA by United States Adopted Names (USAN) Council established by the AMA, USP, and APhA. The INN and USAN names are generally the same but some are not—e.g., acetaminophen (USAN) and paracetamol (INN). Single source (new) and generic drug products frequently are given proprietary trade names by the manufacturer for market leverage—e.g., Tylenol brand acetaminophen and Bayer brand aspirin. In Namibia, a pharmaceutical distributor carried 28 trade name amoxicillin products. A MESS.

7. New Drug Development

8. Generic Drugs A generic drug product is bioequivalent to an “innovator” (new) drug product with respect to pharmacokinetic and pharmacodynamic properties. Generic drugs must –Contain the same active ingredient at the same strength as the "innovator" product –Be bioequivalent –Meet the same pharmacopoeial standards as applicable –Be identical in dose, strength, route of administration, safety, efficacy, and intended use

9. Therapeutic Window – Bioequivalence

10. New vs. Generic Review Processes New Drug (ICH) Generic Drug Requirements Requirements1. Chemistry2. Manufacturing3. Controls4. Labeling5. Testing 6. Animal studies 7. Clinical studies6. Bioequivalence 8. Bioavailability

11. Preparing an API for Patient Use To serve the patient’s needs an API must be provided in the right amount using an appropriate delivery mechanism (i.e., a drug product or dosage form). Excipients are used to make the drug more convenient, palatable, or effective. –325 mg Tylenol tablet excipients include cellulose, corn starch, magnesium stearate, sodium starch glycolate. Some common dosage forms include – Capsules Tablets Chewable tablets Granules Creams Gels Ointments Injections Powder for injection Oral solutions Suspensions Syrups Powder for suspension Rectal suppositories Vaginal suppositories Inhalers Powder for inhalation Transdermal patches

12. Creating a Drug Product Extemporaneous compounding: –Part of the practice of medicine and pharmacy. –Governed by Good Compounding Practices. –In the US, the practice of medicine and pharmacy is regulated by state professional practice boards. Manufacturing: –Governed by current Good Manufacturing Practices. –API and drug product manufacturing are regulated by national drug regulatory bodies (FDA in the US).

13. Manufacturing involves the production, propagation, conversion, or processing of a drug or device, either directly or indirectly, by extraction of the drug from substances of natural origin or by means of chemical or biological synthesis. Manufacturing also includes: (1)Packaging or repackaging of the substance(s) (2)Labeling or relabeling of containers (3)Any preparation of a drug or device that is given or sold for resale by pharmacies, practitioners, or other persons (4)Distribution of inordinate amounts of compounded preparations or the copying of commercially available drug products (5)Preparation of any quantity of a drug product without a licensed prescriber/licensed pharmacist/patient relationship Drug Product Manufacturing

14. Good Manufacturing Practices (GMP) GMPs are intended to assure the production of a uniform, consistent product. The WHO and US have published the flagship guidance. The manufacturing processes must be well-defined, documented and in demonstrated control. The GMP process starts with the quarantine of all received goods that are released to production after verification. The GMP process ends with the review of the finished product to assure that it complies with the stated requirements. It is estimated that the meeting of GMP requirements costs 25-35% of sales revenue.

15. Determinants of Drug Product Quality Drug production –Equipment and maintenance –Plant environment –Drug product manufacturing process Quality control Drug formulation –Active ingredients –Inactive ingredients Packaging—both immediate and external Handling and storage conditions

16. Incorrect amount 17% No active ingredient 60% Other errors 7% Incorrect ingredient 16% 60% No active ingredient + 16% Incorrect ingredient = 76% Would fail ID/TLC test 17% Fail assay 93% of these substandard drugs might be detected by ID and TLC testing Substandard Medicines in Developing Countries (1) Out of 325 Cases of Substandard Drugs, Including Antibiotics, Antimalarials, and Antituberculosis Drugs Reported to WHO

17. Substandard Medicines in Developing Countries (2) Therapeutic groups Analgesics Antihypertensives Antimicrobials Antimalarials Percentage of Samples Found to Be Substandard Rägo, L. 2002. Ensuring Access to Drug Products That Are of Acceptable Quality. PowerPoint presentation, WHO/EDM Technical Briefing, October 2, Geneva.

18. Quality of Antimalarial Products: Both Content and Dissolution Are Problems

19. Reasons for Poor Quality Pharmaceuticals Gaps in regulatory capacity—Improper requirements and no capacity for implementation of requirements. Failure to apply global standards for generics—WHO has guidelines, but country implementation varies. Different quality requirements for export—Very few countries effectively control quality of pharmaceuticals for export; certificates for export are issued more easily than are certificates for domestic markets. Lack of financial incentives—Local manufacturers do not have sufficient incentives to meet international standards No enforcement actions.

20. Definitions of Quality Control and Quality Assurance Quality control: The testing of pharmaceutical samples against specific standards of quality. Quality assurance: The management of activities required to ensure that the pharmaceuticals that reach the patient are safe, effective, and acceptable to the patient. Source: Management Sciences for Health and World Health Organization.1997. Managing Drug Supply, p. 182.

21. Current Testing Methods Color reactions Spectrophotometry Thin-layer chromatography (TLC) Gas chromatography High-performance liquid chromatography (HPLC) Others

22. Testing Standards and Methods Public vs. private standards (i.e., pharmacopoeia vs. manufacturer/registration) Legal vs. credentialed methods (i.e., pharmacopoeia vs. AOAC International)

23. Pharmacopoeial Assessments Rooted in the analytical methods developed in the drug discovery process—technology dependent Discovery technologies are very focused on API and impurity characterization (high-resolution systems) Relatively expensive systems: –Analytical equipment –Maintenance and other consumables –Reference materials –Personnel training

24. Critical Attributes for Testing Dosage Forms Identity Assay (amount of active ingredient) Disintegration (prerequisite for bioavailability) Dissolution (higher level of assurance of bioavailability) Impurities (generally related to active pharmaceutical ingredient, similar toxicities)

25. Implications for Resource-Limited Settings (1) Being largely import-dependent, developing countries need to develop and maintain an effective product testing program. Major hurdles are: –Newer essential therapeutic drugs for which public standards/monographs are not available. –Multi-source essential therapeutic drug products for which the legal reference methods require high-technology support. –Lack of resources to effectively mount an effective product testing program.

26. Implications for Resource-Limited Settings (2) Difficult to implement and sustain effective high-technology testing programs –Complexity of equipment and maintenance needs –Access to reference materials, reagents, and other consumables –Need for highly trained technical staff –High cost to launch and maintain effective program

27. Suriname Case Study 75% of samples could not be analyzed using pharmacopoeial methods Spectrophotometer and high-performance liquid chromatographer not operational at time of study (for 9 and 2 months, respectively) No regular equipment maintenance due to cost Shortage of reference standards and mobile phase for HPLC tests

28. Assuring Pharmaceutical Product Quality Stakeholders Drug regulatory authority Quality control laboratory Procurement agencies Local manufacturers Pharmaceutical importers Port of entry officials Pharmaceutical distributors Providers Patients

29. Quality Assurance: Documentation Country product registration and procurement Prequalification of suppliers –Product technical file –Certification GMP compliant Certificate of free sale Certificate of analysis Certificate of origin WHO certification (Certification Scheme for Pharmaceutical Products Moving in International Commerce) Supply chain management –Distributor invoices or bills of lading –Records of purchases/invoices

30. Quality Assurance: Inspection Manufacturing operations –Good manufacturing practices (GMPs) Wholesalers and distributors –Good storage practices Hospitals, clinics, pharmacies, and drug sellers –Good dispensing practices Pharmaceutical products –Technical specifications and organoleptic characteristics –Sampling for testing

31. Quality Assurance: Product Testing by Resource-limited Countries Use of a tiered testing strategy –Level 1 (local) testing to “screen” products for poor quality using simple methods –Level 2 (secondary) testing to confirm screening results –Level 3 (tertiary) testing capacity at national level for impurity contaminations Prioritize testing based on risk to patients

32. Case # -- ProblemRisk (Possible outcome)Comments #1 – No API or does not disintegrate Safe but not effective (lack of treatment and possible acerbating of resistance development) No API is most common in counterfeit products #2 – Wrong API Generally unsafe (as above plus pharmacogenic diseases and death) Second in frequency; also arises from production cross- contamination, packaging and labeling mix-ups, and use errors #3 – Wrong amount of API or dissolution failure Variable depending on half-life and toxicity (low content may be below therapeutic window and be ineffective; high content may be toxic while content uniformity variations may average out) Generally associated with poor GMPs of manufacture #4 – Presence of impurities Variable depending on genotoxicity and toxicity (birth defects, long-term carcinogenicity, illness, or death depending on impurity) Generally associated with poor API GMP manufacture compliance or storage abuse; thermal, moisture exposure, or light Determining Risk

33. Case # -- Problem Testing LevelTesting Approach and Relative Cost #1, 2, and 3 -- No API or does not disintegrate, wrong API, or significantly sub-standard (too little or too much API) Level 1Thin Layer Chromatography (TLC); visual disintegration test using Minilab Inexpensive; low maintenance #3 – Wrong amount of API or dissolution failure (does not release medicine properly) Level 2Assessments per legal standard (generally USP or BP monographs) using High Performance Liquid Chromatography (HPLC) in addition to other techniques Expensive; high maintenance #4 – Impurity contaminations: Precursors, by-products, degradation products, residual solvents Level 3Complex and Instruments such as Mass Spectrometry are needed to determine Impurities Very expensive; high maintenance Testing Level Needed to Address the Risks

34. Rationale for Testing New essential therapeutic drug products –High potential for counterfeiting (and fraud-motivated noncompliance with legal standards Older essential therapeutic drug products –Mostly “off-patent,” multisource products Sampling –Pharmaceutical products are presumed to be produced under GMP so the collection of a single sample, sufficient for the intended analyses is adequate. Appendix 4, WHO Expert Committee on Specifications for Pharmaceutical Preparations, Thirty-ninth Report, Geneva 2005. See http://whqlibdoc.who.int/trs/WHO_TRS_929_eng.pdf#page=47 http://whqlibdoc.who.int/trs/WHO_TRS_929_eng.pdf#page=47

35. German Pharma Health Fund Minilab www.gphf.org/web_en/projekte/minilab/index.htm www.gphf.org/web_en/projekte/minilab/index.htm

36. Quality Assurance: Product Testing Malaysia Government Pharmaceutical Laboratory purchases in 1992 –GMP certification and product testing Costa Rica Social Security Fund purchases in 1977 vs. 1991 –Product testing program 1977 1991 18% 1% % Provided GMP Certificates % Passed Tests 100% 59%

37. Quality Assurance: Monitoring Product problem reporting –Suppliers –Health care providers –Consumers Supplier and product database –Supplier performance –Product problems Clinical (ineffective, adverse events) Pharmaceutical (physicochemical problems)

38. Quality Assurance: Evaluation and Enforcement Withdrawal of marketing authorization (product license) Delisting from pre- qualified status Rejection of shipment Product recall

40. Detection of Counterfeit Medicines A perfect counterfeit product cannot be detected. A well-made and well-labeled counterfeit is very difficult to detect even if direct comparisons between authentic and fake products can be made. Testing may be the best available option.

41. Summary Many resource-limited countries are planning to purchase generics for HIV/AIDS, TB, malaria, and other diseases, so product quality is becoming a growing concern There are a number of program implications if substandard or counterfeit products are purchased—poor treatment outcomes, potential liabilities, loss of public trust More open (international) procurement can be financially beneficial, but requires a more stringent QA system A three-tier testing program is a less expensive, viable option for quality control—big laboratories are not always necessary