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Ensuring access to drug products that are of acceptable quality WHO Pilot Procurement, Quality and Sourcing (“pre-qualif

Ensuring access to drug products that are of acceptable quality WHO Pilot Procurement, Quality and Sourcing (“pre-qualification”) project. WHO/EDM Technical briefing seminar 2 October 2002 Geneva. Dr Lembit Rägo Quality Assurance and Safety: Medicines Essential Drugs and Medicines Policy

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Ensuring access to drug products that are of acceptable quality WHO Pilot Procurement, Quality and Sourcing (“pre-qualif

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  1. Ensuring access to drug products that are of acceptable quality WHO Pilot Procurement, Quality and Sourcing (“pre-qualification”) project WHO/EDM Technical briefing seminar 2 October 2002 Geneva Dr Lembit Rägo Quality Assurance and Safety: Medicines Essential Drugs and Medicines Policy Health Technology and Pharmaceuticals Cluster, World Health Organization Tel: +41.22.791. Fax: +41.22.791.4730 E-mail: ragol@who.int

  2. Quality of Anti-retroviral Drugs Presentation outline • Is quality of pharmaceuticals a problem? • What WHO is doing to help countries to ensure quality of pharmaceuticals? • Why quality problems of ARVs are not easy to solve? • WHO Pilot Procurement, Quality and Sourcing Project • Why and how? • Expected outcomes • Problems encountered • First results • Future challenges

  3. Is quality of pharmaceuticals a problem? Substandard drugs is a big problem - antibiotics, antimalarials, antituberculosis drugs included. Percentage breakdown of data on 325 cases of substandard drugs - including antibiotics, antimalarials and antituberculosis drugs - reported from around the world to WHO database Incorrect breakdown of data on 325 cases of substandard drugs - including antibiotics, the world to WHO database ingredient 16% Incorrect amount 17% No active ingredient Other errors 60% 7%

  4. Is quality of pharmaceuticals a problem? The quality of anti-malarial products - both content and dissolution are problems

  5. Is quality of pharmaceuticals a problem? The quality of anti-malarial products - both content and dissolution are problems

  6. Is quality of pharmaceuticals a problem? Why is Quality of Pharmaceuticals So Different? • Huge regulatory capacity gaps - if no proper requirements or no capacity for implementation of requirements the quality may vary • No global standards for generics - WHO has a comprehensive set of guidelines but implementation varies • No requirements, or no equal quality requirements for export - very few countries effectively control quality of pharmaceuticals for export; certificates for export are issued more easily than for domestic markets • Know-how gap - if no properly educated people available no good results can be expected • Financial incentives - quality has its price and generic manufacturers work for profit as any other business • Other reasons ...

  7. 1. Rationalselection 3. Sustainablefinancing ACCESS 2. Affordableprices 4. Reliable health & supply systems What is WHO doing to help countries to ensure quality? Four objectives of WHO Medicines Strategy: 2002-2003 1. Policy 3. Quality and safety 2. Access 4. Rational Use

  8. What is WHO doing to help countries to ensure quality? World Health Assembly resolution 52.19, 24 May 1999: Revised Drug Strategy • The Fifty-second World Health Assembly, 24 May 1999, (WHA52.19) resolutionon Revised Drug Strategy noted that … (b) poor quality pharmaceutical raw materials and finished products continue to move in international trade; • URGED Member States: … (2) to ensure that public health interests are paramount in pharmaceutical and health policies; … (4) to establish and enforce regulations that ensure good uniform standards of quality assurance for all pharmaceutical materials and products manufactured in, imported to, exported from, or in transit through their countries;

  9. What is WHO doing to help countries to ensure quality? World Health Assembly resolution 54.11, 21 May 2001: WHO Medicines Strategy … bearing in mind the previous report on the subject, that highlight challenges related to the international trade agreements, access to essential drugs, drug quality and rational use of medicines, together with the urgent need to improve access to treating priority health problems such as malaria, childhood illnesses, HIV/AIDS and tuberculosis, among others; REQUESTS Director-General: … (3) to provide support for implementation of drug monitoring systems in order better to identify developing resistance, adverse reactions and misuse of drugs within health systems, thus promoting rational use of drugs; (6)to provide support to Member States to set up efficient national regulatory mechanismsfor quality assurance that will help ensure compliance with good manufacturing practices, bioavailability and bioequivalence

  10. What is WHO doing to help countries to ensure quality? Quality and safety: global norms, standards, guidelines, nomenclature (http://www.who.int/medicines) • Global norms and standards in • production and inspection, quality control (incl. International Pharmacopoeia), model certificates… • TRS publications, Quality Assurance, vol. 1 and 2 ... • Guidelines for generic drug registration and model legislation • stability testing, bioequivalence, QA in pharmaceutical supply systems ... • classification and self-medication products, internet & pharmaceuticals etc. • but limited guidance in efficacy and safety area • Nomenclatures, classifications • INNs (International Nonproprietary Names) • ATC classification and Daily Defined Doses (DDDs)

  11. What is WHO doing to help countries to ensure quality? What is WHO doing in order to reduce quality and regulatory gaps? (http://www.who.int/medicines/) • Supporting capacity building and training of regulators • Based on norms and standards and guidance materials • Preparing training tools, organizing training seminars and workshops • Validated GMP training modules on CD-rom, GMP training courses • Workshops on quality assurance, drug registration • Facilitating information exchange • WHO Drug Information, WHO Pharmaceutical Newsletter, Rapid Alerts • Increasing information on the web site - guidelines, INNs database etc. • Biennial International Conferences of Drag Regulatory Authorities (ICDRAs) • Supporting regional harmonization initiatives • Favoring networking, providing technical assistance

  12. Why quality problems are not easy to solve? Multisource antiretroviral drugs are in majority of cases not typical “generic” drugs • Usually generic drugs “well established” … • ARVs are relatively new, or very new drugs • Limited information available in public domain • Most antiretrovirals do not have quality standards • Pharmacopoeial monogrphs exist only for three (zidovudine, zalcitabine, saquinavir) • For most ARVs reference standards not readily available • Reference standards available only for those that have pharmacopoeial monographs • Difficulties of proving “interchangeability” • Regulators have limited experience with this group of drugs ...

  13. Pilot Procurement, Quality and Sourcing Project WHO Pilot Procurement, Quality and Sourcing (“pre-qualification”) project: Access to HIV/AIDS Drugs and Diagnostics of Assured Quality • Why the project was launched? • Requests from countries and other organizations to help in terms of assuring quality of HIV/AIDS drugs • Other UN agencies lacking technical knowledge and seeking technical help from WHO • Technically complicated group of drugs

  14. Pilot Procurement, Quality and Sourcing Project Access to HIV/AIDS Drugs and Diagnostics of Assured Quality • Partners* • UNAIDS • UNICEF • WHO • UNFPA • With the support of World Bank • *All organisations are also members of the International Pharmaceutical Co-ordination Group (IPC)m: • Starting - Expression of Interest • Launched by partners in 2001 • Offers from manufacturers of HIV/AIDS drugs and diagnostics received in the 3rd quarter of 2001 ... • WHO role • Provide technical assistance in quality related issues

  15. Pilot Procurement, Quality and Sourcing Project The drugs involved in the pilot project* (I) • Antiretroviral agents • Non-Nucleoside Reverse Transcriptase Inhibitors such as Nevirapine; Efavirenz; Delavirdine • Nucleoside Reverse Transcriptase Inhibitors such as Zidovudine, Didanosine; Zalcitabine; Stavudine; Lamivudine; Abacavir; Lamivudine + Zidovudine. • Protease Inhibitors such as Saquinavir, Ritonavir, Indinavir; Nelfinavir; Amprenavir; Lopinavir + Ritonavir; • Anti-infective drugs listed below: • Antibacterial and antimycobacterial agents, including • Azithromycin; Clarithromycin; Clindamycin; Ceftriaxone; Cefixime; Ciprofloxacin; Rifabutin * Based on the first Expression of Interest

  16. Pilot Procurement, Quality and Sourcing Project The drugs involved in the pilot project (II) • Antiprotozoal agents, including • Trimethoprim/Sulphamethoxazole(IV); Pentamidine; Pyrimethamine; Sulfadiazine; • Folinic acid • Antiviral agents, including • Acyclovir; Cidofovir; Ganciclovir; Forscarnet • Antifungal agents, including • Amphotericin B; Fluconazole; Itraconazole; Ketoconazole; • Anti-cancer drugs • Vinblastine; Etoposide; Bleomycin; Vincristine

  17. Pilot Procurement, Quality and Sourcing Project Access to HIV/AIDS Drugs and Diagnostics of Assured Quality • Key question: what standards to apply? (EOI covered both originator and generic products) • Small group of regulators was asked this question, answers were collected and summarized, outcome discussed and agreed with partners • Conclusions: • 1. Originator products: abridged procedure relying on scientific expertise of well established regulatory authorities • 2. “Generic” drugs: WHO standards used for multisource (generic) drugs both for dossier assessment and GMP inspections - as pharmacopoeial standards not available full assessment necessary • Separate guides cover both 1 and 2 were composed - both available on website:http://www.who.int/medicines/

  18. WHO Basic Requirements for Generic Drugs Access to HIV/AIDS Drugs and Diagnostics of Assured Quality • What is required (1) ? • 1. Details of the product • 2. Regulatory situation in other countries • 3. Active pharmaceutical ingredient (s) (API) • 3.1 Properties of the active pharmaceutical ingredient(s) • 3.2 Sites of manufacture • 3.3 Route(s) of synthesis • 3.4 Specifications • API described in a pharmacopoeia: • API not described in a pharmacopoeia: • 3.5 Stability testing • WHO Expert Committee on Specifications for Pharmaceutical Preparations, Thirty-fourth report. Geneva, World Health Organization, 1996: 65-79(WHO TRS, No 863) • http://www.ifpma.org/ich5q.html#stability

  19. WHO Basic Requirements for Generic Drugs Access to HIV/AIDS Drugs and Diagnostics of Assured Quality • What is required (2)? • 4. Finished product • 4.1. Formulation • 4.2. Sites of manufacture • 4.4. Manufacturing procedure • 4.5 Specifications for excipients • 4.6 Specifications for the finished product • 4.7 Container/closure system(s) and other packaging • 4.8 Stability testing

  20. WHO Basic Requirements for Generic Drugs Access to HIV/AIDS Drugs and Diagnostics of Assured Quality • What is required (3)? • 4.9 Container labelling • 4.10 Product information • 4.11 Patient information and package inserts • 4.12 Justification for any differences to the product in the country or countries issuing the submitted WHO-type certificate(s) • 4.13 Interchangeability (bioequivalence studies, or justificaton, if not provided) • 4.14 Summary of pharmacology, toxicology and efficacy of the product • Based on " Marketing Authorization of Pharmaceutical Products with special Reference to Multisource (Generic) Products: a Manual for a Drug Regulatory Authority,” WHO/DMP/RGS/98.5) and other relevant WHO documents

  21. Pilot Procurement, Quality and Sourcing Project Access to HIV/AIDS Drugs and Diagnostics of Assured Quality • Project has two major objectives • Assessment of HIV/AIDS related drugs quality (pre-qualification) • Creating WHO Model Quality Assurance System for Procurement (MQAS-P)

  22. Pilot Procurement, Quality and Sourcing Project Access to HIV/AIDS Drugs and Diagnostics of Assured Quality - products I • Invisible products for running quality assessment (pre-qualification) project: • First, internal WHO/QSM Quality Assurance System created and implemented • Operations Manual drafted, Standard Operating Procedures and records created and implemented • General Procedure for assessment (pre-qualification)of drugs drafted, circulated for comments and approved by WHO Expert Committee for Pharmaceutical Specifications in Oct 2001 • Quality Manual created (as per ISO)

  23. Pilot Procurement, Quality and Sourcing Project Access to HIV/AIDS Drugs and Diagnostics of Assured Quality - products II • Invisible products done for running quality assessment (pre-qualification): • Code of Conduct for assessors and inspectors created and implemented • More than 180 product dossiers (not only ARVs but also drugs for HIV care) assessed and communicated(to manufacturers) • upon need re-assessment of dossiers • GMP inspections carried out and results communicated, inspections ongoing • What is the value of feedback to manufacturers? (money? knowledge?)

  24. Pilot Procurement, Quality and Sourcing Project Access to HIV/AIDS Drugs and Diagnostics of Assured Quality - products III • Visible products of running quality assessment (pre-qualification): outcome • Products • First set of products and suppliers published 20 March 2002 - all information on web site http://www.who.int/medicines/ • Draft Model Quality Assurance System for Procurement (MQAS-P) created • Pro-active communication and feedback to regulators • Workshops, training courses: Washington DC (PAHO) April 2002, Pretoria (AFRO) June 2002, SEARO (Sept 2002) ...

  25. Pilot Procurement, Quality and Sourcing Project Access to HIV/AIDS Drugs and Diagnostics of Assured Quality • Assessment of dossiers • Carried out by teams of professionals from national DRAs (mix of developed and developing countries) • Manufacturing sites inspections • Carried out by teams of three: WHO representative (qualified GMP inspector), inspector from well established inspectorate (PIC/S countries) and national inspector(s) • Qualified inspectors pool limited, no additional capacities

  26. Problems encountered Access to HIV/AIDS Drugs and Diagnostics of Assured Quality: Quality problems I • General problems and deficiencies identified: • Several substances and products not in pharmacopoeia • Lack of established reference standards • Active pharmaceutical ingredients e.g. route of synthesis unknown, supplier unknown • Unacceptable impurities • No analytical methods and method validation • In vitro dissolution tests of solid dosage forms have not been carried out • Regulatory approval not based on thorough evaluation

  27. Problems encountered Access to HIV/AIDS Drugs and Diagnostics of Assured Quality: Quality problems II • Specific problems : Unacceptable chiral activity, stereo-isomerism of active pharmaceutical ingredient (API) - potentially inactive API • CHIRALITY / ENANTIOMERIC PURITY • Stavudine • Lamivudine • Indinavir (1/ 32 possible stereoisomers) • Saquinavir mesylate (1/64 possible) • Ritonavir Only one enantiomer registered and claimed in the innovator’s dossier EMEA/CPMP/375/96 EPAR : (-) Lamivudine selected because less cytotoxic than (+) Lamivudine and the racemate (50:50 mixture)

  28. Problems encountered Access to HIV/AIDS Drugs and Diagnostics of Assured Quality: Quality problems III • CHIRALITY / ENANTIOMERIC PURITY: Lamivudine example (1): • No information on the stereochemical configuration • No information on how the synthesis can lead to the correct enantiomer  evidence of structure / right enantiomer? • No validation on manufacturing process of the API: only 2 batches with batch size unknown  batch-to-batch consistency not demonstrated/ is the same enantiomer obtained each time? Is it contaminated with the same amount of the undesirable stereoisomer each time? • Absence of control of the undesirable enantiomer in the finished pharmaceutical product including biobatch • ...

  29. Problems encountered Access to HIV/AIDS Drugs and Diagnostics of Assured Quality: Quality problems IV • No, or incomplete data and information on: • Validation of analytical methods • Stability data (both active pharmaceutical ingredient and finished product) • Process validation • Development pharmaceutics • Bio-equivalence

  30. Problems encountered Access to HIV/AIDS Drugs and Diagnostics of Assured Quality: Quality problems V • BIOEQUIVALENCE • Lamivudine examples 1 file for oral solution  no BE study required 6 files for tablets from 4 manufacturers • 2 manufacturers: no BE study • 2 manufacturers: BE study included for at least one formulation strength • Major deficiencies identified in BE studies from both manufacturers (assay validation, relevant test product?)

  31. Pilot Procurement, Quality and Sourcing Project Access to HIV/AIDS Drugs and Diagnostics of Assured Quality: Quality problems III • GMP deficiencies: • Hormones, cytotoxics and ARVs in same area • Qualification and validation lacking (premises, systems, equipment, processes) • Cleaning validation • No verification of air classification of areas for sterile product manufacturing • Sampling and testing of APIs • Loss in traceability of materials used in production • Fraudulent data • … ...

  32. Pilot Procurement, Quality and Sourcing Project Why compliance with WHO standars is needed? All literature about drugs based on originator products: • Thus, the “generic” products have to be interchangeable with originator products! • Pharmaceutical interchangeability - the same active ingredient (with the same route of synthesis), the same dosage form … the same quality • Therapeutic interchangeability - bioequivalence studies in vivo a must for this group to prove the same efficacy and safety • If not interchangeable, then … documentation to support new drug application must be prepared • New toxicological studies • New clinical studies … • Not realistic approach

  33. Pilot Procurement, Quality and Sourcing Project Access to HIV/AIDS Drugs and Diagnostics of Assured Quality Current status: • Good news • Relatively large number of products and suppliers indicated • First pre-qualified suppliers list published • Potential suppliers appreciating feedback and willing to improve • Unique knowledge obtained about generic ARVs • “Good quality” generic ARV products do exist • Bad news • Only limited number of products have met the required standards • Takes time to get into compliance • Data to be generated • GMP upgrade needed • Quality Assurance at a price!

  34. Pilot Procurement, Quality and Sourcing Project Future challenges beyond the HIV/AIDS related drugs • Applying the same approach to other priority diseases like TB and malaria (pre-qualification of these products has started already) • Strengthening procurement quality assurance Globally • Creating WHO Model Quality Assurance System for Procurement through WHO normative procedures • Step-by-step harmonization of Quality Assurance Systems in procurement organizations - long-term commitment needed • Mutual trust between those who start using MQS - exchange of inspection results and other information, less duplication, common pool of pre-qualified products as “public good”

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