Overview • Why counterfeit? • What kinds of counterfeit products are out there? • What technologies are required to detect them? • How does SCMS protect its supply chains? • How does SCMS plan to assist client sovereign states to protect the follow-on supply chains? SCMS Product Integrity Issues Tom Layloff, Quality Assurance Advisor Supply Chain Management System (SCMS) “Providing Quality Medicines for People Living with and Affected by HIV and AIDS” www.scms.pfscm.org [email protected] The views expressed here are those of the author and may not be those of USAID, SCMS, FDA, or MSH. www.layloff.net [email protected] PEPFAR Implementing Partner Why Counterfeit?? What’s Out There • Two Pharmaceutical Markets • Legitimate Market o o o o Products registered or formal waiver Routine inspection of imports GMP inspection of local manufacturers Some pedigree control • Gray Market o Unregistered and no waiver o No inspection or oversight o Unknown pedigrees PEPFAR Implementing Partner PEPFAR Implementing Partner Some Counterfeiters Are Sophisticated Business People Return on Investment? Repeat business? Tiered Analytical Assessments • Minimum Level Investment- One Off Sales -Local • Flour in capsules • To conserve resources the appropriate technologies should be used to perform the assessments. Tiered levels should be instituted. • In addition to capital costs maintenance costs are estimated at 10% of capital costs per year • In addition supply costs are estimated at 510% of capital costs per year • Higher Level Investment- Return Markets -Internet Sales-Cross Border Trafficking-International • Impure drugs • Undeclared therapeutic product substitution • Sophisticated relabelers and manufacturers • Highest Level Investments- Return Markets Diversions into Legitimate Supply ChainsInternational • Designer Unapproved New Drugs • Sophisticated relabelers and manufacturers PEPFAR Implementing Partner PEPFAR Implementing Partner 1 Level One Product Quality Assessments Right Drug? About Right Amount? Level Two Product Quality Assessments Comply with legal standards? • Technical Resources • Technical Resources • Thin Layer Chromatography • Colorimetric Tests • Near Infrared or Raman Spectroscopy • Chromatography systems HPLC, GC , TLCDensitometry • Spectroscopic procedures UV-Visible • Personnel Qualifications • Personnel Qualifications • Trained laboratory personnel-GMP levels • Basic Laboratory Skills • Facility Requirements • Facility Requirements • Controlled temperature space • Stable power required • Good ventilation • Minimal power requirements • Capital Investment • Capital Investment • Tens to hundreds of thousands USD • Tens of thousands USD PEPFAR Implementing Partner PEPFAR Implementing Partner Level Three Product Quality Assessment New Drug? Impurities? Bioavailability? Overview SCMS Supply Chain Product Integrity • Technical Resources-Forensic Levels • SCMS Support for Client Requirements • Chromatography coupled Mass Spectrometry • Near Infrared or Raman Spectroscopy • Procurement o Contracts • Warehousing and Customs • Distribution to Client Sites in Sovereign States • Personnel Qualifications • Highly trained personnel • Ph.D. with experience o Central Medical Stores--Most o District Level--Few • Facility Requirements • Sovereign States • Controlled temperature • Stable power supplies • Ministry of Health o Regulatory Authority o Internal Distribution System o Health Care Delivery Workers • Capital Investment • Hundreds of thousands to millions USD PEPFAR Implementing Partner PEPFAR Implementing Partner The Need for Rapid Scale-up What We Buy • ARVs (including FDA tentatively approved generics) • Rapid HIV test kits • Laboratory equipment [e.g., Enzyme ImmunoAssay (EIA), CD4, Nucleic Acid Amplification Testing (NAT)] • Drugs for Opportunistic Infections • Drugs for Sexually Transmitted Infections • Drugs for home care and palliative care • Drugs for Tuberculosis • Medical supplies • Miscellaneous (e.g., vehicles) Number of people in low- and middle-income countries on antiretroviral therapy (in 8millions) 7 6 5 4 3 2 Global progress to date 1 2000 Dec. 2006 Source: UNAIDS PEPFAR Implementing Partner PEPFAR Implementing Partner 2 SCMS Quality Assurance SCMS has established routine and with-cause sampling and testing procedures to pose a creditable threat of detection to unscrupulous suppliers. • Routine sampling is conducted at SCMS Regional Distribution Centers • With-cause sampling is performed for complaints or any deviation in processes. Value of Commodities Delivered Value of delivered commodities $30,000,000 $25,908,823 $25,000,000 OTHER $18,501,044 $20,000,000 Dollar value (USD) OI/STI LAB $15,000,000 TEST KIT $10,000,000 $5,000,000 ARV $7,962,651 $3,213,304 $4,447,307 $0 Y1Q4 Y2Q1 Y2Q2 Y2Q3 Y2Q4 Quarter PEPFAR Implementing Partner PEPFAR Implementing Partner Definition: The dollar value of commodities delivered to clients. Where We Work Regional Distribution Centers PEPFAR Implementing Partner Botswana Côte d’Ivoire Ethiopia Guyana Haiti Kenya Mozambique Namibia Nigeria Rwanda South Africa Tanzania Uganda Vietnam Zambia Zimbabwe Regional Consolidation Centers PEPFAR Implementing Partner Beyond the SCMS Supply Chain • SCMS is establishing Regional Consolidation Centers in India • Rapid access to Indian generic products afforded by the Tentative FDA-Approval process • Inspection and sampling at RCCs prior to consolidation and shipping. • Chain of custody • Controlled packing of shipments at the RCC and unloading them at the RDC • Customs inspections under SCMS observation • Visibility of any in-transit security breaches (RFID seals) PEPFAR Implementing Partner • RDC Advantages: • Efficiency and cost • Smaller, regular shipments to protect local systems • Timely, accurate and safe transport including cold/cool chain • Delivery of drugs and commodities door-to-door • Physical security • Chain of custody from supplier to recipient • Rapid response to emergency requests To protect their sovereign markets the National Drug Regulatory Authorities (NDRA) must have in place the basic regulatory functions including: product registration, product and premises inspection, product testing, stringent laws and regulation for standards enforcement. PEPFAR Implementing Partner 3 Registration Just Looking Improves the Marketplace • Defines what products may be legally marketed in the country • WHO prequalification Q&A states: “quality assessment is product and manufacturing site specific” • Registration is product, manufacturer, and site specific PEPFAR Implementing Partner Registered 5.6% Substandard Standard PEPFAR Implementing Partner Testing Drug Registration Improves Drug Quality • Registered 5.6% • Product testing shows that registered products (5.6% substandard) are much less likely to be substandard than unregistered products (23.6% substandard). • Substandard • Standard PEPFAR Implementing Partner Product testing is the most expensive tool in the regulatory process. Product testing is the only way to prove that a product is substandard or is counterfeit. Product testing results may be contested in courts, so chain-of-custody and rigorous adherence to good practices and legal standards are essential. PEPFAR Implementing Partner 2007 WHO Survey of ARVs in Seven African Countries Survey Results Ports-of-Entry and Post-Marketing Surveillance in Tanzania • 394 ARV samples collected from seven African countries • • • • • • Products not legally imported or marketed were rejected or seized and not screened • 1,257 samples of the targeted drugs were screened; ca. 500 per annum • 3.7% or 46 of the samples tested failed screening tests. 1 failed appearance (NPQ) 2 failed labeling (NPQ) 1 failed disintegration (NPQ) 2 failed dissolution (1 NPQ, 1 PQ) 1 failed assay (PQ) 1.8% failure rate with no serious failures 84% of the products were registered in the country 60% were WHO pre-qualified No samples were collected from unofficial sources or remote sites • Non-registered products primarily from the private sector • 41sulfadoxine-pyrimethamine products failed dissolution—all locally manufactured • 5 samples failed screening test-wrong drug or markedly sub-potent • • • • PEPFAR Implementing Partner Not registered 23.6% •A Comparison Study of Testing Products Registered and Not Registered in Myanmar and Vietnam 1996−1997 WHO Data o 3 samples of quinine tablets o 2 samples of erythromycin tablets. Tanzania FDA Data in press PEPFAR Implementing Partner 4 Tanzania Pharmaceutical Market Defense US FDA Counterfeit Detection Efforts The following five slides concerning detection of illegal Erectile Dysfunction (ED) drugs are taken from a presentation by the US FDA Forensic Chemistry Center in Cincinnati, Ohio. • TZ surveillance focused on legal products which had passed the registration requirements and were stored in approved premises • Upstream compliance activities: registration, record inspection and physical examination are reflected in improved quality of marketed products • This overall regulatory activity provides a significant deterrent. • Therefore legitimate conscientious manufacturers and distributors can compete. PEPFAR Implementing Partner SCMS does not distribute ED drugs and these slides are intended only to illustrate the level to which some unscrupulous manufacturers will go to sell products. PEPFAR Implementing Partner VIAGRA Summary “Counterfeit” and unapproved Example Erectile Disfunction (ED) Drugs FDA FCC Materials • • • • FDA FCC Slide The three approved products for ED treatment are: Sildenafil Citrate (VIAGRA®) FDA approval - 1998 Tadalafil (CIALIS®) FDA approval - 2003 Vardenafil HCl (LEVITRA®) FDA approval - 2003 Suspect Counterfeit Products SubPotent Potent 72 # of Samples SuperPotent 59 No Active 30 Mixed Actives 1 3 Unapproved Products Potent # of Samples PEPFAR Implementing Partner PEPFAR Implementing Partner Cialis Summary Levitra Summary “Counterfeit” and unapproved “Counterfeit” and unapproved FDA FCC Slide 19 SuperPotent No Active 1 0 Mixed/Wrong Actives** 15 FDA FCC Slide Suspect Counterfeit Products # of Samples Suspect Counterfeit Products Potent SubPotent SuperPotent No Active Mixed/Wrong Active 26 4 19 5 19/17 # of Samples Potent SubPotent SuperPotent No Active Mixed/Wrong Active 1* 0 0 1 16/19 # of Samples * vardenafil polymorph Unapproved Products PEPFAR Implementing Partner 34 SubPotent Potent SubPotent SuperPotent No Active Mixed/Wrong Active 52 17 4 0 7/4 # of Samples PEPFAR Implementing Partner Unapproved Products Potent SubPotent SuperPotent No Active Wrong Active 2 0 0 0 3 One sample was bulk powder declared as “sodium pyruvate” contained 82% pure vardenafil 5 Analytical Approach at FCC Scope of The Analog Analytical Problem Sample FDA FCC Data Compound M.W. Rel Retention Time Sildenafil 474.21 1.00 Homosildenafil 488.22 1.01 Supplement/Herbal O O O N O N HN S Physical Characterization (dimensions, markings, mass, color) O Not authentic N N N N O N Authentic LC-MSn N HN S N N O Dosage Form Approved API Analog LC-MSn FTIR HS GC-MS O LC Assay sildenafil (accurate mass) homosildenafil PEPFAR Implementing Partner PEPFAR Implementing Partner US FDA Forensic Chemistry Center Summary FTIR LC Estimate Authentic Not authentic Complete LC Assay Quality Products in the Marketplace • The presence of ED drugs and numerous analogs is widespread among herbal products, supplements and dosage forms. • Screening procedures that target only approved APIs are inadequate. • Preliminary results suggest that polymorphs may also be a factor for this class of compounds. • Those who produce and market these illegal products are becoming more clever. Those trying to prevent it must adjust accordingly PEPFAR Implementing Partner ICR FTMS • Establish a strong well-publicized regulatory posture including enforcement • Purchase products which are approved AND marketed in ICH or PIC/S countries or WHO prequalified products • Watch the pedigrees of incoming products PEPFAR Implementing Partner Client Countries Inspection Levels Technical Assistance to Strengthen National Drug Regulatory Authorities • Level One • Strengthen level one drug product and premises regulation-registration, inspection • Strengthen level one assessment technologies • Technical assistance to strengthen level two assessment technologies • Assist in regional coordination of efforts to strengthen level three assessment resources • Technical assistance to strengthen regional and international communications and alerts • Product and premises compliance to standards • Level Two • GMP inspection of manufacturers • GLP inspection of testing laboratories • Level Three • Sterile operations o Terminal sterilization o Sterile filling o Lyophilized products PEPFAR Implementing Partner PEPFAR Implementing Partner 6 SCMS Internal Use Form to Report Product Quality Issues Web Based Internal Reporting Form for SCMS Staff • Report immediately issues relating to the quality, safety, and/or efficacy of products to the SCMS quality team. Your quick reporting will help ensure the quality of products procured and distributed by SCMS. • Access Form on SCMS Intranet to report issues, incidents, or complaints relating to product quality. PEPFAR Implementing Partner PEPFAR Implementing Partner Things to Ponder • “In a lawless world, the exigencies of competition tended to drive commercial practices toward the level of the most unscrupulous.” – James Harvey Young • “If you have no defense you can’t defend yourself.” – Tom Layloff PEPFAR Implementing Partner PEPFAR Implementing Partner Requirements for Successful Defense Questions? Society commitment Political will Financial resources Thank You!! Contacts [email protected] [email protected] PEPFAR Implementing Partner PEPFAR Implementing Partner 7
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