Renu'

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Renu.
India WHO Pallava Bagla
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Substandard and Fake Medicines a Threat to
Global HealthMAQ 2005 Mini UniversityOctober
14, 2005

• Joyce Primo-Carpenter, B.S. Pharm., M.D.,
  Associate Director
• Abdelkrim Smine, Ph.D., Manager, Drug Quality
  Control and Laboratory Training
• USP Drug Quality and Information Program-Global
  Assistance Initiatives
• United States Pharmacopeia

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Presentation outline

• What are poor quality drugs or medicines
• Factors/causes
• Importance
• Case Examples
• Consequences
• Possible Solutions
• Addressing the problem
• Conclusions

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Why be concerned about drug quality?

• Because counterfeit and substandard drugs are
  widely available which are a constant threat to
  global health

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What are Good Quality Medicines?

• Good quality medicines meet official
  standards/specifications for identity, strength,
  purity, quality, packaging and labeling.

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Two terms describing poor quality drug products

• Fake/counterfeit deliberately and fraudulently
  mislabeled with respect to identity and/or
  source. (usually no active ingredient or a
  different active ingredient than on the label)
• WHO definition
• Substandard legal innovator or generic product,
  but does not meet official standards for
  identity, quality, purity, strength, packaging
  and labeling.

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What are the factors/causes of poor quality drugs?

• Lack of legislation and/or weak penal sanctions
• Absent/weak drug regulatory authority
• Corruption/conflict of interest
• Trade involving many intermediaries
• Demand exceeding supply
• High prices
• Inappropriate use of medicine
• Inefficient cooperation between stakeholders
• Lack of control over export
• Sophistication in clandestine operation
• Lack of Good Manufacturing Practices compliance

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ALARMING FIGURES

• estimated 10 of global pharmaceutical commerce
  (US21 billion) are counterfeit
• (WHO/EDM/QSM/99.1)
• gt 50 of the drug supply in some countries are
  counterfeit
• (www.fda.gov)

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Geographic distribution

• WHO report (1982-1999) on documented cases of
  drug counterfeiting by region
• 48.7 - Western Pacific developing countries
• 19.7 - Africa developing countries
• 13.6 - Europe industrialized countries

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What drugs are being counterfeited?
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Malaria

• 300 to 500 million cases annually
• 1.5 to 3 million deaths (mostly children)
• Increasing drug resistance in Southeast Asia,
  Africa, and South America
• www.who.int

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Malaria drugs Artesunate in Southeast Asia

• One study showed 38 of "artesunate" samples
  collected from drug shops in Burma, Cambodia,
  Laos, Thailand, and Vietnam contained
  insufficient or no active ingredient.
• Source Newton P, et al. Lancet 2001 357
  1948-1950.

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Malaria Drugs Fake artesunate
Artesunate 50 mg 002-03 PVH lot 000902 of Guilin
Pharmaceutical Co.
Genuine artesunate hologram of Guilin
Pharmaceutical Co.
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Malaria Drugs Fake artesunate
Artesunate 50 mg 071-03 PS lot 010401of Guilin
Pharmaceutical Co.
Genuine artesunate hologram of Guilin
Pharmaceutical Co.
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Availability of poor quality chloroquine

Source Maponga and Ondari. The quality of
antimalarials A study in selected African
countries. WHO/EDM/PAR/2003.4
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Tuberculosis

• 1/3 of the worlds population is currently
  infected with TB
• 1.7 million deaths in 2003
• Incomplete treatment is largely responsible for
  development of resistance
• For MDRTB, the probability of cure is lt50
• Sources www.who.int
• Iseman MD et al.Drug-resistant tuberculosis.Clin
  Chest Med 1989 10 341-53.

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TB Drugs Isoniazid (INH) Rifampicin (RMP)

• In one study, overall, 10 of all INH RMP
  samples collected from selected TB
  programs/pharmacies in Colombia, Estonia, India,
  Latvia, Russia and Vietnam were tested and found
  to be substandard.
• Source Laserson KF et al. Int J Tuberc Lung Dis
  2001 5(5) 448-54.

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HIV/AIDS

• 4.8 million new cases of HIV
• 37.8 million living with HIV
• 2.9 million died of HIV
• Drug resistant HIV-1 variant can be caused by
  sub-optimum treatment

Sources www.unaids.org-- Hirsch et al.
Antiretroviral drug resistance testing in adults
with HIV infection. JAMA 1998 279 1984-91
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AIDS Drugs Ginovir 3D (zidovudine, lamivudine,
indinavir)

• Analysis of this ARV triple drug combination
  showed the samples did not contain lamivudine or
  indinavir but instead, contained zidovudine,
  stavudine and an unidentified substance.
• Source Counterfeit triple antiretroviral
  combination product (Ginovir 3D) detected in Cote
  dIvoire. WHO QSM/MC/IEA.110, Nov 28, 2003.

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What are the consequences of using poor quality
medicines?

• Health risks
• Non-treatment
• Ineffective treatment/Under-treatment
• Public health risk (ineffective
  antibiotics/vaccines)
• Drug resistance thereby requiring more expensive
  treatment and loss of life-saving therapies
• Toxicity
• Increased morbidity
• Mortality

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Poor quality drugs are dangerous

• Substandard and counterfeit drugs can kill
• Substandard e.g., diethylene glycol
• US 1938 120 died
• Nigeria 1990 109 children died
• Bangladesh 1992 223 children died
• Argentina 1992 23 patients died
• Haiti 1995/1996 89 children died
• Counterfeit e.g., meningitis vaccine with no
  antigen
• Nigeria 1995 around 2500 deaths
• Source WHO

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Additional consequences of using poor quality
medicines?

• People living in countries with limited
  regulatory capacity and resources are most
  affected
• Waste scarce financial resources
• Erodes public confidence in medical care

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So what can we do about it?

• No simple solutions
• Drug quality assurance
• Effective drug regulatory agency
• Use recognized standards
• Good Manufacturing Practices (GMP)
• Awareness
• information dissemination
• Legal actions
• counterfeiting as criminal offense
• Collaboration of stakeholders (govt, pharma,
  healthcare professionals, consumers, law
  enforcers, etc)

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Build local capacity

• Drug regulatory authorities- evaluate and approve
  drugs legally in the country
• Drug Quality control laboratories test products
  at registration and postmarketing surveillance
• Local industry improve compliance to good
  manufacturing practices
• Storage and distribution ensure facilities and
  systems preserve stability and purity
• Law enforcement confiscate counterfeits, work
  with DRA, MOH, customs, inspectors

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USAID-USP DQI Role in Drug Quality

• Drug quality surveillance
• TA in quality control labs, GMP and drug
  registration
• Database of reported drug quality problems
• Collaborative testing
• Operational Guide for Low-Income Countries
• Centers of Excellence in drug quality
• Drug information center
• Drug regulatory drug QA/QC assessment
• Tool development assessment, sampling, TLC
  video, visual inspection for medicines tool
  (developed jointly with Intl. Council of Nurses)

Cambodia, China, Ecuador, Ghana, Kazakhstan,
Laos, Madagascar, Moldova, Mozambique, Nepal,
Paraguay, Peru, Romania, Russia, Senegal,
Thailand, Vietnam, Kenya, Ethiopia, CAR republics.
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How to test for Drug Quality?
Three-level testing program
Purpose
Where
Level
Specialized testing
Determine e.g. unusual impurities, BA/BE.
International/regional labs, research institutions
Authentic testing(pharmacopeial specifications,
validated industry methods)
Determine legal compliance regulatory decision
support
National/regional labs,independent labs
Basic testing(PV-inspection, colorimetric, TLC,
simple disintegration)
Wholesaler, import-export, national programs,
main warehouse, field inspectors
Screen for detection of substandard and
counterfeit drugs
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Basic Testing What can you do with less
resources?

• Visual inspection
• Disintegration test
• Color reaction
• Thin layer chromatography (TLC)

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Results Preliminary data from countries
Figures in red are fake drugs 1 fake and 1
substandard a disintegration b - low API
content
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Results Antimalarials GHANA 2005
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What can this data result in?

• Vietnam Recall ordered of a specific lot number
  of fake artesunate tablets from all 64 provinces
• Laos Recall issued to all 17 provinces, products
  confiscated and legal action underway.
• Cambodia IEC on fake drugs in general. FDD
  organized workshop with police, customs,
  manufacturers, distributors and providers.
• China Substandard quinine injections,
  chloroquine tablets and fake artesunate were
  confiscated and drug outlets and clinics were
  fined and had licenses revoked.
• Thailand working with local manufacturers and
  distributors to improve GMPs.

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Conclusions

• Poor quality drugs are widely available and
  continue to be a global problem
• Incidences are increasing
• Health is at risk
• Urgent measures are needed
• Increased collaboration among stakeholders is
  necessary

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U.S. Pharmacopeia

• Private, not-for-profit organization since 1820
• Establishes official pharmaceutical manufacturing
  standards enforceable by the U.S. FDA and many
  other countries
• Publishes USP/National Formulary annually
• Distributes chemical reference substances used to
  carry out tests for product identity, strength,
  quality, and purity
• 400 member organizations/650 volunteer experts
• USP DQI (www.uspdqi.org) focuses on ensuring the
  quality of pharmaceuticals and their informed and
  appropriate use worldwide, continuing education
  for healthcare professionals, and developing
  evidence-based drug and therapeutic information.
• Patient Safety, Dietary Supplements Verification