Uneven Manufacturing Quality

Any company can make mistakes, but adherence to good manufacturing practices makes mistakes less likely and easier to correct. A factory run in accordance with best practices does not need to be the most technologically advanced or use state-of-the-art equipment, but there are costs to bring a factory up to standard, train staff on appropriate protocols, and observe them consistently. There are many exemplary manufacturers in developing countries that observe international best practices. There are also many that do not, but they operate anyway, either because the regulatory authority is unaware of the problem, or because regulators are under pressure to ignore it in the name of promoting industry.

Quality control is a part of good manufacturing practices sometimes neglected in developing countries. The WHO compendium on pharmaceutical manufacture describes the importance of having quality-control staff who are separate from production staff, working in an independent department (WHO, 2007b). A manager trained in quality control should supervise this department and run an equipped quality-control laboratory (WHO, 2007b). Quality-control staff should verify that everything that is a part of the factory's product, including packaging, starting materials, intermediates, and finished products, meets requirements (WHO, 2007b). They may also do internal inspections and quality audits and evaluate the quality controls used by their suppliers (WHO, 2007b). The majority of the pharmaceutical industry in the poorest countries only formulates and repackages finished medicines, also called secondary and tertiary production (see Box 4-1). Confirming the quality control measures used by suppliers, who are often in other countries, is particularly difficult for these firms.

BOX 4-1

The Medicines Manufacturing Process. Drugs are made with four or five main steps between the raw materials and the packaged final formulation (Figure 4-1). Medicines manufacture in the poorest countries is generally limited to the last steps in this process: (more...)

Formulation companies have about a 6-month lag between placing an order for an active ingredient and selling a finished drug (Bumpas and Betsch, 2009). This delay can be even longer for firms in landlocked countries or places where customs clearance and transportation from the port of entry are slow or unpredictable (McCabe, 2009). It takes substantial working capital to cover costs during those lags (Bumpas and Betsch, 2009). Adding to the expense are the active ingredients themselves, which can cost thousands of dollars per kilogram; buying from WHO-prequalified or stringent-regulatory-authority—approved suppliers can add a 100 percent markup to the sale price (Bumpas and Betsch, 2009). The market for active ingredients has been especially volatile in recent years because of increasing costs of raw materials and growing environmental regulation in India and China (Bumpas and Betsch, 2009). Price volatility further complicates business for smaller firms, who tend to deal with less consistent (therefore cheaper) suppliers who are more vulnerable to market shocks. Although proper quality-control measures require purchasing only from suppliers who observe good manufacturing practices, supplier quality is often neglected because of logistical and financial obstacles. And, because the cost of active ingredients is by far the largest fraction of overall cost, a small reduction in active ingredient can vastly increase the profit margin.

Good quality comes at a price, either from equipment costs, better ingredients, or the higher process cost of quality assurance. The water filtration system is a high risk for microbial growth in any pharmaceutical plant and should be monitored vigilantly (WHO, 2007b). Microbial contamination is more of a threat in countries with poor water quality; much equipment cannot run on erratic power supplies (Anderson, 2010). Drug manufacturers also need an air handling system that will prevent dust and residue from one work area from contaminating other parts of the factory (WHO, 2007b). The adequacy of the air handling becomes more important in areas of the factory where different products are being processed at the same time and opportunities for cross-contamination abound (WHO, 2007b).

Some small-scale pharmaceutical companies make few finished formulations, but others make a wide range of products. Small firms are not generally able to dedicate equipment to specific products; equipment cleaning and cleaning validation become especially important. When equipment used for multiple products is not properly cleaned, and the cleaning not validated prior to changing the product line, the drugs produced can become contaminated. This type of contamination is difficult to detect. Quality-control assays generally test for the presence of the known ingredients, not the wide range of possible unknown contaminants. Good pharmaceutical manufacturing requires drug producers to follow a cleaning protocol laid out in their standard operating procedures and to follow cleaning with validation testing (APIC, 1999; WHO, 2007b).

There is significant expense necessary for pharmaceutical companies to follow good manufacturing practices. Multinational companies, both innovator and generic, operate on a scale that allows them to recover the costs of running high-quality factories. This is not true for many smaller manufacturers in developing countries. In India, for example, large pharmaceutical companies supply medicines and vaccines of the highest quality to every country in the world, but thousands of small manufacturers struggle to implement quality-assurance and quality-control procedures (Kaplan and Laing, 2005). A World Bank study found that one-tenth of Indian registered pharmacies report substandard medicines, most of them coming from small- and medium-sized producers (Kaplan and Laing, 2005). Because the registered pharmacy is the most strictly regulated medicines outlet in India, the proportion of substandard medicines sold in the informal market is presumably much higher. The problem is not limited to India. In a survey of antibiotic quality in Indonesia, investigators found 89 percent of samples of one local company's cotrimoxazole were substandard (Hadi et al., 2010).

Critics of local manufacture have cited these problems as reasons against pharmaceutical manufacturing in low- and middle-income countries (Ahmed, 2012; Bate, 2008). This may be a short-sighted argument. Domestic manufacture of medicines is an important part of health and industrial policy in many countries. Governments are understandably eager to ensure a safe drug supply for their population. In theory, locally made products could be cheaper because of lower shipping costs incorporated into the final price (Kaplan et al., 2012). Manufacturing medicines also gives people jobs and facilitates technology transfer (Wilson et al., 2012). Companies that start out packaging only finished drugs will slowly develop the trained workforce needed for more complicated secondary and primary manufacturing.

Initial capital investments and infrastructure problems stand between quality medicines and many small- and medium-sized medicine manufacturers. There are companies in developing countries that want to meet international quality standards and buy from reliable suppliers, but they fail to do so for reasons beyond their control. Governments alone cannot supply the technical depth or money to fix these problems (Wilson et al., 2012). The private sector must be involved. The International Finance Corporation (IFC) and the Overseas Private Investment Corporation (OPIC) can work to encourage private sector growth in developing countries. With the initial investments made, governments can take on the more manageable role of encouraging partnerships with foreign manufacturers.

Recommendation 4-1: The International Finance Corporation and the Overseas Private Investment Corporation should create separate investment vehicles for pharmaceutical manufacturers who want to upgrade to international standards. Governments can complement this effort by encouraging partnerships between local and foreign manufacturers.

Poor infrastructure, management problems, and insufficient training for staff can all hold back pharmaceutical manufacturers in low- and middle-income countries. While the extent to which each of these factors impedes progress varies among countries, there is a common problem of lack of capital (Cho et al., 2012; Patricof and Sunderland, 2005). Small- and medium-sized businesses have a particularly difficult time securing business improvement loans, as do firms in Africa (Patricof and Sunderland, 2005).

The only capital available to many small- and medium-sized drug manufacturers is the company's already meager profits. Reinvesting profits in capital improvements is not a quick or reliable path to develop a modern manufacturing infrastructure (UNDP, 2004). In developed countries small-and medium-sized firms might mortgage their assets to raise money, but mortgage laws and bank policies often disallow this in low- and middle-income countries (UNDP, 2004). The equipment and supplies needed to observe good manufacturing practices must be bought on foreign markets with hard currency, which banks in poor countries may only have at certain times of year (McCabe, 2009).

Manufacturers in developing countries often have to absorb their customer's debts, further reducing their working capital (McCabe, 2009). Therefore, small- and medium-sized companies are risky investments. Their national banks find the costs of the initial risk assessment both too costly and too complicated to make loans attractive (UNDP, 2004). Barriers to accessing capital hold back small- and medium-sized businesses, the “engines of job creation,” in the parts of the world most desperate for more and better jobs (Economist, 2012b; UNDP, 2004, p. 4). When these enterprises are drug companies, there is an added drawback. For want of investment capital, the poor pay higher prices for substandard drugs (UNDP, 2004).

Tiered Production

In practice it is difficult to distinguish the quality failures that are to blame on a manufacturer's inability to meet international best practices from those which come from a decision to cut corners and produce inferior products for poorly regulated markets. When a producer capable of meeting international standards fails to do so consistently and only in product lines sold to the poor, one may conclude that the noncompliance is part of a more insidious system.

Rich countries enforce high quality standards for medicines, and manufacturers recognize the need to use good-quality ingredients and good manufacturing practices to sell in these markets. United Nations (UN) agencies and the larger international aid organizations will also refuse to do business with companies that cannot meet stringent regulatory authority quality standards. Manufacturers are aware, however, that low- and middle-income countries are less likely to enforce these standards. Some companies exploit this and produce drugs of lower quality for the loosely regulated markets (Caudron et al., 2008). When a manufacturer produces medicines of inferior quality for less exacting markets, it is known as tiered or parallel production (Caudron et al., 2008; World Bank, 2007).

Tiered production is a complicated problem, in part because some kinds of tiered production are legal. International manufacturers may supply to multiple markets which use different legal product quality standards. For example, the British Pharmacopoeia monograph for amoxicillin gives no dissolution standard (British Pharmacopoeia, 2012); the U.S. Pharmacopeia does (USP-NF, 2010). Assay limits may also be different, making a product illegal by one pharmacopeia but legal by another. A manufacturer may supply to one country that stipulates a uniformity of dosage at 90-120 percent of declared dosage and to another country that stipulates 85-115 percent, for example. Both these standards aim to correct for the fact that drugs such as antibiotics degrade quickly, making a high initial dose acceptable. However, manufacturers could technically aim to fill only the lower bound of the dosage requirements and be within the letter of the law. A study of amoxicillin samples in Arab countries found that most samples' active ingredient concentrations were bordering the U.S. Pharmacopeia lower limit (Kyriacos et al., 2008). The authors admitted, however, that many of the problematic samples would have been judged acceptable by the wider British Pharmacopoeia standard (Kyriacos et al., 2008).

Participants at the public meetings for this study mentioned concerns with parallel production, but evidence for it is largely anecdotal. There is reason to suspect tiered manufacturing when the dose of active ingredient is consistently lower, never higher, than the label claim (Bate et al., 2009b). Drugs, especially tablets, of less than half the labeled potency before the expiry date are particularly dubious. In a hospital dispensary in rural Nepal, a bottle of pediatric amoxicillin from a WHO-certified producer with many obvious labeling and packaging defects also suggests either parallel manufacturing or diversion, a problem discussed in Chapter 5 (Brhlikova et al., 2007).

Tiered manufacturing is a rising problem in emerging manufacturing nations. A 2006 Lancet report described a shift in Russia from most bad medicines being falsified drugs made “in basements and small backroom enterprises” to ones coming from legitimate companies running “a ‘night shift’ to produce extra quantities of a certified drug that does not pass quality control, or sophisticated copies of well-known drugs … often with reduced levels of expensive active ingredients” (Parfitt, 2006, p. 1481). The United Nations Office on Drugs and Crime (UNODC) described a similar case in India. The U.S. Food and Drug Administration (FDA) revoked market authorization from an Indian drug manufacturer found to be producing antibiotics with no active ingredients (UNODC, 2010). After losing its license, “the factory continued to operate at night, until an evening raid by police uncovered an underground cellar in the factory, where exact look-alikes of several popular, fast-moving, high-cost medicines were being manufactured, most of which contained no active ingredient” (UNODC, 2010, p. 187).

Jiben Roy reported on a similar case: A Bangladeshi company deliberately kept the active ingredients in paracetemol, ampicillin, and cotrimoxazole below the labeled concentrations after repeated warnings from the regulatory authority (Roy, 1994). In the same paper he attributed the manufacturer's quality failures in their cheaper product lines to negligence alone. Their B-vitamins, for example, contained the proper ingredients, but in erratic doses (Roy, 1994). This paper was able to make distinctions between the deliberate quality failures and negligence because the author had close knowledge of the manufacturer and its history. Usually only the national regulatory authority could have the information needed to make this distinction. In many countries, even the regulatory authority would not have that information or the political will to act on it (Christian et al., 2012b).

Pinpointing cases of deliberate tiered manufacturing is difficult to do, though it is easier to see practices that allow it happen. Poor oversight of contract manufacturers is one such practice. A combination of technological sophistication and low labor costs in some developing countries attract drug companies, both innovator and generic, to contract with manufacturers abroad (PWC, 2010). Setting up a drug factory in India, for example, costs companies about 40 percent of what they would pay in North America or Europe (PWC, 2010).

Companies provide contract manufacturers with the materials, including packaging, to make their products. As Dilip Shah, Secretary General of the Indian Pharmaceutical Alliance, explained to a committee delegation in India, “Very few companies, foreign or domestic, monitor the [contract manufacturer's] process loss of raw materials, active ingredients, and packaging materials. I have known of cases of 15 to 20 percent packaging material losses and companies are not bothered.” These contract manufacturers have established distribution channels; it is not difficult for them to introduce falsified drugs into the market. Because the contract manufacturers have the processes and materials needed to produce a proper drug, they will sometimes sell perfectly made drugs outside of the licit distribution system. More often, they will use legitimate packaging to disguise a false product.

Pharmaceutical exporting countries can also unintentionally facilitate tiered manufacturing by not requiring the same evaluations for exported drugs as for those sold domestically (Caudron et al., 2008). In general, regulatory agencies are responsible for protecting their country's domestic medicine supply; ensuring quality for exported products is often beyond their mandate and budget. Importing countries' regulatory agencies have the right to inspect producers abroad, but the breadth of international supply chains makes this a difficult job even for the most mature agencies (IOM, 2012). It is more difficult for low- and middle-income countries to ensure checks on drug quality during manufacture, a problem discussed later in this chapter.

Procurement and Substandard Medicines

When regulatory checks on production are inconsistent, procurement practices can help ensure that quality medicines get the largest market share. The Global Fund explains the goal of good procurement as supplying medicine “meeting agreed quality standards at the lowest possible price and in accordance with national and international laws” (Global Fund, 2009, p. 6). Government agencies procuring medicines have to reconcile a tension between quality and price (Torstensson and Pugatch, 2012). The WHO Operational Principles for Good Pharmaceutical Procurement discusses the hidden costs of cheap drugs, including poor shelf life and health threats (WHO, 1999, 2002a). The firms that offer the cheapest prices may do so by buying impure ingredients or cutting corners in formulation.

Good procurement dictates that the cheapest tenders are not accepted if they are of dubious quality, but it is difficult not to be swayed by price, especially for provincial health offices and other small procurement agencies (Bate, 2007; Harper et al., 2007). Chinese provincial procurement, for example, is known for “pressuring manufacturers to produce the lowest cost possible while preserving their profits” (Burkitt, 2012). These agencies face pressure to supply medicines for entire populations on tight budgets; sometimes there is added demand to support local manufacturers (Dickens, 2011; Torstensson and Pugatch, 2012). Openness in procurement can balance these pressures by exposing unnecessarily high costs or bad quality, but transparency, which also includes vetting procurement officers for conflicts of interest, auditing suppliers, documenting decisions, and scrutinizing procurement agents, adds costs to the process (Torstensson and Pugatch, 2012). For these reasons the Organisation for Economic Co-operation and Development (OECD) recommends “an adequate degree of transparency in the entire procurement cycle to promote fair and equitable treatment for potential suppliers” (OECD, 2009, p. 11).

Over the longer term, more openness is a good investment. In Argentina, for example, a health transparency program brought down the procurement costs of medicines (Lewis, 2006). Reducing costs of procurement would be especially helpful in the poorest countries, which tend to spend a higher proportion of their health budget on drugs and where medicines are often expensive (Torstensson and Pugatch, 2012). In a study of 36 low-and middle-income countries, Cameron and colleagues found that public procurement agencies in the western Pacific, Africa, and the former Soviet bloc pay an average of 34 to 44 percent above the international reference prices (Cameron et al., 2008).

Donors may attempt to cover unmet demand for drugs, though donor procurement also has problems. Methods for assuring the quality of donated medicines vary by donor. The United States Agency for International Development (USAID) requires FDA, or other stringent regulatory agency, approval on donated medicines. It also has a prequalification process to vet the wholesalers it works with (GAO, 2012). USAID contractors are often responsible for implementing these rules in the field (Moore et al., 2012). The Global Fund will accept WHO prequalification, the approval of stringent regulatory authorities, or the review of an expert panel, especially for finished pharmaceuticals that are not prequalified by the WHO (GAO, 2012). Many European donors ask their recipients to assure quality of medicines procured with donated funds (Moore et al., 2012). Table 4-1 gives an overview of different agencies' quality assurance policies.

TABLE 4-1

Overview of Selected Donors', Procurement Service Agencies', and Quality-Assurance Organizations' Quality-Assurance Policies.

Proper precaution in the medicines procurement process can prevent poor-quality products from infiltrating the market. Good procurement involves separating the various steps of procurement process identified in Table 4-2. Good procurement also puts a strong emphasis on controlling corruption and promoting transparency. The WHO's Model Quality Assurance System for procurement lays out the steps necessary for efficient and open procurement of the best-quality medicines possible (WHO, 2007a).

TABLE 4-2

Pharmaceutical Procurement Best Practices.

Recommendation 4-2: Procurement agencies should develop a plan, within the next 3 to 5 years, to comply with the World Health Organization's Model Quality Assurance System for procurement agencies and work to remove any barriers to compliance.

The technical aspects of good pharmaceutical procurement and distribution practices have always been part of training courses on medicine supply management (MSH, 2012). The most complete and modern procurement guideline is the 2006 Model Quality Assurance System for Procurement Agencies, a United Nations interagency document endorsed by the WHO, Unicef (the United Nations Children's Fund), the UN Development Program and Population Fund, and the World Bank (WHO, 2007a). The model draws on the accumulated experience of these agencies' procurement experts and combines advice on the procurement of medicines, vaccines, diagnostic kits, and devices. The model focuses on four key activities: prequalification of pharmaceutical products and manufacturers and drug purchase, storage, and distribution. It presents the recommended practices in great detail (WHO, 2007a).

At its launch in 2006, the model had an aspirational element; it described standards that few if any of the international procurement agencies were able to maintain at that time. In the past 6 years, large procurement agencies have made great progress toward meeting the standards laid out in the model (van Zyl et al., 2012). The committee sees the model quality assurance system as a useful independent standard to assess procurement agencies. The system is a practical tool that can be used by national and international procurement agencies. Eventually, agencies can use the WHO tool to prequalify suppliers; prequalification is a recommended piece of a procurement system (MSH, 2011).

Modern pharmaceutical chains are international. No country is self-sufficient in its medicine supply. Pharmaceutical procurement almost always means working with foreign suppliers; a practice that exceeds capacity of national regulators, who cannot hope to inspect foreign manufacturers as they would domestic ones. Good procurement also means that only organizations that follow the model system should import medicines. Small-scale importation and procurement by small actors threaten the medicines supply chain. This risk is not only present in developing countries. In many OECD countries, pharmacies and private clinics import drugs directly from suppliers, greatly increasing the risks of introducing a poor-quality product to the market.

Corruption and Organized Crime

Making fake medicine is not difficult. The least sophisticated operations manage with empty capsules bought in the open market or a hand-held pill press and any powder to load into it. Production costs on fake drugs are low (Clark, 2008; Perrone, 2012). And, because the licit and illicit supply chains mix in unregulated markets (described in Chapter 5), the odds of getting away with the crime are good. As Chapter 3 describes, the global burden of falsified and substandard medicines is borne disproportionately by low- and middle-income countries. There is wide evidence that criminals frequently target inexpensive anti-infective medicines, mostly because they are bought often and by the largest segment of the population. The UNODC therefore describes making falsified medicines as an “opportunistic crime, emerging where regulatory capacity is low, not where profits would be highest” (UNODC, 2010, p. vi).

This is not to say that profits generated from falsifying drugs are insignificant. In a study of fake malaria medications in Southeast Asia, Dondrop and colleagues found the falsified artesenuate to be cheaper, but only somewhat, than the authentic one (Dondorp et al., 2004). By pricing their product just slightly under the legitimate drug, criminals can guarantee market share, but they avoid pricing it so low as to arouse suspicion. Falsified medicines can be priced less cautiously in the wholesale market, however, because these markets are less regulated and customers are not the general public but buyers for retail who are sometimes complicit. Tempo, an Indonesian news magazine, reported on “astonishingly low” prices in a medicines wholesale market in Jakarta (Silverman et al., 1992). The story described how pharmacists unwilling to buy from the illegal markets probably could not survive in business (Silverman et al., 1992). Box 4-3 describes the profit motive of one American pharmacist dealing in diluted cancer drugs.

BOX 4-3

Adulterated Cancer Drugs. Robert Courtney, a pharmacist in Kansas City, Missouri, made millions selling adulterated drugs to patients and physicians throughout the 1990s until 2001, when he was prosecuted for his crimes. Most famous for diluting chemotherapy (more...)

Interpol uses the term pharmaceutical crime to describe “the manufacture, trade and distribution of fake, stolen or illicit medicines and medical devices” (Interpol, 2012b). Pharmaceutical crime includes theft, trade, and the money laundering criminals use to cover their tracks (Interpol, 2012b). Corruption allows the crime to continue. Complicit government officials are often bribed with revenue from the underground pharmaceutical business (UNODC, 2010); criminal executives may be embedded in the government hierarchy (Parfitt, 2006). Threats and bribery are the purview of members of organized crime, who are often responsible for trafficking falsified medicines, perhaps attracted by the mild punishments discussed below (Beken and Balcaen, 2006; Interpol, 2012a). Interpol has evidence linking the trade in falsified drugs to Al-Qaeda and transnational crime syndicates (Beken and Balcaen, 2006; Liberman, 2012).

A medicines seizure in Shagamu, Nigeria, 2007

SOURCE: © 2007 Opara Adolphus, Courtesy of Photoshare.

Enforcement and Punishment

When falsified medicines are also counterfeits that infringe on the trademarks of multinational pharmaceutical companies, the company targeted tries to respond. Major pharmaceutical firms have designated security departments that work with regulators and law enforcement to gather evidence for criminal prosecution (Cockburn et al., 2005). In general these companies collect evidence and build 80 percent of the case against the criminals, then hand the investigation over to law enforcement (Economist, 2012a).

Law enforcement agencies, for their part, are cracking down more on pharmaceutical crime. The Chinese government, perhaps driven to improve China's reputation as the world leader in fake drugs, arrested more than 1,900 suspects from about 1,100 manufacturers in late July 2012 (Burkitt, 2012; Palmer, 2012; Quingyun, 2012). The 18,000 police officers working in simultaneous raids across the country seized a range of falsified products, including saline labeled as rabies vaccine and an obesity drug recalled from the Chinese market because of toxic side effects (Quingyun, 2012). It was not clear what products were destined for the domestic market and which were meant for export (Palmer, 2012).

In an analysis of the Brazilian federal police reports, Ames and Souza found that police seizure of falsified medicines roughly tripled between 2007 and 2010 (Ames and Souza, 2012). Most falsified products entered Brazil from Paraguay, and the arrests were made at the border (Ames and Souza, 2012). Some data suggest that arrests at the point of sale, manufacture, and distribution are more common, however (see Table 4-3). Box 4-4 presents the Pharmaceutical Security Institute's (PSI's) 2010 and 2011 data on arrests for pharmaceutical crime.

TABLE 4-3

Top Countries for Arrests, 2011.

BOX 4-4

Pharmaceutical Security Institute Crime and Arrest Data. The Pharmaceutical Security Institute, a nonprofit network of 25 major pharmaceutical companies' security departments, maintains a database on compromised medicines (PSI-Inc., 2012c). In PSI records, (more...)

PSI data indicate that China and Brazil took the most police action against falsified medicines in 2011. Table 4-3 presents the number of arrests in the PSI incident database by country. The countries with the most serious problems might have no arrests in a year, as arrests depend on government motivation to marshal the police. The momentum for labor-intensive police raids is difficult to sustain. Only half of the countries on PSI's 2006 arrests list appear on the same list in 2011 (see Table 4-4). In 2006 Russia led in arrests for pharmaceutical crime after a series of raids reported in the Lancet (Parfitt, 2006). At the time, Gennady Shirshov, director of a Russian pharmaceutical industry association, predicted that other criminal manufacturers would quickly replace the closed ones (Parfitt, 2006). Mr. Shirshov mentioned insufficient law enforcement interest in the problem but concluded, “The legislation is inadequate. It's a civil liability, not a criminal one … and the fines are negligible” (Parfitt, 2006, p. 2).

TABLE 4-4

Top 10 Countries Ranked by Number of Counterfeit Drug Seizures and Discoveries in 2006.

As Box 4-5 mentions, perpetrators who are caught falsifying medicine are punished leniently in some countries (Kyriacos et al., 2008; WHO, 2012a). In the United States, the Food, Drug, and Cosmetic Act dictates a penalty of 1 year in prison, a fine of no more than $1,000, or both (Donaldson, 2010). Even repeat offenders are punished with no more than 3 years in prison or a fine of $10,000 (Donaldson, 2010). Considering that the profit margin for falsified drugs runs in the billions, the risk-to-profit analysis favors the crime. Table 4-5 shows the penalties for falsifying medicines in a selection of countries. The leniency in many countries may be a function of outdated laws. Tables 4-6 and 4-7 show penalties for patent and trademark infringement, which are dealt with more severely in some countries.

BOX 4-5

Manuel Calvelo. From 2005 to 2008, Manuel Calvelo operated internet pharmacies selling misbranded and falsified drugs for sale without prescription (DOJ, 2011). Calvelo sold $1.4 million worth of drugs on websites such as allcheapdrugs.com, cheapdrugspharmacy.com, (more...)

TABLE 4-5

Penalties for Falsifying Medicine.

TABLE 4-6

Penalties for Patent Infringement.

TABLE 4-7

Penalties for Trademark Infringement.

Stricter and more consistent penalties could do much to fight the public health crime of producing and trading fake medicines. Chapter 7 discusses this solution in more detail, describing how a global code of practice could encourage consistent strict minimum punishments for these offenses.

Expense and Scarcity

Medicines are what economists describe as a comparatively inelastic good (Arnold, 2008); changes in the unit price of the medicine have proportionately little effect on the demand (Siminski, 2011). Price inelasticity, combined with a high relative price, make medicines a major expense for patients around the world. In the United States, health expenditures on medicine rise sharply in middle life and average between $1,000 and $2,000 per person per year after age 45 (Paez et al., 2009). The cost of medicine is even more of a burden in low- and middle-income countries, where it accounts for 20-60 percent of health spending, and 90 percent of the population pays for medicine out-of-pocket (Cameron et al., 2008; WHO, 2004a,b).

The drug market is not stable; both price and supply fluctuate. Sometimes the supply falters because of shortages in the raw materials, as in 2004 when increased demand for artemisinin, combined with a poor Artemesia annua harvest, drove up the price and led to stock-outs (Kindermans et al., 2007; Newton et al., 2006b; Pilloy, 2009). More generally, drug supply problems are driven by the economy. In the United States, for example, manufacturers sometimes stop producing products with low profit margins, such as sterile injectables—inexpensive products that are complicated to make (Hoffman, 2012). Manufacturers also can lose interest in a drug after its patent expires, when revenues from the product drop (Hoffman, 2012). Although the United States has a more stable drug supply than most developing countries, there have been regular shortages for the past 15 years, especially among injectables, cancer drugs, and antibiotics (Hoffman, 2012).

Drug shortages are more common in developing countries (MDG Gap Task Force, 2008). Survey data from the WHO and Health Action International suggest that although medicines may be available free or cheaply in public health centers, these centers often do not have the medicines needed; availability is generally better in the private sector but for a much higher price (Cameron et al., 2008; MDG Gap Task Force, 2008). Figure 4-3 shows that although private-sector outlets have a higher percentage of drugs available than public-sector ones, there is still a great deal of unmet need. A month's course of the lowest-priced generic ulcer medication, for example, is still more than 3 days' wages for a low-paid government worker in much of Africa, Eastern Europe, and the Middle East (Cameron et al., 2008).

FIGURE 4-3

Average of country-level mean percentage availability of medicines by World Bank income group. Data are mean(maximum/minimum). SOURCE: Cameron et al., 2008. Reprinted from the Lancet with permission from Elsevier.

Reducing the costs and increasing the availability of medicines would remove some of the financial incentive to produce and procure falsified and substandard medicines. If patients had a plentiful supply of reliable, affordable medicines, there would be less need to shop at unregulated gray markets.

The WHO has recommended generic substitution as a way to keep medicines costs down (MDG Gap Task Force, 2008), but this depends on a supply of high-quality generic medicines on the market. For generic manufacturers, companies that generally run on low margins, the costs of proving bioequivalence and preparing a manufacturer's dossier for regulatory review can be prohibitive to market entry (Lionberger, 2008). Different regulatory authorities have different, often widely divergent, requirements for establishing bioequivalence (Mastan et al., 2011). To complicate the problem, many small regulatory authorities lack the technical depth to evaluate the bioequivalence data that generics manufacturers submit (Hill and Johnson, 2004).

Weak Regulatory Systems

A competitive generics market benefits consumers, as does a rigorous and unpredictable inspection regime (Mackintosh et al., 2011). In many developing countries, lack of confidence in the regulatory system breeds low enthusiasm for generic medicines (Hassali et al., 2009; Kaplan et al., 2012; Russo and McPake, 2010). Doctors and patients may perceive these products as lower quality (Chua et al., 2010; Gossell-Williams, 2007). An influx of generic medicines will only reduce the circulation in falsified and substandard drugs when there is a system to assure consumers of medicines quality. In their review of policy actions to promote generic medicines, Kaplan and colleagues conclude that a functioning medicines regulatory authority is a necessary condition for a robust generic medicines market (Kaplan et al., 2012).

The drugs regulatory authority has the ultimate responsibility for the quality of medicines in the country. That includes registering medicines, issuing licenses and market authorization, postmarket surveillance, quality control testing, oversight of drug trials, and manufacturer and distributor inspections (IOM, 2012; WHO, 2010a). The regulatory authority also provides health workers and the public with accurate information on the rational and safe use of medicines and punishes illegal trade in drugs (WHO, 2012b). This range of responsibilities requires significant technical depth in staffing and political will to enforce regulations. Staffing shortages are often a problem in the public sector in low- and middle-income countries, where regulators are poorly paid and not well respected (IOM, 2012).

Staffing shortages at the regulatory authority are a particularly serious problem in India and China, two main pharmaceutical producing nations with massive industries to oversee. In 2003 the Mashelkar Commission estimated about 5,877 licensed manufacturers in India; other estimates cite as many as 20,000 Indian drug manufacturers, some very small (Government of India, 2003; KPMG International, 2006). In any case, only 250 to 300 of them are major producers (KPMG International, 2006). China has a comparatively more manageable 3,500 companies, down from roughly 5,000 in 2004; the reduction is partly the result of heightened enforcement in the wake of a series of drug contamination scandals (Reuters, 2008).

The pharmaceutical industry in both countries is exceptionally fragmented. The top 10 pharmaceutical companies in India cover about 30 percent of the domestic market (KPMG International, 2006); in China the top 10 companies account for only 10 percent (Sun et al., 2008). In contrast, the top 10 innovator pharmaceutical companies control about 42 percent of the international market (Sun et al., 2008). Inspecting and licensing so many factories would be an overwhelming task for a well-funded regulatory agency with sufficient staff. In both China and India, the understaffed provincial authorities oversee licensing and inspecting manufacturers, with uneven results. In 2007 a Chinese provincial regulator issued 67 forged manufacturing licenses for a bribe (Liu, 2010). Indian regulators sometimes approve medicines without trials or valid expert review and authorize irrational, even dangerous, fixed-dose formulations of multiple active compounds (Vaidyanathan, 2012). Drugs that neighboring countries ban are often available in India because the regulatory agencies cannot enforce bans or execute recalls (Shaji and Lodha, 2010).

There are similar problems in less industrialized countries. A WHO survey of 26 drug regulatory authorities in sub-Saharan Africa found that only one country's regulator published guidelines on good distribution, while only 20 percent published internationally rigorous manufacturing practices (WHO, 2010a). The same study found that several regulatory authorities grant licenses and renewals with no inspections, that operating procedures for conducting inspections were woefully weak, and that 35 percent of the regulatory authorities have no legal authority for inspections (WHO, 2010a). Figure 4-4 shows the number of agencies out of the 26 surveyed that can perform drug regulatory functions. All of these weaknesses allow for falsified and substandard drugs to circulate. As one of the participants in the WHO study explained, “The illicit medicines market has become a real plague…. All therapeutic classes can be found, including psychotropic medicines, and there is no national strategy to combat this situation” (WHO, 2010a, p. 16).

FIGURE 4-4

Number of sub-Saharan African countries out of 26 surveyed meeting the main functions of a regulatory authority. NOTE: NMRA = National Medicines Regulatory Authority. SOURCE: WHO, 2010a.

Governments in low- and middle-income countries need a strategy to act against falsified and substandard medicines. Any viable solution will include strengthening the drug regulatory system, including building the inspectorate, enforcing quality standards, and licensing in accordance with international standards. Without a competent regulatory authority to inspect wholesalers, distributors, and manufacturers, opportunities to corrupt the drug supply abound. Box 4-6 describes a patient safety disaster following the disbanding of the Pakistani national regulatory authority.

BOX 4-6

Dissolution of the Pakistani Drug Regulatory Authority. Over the course of several weeks in January 2012, more than 120 patients in Lahore, Pakistan, died of drug overdoses and hundreds more suffered adverse reactions after being treated with contaminated (more...)

A 2012 Institute of Medicine report called for greater international investment in building food and drug regulatory systems in developing countries and for an international training and credentialing system for regulators (IOM, 2012). This committee supports these recommendations. It also recognizes that the magnitude of the task facing these agencies is overwhelming and that governments need to make drug quality a priority, and then empower their regulatory agencies to improve.

Recommendation 4-4: Governments in low- and middle-income countries should support their regulatory agencies to develop strategic plans for compliance with international manufacturing and quality-control standards. In the least developed countries, international organizations should support their efforts.

International quality standards for drug manufacture depend on the competence of the national regulatory authority. Regulators in low- and middle-income countries need training, equipment, technology, and reference standards (IOM, 2012). The agencies' budgets do not allow for improvements in all these areas, and the scope of the needs can overwhelm the agencies, leading to inaction. It is important for regulators to make strategic decisions about what to invest in first. A strategic plan can help identify an organization's priorities and guide activities that advance these priorities (Tominaga, 2012).

The committee believes that making a strategic plan is feasible for almost all poor countries. The process of making the plan helps regulators advocate for better support from their ministers and identify places for donors to contribute. At a strategic planning workshop in 2010, for example, the Namibian health minister asked the regulatory authority to propose ways to build capacity in the agency and to advance harmonized regulatory systems in southern Africa (TIPC, 2010).

Agencies in the poorest countries should first enforce standards in manufacturing, wholesale, and retail. The WHO and more developed regulatory agencies should support these improvements. There is good precedent for such collaboration. The WHO prequalification program has a capacity-building function. As part of the program, regulators from low- and middle-income countries serve 3-month rotations at WHO headquarters (WHO, 2010b). Their rotations require close work with prequalification assessors and allow for sharing ideas about how to monitor manufactures (WHO, 2010b). A similar partnership among regulators could also be useful. Some regulatory agencies in emerging economies have made great progress in a relatively short time. These agencies are well positioned to help their counterparts in other developing countries set out their goals. For example, experts from the Brazilian drug regulatory agency, Anvisa, could work with their counterparts in Mozambique or Angola to help develop realistic plans.

A strategic plan for compliance with international standards can help reduce redundant work and fragmentation. Both industry and regulators would agree to work toward the priorities identified on the strategic plan, and all work would be directly related to the plan, an openly shared document (Tominaga, 2012). For many smaller countries the plan should include a strategy for sharing work and pooling resources. At the regional level, the New Partnership for Africa's Development recently published a 5-year strategic plan for regulatory harmonization (NEPAD, 2011). This document identified the technical barriers facing African regulators, clarified the mission of the African Medicines Regulatory Harmonization (AMRH) project, and identified objectives for 2011–2015 (NEPAD, 2011).

Multilateral agencies, such as development banks, should support the development and implementation of strategic plans for compliance with international standards. The pharmaceutical market is international, and everyone has an interest in promoting global standards. There is precedent for such investment. The Bill & Melinda Gates Foundation, the British Department for International Development, the World Bank, and the WHO all support the AMRH program (AMRH, 2012). Donor agencies can do similar work, as USAID has in support of postmarket surveillance in Latin America, Southeast Asia, and Africa (Miarlles, 2011).

Regulators will welcome the strategic investments this planning would bring. Governments need to support these investments as well. Compliance with international standards will demand a wide range of activities, including research, education, supply chain management, and incentives for the private sector. The regulatory agency alone cannot effect change and will need government support to marshal the involvement of all stakeholders.

Developed country governments also need to improve support for their regulatory agencies. At the time this report was prepared, substandard injectable drugs caused a fungal meningitis outbreak in the United States, bringing the topic of drug regulatory oversight to the forefront of the U.S. political discourse.

Lack of Awareness and Action

As Chapter 3 explains, there is a dearth of reliable estimates of the scope of the problem of falsified and substandard medicines. Without a clear picture of the extent of the problem, which products are compromised, and where the products surface, it is difficult to develop an appropriate prevention strategy and monitor progress. An insufficient understanding of the scope of the problem also contributes to a lack of awareness about substandard and falsified drugs among health workers and the general population. Increasing public awareness will not in and of itself decrease falsified and substandard medicines, because consumers cannot distinguish safe and unsafe medicine in the marketplace. However, public awareness is a useful way to drive political will for correcting the problem and to educate people on warning signs of compromised medicines.

Uneven Awareness

Starting in the early 2000s, medicines counterfeiting (as it was then called) has been the topic of some media attention. General awareness of the problem was still poor, however (Cockburn et al., 2005; Newton et al., 2006a). Reporting was “alarming[ly] low”: between 2002 and 2004 the WHO received no reports of fake drugs from any member states (Newton et al., 2006a). This began to change in 2006 when the International Medical Products Anti-Counterfeiting Task Force (IMPACT) made raising awareness one of its main goals (Liberman, 2012).

IMPACT, and the larger debate about pharmaceutical fraud that it was a part of, appears to have had success in raising awareness of the problem in some parts of the world. A 2010 Gallup poll in sub-Saharan African countries found that the majority of the public in 15 of the 17 countries surveyed were aware that fake medicines were a problem (see Table 4-8) (Ogisi, 2011). The leadership of drugs regulators in Nigeria, one of the largest and most influential African countries, might have contributed to the public consciousness in Africa (see Box 4-7). More recently, Interpol launched an awareness campaign featuring South Africa's Yvonne Chaka Chaka and Senegal's Youssou N'Dour, two of the continent's biggest celebrities (Interpol, 2011). Awareness of the problem is also growing in Southeast Asia (Christian et al., 2012a; Gleeson, 2012).

TABLE 4-8

Response to the Question “Are You Aware of the Presence of Fake Medicine in This Country?”.

BOX 4-7

A National Awareness Campaign in Nigeria. In February 2005, the Nigerian drugs regulatory agency launched a national awareness campaign about fake medicines in Nigeria (Akunyili, 2005). The success of this program may account for Nigerians' high (83 percent) (more...)

Other research suggests gaps in awareness, especially among the poorest people in society. A qualitative study of Sudanese policy makers and pharmacists suggested that awareness of counterfeit products is lowest among the poor and people living in remote areas (Alfadl et al., 2012). Participants at overseas site visits for this study mentioned similar patterns in many developing countries. Often, well-educated urban consumers understand the threat of fake drugs and take precautions to avoid them. The poorest patients, and those living in areas with few to no reliable pharmacies, are often the least aware. Moreover, as Chapter 5 will discuss, they often have no choice but to buy medicines in the open market or have no money to buy from a registered pharmacy.

It is not clear how well informed populations in other parts of the world are about falsified and substandard drugs. People in developed countries, who have long taken medicines regulation for granted, are among the least knowledgeable. An Inter-Press Service story reported that 20 percent of Western Europeans did not consider it dangerous to circumvent traditional pharmacies to buy medicine (Stracansky, 2010). The same behavior has long been normal in the United States, where pharmacy tourism to Canada and Mexico has been common since the 1970s (Rabinovitch, 2005). Chapter 5 will discuss the internet pharmacies that have largely replaced in-person cross-border shopping.

Public Action

Educating the public on the problems of falsified and substandard medicines is important, but only insomuch as education empowers people to act. In an international site visit for this report, a procurement agency informed the IOM delegation that when they uncover manufacturers making substandard drugs they do not report the offense to the authorities. The reasons they gave included doubt that the regulator would act on their information and fear of litigation.

Similar attitudes may underlie a lack of reporting of adverse drug reactions among health workers in developing countries. Health workers are the first line for monitoring the safety of medicines. Their role in surveillance is important in low- and middle-income countries, where falsified and substandard drugs are common, and less than 27 percent have functional pharmacovigilance systems (Pirmohamed et al., 2007). Reporting of adverse drug events is generally low in these countries (Chedi and Musa, 2011; Fernandopulle and Weerasuriya, 2003; WHO, 2002b). Few staff are trained in pharmacovigilance, a practice sometimes seen as adding to the responsibilities of already overworked health professionals (Olsson et al., 2010; Sharma and Ahuja, 2010).

The increasing awareness of falsified and substandard medicines could drive improved pharmacovigilance in developing countries. Awareness campaigns and investigative reporting reach health workers as well as they reach the rest of the public. There is also a need for targeted health worker education on falsified and substandard medicines, emphasizing the correct reporting channels health workers can use to confirm suspected cases of falsified and substandard drugs. Much useful work has been done on the first steps of this process; clinicians struggling to broach the topic with their patients can consult the World Health Professionals Alliance guidelines on how to inquire about suspicious medicines (see Box 4-8).

BOX 4-8

Health Worker Guidelines. It is important for health care workers to query gently, by asking Where patients will or did buy the medicine. Emphasis can be placed on the importance of buying medicine from a pharmacy or other known and reliable sources.

Chapter 3 describes governments' and drug companies' reluctance to share information on substandard and falsified drugs (Cockburn et al., 2005). Pharmaceutical companies fear damage to their branding from rumors of poor quality, whereas governments can see such information as undermining confidence in the health system (Cockburn et al., 2005). These concerns are well grounded, and an appropriate communication strategy will convey accurate information is a way that is sensitive to all stakeholders. Falsified and substandard medicine is a sensitive and dynamic problem, and the public has a right to accurate information about it. This information can be presented in such a way as to empower the consumer to make safe choices and to build confidence in the regulatory system. A professional communication strategy provides the best guarantee that sensitive information is conveyed clearly and well.

Recommendation 4-5: Governments and donor agencies should fund development of effective communication and training programs for consumers and health workers on understanding the quality and safety of medicines.

Falsified and substandard drugs are a potential threat around the world, though risk varies widely from country to country. Awareness of the problem also varies and may be most limited in countries with strong regulatory systems but where, because of the global drug supply chain, substandard and falsified drugs still reach consumers. An effective communication campaign should present accurate information in a way that empowers patients to protect their own health. For example, the FDA website discourages buying drugs from foreign websites (see Figure 4-5) (FDA, 2012c). The CDC website gives similar guidance, discussing poor-quality antimalarials and alerting prospective travelers to avoid buying drugs abroad (CDC, 2010).

FIGURE 4-5

An FDA public service announcement that promotes the Verified Internet Pharmacy Practice certification discussed in Chapter 5. This is an example of an empowering consumer education message. NOTE: The poster uses the term counterfeit broadly, the way (more...)

Education and communication are feasible in rich and poor countries alike. Representatives of 200 WHO member states stressed the importance of educational initiatives for consumers and health workers at the first meeting of the WHO global mechanism against falsified and substandard drugs (WHO, 2012c). Many developing countries have already made headway in consumer education. Figure 4-6, for example, shows a Cambodian health education poster promoting licensed pharmacies. Similarly, as Box 4-7 explains, the Nigerian drugs regulatory authority improved public understanding of the problem with relatively simple steps: public service announcements, newspaper ads, and school essay contests. This kind of campaign is realistic in many low- and middle-income countries.

FIGURE 4-6

The English translation of a Cambodian poster encouraging consumers to buy medicines only from licensed pharmacies and to examine the drug's color, shape, and taste for abnormalities. NOTE: The poster uses the term counterfeit broadly, the way this report (more...)

While information about the problem is important, it is also important to link this information to action. The messages communicated and the action promoted will vary by country or region. In many countries, the most useful messages will be about specific drugs and vendors. Buying antimalarials from street markets, for example, is a dangerous behavior in most of Africa and Southeast Asia. Chapter 5 discusses some of the safe medicine outlets that the communication campaigns could promote.

The most wide-reaching communication strategies make use of many channels, including print media, television, radio, the internet, mobile devices, and social media. Governments and NGOs have made good progress using these channels to promote understanding of the problem (Besançon, 2008, 2012; Elliot, 2012; FIP, 2011). Educated consumers may now be more receptive to messages about the correct appearance or taste of medicines, the normal responses to it, and possible side effects. Patients who understand the correct attributes of their medication will be better able to identify suspicious products.

Therefore, governments and donors should consider developing medicine checklists that remind patients of dangers and help them identify problem drugs. A checklist or authentication database might include the reasonable price range for the drug (thereby reminding people that low costs are suspicious); a check for sealed, complete packaging; a check for the correct shape and markings on the pills; and a check for other physical properties such as stickiness or hardness. Mobile phones might be the most efficient way to disseminate this information. Consumers could also use their phones to photograph suspicious drugs and relay the image to a central site for review. Mobile phones and the internet have a wide reach and will be useful tools for promoting such a checklist. Patients and providers could use mobile phones to access a database with information about poor-quality drugs.

Health workers are the first line of pharmacovigilance and will be point persons in any consumer education campaign. Their training should include information on falsified and substandard drugs. Providers should be made more aware of their role in the postmarket surveillance of medicines, a new responsibility in many developing countries (Sharma and Ahuja, 2010). A health worker checklist might remind providers to ask patients for information about lack of response to treatment, slow response, and appearance of unusual symptoms. The list would also remind health workers about the proper channels for reporting an adverse event.

The next 10 years will see the introduction of many new drugs and vaccines in low- and middle-income countries (Kaufmann et al., 2011; Lienhardt et al., 2012). Messages of caution about dangerous medicines should not be presented in such a way as to scare people or to discourage appropriate use of medicines (Larson et al., 2011). To this end, awareness and communication campaigns could take some inspiration from successful vaccine safety campaigns (Leitmeyer et al., 2006; Mansour-Ghanaei et al., 2008). Awareness campaigns should also be tailored for their audience. Programs for policy makers would include a broader summary of the conditions encouraging the trade in falsified and substandard medicines, as presented in this chapter.

In summary, careless manufacturing, whether deliberate or accidental, causes substandard medicine. Making falsified medicines is driven by the interests of criminals, who weigh the millions of dollars in potential profits against low odds of getting caught. To complicate the problem, medicines are expensive and often scarce. There is a financial incentive to produce a poor-quality or imitation drug. These products circulate because national regulatory authorities are often poorly equipped to detect problems and act against them.