In the past 20 years, antimicrobial resistance (AMR) has grown from hypothetical hazard to dire global threat. Across the world, a growing number of potentially deadly infectious pathogens, including those that cause tuberculosis, HIV, malaria and staph infections, have developed resistance to treatment regimens. Drug-resistant bacteria account for 700,000 deaths globally every year, and if left unchecked this number could reach 10 million per year by 2050. A 2014 report from the World Health Organization (WHO) declared that “the problem is so serious it threatens the achievements of modern medicine.”
Antimicrobial resistance demands a global response. Many organizations and governments have devised approaches to address the multiple factors that lead to AMR; however, medicines quality, which is one of these drivers, is often overlooked. For example, a comprehensive and systematic Global Action Plan formulated in 2015 by experts convened by the WHO underemphasizes medicines quality. Without quality-assured medicines, doctors and patients can inadvertently create optimum conditions for resistance by exposing pathogens to sub-therapeutic doses of medicine.
On 19 September, USP — a global nonprofit that focuses on drug quality — co-hosted a panel of experts at the Harvard Club in New York City to explore the connection between the quality of medicines and AMR. “Poor-quality medicines, though less heralded, are one of several factors that have been proven to contribute to antimicrobial resistance. Most interestingly, it is the one factor we most know how to solve,” said USP CEO Ronald T. Piervincenzi. “We know what it takes to assure the quality of medicines. We have and understand the tools and are deploying them on a daily basis, though not evenly around the world. Right now, the challenge is to define the extent of the impact of poor-quality medicines on public health in order to help guide strategic and fact-based decisions, policy making and investments by governments and donor organizations as world leaders work to address this global crisis.”
The WHO’s Global Action Plan establishes five primary objectives for combating AMR: awareness, surveillance, reducing infection, ensuring appropriate use, and R&D investment. It acknowledges the importance of medicine to the plan’s success, but does not explicitly focus on medicines quality as a priority. Hajime Inoue, the WHO’s special representative for antimicrobial resistance, pointed out that this issue underpins all five objectives. For example, “we need to include drug quality issues in our surveillance system,” he said, “and the quality of medicine issue is actually the prerequisite of reducing the prevalence of infections.”
The Global Action Plan also called on member states to develop national plans. According to Dr. Inoue, many of the 130 countries which have done so have routinely overlooked medicines quality issues. Jude Nwokike, director of the USAID-funded and USP-implemented Promoting the Quality of Medicines (PQM) program, concurred. “What we see in most countries is that product registration and quality-assurance issues are not sufficiently addressed when new treatment programs are being designed, and that product quality issues are usually the orphan,” he said.
As Piervincenzi noted, although the connection between quality of medicines and AMR is strong, it very much needs to be more clearly characterized and quantified. And as Inoue pointed out, “one of the biggest challenges as a science-based organization in this field is a lack of robust data.”
This will be a top priority for the USP Quality Institute, a new initiative launched at an event that followed the panel discussion. Its goal is to conduct research to support evidence-based policymaking on medicines quality-related issues. “It is broadly agreed that quality medicines are important,” said Piervincenzi, “but more data is needed to inform strategic policy interventions.” This Institute’s research priorities will be set by an advisory group comprising medicines quality experts from academia, a variety of non-governmental organizations and the pharmaceutical industry. It will support external research through fellowship programs, the first of which was established with Georgetown University Medical Center.
A Challenging Ecosystem
There are several obstacles between patients and quality-assured drugs, and substandard and falsified medicines are the most damaging. In 2017, the WHO estimated that the total spending on substandard and falsified medicines in low- and middle-income countries is approximately US$30.5 billion. Antimicrobial drugs — in particular, antibiotics and antimalarials — are among the most commonly reported poor-quality classes of drugs in the marketplace. “We’ve gathered more than 1,500 reports of substandard, falsified medicine from more than 100 countries,” said Inoue.
According to Irene Koek, Senior Deputy Assistant Administrator for the U.S. Agency for International Development (USAID) Global Health Bureau, the prevalence of poor-quality medicines is exacerbated by poverty. “People want to buy antimalarials because their kids are sick, so they are going to go anywhere and buy what they can buy cheaply,” she said. “Similarly with antibiotics.” The danger is compounded by the fact that in many of the world’s poorer communities, there are no professional ‘gatekeepers’, such as pharmacists, to ensure that patients are receiving quality medicines. Antibiotics “are bought over the counter from shops, much like someone would buy matches or sugar,” said the panel’s moderator Ramanan Laxminarayan, Director of the Center for Disease Dynamics, Economics & Policy. The result is that even with policy changes upstream, Inoue said, “The majority of substandard and falsified medicines are actually penetrating into the system in just the ‘last one mile’ before the patients.”
Even if a community has access to legitimately manufactured medications, quality control can be threatened by inappropriate care and handling. For example, improper shipping, handling and storage — whether in warehouses or in homes — can result in the degradation of the medicine, potentially resulting in toxic impurities or reduced potency. “In Sub-Saharan Africa, where I come from, we have a big problem with storage of medicines,” said Mimi Darko, CEO of the Food and Drugs Authority, Ghana. “This has led to deterioration, especially in public facilities and ministry facilities.”
A Multi-Pronged Effort
In response to these challenges, both national and international agencies have mounted efforts to improve in-country quality-assurance systems, adopt international standards for quality control laboratories, and strengthen post-market surveillance. For example, Nwokike described how the Promoting the Quality of Medicines (PQM) program has supported country-led efforts for 17 laboratories to reach international standards that attest to their capacity to test the quality of products and produce reliable results. PQM also established the Medicines Quality Database as a centralized resource for aggregating and sharing drug-quality testing data collected from laboratories around the world.
Identification of trusted pharmaceutical manufacturers is also critical, and Nwokike noted that the PQM program has worked with producers to meet WHO prequalification and stringent authorities’ approval for 26 active pharmaceutical ingredients and finished products.
The U.S. Food & Drug Administration (FDA) has also stepped up efforts to ensure quality manufacturing and regulatory compliance globally, with five foreign offices and a network of international collaborations to monitor the production of pharmaceuticals that will ultimately be released for sale in the U.S. and elsewhere. “The FDA is focusing on good manufacturing, distribution and pharmacy practices and leveraging global standards to create a more level playing field for legitimate supply chains,” said Larry Kerr, Director of the Pandemics and Emerging Threats Office at the U.S. Department of Health and Human Services.
Quality control is also a community- and household-level issue. Koek spoke of the new USAID-backed Accredited Drug Dispensing Outlet (ADDO) program, which established a network of trained and quality-assured pharmacists throughout Tanzania. Meanwhile, the ADDO program mounted a community outreach effort to inform the public on how to recognize these trustworthy medicines dispensaries. “Those kinds of techniques are ways to put the control in the hands of the consumers, so they have information about where to get good, quality-assured drugs,” Koek said. Other organizations have taken on similar programs within hospitals, training doctors and nurses on proper drug storage.
The ability to fend off infection is essential to virtually every aspect of modern medicine, and success in the fight against AMR depends in large part on the ability to ensure that antimicrobials are accessible, quality-assured and appropriately used. In closing, Laxminarayan expressed the hope that efforts to draw a clear connection between medicines quality issues and the widely-reported AMR crisis might generate broader awareness and investment. “I think if we can use the agenda to pull the quality of medicine agenda along, then we will have done a lot of good that goes beyond just AMR,” he said.
What is Quality-Assured Medicine?
At its simplest, a quality medicine is what it purports to be on its label — no more and no less. Quality assurance is obtained through a balanced, risk-based set of predetermined characteristics, systems, and requirements that consistently ensure a medicine’s delivery of stated and implied clinical outcomes for patients. It considers aspects of a medicine’s life cycle, including design, manufacturing, supply chain, storage, distribution, and falsification. It does not consider quality of treatment guidelines or clinical practice dimensions.
Quality is assessed using two types of standards:
Documentary standards (also known as monographs) are technical documents which cover everything from developing a drug to storing it, and often appear in reference texts called pharmacopeia.
Reference standards (also known as physical standards) are known quantities of a drug substance or ingredient, developed in alignment with the specifications outlined in the monograph. These standards come in small vials and enable pharmaceutical manufacturers and regulators to test their product against public standards to ensure it meets published specifications.
USP is an independent non-profit organization that collaborates with the world’s top health and science experts to develop high-quality standards that set the bar for manufacturing and distributing safe and effective medicines, supplements and food around the globe. Two billion people world-wide have access to quality medicines, dietary supplements and food as a result of USP’s standards, advocacy and education.
To learn more about the need for quality standards in medicines, visit The Science of Quality.