// May 24, 2016

Pharmaceutical Manufacturing in LMICs: Where Things Go Wrong

Root Causes of Substandard Medicines

The Root Causes of Substandard Medicines in Lower and Middle Income Countries (LMICs)

In LMICs, the availability of medicines manufactured locally that do not meet quality standards is a leading cause of treatment failure and adverse events in patients and is undermining public health interventions. But where do things go wrong during pharmaceutical manufacturing in LMICs that gives rise to this problem?

The World Health Organization (WHO) defines substandard medicines as “'genuine medicines produced by manufacturers authorized by the National Medicines Regulatory Authority (NMRA) which do not meet quality specifications set for them by National standards.”[1] Unlike counterfeit medicines, which receive greater attention due to their immediate dramatic consequences, substandard medicines and their negative effects, which are more gradual, are often unnoticed. 

This article sheds light on the problem of substandard medicines and the key root causes that lead to their production in LMICs.

Poor Quality Active Pharmaceutical Ingredients (APIs) Used to Make Finished Pharmaceutical Products (FPPs) 

APIs used to make medicines by manufacturers in LMICs are often imported, particularly from India and China. This importation trend is not unique to LMICs, as many countries around the world import APIs from manufacturers located in these countries. For example, 80 percent of the APIs used in drugs manufactured in the United States (US) are imported, with the largest suppliers from India and China.

But, unlike the US and other developed countries, LMIC manufacturers do not often check the quality of APIs prior to using them to make finished pharmaceutical products (FPP). Why? Local manufacturers in these markets are not compelled to do so. While the quality of APIs may be a stipulated requirement in their laws and regulations, it is often not enforced in contrast to well-regulated markets.

Without a process in place to assure API quality, the resulting FPP will be of poor quality. In many cases, if poor-quality APIs are used, then bad things can happen to FPP. The old adage “Garbage In, Garbage Out” applies.

API quality can often be constrained by the presence of chemical impurities arising from toxic and banned solvents and reagents used in synthesis (because they are inexpensive). Also some of the APIs have undesired physical properties, such as large particle size or an uncharacterized polymorphic that can make the resulting FPP have undesirable quality attributes that prevent adequate uptake of APIs and reduce their intended therapeutic effects in patients. 

API quality, therefore, should not be left unmonitored. Currently, the regulatory process in LMICs is heavily weighted on FPPs, leaving a noticeable gap in regulation of APIs used in their synthesis. NMRAs rely only on certificates of analysis from the API manufacturers, which are often unverified, and focus solely on quality control tests of FPPs. But it should be noted that quality control of FPPs only focuses on select quality attributes and does not usually include other quality attributes (such as residual solvents and polymorphic state) that can only be checked in the API. Any quality defect of the API is transferred to the FPP during production. Hence, by not testing the quality of the API, significant quality attributes of the FPP can be missed.  

Poor quality APIs often cost less. Many manufacturers in LMICs find their cost-savings potential appealing and use them in FPPs unaware of their poor quality. But in the end, the burden this poses on health systems of LMICs is more costly. This was the case in 2008 when 81 people died in the US when a poor quality API, oversulfated chondroitin sulfate, was imported from China, and used to make heparin, an anticoagulant.

To reduce production of substandard medicines in LMICs, regardless of where APIs are made, NMRA’s of importing countries should inspect and regulate the quality of APIs as they would FPPs. In addition, API manufacturers must adhere to quality standards set by importing countries, and where there are none, should adopt an international quality standard, such as those set by the WHO, US Pharmacopeial Convention (USP), or European Union.

Contamination during Production

Substandard medicines are also caused by contamination during the manufacturing process. When Good Manufacturing Practices (GMPs) are not followed, cross-contamination can occur among products manufactured at the same facility, leading to FPP with dangerous levels of other medicines manufactured at the facility. Cross-contamination of this type happens when equipment are not properly cleaned before changeover of products, or lack proper air handling systems to prevent movement of dust particles from one medicine in production to the next.

In addition, using contaminated water during manufacturing processes also leads to high microbial burdens in oral suspension and intravenous solution FFPs. Also, when equipment and processes used to test the quality of medicines are flawed, substandard medicines can inadvertently pass quality control tests.

Drug contamination can easily go unnoticed since quality control tests are designed to only assess levels of expected impurities in the FPP. It is only after these products are used by patients —and deaths or illnesses result—that contaminated medicines are noticed by LMICs.

When adhered to, GMPs standards ensure consistent manufacture of products free of contamination. They help ensure that products are consistently produced and controlled according to uniform quality standards, and are designed to minimize the risks involved in pharmaceutical production. Moreover, calibration of production and analytical equipment ensures reliability and accuracy of quality control test results. These processes cannot be short-cut.

The cross-contamination of a heart drug, Isotab, with large amounts of an antimalarial medicine, pyrimethamine, manufactured at the same facility, resulted in hundreds of deaths in Pakistan, and provided a wakeup call to all LMICs regarding the dangerous consequences of not adhering to GMPs. 

Poor Formulation of Finished Pharmaceutical Products

How medicines are formulated using inactive ingredients (called excipients) affects their stability, bioavailability, and ultimately their efficacy. Medicines that are poorly formulated can become unstable and degrade. This compromises their shelf-life. Degradation processes are often expedited in high temperatures and high humidity, conditions common to many LMICs, causing products to lose efficacy over time. Poorly formulated medicines often fail to deliver the right amount of drug substance to the right part of the body at the right time, resulting in reduced therapeutic effectiveness in patients.

For example, poorly formulated paracetamol (acetaminophen), a medicine commonly used to reduce pain and fever, can degrade to 4-aminophenol, a toxic and hazardous substance that causes liver and kidney failure. If medicines with reduced efficacy, toxic impurities, or degradants are consumed by patients, treatment failure, drug resistance, or even worse, death or illness may occur from exposure to FPPs that have degraded.  

These root causes contribute to production of a significant proportion of substandard medicines in LMICs. Understanding how they come about will help in designing programs that effectively address deficiencies in manufacturing and regulatory processes that allow them to flourish in supply chains in LMICs. To date, efforts that address substandard medicines, relative to counterfeits, have been underprovided and under-resourced. Now is time to reshape the development focus and put a spotlight on efforts that address and provide solutions to the root causes of substandard medicines in LMICs. Local manufacturers must be encouraged to address the deficiencies that result in medicines that fall short of quality standards, and LMICs supported to enhance their capacity to resolve the root causes. Significant progress has been made by many well-intended players in LMICs, but more work remains to be done.

To learn more about this topic, see Shedding Light on Impurities in Medicines.

Patrick Lukulay, Ph.D. is the Vice President of USP’s Global Health Impact Programs in Africa. Contact him at phl@usp.org, or on Twitter @PatLukulay.

**Editor's Update, September, 7, 2017: Dr. Patrick Lukulay is the former Vice President of USP's Global Health Impact Programs in Africa**

[1] World Health Organization. 2016. Definitions of SSFFC Medical Products.  Accessed May 23, 2016.