Ethical drugs, unethical practices

by Geewananda Gunawardana, Ph.D.

Ensuring the quality, safety, and efficacy of pharmaceuticals requires a high level of constant vigilance. A good example is the four deaths caused by contaminated eye drops in the USA last May despite the well-regulated and best prepared monitoring of the drug supply by the US Food and Drug Administration. Unfortunately, the consumers in places where regulations as well as their implementations fall short of ideals can fall victims much more frequently: A World health Organization (WHO) report finds that about 10% of the world’s drug supply is either subpar or fake. Global deaths among children alone due to subpar drugs is over 150 thousand annually while the economic cost is estimated to be about US $ 200 billion.

While loss of life is a tragedy, the failure to ensure the quality of medicinal products can have far reaching and long-lasting consequences of much larger magnitude. The emergence of drug resistant infections and parasitic diseases and genetic disorders due to subpar drugs will only come to light in the long run.

To get some idea about the vulnerability of pharmaceuticals, it is important to know the way the regulatory process works. Almost 90% of the new drug development takes place in North America and Europe. The rest is divided among Japan and Israel. India and China, leaders in generic drug manufacture, are only beginning to enter this field through collaboration with American and European pharmaceutical companies. When a drug is invented, the inventor obtains a patent, which is an exclusive right to market it for 20 years. However, a patent only keeps the competition away, and it does not give the authority to market the drug, which must be obtained from the regulatory agency of the respective country.

To get the marketing authority, a vast amount of data must be produced showing efficacy, safety, and manufacturability of the drug. This process takes 10 to 12 years on average and over US $ 1.5 billion in R&D costs. As the development takes up to 8 to 10 years, the actual patent life left when it goes to market is reduced to 10 to 12 years, during which time the company must recoup all the costs and make a profit. A drug marketed under patent is known as a brand name drug. These initial R&D costs make the brand name drugs expensive.

The manufacturer of the brand name drug must follow all the current good manufacturing practices (cGMP) as specified by the regulatory agency of the marketed countries. The International Conference on Harmonisation (ICH) has standardised these guidelines and are followed by the major pharmaceutical manufacturing countries. Adherence to the cGMP regulations assures the identity, strength, quality, and purity of drug products by requiring that manufacturers of medications adequately control manufacturing operations.

The consequences of failing to meet guidance can be harsh. For example, the UK based Glaxo Smith Kline was fined US$ 3 billion in 2012, the highest in history for cGMP violations. The brand name drug manufacturers avoid taking any risks as the stakes are very high. There are some companies that were forced to shut down for failing to follow cGMP. A common problem with brand name drugs is the manufacture of counterfeit drugs sold in small markets despite the best efforts of the patent owner to avoid such piracy. The commitment to quality and the stringent regulatory vigilance makes brand name drugs less susceptible for quality issues.

Once the patent expires, anyone with the right capabilities can manufacture the drug and seek marketing authorisation in selected countries. These drugs are referred to as generic drugs. Since the generic manufacturers do not have to bear the billion-dollar R&D costs, they can afford to lower the price. The competition for market share also drastically reduces the cost of generic drugs, often by over 80% of the original price. The costs can be further reduced by moving the manufacturing into places where the labor and operating costs are lower and occupational safety and environmental regulations are lax or lacking altogether. The affordability and wide availability are the beneficial outcomes of generic drugs. For example, 91% of the drugs prescribed in the USA in 2022 were generic drugs. Except for a rare event, the US drug supply remains safe and reliable, mainly thanks to the diligence of the US Food and Drug Administration.

The bulk of these cost-effective generic drugs are destined for low- and middle-income countries. Unfortunately, that is where the troubles begin. The WHO has formulated international regulatory standards to ensure the safety and efficacy of the drugs in places where ICH guidance is not implemented. They also have a program for pre-qualification of drug manufacturing facilities when requested. While international organisations require WHO prequalification for drug purchases, individual governments can follow their own regulations. Knowing the presence of potential buyers who are willing to forgo cGMP requirements, some manufacturers tend to ignore the need for costly qualification or certification programms. This practice is also encouraged by the premise on the buyers’ side that testing alone can ensure the quality of drugs. However, the truth is that failing to follow cGMP can lead to unintended release of subpar drugs to markets even if the standard testing procedures are followed.

Two processes where this can happen easily are sterilisation and achieving content uniformity. Failure to ensure that every single unit of the drug, be it a pill or a vial of many thousands manufactured, is compliant could result in subpar drugs reaching the market. In the case of uneven sterilisation, microbial contamination can occur as was seen with eye drops. Failure to ensure uniformity can result in drug units containing either higher or lower doses than shown on the label.

Most of the generic drugs are manufactured in Asia. Drug manufacturing is a multistep process conducted in multiple locations under varying levels of regulatory control. A routine drug manufacture can have the following basic steps: procurement of raw materials, synthesis of starting materials and/or intermediates, synthesis of the active pharmaceutical ingredient (API), procurement of excipients, and formulation of the API into the drug product – capsule, tablet, syrup etc. This can vary for biologics such as vaccines and recombinant proteins etc., which make up only about 2% of all drugs used. In either case, at every step, the product must be stored in proper containers under the right conditions as determined based on its stability to prevent degradation and contamination.

Except for biologics, almost all drugs are produced by chemical synthesis. A small portion are either plant or microbial origin. The generic drug manufacturers come up with alternate synthetic routes that are cost effective. This creates a major problem: Any synthetic process generates impurities or side products in addition to the desired product. These impurities could have unknown properties, including toxicity, and must be removed or kept to a minimum using various purification steps. The processes and analytical methods used for this purpose by the brand name manufacturer are optimized to monitor and control any impurities specific to the raw materials, starting materials, and excipients they used. However, if the generic manufacturers introduce any changes, the standard quality control methods may not work, and undesired impurities will end up in the drug causing potential adverse events. Another potential problem, particularly in the warm and humid tropics, is microbial contamination, as happened with eye drops when handling and storage conditions are deviated.

With complicated supply chains, it is very difficult for the drug purchaser to track if all processes used in the manufacture of the drug were conducted under cGMP. Either they do not have the wherewithal or have no impetus altogether as happens when questionable drug procurement methods are followed. There are other ways the purity of drugs can be compromised. All drugs have a limited lifetime as specified by the expiration date. The expiration date is set assuming the storage of the drug under certain conditions and in designated containers. Any deviation, which can happen easily when transported between tropical locations, the drug can degrade reducing the potency or efficacy and introducing impurities. Without proper cGMP, it is not possible to know if such deviations have occurred.

If the drug is degraded, the desired therapeutic effect may not be achieved. In addition to that, in the case of antimicrobial and antiparasitic drugs, the administration of lower doses can lead to the development of drug resistant varieties. Infections caused by resistant organisms can be difficult, and sometimes impossible, to treat. Antimicrobial resistance is an urgent global public health threat that killed around 1.27 million people worldwide in 2019. If not controlled, this could render the current anti-infective drugs virtually useless and makes it one of the world’s most urgent public health problems.

The impurities or contaminants in drugs can have numerous undesired results including death. The deaths of 66 children in Gambia last year caused by taking contaminated cough syrup, imported from India, is just one example. A serious problem is contamination with genotoxic compounds. If not detected promptly, the consequences would not be known for many generations. The genotoxic impurities can be harmful when present in as low as parts per million amounts in the drug. The analytical techniques for detecting such low amounts require specific instruments not readily available in most laboratories. Recently, a whole family of hypertension drugs were found to contain genotoxic impurities and were withdrawn from the US markets.

These are the problems that can arise under normal operating procedures, and fortunately, the ones that can be eliminated if proper cGMP are observed. To worsen things, there are added problems that go beyond manufacture and cGMP. Unscrupulous drug companies and corrupt administrations contribute to the problem by knowingly allowing substandard drugs into healthcare systems with total disregard for life and limb. Pharmaceutical industry is notorious for its “gift” system for buying or prescribing their drugs. In one reported incident, a company sold 45 years’ worth of antibiotics to a developing country when the shelf life of the drug is only 2 years. Unloading drugs that are nearing expiration or not suitable for their own countries into low-income countries is a common practice.

The subpar drug related adverse events are predictable but also preventable. Generic drugs in general are safe and effective as international organizations have provided the means to ensure their safety and efficacy. Every step from the supply of starting materials to the dispensing of the drug to the patient must be controlled according to the guidance to receive the full benefits of drugs and avoid adversities. Sri Lanka has incorporated most of those rules and regulations to their own. However, their complete implementation remains questionable. Purchasing drugs without knowing its complete history is inviting trouble. Neglecting to do so puts future generations at risk in addition to wasting hard-earned foreign exchange.