Diethylene Glycol Contamination in Cough Syrups

 

Introduction:

Cough syrups have long been trusted as a remedy for relieving symptoms associated with respiratory illnesses, providing comfort during cold and flu seasons. However, the discovery of diethylene glycol (DEG) contamination in certain cough syrups has raised serious concerns about the safety and quality of these products. DEG, a toxic substance primarily used in industrial applications, poses significant health risks when ingested or absorbed by the human body. This article explores the issue of DEG contamination in cough syrups, its implications for public health, and the measures which should be taken to address this alarming problem.

Understanding Diethylene Glycol Contamination:

Diethylene glycol is an organic compound primarily used as an industrial solvent, particularly in the production of polymers, resins, and antifreeze. It is significantly cheaper than other common solvents and additives used in pharmaceutical dosage forms such as Propylene glycol and Glycerine. Unfortunately, its chemical properties and low manufacturing costs have led to instances of DEG being fraudulently or unintentionally used as a substitute or adulterant in the additives such as Propylene glycol and Glycerine used in pharmaceuticals including cough syrups.

Health Risks Associated with DEG:

The ingestion or absorption of diethylene glycol can have severe consequences for human health. It can cause kidney failure, damage the liver, affect the central nervous system, and even lead to death in extreme cases. Symptoms of DEG poisoning include nausea, vomiting, abdominal pain, dizziness, seizures, and respiratory issues. Children, due to their smaller body size, are particularly vulnerable to the toxic effects of DEG

Cases of DEG Contamination in Pharmaceuticals-

Over the years, several incidents of DEG contamination in cough syrups and other pharmaceuticals have come to light, causing significant harm and loss of life.

The first and one of the largest outbreaks, which resulted in 105 deaths, occurred in the United States of America (USA) in 1937. In this case DEG was used by development scientist as solvent for formulating sulphanilamide elixir due to lack of knowledge about it’s toxicity. This incident led to the passing of the 1938 Federal Food, Drug and Cosmetic Act. The Act requires manufacturers to establish safety and efficacy of the drugs before they are introduced into the marketplace. Since that time, there have been no DEG mass poisonings in the USA, but many have occurred in the developing world.

Cough syrup contaminated with DEG led to the deaths of 33 of 36 children known to be affected in India in 1998 and 85 of 109 children known to be affected in Haiti in 1995–1996. In both outbreaks, patients had unexplained acute renal failure, a characteristic of moderate-to-severe DEG poisoning.  In 1995, an American Physician volunteering in Bangladesh reported deaths in children due to Government issued cough syrup. Although the government denied that anything was wrong with the syrup, but the sample when tested in US was found to be contaminated with DEG. No specific actions to prevent recurrence were taken post these incidences.

A case of cough syrup containing DEG resulting in the deaths of 365 people, mostly children was reported in Panama in 2006-07. The diethylene glycol used in the contaminated syrup originated from a Chinese manufacturer, which exported it as industrial "TD glycerine" with a shelf life of one year. The letters "TD" were short for "substitute" in Chinese. When Panama-based company received the material from a Spanish trader, it changed the name to "glycerine" and the expiration date to four years before selling it to the government of Panama. Neither the trading companies involved nor the government lab in Panama that processed the ingredient tested the substance for verification. Responsible people were severely punished including death penalty to seniormost person involved.

In 2020-21, another 12 children died in India (J&K) after consuming cough syrups.

In  death of more than 100 children were reported in Indonesia due to acute kidney injuries after consuming cough syrup contaminated with DEG and ethylene glycol.

Recently WHO reported deaths in more than 100 children in Marshall island, Gambia and Uzbekistan due to consumption of cough syrups made by three different drug manufacturers from India. After initial denial and attempts to prove that nothing was wrong in the cough syrups, CDSCO conducted audits at the manufacturing sites and eventually suspended their manufacturing licences due to lapses seen during the audits. Pharmexcil suspended the membership of one of the company and Commerce ministry issued notice that all the cough syrups need to be tested at government laboratories before export.

Except for the first incident which occurred in US, no comprehensive measures have been taken to ensure that such incidences don’t get repeated. For the incidences which occurred in India or related to products manufactured in India, I haven’t seen any comprehensive investigation conducted by regulatory agency to understand the root cause/s and taking concrete actions to ensure that all medicines manufactured and distributed in India are safe.

Potential causes for DEG contamination

Based on limited information available in public domain related to these incidences and the knowledge of Pharmaceutical quality systems, following are likely causes for DEG contamination in cough syrups and other pharmaceutical preparations –

1.      Intentional use of diethylene glycol by the manufacturer to save cost. This is highly unlikely because the toxic effects of DEG are now well known and no manufacturer with sane mind will intentionally add toxic chemical which can result in death, in their products, as it will damage their reputation and destroy their business.    

2.      Contamination of commonly used pharmaceutical ingredients such as Propylene glycol and Glycerine with DEG. Such contamination can occur due to intentional adulteration by manufacturer or the trader to reduce cost or accidental contamination due to mix-up or wrong labelling of containers if these chemicals are manufactured or handled in common facility.

3.     Present in the ingredients, being by-product of manufacturing process.

Manufacturing processes of Glycerine & Propylene glycol

To understand what impurities can come from the manufacturing processes, we need to first understand various paths by which Glycerine and Propylene glycol are manufactured. Various commonly used manufacturing processes for the two ingredients and likely by-products by these routes are summarized below –

Ingredient	Method of production	Potential contaminants
Glycerine	Hydrolysis, saponification, alcoholysis of animal fats and vegetable oils	Tri methylene glycol, Formic acid, Various aldehydes, ketones, sulphur compounds, etc
	From petrochemicals (synthetic glycerine)	Acrolein, Methanol & Di chlorohydrin / Epichlorohydrin
	Microbial fermentation of sugars followed by purification using solvents	Residual solvents such as dioxane, ether, butanol By-products such as polyols and polyhydroxy alcohols.
Propylene glycol	Hydration of Propylene oxide	Di & Tri-propylene glycols along with other glycols, Chlorohydrin, Hypochlorous acid & Propylene oxide

Review of manufacturing processes and likely by-products did not indicate possibility of DEG contamination in these ingredients during manufacturing although there is possibility of formation of other toxic contaminants.

Based on above information the most likely cause for DEG contamination in Glycerine or Propylene glycol appears to be intentional adulteration for profiteering or un-intentional mix-up or wrong labelling.

While above are the technical causes for the contamination, the major underlying root cause for such repeated issues and poor quality of drugs in India is outdated drug laws and regulatory system. Some of the major flaws in our drug laws which have resulted in such incidences are –

1.      The Central drug control organization does not have direct control over the state FDAs which work as parallel controlling agencies.

2.      Lack of scientific evaluation of drug applications. After initial 4 years, state licensing authority can grant product permission. Each state follows different process for granting manufacturing licenses and many states grant such licences based on review of just limited administrative information without doing any technical evaluation to ensure safety and efficacy of the drugs.

3.     There is no procedure for controlling changes to the process and product, So the manufacturers are at liberty to make any changes including changes in formulation, changes in vendors, changes in process etc without even informing to regulatory agency.

4.      Recall process is extremely ineffective in India due to loose regulations.

5.      There is no regulation for control of vendors and supply chain.  

Corrective and Preventive actions required

Based on the potential causes identified earlier following controls need to be established to prevent recurrence of issues like DEG contamination and preventing occurrence of other serious contamination issues –

1.      Vendor Qualification

The ingredients should be sourced only from approved vendor. Sourcing should be done directly from the manufacturer or their authorized distributor.

The vendor qualification should not be restricted to just review of self-assessment questionnaires and the data sheets provided by the vendor but should also include the audit of manufacturing site. The manufacturer as well as the distributor should be covered in vendor qualification process. Apart from reviewing the systems & processes and compliance to them, the audit should focus on understanding the manufacturing process to evaluate adequacy of process controls and specifications to effectively control the quality of the ingredients.

2.      Quality agreement

Quality agreement should be signed with the vendor, clearly defining the terms and conditions, responsibilities and specifications. Responsibility of the vendor should include providing timely information about quality and process related changes to enable evaluation of the impact of those changes on the quality of the material and the drug product.

3.      Incoming material inspection

Indian drug laws require all the raw materials to be used in Pharmaceuticals to be tested to ensure compliance to specifications. The law and rules thereunder however are silent about sampling process. Most companies collect sample from multiple containers selected from total containers, following inhouse developed sampling plans and make pool sample for performing the testing as per specifications which are largely derived based on the Pharmacopoeial monographs. IP and USP monographs for Glycerine and Propylene glycol have prescribed GC method for quantitative determination of Diethylene glycol and Ethylene glycol with limit of not more than 0.1%.

Just relying on testing of pool sample however provide very little assurance. For example, if out of total 10 containers received, company samples 4 containers following commonly used formula of √n+1, remaining 6 containers will not be sampled at all and if one or more of those contain DEG or EG fully or partially, it will go undetected. Similarly, if one of sampled container contain DEG or EG up to 0.3%, the pooled sample will show result below 0.1% and the material will get released. The syrup produced using one contaminated drum will however have higher level of DEG and may result in adverse event.

To address such issues following actions should be implemented in addition to vendor qualification described earlier.

1.      At the time of receipt, it should be verified that the material is received in manufacturer’s original container with manufacturers seal (preferably serialized).

2.      Unless the ingredient is manufactured in a dedicated facility and the systems and processes including labelling process has been validated, each drum should be sampled and subjected to ID test. Since Identification tests for Glycerine and Propylene glycol in USP monograph includes test for DEG and EG, contamination in any drum will get detected. Unfortunately, the test for DEG and EG is not part of Identification test in IP monograph for Glycerine. So apart from ID check on all individual containers, DEG/EG check also needs to be conducted on individual samples.

3.      Rest of the tests may be done on the pooled sample provided consistency in the supply has been assured based on audit of manufacturing facility and results of past shipments. Number of containers which can be pooled together should be based on the sensitivity of the method, limits and the criticality of the test.

4.   Regulatory changes

Many Indian companies, especially those who are doing business in advanced countries have implemented all or some of above-mentioned controls. To ensure that all the Pharma companies operating in India adopt these controls, Indian regulatory agency need to overhaul the antiquated drug laws to incorporate them in the law. The process for review of drug applications needs to be strengthened to identify all possible contaminants and impurities and to ensure that adequate controls are in place to ensure safety of the product. Drug law should also include procedure for controlling changes to approved application to ensure that manufacturer’s do appropriate risk assessment while doing changes to the product and process. It is also necessary to revamp Pharmacovigilance system in India. Most adverse events are not getting reported due to lack of awareness or simple laziness. This may result in failure to detect early warnings. Government should develop PV portal accessible to everyone where, patients and healthcare givers can report any adverse events noticed while using a drug. India currently has very low causality determination rate in most states. Due to this many deaths occurring due to such issues may go unreported and may not get investigated resulting in delay in controlling further damage. Regulations need to make it mandatory to correctly determine the cause of death and recording in national data base. Any abnormal trends should be investigated. Government also need to develop effective recall system in India so that in the event of any serious defect detected in the distributed medicines, further distribution can be quickly stopped there by preventing further damage.    

4.      Consumer awareness

While regulatory measures are crucial, consumer awareness is equally important in mitigating the risk associated with DEG contamination and other serious quality defects. Consumers should be educated and encouraged to report any suspected side effects (adverse events) immediately to the healthcare professionals and also report to Pharmacovigilance cell of manufacturer or government portal. Any abnormal trends should be detected and investigated. AI could be good tool for such signal detection.

Conclusion:

The presence of diethylene glycol contamination in cough syrups and other medications poses a significant threat to public health. The ingestion or absorption of the toxic substance can lead to severe health complications, making it imperative to address this issue effectively. Governments, regulatory bodies, and pharmaceutical manufacturers must work collaboratively to implement stringent quality control measures and raise awareness among consumers. By ensuring the safety and integrity of medications, we can safeguard the well-being of individuals and restore public confidence in these essential medications.

-Ganadhish Kamat