The high cost of compromise: Why patient safety must come first

It’s a very sad situation in India today in the pharmaceutical world. I have been quoting in my several talks globally, about our “Pharmacy of The World” very proudly. But there is a dent in the last few years due to Diethylene Glycol (DEG) and Ethylene Glycol (EG) issues causing several deaths. In the era of Pharma 4.0, such incidences are very painful.

Global history of DEG / EG contamination issues in syrups

• 1937 in USA – 100 died after taking Sulphanilamide Elixir

• 1969 in South Africa – 47 children died.

• 1990 in Nigeria and again in 2008 – 84 died.

• 1990 and 1992 in Bangladesh – 236 died.

• 1992 in Argentina – 29 died.

• 1996 in Haiti – 75 died.

• 2007 in Panama – more than 400 died.

• 2022 in Gambia – 69 children, and in Uzbekistan – 18 children died (products supplied by Indian companies).

In India

• 1972, Chennai – 15 children died

• 1986, Mumbai (JJ Hospital) – 14 patients died

• 1988, Bihar – 13 died

• 1988, Gurgaon – 33 children died

• 2019, Jammu (Ramnagar) – 12 children died

After the 1986 Mumbai incidence and the Lentin Commission’s serious remarks for a major overhaul, now 38 years later, a similar situation arises in India again. In Madhya Pradesh, 23 died of toxic DEG contamination. This was manufactured by Srisen Pharmaceuticals – Tamil Nadu. We haven’t learnt from history even after 38 years of issues of DEG/EG contamination in cough syrups.

Deaths of children in Rajasthan and Madhya Pradesh due to contaminated Coldrif cough syrup expose serious issues in Indian pharma companies manufacturing such cough syrups. A DEG content of 48.6 per cent in syrup meant for common cold reflects serious quality issues.

How is diethylene glycol harmful?

Diethylene glycol is an industrial solvent used in antifreeze, brake fluids, plastics, and other industrial products and is not approved for pharma use in significant amounts.

Why does this happen again and again?

• Is it due to improper checks by manufacturers of Glycerine/Propylene Glycol/Sorbitol and the manufacturers of liquid syrups, in manufacturing and quality checks, cross contaminations, packaging containers, facility issues, water systems etc.?

• Are such suppliers inspected by end-user companies/regulatory agencies and how often?

• Is it that the suppliers are using contaminated drums, without proper cleaning procedures (earlier used for DEG/EG), in packaging of Glycerine/Propylene Glycol/Sorbitol and sent to end-user companies?

• Is it laxity by Quality Operations at supplier and end-user companies?

• Is it that quality analysts are not trained properly?

• Is it due to lack of facility to test by Gas Chromatograph?

• Is there a pressure on public testing labs?

• Is the right testing SOP implemented?

• Is it due to internal pressures to meet the targets?

• Is it due to lack of internal/external inspections?

• Is it that top management is not serious about product quality and safety of patients?

• Is there something beyond this?

Such questions keep coming to our minds often. It’s important to note here that in the US such a situation did not recur again after the 1937 Sulphanilamide syrup. Why? What did the US FDA and US manufacturers do?

Very strict actions and responsibilities were placed on manufacturers in 1938, to share evidences of safety of new drugs before marketing and to comply with CGMP norms strictly, in addition to proper labelling. Later, they continued further improvements in various regulations and had continuous, strict and serious inspections ensuring CGMP.

The deaths of children in Rajasthan and Madhya Pradesh from contaminated “Coldrif” cough syrup show serious problems in how some Indian pharma companies make their medicines. Finding 48.6 per cent diethylene glycol (DEG) in a cough syrup is a clear sign of poor quality control.

Basically, Revised Schedule M – Good Manufacturing Practices (GMP) is implemented to prevent such contaminations in the finished products. The Indian Pharmacopoeia monographs mandate rigorous testing of raw materials and finished product analysis in addition to in-house in-process quality checks, before release of the finished products to the market, for the quality and safety of patients.

Following the crisis, other cough syrups were also flagged for higher-than-permissible limits of DEG, including Respifresh (1.3 per cent DEG) and Relife (0.6 per cent DEG).

As per news reports, the Srisen factory has been operational for almost 14 years. TN inspectors observed rusty, cracked and leaking equipment with high risk of contamination, improper QC testing, improper facility etc. DCGI/CDSCO said manufacturers had failed to comply with Rule 74(c)/78(c)(ii) of Drug Rules, which require every batch of both raw materials and finished formulations to be tested for quality either in-house or at an approved lab. It has been observed that several companies were not testing every batch of raw materials and active ingredients before using them to make medicines.

So then what needs to be done?

By pharma industry

• Enhanced raw material and excipient controls

• Strengthening supplier qualifications and risk-based inspections

• Unannounced on-site audits of high-risk suppliers to verify compliance with Revised Schedule M and Good Distribution Practices (GDP)

• Quality agreements with every key supplier detailing quality standards, change control, and notification requirements for any manufacturing process changes

• Testing each drum of Glycerine IP, Propylene Glycol IP, Sorbitol IP supply for absence of DEG/EG by GC method, and if present, ensure it is within limits

• Quality culture and quality mindset to be topmost priority

• Top management responsible to ensure quality of products and safety of patients

• Quality team must have freedom to take decisions and report to top management

• Focus on training, training and training

• Transparency and fearless reporting of quality compliance issues to the top is a must

• Management must provide adequate resources wherever required

• Validation/data integrity policies must be very clear

• Compliance to Revised Schedule M is a must without any excuses

I remember, during my Pfizer days, we gave our SS-316 drums to the supplier along with our officer in a truck. The supplier used our drums to supply Glycerine after verifying the test reports and inspection by our officer. The same drums were loaded in our truck and sent to our site. This procedure was initiated as a part of a proactive approach from safety perspectives much before the JJ Hospital issue in Mumbai.

By regulatory agencies

• Ensure adequate resources are available for periodical inspections. Risk-based inspection concept is already implemented but due to inadequate staff, timely inspections of 10,000+ companies in India are not possible. Hence adequate resources are a must.

• Identify proactively, risks of having such and similar issues in future. Necessary guideline in Revised Schedule M to have the zero-defect concept to be considered.

• CDSCO has already directed all State and UT drug controllers to intensify inspections of liquid manufacturers, ensure manufacturers test every batch before release and verify that raw materials are sourced from only approved and reliable vendors.

• Consider harsher penalties for serious quality and data integrity violations, including significant fines, seizure of assets and criminal prosecution of responsible corporate officers.

• Recently, the West Bengal Health Dept. has issued an advisory to pharma companies in the state to:

  — Ensure purchases of Glycerine IP, Propylene Glycol IP, Sorbitol IP from authorised sources only.

  — Recheck the above three liquids for presence of DEG/EG, if any.

  — Submit such analytical testing reports to licensing authorities.
  Similar procedures may be implemented all over India.

By pharmacies

• To sell prescription products only with doctor’s prescriptions.

Since the last few years, the USFDA is educating the pharma industry to have a patient-centric approach during development, manufacturing and testing of products in the interest of patient safety. This is a step moving towards “Quality Management Maturity.”

Both the pharma industry and regulatory bodies must take comprehensive and collaborative actions to prevent future issues like toxic contamination, ensuring the safety and integrity of the global medicine supply. The Lentin Commission Report of 1988 may be useful for regulators as well as the pharma industry.

Quality cannot be compromised at any cost.

Joint efforts by the pharma industry and regulatory agencies will help tremendously to sustain the credibility of ‘Pharmacy of the world’ globally and ensure the safety of patients. I am very positive about the expected outcomes and learnings from such incidences.

To be proactive rather than reactive is the need of the hour by all stakeholders in the interest of patient safety. No doubt business is important — but not at the cost of patient safety.