By Jerry Chapman, Editor-In-Chief at Xavier Health, and GMP Quality Expert
What happens when a company submitting a marketing application for a drug is located in a country with an unstable and hostile environment, but an inspection of the manufacturing facility needs to take place to approve the application?
Some least developed countries (LDCs) with tenuous political environments have emerged as drug manufacturers exporting to Western nations. Although there may be government-issued travel advisories cautioning against visiting these countries, their factories still need to be inspected to ensure adherence to good manufacturing practice (GMP).
Conducting an inspection in a dangerous LDC was discussed by UK Medicines and Healthcare products Regulatory Agency (MHRA) Senior GMDP inspector Tracy Moore in a presentation at an FDA/PharmaLink Conference at Xavier University in March. The conference is part of a series of drug,medical device, and artificial intelligence (AI) conferences sponsored annually by Xavier Health.
Moore described how her team needed to travel to Bangladesh – an LDC located in the Indian subcontinent – for a manufacturing facility inspection, and what it was required to do prior to the trip.
Consult the Security Experts
The first step before going to an LDC is to seek expert travel advice, Moore explained. Current advice on travel to Bangladesh supplied by the British government includes the following:
“In Bangladesh, protests and demonstrations can quickly turn violent and lead to clashes with law enforcement agencies. In cases of political unrest, incidents of arson, violence and vandalism can suddenly break out across the country, mainly in towns and cities. Be vigilant at all times. If you see a demonstration developing, or are in a situation in which you feel unsafe, move away to a place of safety.”
In addition to the British government travel advice, Moore said that several subscription services are consulted.
One well-known service is Intelligent Protection International Limited. Its recent advice on travel to Bangladesh assessed the threat level as “Medium-High.” The report includes details on suicide bombings at the Dhaka international airport on March 17 and March 24 – right after the PharmaLink conference where Moore spoke.
Measures Taken To Ensure Safety of the Inspectors
To travel to Bangladesh, Moore explained, “You must have certain training and other things. The travel advice I had from the insurance intelligence analysts included things like, ‘you must go through a HEAT [Hazardous Environment Awareness Training] course, and you must have close protection officers with you’ because the risk is that high.” A close protection officer is also known as a personal body guard.
The overall objective of a HEAT course is to prepare participants to understand and react to safety and security incidents in hostile or hazardous environments, including worst-case scenarios. Classroom discussion is generally complemented by simulations of real-life situations.
Moore also explained that without undergoing the HEAT training and consenting to having bodyguards accompany the inspectors, that the inspectors would not have been able to obtain travel insurance.
“From an insurance perspective, had we not had it, had we not had the training, we would not have been assured of repatriation,” she said.
Without the insurance, “If something had happened, I would then be scrambling around trying to get my inspectors out,” Moore explained. “I take my role as a manager very seriously. In the UK I have a requirement by law – a duty of care. If I am being told by experts that is what is required, whether I think it is or not, I am going to follow that advice.”
An alternative to going to Bangladesh was the possibility of doing a “desktop inspection.” Moore pointed out that “the way the European framework works is that you can only do that once. You have to then physically inspect on the second occasion. Facilities in Bangladesh are actually so far removed from us that it is hard to keep your finger on that pulse” without visiting the facilities.
The Bangladesh Supply and Inspection Landscape
Moore noted that Bangladesh supplies “quite a large volume” of generics drugs to the EU, “so they are critical vendors just based on volume.” The EU is the largest export destination for products manufactured in Bangladesh.
Only two drug products from Bangladesh are marketed in the US, both by Beximco Pharmaceuticals Limited – Sotalol Hydrochloride, a generic version of the cardiovascular drug Betapace, and Carvedilol, a generic version of blood pressure medication Coreg.
A search of European Medicines Agency (EMA) and US FDA inspection databases shows how few drug GMP inspections have physically taken place in Bangladesh.
The EudraGMDP database only includes data on inspections for which a Non-Compliance Report (NCR) was issued. The database shows only one NCR issued in Bangladesh. It was given to Acme Laboratories in Dhaka in December 2017 by inspecting agency MHRA. EMA has issued thirteen GMP Certificates to firms in that country.
The FDA inspections database shows that only two drug GMP inspections have taken place in Bangladesh, of Beximco Pharmaceuticals and Square Pharmaceuticals, both in January 2015. Each was classified No Action Indicated (NAI). On the food side, FDA’s Center for Food Safety and Applied Nutrition conducted 30 inspections in Bangladesh from 2009 to 2015.
The World Trade Organization as an Enabler
The World Trade Organization (WTO) extension of a medicine patent waiver is enabling the development of a strong manufacturing base in Bangladesh. This was done to promote public health by fostering better access to medicines at reduced cost for the people of Bangladesh.
In November 2015, the WTO Trade-Related Aspects of Intellectual Property Rights (TRIPS) Council granted LDCs an exemption until 2033 from obligations to implement patents and data protection for pharmaceutical products. This effectively allows the pharma industry in those countries to disregard patents on medicines filed in other countries.
According to the WTO, there are 257 registered pharmaceutical companies in Bangladesh, 194 of which are in operation. The industry manufactures about 5,600 brands of medicines in different dosage forms.