The US Food and Drug Administration (USFDA) seems to have sent out a strong message to pharmaceutical companies in India on the need to adhere to a quality culture and on matters relating to data integrity. This was as part of 'Advanced GMP (good Manufacturing Practices' workshops that the US and European regulators conducted across four city of India between November 6th and 17th. Various presentations were made during these but one that needs particular mention is the USFDA paper titled: "Current Trends in Quality and Data Integrity Trends - Is it a Myth or tip of the iceberg?"
As is apparent from the paper, now posted on the website of the Indian Pharmaceutical Alliance, the number of warning letters issued by the Office of Manufacturing Quality of the USFDA to pharmaceutical companies has shot up and this is mainly on account of increase international warning letters (that is those outside of the US). And, in the international warning letters, India and China are two leading countries.
These warning letters used to average around 20 in a year in the calendar years 2013, 2014 and 2015. But these shot up to 43 in calendar year 2016. And so far 2017, seems to be no better, since already 35 warning letters have been issued.
Going by the numbers from this presentation, in 2017, out of about 45 warning letters in all, some 35 were international. In 2015, India accounted for the maximum number of warning letter. There was an improvement for India in 2016 and that year, China and others (those other than US, China and India) accounted for the maximum. However , in 2017, India and China are more or less on par in terms of warning letters received.
The key point therefore is that international account for a significant proportion of all the warning letters issued and while India was less than China in 2016, it is more or less equal in 2017.
What may be disturbing for pharma companies is the summary of the findings that the agency has arrived at based on the recent warning letters. For instance, it points out:
1, Releasing failing product as if it had passed.
2, Testing into compliance (in other words read: you keep on testing till you get a positive result)
3, Not saving electronic or hard copy data that would confirm the failing results (which in a sense implies fabrication)
4, Disabled audit trail feature.
5, Inadequate out of specification investigation.
6, Inadequate CAPAs (Corrective and Preventive Action).
7, Root cause lacking scientific evidence.
As is apparent, the points one to four seem the findings but the rest from points 5 to 7 seem like analysis and remedial action. Next, the most cited observations are also listed with the section numbers also and here, Take two observations for example:
1, section 211.22(d): The responsibilities and procedures applicable to the quality control unit are not in writing or fully followed;
2, section 211.160 (b): Laboratory controls do not include the establishment of scientifically sound and appropriate specifications, standards, sampling plans, and test procedures.
But it is really the pointers on why it feels these happen that need mention. Of the six pointers, two have been highlighted as these attribute the reasons to
1, immature quality culture.
2, Investigation focused on giving any explanation that may work, and not on what caused the problem in order to prevent recurrence and predict outcome.
Last but not the least, there is mention of symptoms and foundation problems. The symptom is that companies may be driven by production goals. One of the foundational problems cited is: 'lacking understanding of science.' Bad behaviour in terms of poor culture quality has also been pointed.
Ask Indian companies on what they think of these and while no one is willing to comment or get quoted, some felt that these are what the USFDA is finding world wide and not just in India.
Others felt these need to be perhaps seen as a warning letters issued based on the conclusions that these might have happened and that it is now for the companies to prove that it has not happened. While some others felt, these are concerns which may not necessarily mean all have them. All were however agreed that these are the expectations of the regulator and companies have no option but to satisfy them and therefore move in the direction of what is expected. Also, some felt it also goes to show that it is not as if US companies are doing any better because the points listed out are for all the warning letters issued by the US regulator.
But at the end of it all, the key point remains that it is important for the US regulator and especially in India. Take one statistic that does the round in the pharma circles is that typically of the total number of ANDA applications that the USFDA receives in a month, about 50 per cent would be from India. In this respect, India is ahead of China, the other important hub for pharmaceuticals.
But that is not to say, it is the only reason. As the presentation pointed out, the big worry is that the cases of non-adherence to some of the quality norms have also increased. There are some recurring citations and there are newer challenges too that need to be kept in mind.
In all, the workshops attracted some 400 odd participants all across four cities - Chandigarh, Ahmedabad, Goa and Hyderabad and these numbers also included some 100 odd domestic regulators, who also took part in these workshops. The goal of the meetings, organized by the Indian Pharmaceutical Alliance, but open to all pharma companies and not just its own members, was to educate people directly involved in various companies in India on issues around gaps in meeting global quality and monitoring requirements.
The regulators present at these workshops were from the US Food and Drug Administration's (US FDA), the UK Medicines and Healthcare Products Regulatory Agency (UK MHRA), the European Medicines Agency (EMA) and off course the India's Central Drugs Standard Control Organisation (CDSCO) and all seem focused on the need to adhere to better quality culture.