Strategies for making high pharma quality affordable

Ajaz S Hussain

Perception/belif can change efficacy and safety of a drug product via placebo and nocebo effects. It is time to ensure we move towards the same standards of quality for all citizens of the world.

We must improve our ability to identify and correct the cause of human error (in development, technology transfer, and manufacturing, quality control and quality assurance). We also need objective ways to distinguish human error from misconduct early on. I posit that the solution is in incentivising the right human behaviors and for this senior management involvement, understanding and direct support of quality a key to effective solution.

I believe the period 2014 – 2020 is critical for Indian pharma sector to reevaluate, modify, strengthen and effectively execute their business strategies to ensure their ability to grow and succeed in India, US/EU, Asian markets, and rest of the world.

Maximising revenues and profitability in the process of making high quality drug products that patients all over the world can access is an ideal goal for a pharmaceutical company. Several challenges have to be addressed in achieving this goal; understanding what is high quality and how to deliver it reliably is one challenge that we often take for granted.

The recent cluster of US FDA observations of cGMP non-compliance, import alerts and warning letters issued to leading companies in India has come as a surprise to many. The serious implication of these observations and an apparent thread of similarity in these observations across several companies has contributed to making this a topic of frequent discussions and comments in the local and international news and social media. The question – “Is the quality of products available in India different from quality of product exported to the US?” – is often raised in these discussions.

Significant cGMP non-compliance are also observed in the US and elsewhere; yet, somehow, there is a palpable concern – within and outside the Indian pharma sector -that something is different about the current cluster of findings in India. Why may the US FDA observations on cGMP non-compliance in India be different and pose a serious concern?

Other important questions confronting the sector are: How can the impacted companies’ best overcome this challenge? And, what specific steps, if any, should be considered by the sector to ensure that these observations do not hold back progress towards the aspirational goal of being recognised as ‘pharmacy to the world’?

In this article, aimed primarily at an audience in India, I seek to provide an Indian-American and an ex-US FDA leader’s perspective on the current challenges related to cGMP noncompliance. I have selected to do so by answering the four questions described above.

Is the quality of products available in India different from quality of product exported to the US?

The notion of ‘domestic’ and ‘export’ quality has been embedded in the fabric of many developing economies and over time, as these economies grow, these differences are minimised. Growing up in Powai, in the northern part of Mumbai, I can recall many instances within my circle of friends, when someone would often note with pride that a certain item he had acquired was of ‘export’ quality. This notion of ‘domestic’ vs. ‘export’ quality is still prevalent in the Indian economy.

Living abroad (e.g., America) it is not uncommon to receive requests from friends and relative in India to bring for them, on the next visit, certain over the counter drugs and house-hold products because they perceive these products to be ‘more effective’. Similarly, when a relative is in a hospital in India and there is a need to arrange for medications – we often take significant steps to seek out drugs from ‘trusted’ companies and suppliers. These subjective anecdotes suggest that many perceive/believe that quality of drugs available in the US to be superior to those available in India; is this perception/belief fact-based and accurate?

Consider the conclusions of a study, conducted at the Massachusetts Institute of Technology (MIT) published in the Journal of the American Medical Association, March 5, 2008—Vol 299; in which 82 healthy subjects were randomly assigned to two groups, Group 1 received a product which was described as an expensive ($2.50/tablet) drug for reducing pain and Group 2 a product described as a cheap (10 cents/tablet) drug for reducing pain. The two groups were subjected to carefully calibrated electric shock sessions and had to note the pain reduction from the products they received. Subjects in Group 1, who were told they received the expensive drug, experienced a significantly greater pain reduction (p=0.02) than those in Group 2, who were told they received the cheaper drug. However, both groups had received the same placebo (i.e., inert sugar pill) product. sugar pill) product. This study points to certain challenges in general acceptance of generic drugs; now consider generic drug associated with concerns related to their manufacturing and quality.

The Indian and US regulatory requirements for pharmaceutical quality are perceived to be sufficiently different that many companies maintain distinct facilities for these markets; therefore, the quality of products available in these markets must be different in some aspects. How relevant is this difference to patients in terms of clinical efficacy and safety? A complicated question to address when considering that lack of access (e.g., affordability) is a serious risk factor. However, for the growing middle class and the elite – wouldn’t the perceptual difference be sufficient? Perception/belief can change efficacy and safety of a drug product via placebo and nocebo effects. It is time to ensure we move towards the same standards of quality for all citizens of the world.

Why the US FDA observations on cGMP non-compliance in India may be different and pose a serious concern?

A thread of concern regarding ‘data integrity’ runs through many of the recent US FDA observations. This aspect makes the issues at hand more serious – as this brings the intention of impacted companies, and possibly the sector, under a cloud of suspicion.

Many in the Indian pharma sector would agree with my concern that there is a tendency to incentivise behaviors on outcome at the expense of the process of getting to the outcome and this is a potential problem. Organisations that have not strengthened their corporate quality policies and business decision systems would specially be in a vulnerable position and would find it difficult to overcome the suspicion of data integrity.

Although the regulatory requirements in India have all the same elements in what constitutes cGMPs; the expectations and inspectional approaches are different from that of the US FDA. For example, final product testing appears to be considered ‘conclusive’ and the role of procedural documentation is not considered as seriously as in the case of the US regulatory expectations. For most pharma processes the type of quality control testing conducted is primarily for the purpose of verifying that a product is conforming to pre-set specifications when all set procedures have been followed (and documented). For QC testing to be conclusive, in and by itself, it would need to be far more extensive and statistically justified.

The cliché “Where there is smoke there must be a fire?” may be relevant here. I would argue that a segment (which may be a minority segment) in the Indian pharma sector have misunderstood the importance of following set procedures in cGMPs and have rationalised that the product produced is good by virtue of testing conducted. By this mind-set their practices have brought into suspicion the reliability of documentation produced for cGMP compliance. And, data integrity concerns undermine the credibility of testing conducted. Furthermore, considering that judicious compliance with cGMPs brings with it costs that impact manufacturing efficiency – deviations, root cause investigations, batch rejections, etc. Data on manufacturing efficiency at Indian companies will now be suspect; often FDA investigators have casually commented that manufacturing data at some companies in India appears to be “too good to be true”. Now with a cloud of suspicion one should expect more rigorous and frequent inspections with a focus on exposing issues pertaining to data integrity.

How can the impacted companies’ best overcome this challenge?

Remediation of cGMP issues is a difficult and a very expensive challenge. For example, recently in the US several companies (e.g., Novartis, Ben Venue, etc.) opted to shut down some facilities after spending hundreds of millions of dollars on improvement and consulting fees on cGMP remediation. The high profile case of Ranbaxy in India is another example – after many years of cGMP remediation efforts another, newer, plant was recently implicated.

Why is this so?

Clearly the remediation efforts are not getting to the root cause of non-compliance. Then, any corrective and preventive actions taken may only create the illusion that issues have been corrected and their recurrence prevented. To improve root cause investigations in the cGMP environment, we have to go beyond SOPs and checkbox verification of training records. We must improve our ability to identify and correct the cause of human error (in development, technology transfer, and manufacturing, quality control and quality assurance). We also need objective ways to distinguish human error from misconduct early on. I posit that the solution is in incentivising the right human behaviors and for this senior management involvement, understanding and direct support of quality a key to effective solution.

Hiring of a cGMP expert consulting firm from the US will only be effective when their expertise is optimally utilised in the context of company culture and systems. It is essential that the senior management recognise and address potential ‘blind-spots’ in the organisation before embarking on a remediation plan.

Senior management’s understanding of what it takes to deliver high quality, their involvement in quality policy and planning, monitoring, review and incentives they provide are essential elements for success. Working with external experts’ to confirm data integrity is an important step and should occur prior to other improvement efforts to be undertaken. Without this step the quality of data and decisions taken may not be correct. A comprehensive remediation plan that adequately considers – across several functions or departments – the development – technical factors, SOP’s and human factors linked to effective training (preferably in local languages) can then be executed.

On a recent visit to India I had an opportunity to meet several leaders of the pharma sector. In my discussions the point that ‘the product produced is good’ invariably comes up; in part, possibly a means for rationalisation. Does this suggest a ‘blind spot’ that could be holding back many from making tough decisions needed to make the necessary corrections?

Note that with an elaborate pharmacovigilance system and adverse event reporting in countries like the US it is still difficult to identify negative impact of quality issues on patients. This is often due to inadequate reporting, lack of availability of reported data for analysis at the right time and place and the bluntness of available tools to detect a signal from the noise in the available databases. Lack of reports does not mean that issues are not present. Hence, we must take proactive steps as per our current scientific understanding to prevent poor quality products to be released in market.

The heparin contamination tragedy of 2008 in the US where many were injured and some lost their lives was due to a contaminant which was not detectable by quality control tests that had been established at that time. And, the tragedy of repeating cases of diethylene glycol (DEG) contamination of medicinal products is another example of lax or non-compliance with cGMPs; the US Center for Disease Control website reports that over the past 70 years at least 12 occurrences of DEG contamination in oral and topical medications have resulted in at least 450 deaths in developing countries.

What specific steps, if any, should be considered by the sector to ensure that these observations do not hold back progress towards the aspirational goal of being recognised as ‘pharmacy to the world’?

For the Indian pharma sector to claim and maintain the title “pharmacy to the world” a major portion of the sector needs to be successful and not just one or two companies. Leaders of the sector should consider working together in pre-competitive space such as training and education of new entrants, current staff and creating venues for dialog with regulators to improve understanding and to seek out solutions to common challenges.

I recognise that not all of the US FDA requirements may clearly contribute to ensuring the quality, safety and efficacy and sometimes it may appear that GMP is an acronym for Great Mounds of Paper. One must constantly work to improve the system and this is done by working collectively as a scientific community.

US FDA itself continues to improve the system, e.g., the initiatives on Process Analytical Technology and the Pharmaceutical Quality for the 21st Century. It is interesting to note that these initiative were in response to warning letters and consent decrees in the US. Fourteen years later the cycle seems to repeat but now in India.

Where are we today with these initiatives?

Reflecting back to the November 28, 2001 meeting of the US FDA’s Advisory Committee for Pharmaceutical Science where I had articulated “Vision 2020 – I can see clearly now” for the PAT Initiative: (1) Quality & performance by design + Continuous “real time” monitoring of quality, (2) Specifications based on mechanistic understanding of how formulation and process factors impact product performance, (3) High efficiency and capacity utilisation, and (4) “Real time” review and inspection from Rockville, White Oak, NJDO, etc.

Today, with the active encouragement of the US FDA, there is visible progress in the area of continuous monitoring and manufacturing of pharma API’s and products in an integrated manner – a potential shift in paradigm in the making. Companies such as Novartis and others in Europe and the US have progressed this concept beyond pilot scale and are planning commercial facilities by 2015. They have taken a different path for making high quality affordable and by this laid a foundation for a different platform to reclaim the title – “pharmacy to the world.”

I believe the period 2014 – 2020 is critical for Indian pharma sector to reevaluate, modify, strengthen and effectively execute their business strategies to ensure their ability to grow and succeed in India, the US/EU, Asian markets, and rest of the world.

Increasingly patients across the globe will ask the question “who makes the drug I take”; and trust and credibility will be critical. Let’s hope the strategy that reliably makes high quality affordable wins!