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Strategies for making high pharmaceutical quality affordable: Part II

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Dr Ajaz S Hussain, Former Deputy Director Office of Pharmaceutical Science, US FDA, currently Founder of Insight, Advice & Solutions, US and President, National Institute for Pharmaceutical Technology and Education (NIPTE), US, gives an Indian-American and an ex-USFDA leader’s perspective on the current challenges related to cGMP non-compliance and quality of generic drug applications. He urges academia all over the world to work toward a reform of pharmaceutical science and  technology education and develop a meaningful certification process for the 21st century

Dr Ajaz S Hussain

Generic drugs are the most effective means to enhance the affordability of medicines in the US. The Hatch-Waxman Amendments to the FD&C Act achieved a sustainable way to ensure generic drugs would be available immediately following statutory patent protection, and marketing exclusivity for new (or brand) drugs had expired. The affordability (public health) objective was balanced with innovation (public health) objective by providing new (or brand name) drug manufacturers a significant statuary patent protection and a period of marketing exclusivity so that the investment in the development new drugs is recovered.

In 2016, the faculty of National Institute of Pharmaceutical Technology (NIPTE) deliberated within and with the US FDA on how to confidently ensure availability of First generic. Also, the collaboration between Sun Academy and NIPTE on Quality by Design Education and Certification was progressed (1).

In this report, which builds on Part I published in Express Pharma November 1-15, 2013 (2), I wish to share with the target audience in India what NIPTE (a not-for-profit collaboration among 17 top US University) aims to contribute. Specifically, about New Prior Knowledge (note the oxymoron is by design) and Education with Certification. However, before doing so, I wish to position this discussion in a broader context particularly the on-going discussion in India triggered by Prime Minster Modi ji’s proposal to progress a legal framework which essentially seeks to create an automatic substitution mechanism for generic drugs in India (as in the US).

Generic substitution in India and the question- Who makes the drug?

“We will bring in a legal framework by which if a doctor writes a prescription, he has to write in it that it will be enough for patients to buy generic medicine and he need not buy any other medicine,” he [Prime Minister Modi ji] said. Various news reports, April 17, 2017.

The ensuing debate in India has just begun. Among the many nuances in this debate, one of the most prominent is the adequacy of regulatory mechanism, and the obligation of Indian physicians to be assured of the quality; and to gain this confidence why they perceive a need to rely on the ‘reputation’ of companies they believe are committed to quality.  Unfortunately, perceptions of quality are not factual true assurance of quality.

In principle, this need for assurance was the concluding statement of my 2013 (Part I) report (2): 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! Déjà vu.

Back to a discussion on the US context: What does the nation need?

About 40 per cent of the generic drugs on the US market are imported from India. Over the past few years significant violations of US cGMPs have been noted at many companies in India. These violations are clear indication to the US consumer that companies are failing to deliver the committed the level of quality assurance.

In 2013, Janet Woodcock’s (Director CDER/USFDA) testimony to the US Congress entitled FDA Check Up: Drug Development and Manufacturing Challenges outlined the problem and proposed a strategy.(3)

Problem: Use of foreign-sourced materials creates vulnerabilities in the US drug supply.

Solution: FDA has been working diligently for over a decade, in collaboration with the pharmaceutical industry, to improve drug manufacturing [she was referring to PAT and QbD]. Building on this foundation, and utilising new technologies, groundbreaking new manufacturing methods are within reach [she was referring to PAT-based real-time controls and continuous manufacturing]. These new ways of making drugs could, with the proper strategies, revitalise pharma manufacturing in the US.

On January 28, 2016, Woodcock gave her testimony to the US Congress on the Implementation of the Generic Drug User Fee Amendments of 2012 (GDUFA) (4). In it, she (again) highlighted four ongoing challenges. The two challenges most relevant to this discussion include: (i) Quality of the ANDA submissions, and (ii) Need to better  assure quality in an increasingly globalised industry. The sustained expression of (her) concern about the quality of generic drugs and its assurance is one of the highest regulatory priorities in the US.

Where are we today with these [PAT and QbD] initiatives?

In part I of this report (2013) I had noted – Today, with the active encouragement of the US FDA, there is visible progress in continuous monitoring and manufacturing of pharma API’s and products in an integrated manner. A potential shift in paradigm in the making.

Where are we today (in 2017)? At the tipping point!

Today there is an unprecedented juxtaposition of the main forces, necessary for a domestic [US] pharma manufacturing renaissance: President Trump’s focus on US manufacturing, the progress in pharma technologies such as continuous manufacturing and real-time controls, and legislative recognition of the need for efficient pharma manufacturing as in the 21st Century Cures Act. Let us not underestimate how exceptional this celestial alignment can be for efficiently catalyzing technologically modern, efficient, and profitable pharma manufacturing in the US (5).

A global stance: Let strategy, that reliably makes high-quality affordable medicines, win

At NIPTE, we are passionate about making high-quality affordable medicines for all in need. We  take a comprehensive approach. As we pursue developing our programmes, we are building and supporting international efforts. This includes the recognition of the critical contribution India pharma makes.

For example, on the topic of continuous manufacturing, I hope to meet many readers of this report in Mumbai at the USP Pharmaceutical Continuous Manufacturing (PCM)—Technology Development and Implementation Workshop (May 16-17 2017) to further discuss the latest development. Although this is not directly an NIPTE effort, it is an effort supported by NIPTE via my participation to facilitate faculty members from University of Rutgers (a NIPTE member) and USP to share exciting information about latest technological development with audience in India.

How can NIPTE help to improve quality of ANDA submissions?

New Prior Knowledge: Multiple review cycles and increasing number of Complete Response Letters is a growing concern, not getting it right (the first time) is a symptom. Inadequate time and inability to utilize prior knowledge, in a regulatory system incentivised (rightly so) for ‘file first,’ leads to ‘file first and figure it out later.’ Effective solutions (while maintaining the ‘file first’ to get the ‘first generic’ on time) requires the availability of usable ‘prior knowledge.’ The NIPTE New Prior Knowledge programme is being developed as a solution to what the nation needs now. Several NIPTE faculty members have begun working to develop this solution. In my report entitled NIPTE 2016: From Roadblocks to Roadmap- 2017, with a 2020 Vision (1) the concept is explained using case examples. The idea of NIPTE Certification (of the prior knowledge) is conceived as the built-in peer review, challenge, and verification that a multi-university collaboration can muster as part of the translational (research to policy to practice) process. Such certification may take the form of NIPTE Monographs (e.g., Quality Target Product Profile based on analytical characterisation of RLD) that can supplement Compendial monographs.

Education and certification: What is the predominant mode of acquiring knowledge about aspects of pharma development and process validation in the regulated industry context, designing effective investigation plans for out of specification observations, establishing QTTP and product specifications, writing SOPs, understanding the correct applicability of pharmacopeias for batch release test, etc.? With very few exceptions, current academic programmes such as pharmacy, pharmaceutics and industrial pharmacy, etc., do not adequately address this need. On-the-job training and experiential or adaptive knowledge acquisition are highly variable. “Experience” is predominantly measured as years on the job; which I propose is not a reliable metric.  Therefore, it is expected that there will be considerable heterogeneity in observing, recording, and interpreting cGMP inspection observation; between regulators within the same agency, between regulatory authorities, and, of course, by and within companies. Similarly, there is marked heterogeneity is how we set specification and understand and use pharmacopeias. Education and continuing education programme with meaningful certification (for student, industry and regulatory staff) are urgently needed (6). The Sun Academy – NIPTE collaboration is one such effort many such efforts are needed (1).

Academia needs to step up: Be the third leg of the stool (1)

I wish to conclude this report with a message to the academic communities all over the world. That message is that the gap in what students learn in schools and what they need at work has already become too large. We must catch up and work toward a reform of pharma science and technology education and develop a meaningful certification process for the 21st century.

The debate on generic drugs triggered by Prime Minster Modi ji touches upon how automatic substitution without adequate assurance makes people feel; it is personal and profound. In the US, we still have these debates – today the difference is we want to know which company in India makes the medicine we take.

To academicians who will read this – Let us remember how patients think and feel can have a significant impact on the therapeutic outcome.  In preparing the next generation of medicine makers let us work together to find ways to also teach them how they can (activate their mirror neurons) feel the pain of  compromised assurance. Assurance is a critical quality attribute with direct impact on safety (nocebo effect) and efficacy (placebo effect).

Our families and we need the medicines they will make. Let us secure the assurance fellow humans need and deserve.

1. Hussain, A. S. NIPTE 2016: From Roadblocks to Roadmap- 2017, with a 2020 Vision.  20 December 2016
2. Hussain, A. S.  Strategies for Making High Pharmaceutical Quality Affordable. Express Pharma November 16-30, 2013. (Vol 9, No 1, pages 28-30)
3. Woodcock, J. FDA Check Up: Drug Development and Manufacturing Challenges. Subcommittee on Energy Policy, Health Care and Entitlements Committee on Oversight and Government Reform U.S. House of Representatives. 12 December 2013.  
4. Woodcock, J. Implementation of the Generic Drug User Fee Amendments of 2012 (GDUFA) – House Testimony. February 4, 2016.
5. Hussain, S. A., Gurvich, V. and Pitts, P. How Trump and the FDA Can Create a Pharmaceutical Manufacturing Renaissance. Op-Ed. Morning Consult. 10 April 2017.
6. Hussain, A. S. Pharmaceutical Quality Assurance in the 21st Century: A sharper focus needed on education, training, and experience. Express Pharma. (Vol 11, No 4: pages 20-21). May 16-31, 2016

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