India’s aspiration to be the ‘Pharmacy of the World’ is credible, palpable and indispensable. Progress achieved over the past several decades is remarkable. A key determinant of this success is the talent pool in India; which is relatively young and getting younger. The quality of their education, training and experience is an important determinant of the level of assurance in pharma quality that they can and will deliver.
In the current state, inspectional observations particularly by several global regulatory authorities have given a reason for a ‘pause’ – to reflect on how global regulatory expectations for the assurance of pharma quality should be met. Although this challenge is not unique to India; it points to certain ‘blind-spots’ in the current system. Attention to these gaps are in need for urgent attention.
Many products we develop and manufacture today are complex; and complexity is on a rapid rise. This places a higher demand on scientific evidence necessary to assure quality, safety and efficacy (and equivalence) over the lifecycle of these products. Assurance of data integrity is a critical basis for assuring pharma quality. There is a need to bring more attention, and give more importance, to integrity of evidence. Noted CGMP deviations are, perhaps, a ‘blessing in disguise’; learning from these examples, India’s pharma sector can accelerate its progress towards achieving its goals with better accounting of complexity and uncertainty in their systems.
Unless proactive steps are taken, ‘blind-spots’ such as the following can emerge in any rapidly growing business:
(a) human tendency for optimistic business forecasts and expectations (e.g., rate of ‘right first time’),
(b) under-appreciating intrinsic error rates in the system and
(c) not recognising an increasing complexity in pharma quality assurance. Such cognitive biases can put a high burden on achieving rational assure of quality; especially when results, and the not the process for getting to the result, is the primary incentive.
In such situations, staff and managers can be in over our heads1 and vulnerable to irrational decision making2. Other cognitive biases or blind-spots such ‘it is US FDA approved’, and ‘process is validated’ can sometimes provide reasons for rationalising deviations from established and committed (to regulatory authorities) procedures. Gaps that may have existed in an ‘FDA approved’ submission, for example; attitudes such as “file first and figure it out later”3 can leave gaps in development of a commercial manufacturing process which should be stable and in control. After FDA approval, such gaps are not easy to remember4-7. Again, this scenario can manifest anywhere in the world.
Response to the “pause”, induced by the numerous warning letters and import alerts, has varied. Some have questioned this pause. Others have focused on understanding what needs to be understood more clearly and/or more consistently. This paper seeks to support the latter by sharing some insights on how to strengthen education, training and experience4-7. This paper is organised to consolidate these insights in the current context:
a) Recapitulating insights shared previously, 2013 – “Strategies for making high pharma quality affordable”8;
b) Summarise new insights gathered while conducting a training programme entitled “Culture of Pharmaceutical Quality” at many companies located in diverse geographies of India 5-7; and,
c) Consolidate these in a global context utilising experience gained as a teacher, a regulator (at US FDA)4, and a corporate executive.
Recapitulating previous insights
The table lists insights shared in 2013 and provides an update – where are we in 2016. Among these, the growing evidence on the significance of perception factors, and placebo/ nocebo effects, particularly in the US, is remarkable. It makes the case for corporate – name recognition stronger even for companies making generic products.
In the US, the year 2015 marks a ‘tipping point’ for continuous manufacturing12. As discussed in 2013, this potentially sets up a different strategies and path to the coveted title of ‘Pharmacy of the World’8. India’s pharma will need to factor these technological developments into their strategies. Companies with high interest in serving the markets in the US will also need to consider changes outlined in the FDA’s review and inspections approaches; particularly on FDA’s sharper focus on ‘One Quality Voice’ 14.
The efforts proposed by leaders of India’s pharma sector to collaborate, to engage with global regulators, and in committing to ‘quality excellence’11 are commendable. Some of the insights shared here are intended to encourage and contribute to such efforts.
Insights gathered since 2013
Efforts expended to develop and conduct a training programme on ‘Culture of Pharmaceutical Quality’, for several companies with facilities distributed across India5-7, provided valuable insights. The key take-away from this effort is that “confidence (of/in people, in process/system/results, and in the assurance of product quality) is a critical quality attribute”. Understanding the ‘Why’, ‘What’ and ‘How’ of this critical quality attribute is highly variable and this variability needs to be reduced, significantly.
Education, training and experience in the 21st century must develop curricula and approaches to develop talent in terms of technical know-how, communication skills and maturity to adapt with confidence to environments where complexity and uncertainty is high and increasing. As noted in 2005, in the US context4, industrial pharmacy education was and continues to be in need, for a transformation. For example, material science, process design and control, more rigorous mathematical and statistical skill sets, and systems engineering are some of the areas that are in need for additional emphasis. More importantly, attention to developing adaptive-learning skills – to increase orders of consciousness1, design/ system thinking, and leadership development must be a key areas of focus7.
As leaders of India’s pharma sector progress in their efforts on ‘quality excellence’11, it would be useful to consider establishing world class Global Institutes of Pharmaceutical Quality (GIPQ). Given the aspirations of this sector – it is important to take a global perspective with short-, mid-, and long-term goals. In the short – term, the focus should be on developing adaptive-learning skills, design/ system thinking, improving investigations, rigorous risk assessment, seamless continued process verification and other topics relevant to proactive compliance with cGMP. Mid-term focus could be on improving (e.g., standardisation and reducing variability in) the broader educational system and providing more opportunities for effective training and experience in quality by design, process analytical technology, and control strategies. In the long-term, to be a global leader, focus should be on developing institutions that are recognised as important contributors of knowledge and expertise needed to improve regulatory science and policy across the globe.
Increasing complexity and uncertainty places a high demand on knowledge management and correct analysis of prior knowledge. There are significant gaps (e.g., objective quality risk assessment, establishing clinical relevance of quality specifications and pharma material science as it pertains to functionality and process-ability) and pharma science and technology, as a discipline, has much work to do to fill these gaps. The next decade places a high demand for improving pharma ontology and epistemology such that the benefits of quality by design methodology, which is now an important foundation of the global regulatory system, are fully realised15.
Patients and their care givers need to have trust our systems. India’s pharma is already a major global player. It can and must nurture institutions such as the proposed GIPQ to develop knowledge and expertise needed to support the sector and also to inform on ways to improve domestic and global regulatory policies to best meet the needs of patients. The pharma sector is a major part of India’s economy. India already is and will continue to progress as one of the major economies of the world. Let this journey accelerate 16.
1. Kegan, R. In over our heads: The mental demands of modern life.” Harvard University Press, 1995.
2. Kahneman D. Thinking, fast and slow. Macmillan; 2011.
3. Ted Fuhr and Katy George (McKinsey & Co). Moving Beyond the Business Case for QbD. 13 March 2011. http://www.pharmaqbd.com/mckinsey_beyond_business_case_qbd/ (accessed 28 March 2016)
4. Ajaz S. Hussain. The Nation Needs a Comprehensive Pharmaceutical Engineering Education and Research System. Pharmaceutical Technology, September 2005.
5. Ajaz S. Hussain. Culture of Pharmaceutical Quality: Connecting the Dots. Biopharma Asia, September/October 2015.
6. Ajaz S. Hussain. Culture of Pharmaceutical Quality: Quality Management System. Biopharma Asia, November/December 2015.
7. Ajaz S. Hussain. Culture of Pharmaceutical Quality: Personnel Development. Biopharma Asia, March/April 2016.
8. Ajaz S. Hussain. Strategies for making high pharma quality affordable. Express Pharma. 2 November 2013. http://archivepharma.financialexpress.com/sections/
management/2907-strategies-for-making-high-pharma-quality-affordable (accessed 28 March 2016). Peter A. LeWitt, P A., and Kim, S. The pharmacodynamics of placebo: Expectation effects of price as a proxy for efficacy Neurology, ;84:766–767 (2015)
9. US FDA Guidance for Industry: Size, Shape, and Other Physical Attributes of Generic Tablets and Capsules. June 2015.
10. Indian Pharmaceutical Alliance. Quality Excellence: The next frontier for the Indian pharmaceutical industry (2016) http://ipa-india.org/pdf/ipa-report-quality-excellence-2016.pdf (Accessed 28 March 2016).
11. Eric Palmer. Vertex, J&J, GSK, Novartis all working on continuous manufacturing facilities. FDA supports the move as a way to improve quality in manufacturing. Fierce Pharma Manufacturing. February 2015. http://www.fiercepharmamanufacturing.com/story/vertex-jj-gsk-novartis-all-working-continuous-manufacturing-facilities/2015-02-09 . (accessed 28 March 2016).
12. Caroline Chen and Anna Edney. Generic Drugs: As Imports Rise, Regulators Struggle. Bloomberg, Mar 18, 2016. http://www.bloombergview.com/quicktake/generic-drugs . (accessed 28 March 2016).
13. FDA Pharmaceutical Quality Oversight: One Quality Voice. http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM442666.pdf (accessed 28 March 2016).
14. Visioning the Next Decade: NIPTE-FDA Collaboration. NIPTE Seminar at US FDA, 16 March 2016. http://www.slideshare.net/a2zpharmsci/visioning-the-next-decade-niptefda-collaboration (accessed 28 March 2016).
15. Ajaz S. Hussain. A 21st Century Fable about Pharmaceutical Quality and Preventing a Clash of Cultures. LinkedIn Post. Sep 13, 2015. https://www.linkedin.com/pulse/21st-century-fable-pharmaceutical-quality-preventing-hussain-ph-d- (accessed 28 March 2016).