One of the main themes to emerge in the CPhI Insights Annual Industry Report is that the pharmaceutical industry needs an evolutionary approach to remain sustainable in the longer term and open up access to drugs to more of the world’s population. Girish Malhotra, President of EPCOT International, argues that for too long the industry has relied on selling its drugs entirely to the developed world and has not focused actively on delivering process innovations that would bring cost savings and increased profits, while opening up new markets in the developing world.
Quality by Analysis stifles innovation and creates ripples of inefficiency in other business areas
He calls for a move away from the current regulation-centric approach towards a more process-centric approach through the adoption of Quality by Design (QbD) rather than Quality by Analysis, which he claims is the cause of innovation paralysis in manufacturing technologies and business practice. ‘This “Analysis Paralysis” approach is already inefficient,’ he says. ‘It stifles innovation and creates ripples of inefficiency in other business areas, including how we manage our supply chains and use capital equipment and other assets.’
Malhotra believes a process-centric approach needs to be embedded within the manufacturing and development process from concept to commercialisation, as this would provide an environment where new innovations are encouraged.
The shift to a process-centric model such as QbD would, he says, achieve global revenue savings of 20–25% and increase the pharma customer base by 20–30%, making pharmaceuticals accessible to 70% of the global population. ‘Shifting away from the Quality by Analysis method is vital for the future survival of pharma companies, although the industry is yet to begin the transition,’ he claims.
In the view of Dilip Shah, CEO at Vision Consulting, strong intellectual property rights (IPR) are a major factor in preventing new technologies from disseminating to less developed and developing countries despite the TRIPS agreement. Initially a tool to encourage innovation, IPR is now stifling it by creating ‘legal monopolies’ globally, and there is a danger that without change, over the next five years, pharmaceuticals will continue to increase in price but show only limited increases in efficacy.
The contention that stronger intellectual property rights have a uniformly positive impact on innovation lacks evidence
Distinctions must be made between developed, developing and less developed countries, acknowledging that the global optimal level of IPR protection requires international co-ordination, not harmonisation. Reducing onerous IPR requirements in developing economies – challenges that developed economies did not have to face at a similar stage in their development, Dilip Shah argues – can increase innovation.
‘The contention that stronger intellectual property rights have a uniformly positive impact on innovation lacks evidence,’ he says. ‘In terms of welfare, especially for health and pharmaceuticals, it is an unambiguous finding that greater IPR protection will be seriously detrimental to consumers.’
New technologies that put the emphasis on green chemistry will reduce costs and improve current manufacturing processes and environmental impact
According to Vijay Shah, Executive Director and Chief Operating Officer of Piramal Enterprises, new technologies that put the emphasis on green chemistry will reduce costs and improve current manufacturing processes and environmental impact. Mainly due to the increased complexity of the chemistry involved, the pharma industry has a relatively high ‘E-factor’ (kg of waste produced per kg of product) and therefore stands to benefit from green chemistry more than other peer industry segments; as a result it has many more initiatives focused on developing sustainable processes, he says.
He envisages a new global standard, ‘Green Chemistry by Design’ (GcbD), which he believes should be ingrained within the R&D stage and could ultimately save the industry $65bn by 2020 if fully implemented across the board. ‘Already we are seeing Big Pharma looking increasingly to explore greener ways of working and the manufacturing process is a natural progression of this trend. Technologies such as catalysis, flow chemistry, and parallel screening are revolutionising process research by creating efficiencies and cost savings.’
Developing an effective QbD initiative has to be a bottoms-up approach. We have to create a cadre of researchers and students fully equipped with all the tools to implement QbD
Prabir Basu, Consultant, Pharma Manufacturing, supports the idea of replacing Quality by Inspection by QbD, and calls on the pharma industry to learn actively from other sectors. In the absence of a true Pharmaceutical Engineering discipline, he suggests that QbD in pharma manufacturing should be taught in universities by mechanical/chemical engineering departments, who are familiar and experienced in teaching manufacturing design, manufacturing operations and manufacturing quality. Pharmaceutical manufacturing should no longer be treated just as an extension of pharmaceutical development.
‘I have great doubts whether our pharmaceutical science departments are even qualified to teach the basics of QbD,’ he states. ‘QbD can be taught much more effectively by engineering disciplines, which have established programmes in manufacturing.
‘Developing an effective QbD initiative has to be a bottoms-up approach. We have to create a cadre of researchers and students fully equipped with all the tools to implement QbD.’
Academia and the regulatory agencies will play a bigger part in breaking ground with new techniques as well as developing new chemical entities for the drug companies
Emil Ciurczak, President at Doramaxx Consulting, believes that in the future there will be a broader educational mix within the industry, with the production team including engineers, materials scientists, spectroscopists, physical chemists, statisticians and chemo-metricians. Academia and the regulatory agencies will play a bigger part in breaking ground with new techniques as well as developing new chemical entities for the drug companies, he suggests.
Another advocate of QbD, Ciurczak suggests that the industry will move to real-time release with no need for end product testing in a QC lab. ‘As computers get faster and memory less expensive, instruments can generate larger spectra and have them rapidly generate data. This will lead to the ability to – eventually – analyse every single dosage form… in real time,’ he says.
Another benefit of QbD is that, in combination with process analytical technology, it allows designer experiments to be alterable during a run, making developmental changes far quicker to implement.
As QbD becomes more widely adopted, new excipients will finally start coming onto the market
As QbD becomes more widely adopted, new excipients will finally start coming onto the market, predicts Brian Carlin, Director Open Innovation at FMC. Only three new chemical entity excipients have been launched in the last two decades, he says, attributing this to pharma being risk adverse to excipient development. However, increasing use of continuous manufacturing and the rising Cost of Poor Quality (COPQ) means that more co-processed excipients in particular are likely to be developed in the future.
With regulators starting to use quality metrics and categorising applicants in terms of risk, COPQ is set to rise substantially, he warns. One major step in the right direction has been the United States Pharmacopoeia and its efforts to facilitate the monography of co-processed excipients by publishing guidance on their development.
Increasing price pressures being experienced by API producers worldwide will, if not addressed, result in a rise in GMP issues and threaten patient safety
During the last decade the business landscape for API manufacturing has changed drastically, says Hendrik Baumann, CEO at Arevipharma. While significant price erosion has taken place, regulatory requirements have increased. He fears that increasing price pressures being experienced by API producers worldwide will, if not addressed, result in a rise in GMP issues and threaten patient safety.
He believes that we are at the start of a split within the contract services sector that will ultimately lead to European API producers concentrating on flexible delivery across multipurpose plants, with Asian companies concentrating on single use facilities for low cost commodity type production. ‘Professional operation of multipurpose plants is the “Champions League” in chemistry, requiring an in depth knowledge, experience and safety understanding,’ he says.
Lukas Utiger, President, DPx Fine Chemicals, also expresses concern that there is currently an imbalance between supply and demand of manufacturing capability, especially in API contract manufacturing, which is resulting in unsustainable price pressure.
For the industry to survive there will need to be more consolidation and integration of services across larger CDMO players, with Utiger predicting increased strategic partnerships between pharma and key CDMO providers. ‘Ultimately, this will result in several CDMOs having more than 10% of drug product and substance market chain in as little as three years’ time,’ he says.
Ultimately regulators are not the answer to underlying issues of poor practices within the development supply chain of drugs
Hedley Rees, Managing Director at PharmaFlow, foresees a continuation of the slow progress that has so far blighted government and regulatory proposals to tighten the commercial supply chain. However, he argues that ultimately regulators are not the answer to underlying issues of poor practices within the development supply chain of drugs and the industry will realise that QbD is about engaging with end-users and involving stakeholders that have historically been held at arm’s length.
‘Fundamentally, the industry should treat supply chain management within drug development with the respect it deserves,’ he urges. ‘The entire route to market should be mapped, not just the the preclinical and Phase I stages. All relevant players should be included in the programme management effort, from concept initiation.’
Another major problem within pharma development, Rees suggests, is that many biotechs and virtual companies are looking for an exit part way through development, while larger companies are only looking to develop proven products. This results in a severe ‘commitment dilution’ that is slowing down and hindering innovation, he claims.
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