In a global industry like pharmaceuticals, the interdependencies among quality, access, innovation and regulation can have global implications. That message comes through clearly in the 2018 CPhI Annual Report, the compilation of expert forecasts and analyses that the organization puts together. The articles, with their focus on the future direction, technologies, opportunities and threats in pharma, were highlighted at a media session of the CPhI Worldwide in Madrid recently.<\/p>\n
In a global industry like pharmaceuticals, the interdependencies among quality, access, innovation and regulation can have global implications.\u201d<\/em><\/p><\/blockquote>\n
Several of the report\u2019s authors looked at the role of regulators in facilitating (or hindering) innovation and there was also discussion about how innovation in turn affects regulation. When it comes to quality, the themes included the quality of materials, the quality of data and the quality of people.<\/p>\n
Not surprisingly, there were diverse opinions among the authors about the exact nature of the relationships and what is (or should be) driving what. \u00a0Let\u2019s take a look at some of the analyses and predictions:<\/p>\n
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The impact of regulators<\/h3>\n
Girish Malhotra, president at EPCOT International, argued in his strongly worded article that innovation must come from inside the product manufacturing organizations. He expressed confidence that \u201cCompetitive pressures keep companies on their toes for product quality and safety through manufacturing process technology innovations and continuous improvements.\u201d<\/p>\n
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Competitive pressures keep companies on their toes for product quality and safety through manufacturing process technology innovations and continuous improvements.\u201d<\/em>
\n–\u00a0 Girish Malhotra, president at EPCOT International<\/span><\/p><\/blockquote>\n<\/p>\n
However, he warned that in the next few years \u201cwe will lose valuable process advances if regulators don\u2019t stop dictating approaches.\u201d\u00a0 Furthermore, he questioned the motives behind regulatory bodies that make suggestions about manufacturing processes.\u00a0 The author went so far as to say that a regulator\u2019s endorsement or suggestion of the type of processes or methods that should be used \u201cis unethical or is tantamount to favoritism.\u201d
\nAs an example, he pointed out that the U.S. Food and Drug Administration (FDA) seems to be suggesting that investing in continuous processes will lower costs and lead to higher quality.\u00a0 Malhotra argued that while that might be the case, for a new approach to take hold, it must be economically viable. In his view, \u201cContinuous manufacturing in pharmaceuticals is a long way from reality.\u201d<\/p>\nMalhotra did envision, however, that regulators could have a positive impact. The way for regulators to help innovation, he said, is by simplifying drug approval processes. \u00a0He called for regulators to \u201cenable a manufacturing innovation environment by shortening approval time to three months.\u201d That would then allow commercial and financial considerations to dictate innovations, he said.<\/p>\n
When it comes to contract development and manufacturing organizations (CDMOs), Malhotra argued that, \u201cIf given freedom by forward-thinking pharma companies, CDMOs may have the incentives to innovate new process and manufacturing improvements and be a key part of the solution.\u201d<\/p>\n
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\u2018Modernize or close your doors\u2019<\/h3>\n
Emil Ciurczak, of Doramaxx Consulting, had a very different take than Malhotra on continuous manufacturing (CM). From his perspective, \u201cThe question is no longer, \u2018Will continuous manufacturing work?\u2019 but \u2018When will everyone be doing it?\u2019\u201d<\/p>\n
He said that a \u201cconvergence of more advanced equipment, competitive pressures, a wider pool of trained scientists and the backing of regulators will see exponential growth of continuous manufacturing over the next five years.\u201d<\/p>\n
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The question is no longer, \u2018Will continuous manufacturing work?\u2019 but \u2018When will everyone be doing it?\u2019\u201d<\/em>
\n– Emil Ciurczak, of Doramaxx Consulting<\/span><\/p><\/blockquote>\n<\/p>\n
Ciurczak acknowledged in his article that \u201cinitially these may not be optimally economically efficient, but in five years hence these will bring in tremendous economic and business process advantages, including faster and more efficient drug development.\u201d Ultimately he said he expects that companies will see the payoff: Skipping the scale-up step allows the product to come to market faster, by as much as six months.<\/p>\n
Also, he said that companies are forced to take a close look at their production costs because pharma company prices are under pressure. As an example, he pointed out that Pfizer wanted to increase the price of a dozen drugs but had to put that plan on hold after U.S President Donald Trump tweeted: \u201cYou should be ashamed.\u201d<\/p>\n
One of the ways to control and lower costs is to continue to outsource activities, Ciurczak said. \u201cAs the supply chain (everything from raw materials through delivery to pharmacies and hospitals) stretches over thousands of miles and dozens of countries, the crux of the problem can be distilled to one word: Quality.\u201d He noted further:<\/p>\n
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- Thanks to PAT (process analytical technologies), manufacturers have control and a hard copy of data proving they are in control, throughout the process.<\/li>\n
- Guidelines from the International Conference on Harmonisation<\/em> of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH<\/em>), <\/em>the FDA and the European Medicines Authority (EMA) for the calibration, validation and application of spectrometers in pharmaceuticals ensure that \u201cperforming an analysis in Thailand will give the same results as would be seen in Switzerland.\u201d<\/li>\n
- The author envisioned optimistically (or as he himself called it, \u201cblindly optimistically\u201d) that continuous manufacturing can one day help the industry make the same product at every location.<\/li>\n<\/ul>\n
Ciurczak said generics and CMOs will also need to adopt continuous manufacturing to succeed. He sees a huge opportunity for China to be the fastest adopter of CM in the next five years.<\/p>\n
Basically, he summed up his views as: \u201cModernize or close your doors.\u201d<\/p>\n
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Biosimilars to \u2018push bioprocessing forward\u2019<\/h3>\n
Michiel Ultee, from Ulteemit Bioconsulting LLC, looked at advancements in the biopharma space, where therapeutic proteins can be 100 to 1,000 times larger than chemical drug molecules.<\/p>\n
He pointed out that continuous bioprocessing has finally come to the biomanufacturing area.\u00a0 \u201cWhile most bioprocessing is still performed in batch model, both upstream and downstream, most companies are evaluating ways to decrease the batch nature of their processes to streamline them.\u201d\u00a0 He cited competitive pressures as the reason for companies to invest in more efficient bioprocessing, in pursuit of reduced time and costs.<\/p>\n
Advances in new therapeutics such as chimeric antigen receptor (CAR) T-cell therapy and gene therapies have required a different type of bioprocessing than for standard protein therapeutics. In a situation where the cultured cells themselves become the product to treat the patient, it is paramount that any particular cell culture be matched to the patient to avoid immunological rejection. Yet, despite such challenges, \u201cbioprocessors have risen to the occasion to allow production of clinical trial and more recently commercial material for approval for patient treatment of these exciting new therapies.\u201d<\/p>\n
He wrote that the industry is seeing improvements in the manufacturing of biosimilars as well, \u201cthanks to advanced analytical techniques, improved understanding of molecular biology and recombinant technology, and biochemistry of post-translational modifications and protein degradation\u201d.<\/p>\n
He predicted that \u201cBiosimilars and new applications for cellular and gene therapies will continue to push the field of bioprocessing forward.\u201d<\/p>\n
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Lessons to be learned from pharma<\/h3>\n
Kent Payne, CEO of Socorro Pharmaceuticals, pointed out that a shortage in bioprocessing expertise can translate into bottlenecks in the biomanufacturing space.\u00a0 Recruiting managers in biopharma hot spots like Boston and San Francisco find that the supply of talent doesn\u2019t keep up with the need, he said.<\/p>\n
Fortunately, as a recent survey by BioPlan Associates suggests, there are areas where skills could be portable between pharma and biopharma manufacturing. More than 200 professionals participated in the survey, he noted. \u201cUp to a third of respondents clearly indicated openness for importing talent from pharma into biopharma manufacturing to help close hiring gaps,\u201d Payne said.<\/p>\n
Furthermore, the author suggested that there are lessons to be learned from pharma. \u00a0As he pointed out, \u201cBiomanufacturing has been transitioning from an industry in its infancy to one with tailored, sophisticated optimization data and techniques. As processes for biologics manufacturing continue to mature, there are lessons to be learned from their pharma peers to help drive enhanced productivity and quality while simultaneously lowering costs.\u201d<\/p>\n
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As processes for biologics manufacturing continue to mature, there are lessons to be learned from [pharma] to help drive enhanced productivity and quality while simultaneously lowering costs.\u201d<\/em>
\n– Kent Payne, CEO of Socorro Pharmaceuticals<\/span><\/p><\/blockquote>\n<\/p>\n
According to the survey respondents, there are a number of areas where large molecule biomanufacturing could benefit from small molecule pharma manufacturing experience. On top of the list were:<\/p>\n
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- real-time process control<\/li>\n
- scale-up or process development<\/li>\n
- training operators and technicians<\/li>\n
- quality management.<\/li>\n<\/ul>\n
Approximately 30% considered those skills portable, the survey results showed.<\/p>\n
However, the actual practice is somewhat different. While scale-up or process development and quality management came up on top of the list of actual practice, real-time process control and training operators and technicians appeared toward the bottom of the list.<\/p>\n
The author cautioned against drawing too many conclusions from this limited data set, but they did point out that, in an environment where \u201cthe only constant is change,\u201d \u201clearning agility needs to be high on the list of core competencies in recruiting.\u201d<\/p>\n
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Risk-based control via scientific insight<\/h3>\n
In his presentation, Bikash Chatterjee, president and chief scientific officer of Pharmatech Associates, looked at the impact of innovation on regulations. He predicted that \u201cinnovation convergence and science-based approaches will allow for divergent yet integrated regulatory pathways.\u201d<\/p>\n
He added that \u201cThe future will be constructed on science-based regulatory frameworks \u2013 for example, with process validation done for individual patients, not batches.\u201d<\/p>\n
Chatterjee brought up CAR T-cell therapies, as well, and mentioned that these therapies, personalized to an individual, \u201crequired shifting the FDA\u2019s expectation regarding process validation as only one batch is made per patient and each batch is unique to that patient.\u201d<\/p>\n
Chatterjee did point out that \u201cThe regulatory philosophies of the U.S. and Europe are not completely aligned in their approach to fostering innovation while ensuring patient safety.\u201d\u00a0 Nevertheless they \u201cboth have their foundation in a desire for risk-based control derived from scientific insight.\u201d<\/p>\n
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The regulatory philosophies of the U.S. and Europe are not completely aligned in their approach to fostering innovation while ensuring patient safety [but] both have their foundation in a desire for risk-based control derived from scientific insight.\u201d<\/em>
\n– Bikash Chatterjee, president and chief scientific officer of Pharmatech Associates<\/span><\/p><\/blockquote>\n<\/p>\n
Like several other authors, he made some predictions about China. He anticipated that China will be very quickly harmonizing with ICH and that we\u2019ll see poorer quality manufacturers dropping out quickly.<\/p>\n
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Focus on excipients<\/h3>\n
Brian Carlin, director of QbD\/regulatory at DFE Pharma, and co-authors looked at the evolution of regulation when it comes to excipients. In the article, they focused on data integrity, which \u201crefers to the completeness, (logical) consistency and accuracy of data over its lifecycle, and is applicable to both paper and electronic records.\u201d<\/p>\n
According to Carlin and his co-authors, several regulatory agencies \u2013 the FDA, the EMA, the Pharmaceutical Inspection Co-operation Scheme (PIC\/S), the World Health Organization (WHO), Australia\u2019s Therapeutic Goods Administration (TGA) and the Medicines and Healthcare Products Regulatory Agency (MHRA)\u2013 have issued guidance documents in recent years on data integrity. None of them explicitly references excipients, but a PIC\/S draft refers to raw materials, which may cover excipients. WHO guidance references \u201ccontract acceptors\/suppliers from the perspective of pharma, so that can also be interpreted as covering excipients.\u201d<\/p>\n
The guidances differ slightly in approach, but all are tightly connected to the wider regulatory framework covering active pharmaceutical ingredients (APIs) and drug products. Meanwhile, most excipients were not designed for pharma use. Furthermore, pharma usage may be just a small part of the overall usage of the product. So, most excipients are not manufactured under API or drug product cGMPs.<\/p>\n
Carlin emphasized that judgment will be required in the application of specific pharma data integrity requirements to excipients. When it comes to excipients, he added, \u201cQuality culture is perhaps more important than integrity of specific data.\u201d<\/p>\n
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Pessimism around trade agreements<\/h3>\n
Dilip Shah, CEO of Vision Consulting Group and secretary general of the Indian Pharmaceutical Alliance,<\/strong> looked at the impact of regulations and trade agreements on access to medicines.<\/p>\n
He took quite a pessimistic view. He predicted that the new trade agreements \u201cwill delay access to generics.\u201d And he said he sees a \u201cglobal trend towards patent term restoration\/extension.\u201d The net result, he said, \u201cis that patients may need to wait five to 10 years longer for access to generic medicine.\u201d<\/p>\n
Shah said this would significantly increase the overall cost of healthcare in developed and developing countries by as much as $100 billion over the next five years. \u00a0Shah also predicted that these developments will cause reputational damage to the pharma industry, with pharma facing a backlash from government, health activists and wider society which may lead to a \u201cfundamental reform on how companies are reimbursed for innovative medicines.\u201d<\/p>\n
Shah pointed out that the new approach to trade by the U.S. is likely to have an impact on access to medicines. Shah said that he anticipated that \u201cthe barriers to access will grow because of many countries\u2019 reluctance of adding new fronts of conflict with the U.S.\u201d<\/p>\n
Shah also wrote about the Special 301 report, the annual review of the state of intellectual property rights (IPR) protection and enforcement which is conducted by the Office of the United States Trade Representative (USTR). As Shah pointed out, the top priority for the Trump administration is \u201cto use all possible sources of leverage to encourage other countries to open their markets to U.S. exports of goods and services, and provide adequate and effective protection and enforcement of U.S. intellectual property (IP) rights.\u201d<\/p>\n
Among the countries called out in the report were China and India:<\/p>\n
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- China was called out for trade secret theft, online piracy and counterfeiting, as well as tech transfer requirements imposed as a condition to access to the Chinese market.<\/li>\n
- India was cited \u201cfor lack of sufficient measurable improvements to its IP framework.\u201d The report also questioned \u201cwhether India is serious about pursuing pro-innovator and creativity growth policies.\u201d<\/li>\n<\/ul>\n
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For more from CPhI Worldwide,<\/em> see \u201c<\/em><\/strong>Generics companies, responding to tough times, steer towards higher-risk portfolio strategies,\u201d written by Brandon Boyd, industry strategist at Clarivate Analytics<\/em>, a paper on which his CPhI presentation on the same topic was based.<\/strong><\/p>\n
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