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.
In a global industry like pharmaceuticals, the interdependencies among quality, access, innovation and regulation can have global implications.”
Several of the report’s 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.
Not surprisingly, there were diverse opinions among the authors about the exact nature of the relationships and what is (or should be) driving what. Let’s take a look at some of the analyses and predictions:
The impact of regulators
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 “Competitive pressures keep companies on their toes for product quality and safety through manufacturing process technology innovations and continuous improvements.”
Competitive pressures keep companies on their toes for product quality and safety through manufacturing process technology innovations and continuous improvements.”
– Girish Malhotra, president at EPCOT International
However, he warned that in the next few years “we will lose valuable process advances if regulators don’t stop dictating approaches.” Furthermore, he questioned the motives behind regulatory bodies that make suggestions about manufacturing processes. The author went so far as to say that a regulator’s endorsement or suggestion of the type of processes or methods that should be used “is unethical or is tantamount to favoritism.”
As 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. Malhotra argued that while that might be the case, for a new approach to take hold, it must be economically viable. In his view, “Continuous manufacturing in pharmaceuticals is a long way from reality.”
Malhotra 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. He called for regulators to “enable a manufacturing innovation environment by shortening approval time to three months.” That would then allow commercial and financial considerations to dictate innovations, he said.
When it comes to contract development and manufacturing organizations (CDMOs), Malhotra argued that, “If 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.”
‘Modernize or close your doors’
Emil Ciurczak, of Doramaxx Consulting, had a very different take than Malhotra on continuous manufacturing (CM). From his perspective, “The question is no longer, ‘Will continuous manufacturing work?’ but ‘When will everyone be doing it?’”
He said that a “convergence 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.”
The question is no longer, ‘Will continuous manufacturing work?’ but ‘When will everyone be doing it?’”
– Emil Ciurczak, of Doramaxx Consulting
Ciurczak acknowledged in his article that “initially 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.” 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.
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: “You should be ashamed.”
One of the ways to control and lower costs is to continue to outsource activities, Ciurczak said. “As 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.” He noted further:
- Thanks to PAT (process analytical technologies), manufacturers have control and a hard copy of data proving they are in control, throughout the process.
- Guidelines from the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), the FDA and the European Medicines Authority (EMA) for the calibration, validation and application of spectrometers in pharmaceuticals ensure that “performing an analysis in Thailand will give the same results as would be seen in Switzerland.”
- The author envisioned optimistically (or as he himself called it, “blindly optimistically”) that continuous manufacturing can one day help the industry make the same product at every location.
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.
Basically, he summed up his views as: “Modernize or close your doors.”
Biosimilars to ‘push bioprocessing forward’
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.
He pointed out that continuous bioprocessing has finally come to the biomanufacturing area. “While 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.” He cited competitive pressures as the reason for companies to invest in more efficient bioprocessing, in pursuit of reduced time and costs.
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, “bioprocessors 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.”
He wrote that the industry is seeing improvements in the manufacturing of biosimilars as well, “thanks to advanced analytical techniques, improved understanding of molecular biology and recombinant technology, and biochemistry of post-translational modifications and protein degradation”.
He predicted that “Biosimilars and new applications for cellular and gene therapies will continue to push the field of bioprocessing forward.”
Lessons to be learned from pharma
Kent Payne, CEO of Socorro Pharmaceuticals, pointed out that a shortage in bioprocessing expertise can translate into bottlenecks in the biomanufacturing space. Recruiting managers in biopharma hot spots like Boston and San Francisco find that the supply of talent doesn’t keep up with the need, he said.
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. “Up to a third of respondents clearly indicated openness for importing talent from pharma into biopharma manufacturing to help close hiring gaps,” Payne said.
Furthermore, the author suggested that there are lessons to be learned from pharma. As he pointed out, “Biomanufacturing 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.”
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.”
– Kent Payne, CEO of Socorro Pharmaceuticals
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:
- real-time process control
- scale-up or process development
- training operators and technicians
- quality management.
Approximately 30% considered those skills portable, the survey results showed.
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.
The author cautioned against drawing too many conclusions from this limited data set, but they did point out that, in an environment where “the only constant is change,” “learning agility needs to be high on the list of core competencies in recruiting.”
Risk-based control via scientific insight
In his presentation, Bikash Chatterjee, president and chief scientific officer of Pharmatech Associates, looked at the impact of innovation on regulations. He predicted that “innovation convergence and science-based approaches will allow for divergent yet integrated regulatory pathways.”
He added that “The future will be constructed on science-based regulatory frameworks – for example, with process validation done for individual patients, not batches.”
Chatterjee brought up CAR T-cell therapies, as well, and mentioned that these therapies, personalized to an individual, “required shifting the FDA’s expectation regarding process validation as only one batch is made per patient and each batch is unique to that patient.”
Chatterjee did point out that “The regulatory philosophies of the U.S. and Europe are not completely aligned in their approach to fostering innovation while ensuring patient safety.” Nevertheless they “both have their foundation in a desire for risk-based control derived from scientific insight.”
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.”
– Bikash Chatterjee, president and chief scientific officer of Pharmatech Associates
Like several other authors, he made some predictions about China. He anticipated that China will be very quickly harmonizing with ICH and that we’ll see poorer quality manufacturers dropping out quickly.
Focus on excipients
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 “refers to the completeness, (logical) consistency and accuracy of data over its lifecycle, and is applicable to both paper and electronic records.”
According to Carlin and his co-authors, several regulatory agencies – the FDA, the EMA, the Pharmaceutical Inspection Co-operation Scheme (PIC/S), the World Health Organization (WHO), Australia’s Therapeutic Goods Administration (TGA) and the Medicines and Healthcare Products Regulatory Agency (MHRA)– 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 “contract acceptors/suppliers from the perspective of pharma, so that can also be interpreted as covering excipients.”
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.
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, “Quality culture is perhaps more important than integrity of specific data.”
Pessimism around trade agreements
Dilip Shah, CEO of Vision Consulting Group and secretary general of the Indian Pharmaceutical Alliance, looked at the impact of regulations and trade agreements on access to medicines.
He took quite a pessimistic view. He predicted that the new trade agreements “will delay access to generics.” And he said he sees a “global trend towards patent term restoration/extension.” The net result, he said, “is that patients may need to wait five to 10 years longer for access to generic medicine.”
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. Shah 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 “fundamental reform on how companies are reimbursed for innovative medicines.”
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 “the barriers to access will grow because of many countries’ reluctance of adding new fronts of conflict with the U.S.”
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 “to 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.”
Among the countries called out in the report were China and India:
- 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.
- India was cited “for lack of sufficient measurable improvements to its IP framework.” The report also questioned “whether India is serious about pursuing pro-innovator and creativity growth policies.”
For more from CPhI Worldwide, see “Generics companies, responding to tough times, steer towards higher-risk portfolio strategies,” written by Brandon Boyd, industry strategist at Clarivate Analytics, a paper on which his CPhI presentation on the same topic was based.