Globally, the pharma industry has witnessed waves of changes during the last century; we have evolved, writes Ajit Kanetkar, Head, Process Technology, ACG, from maintaining a conservative outlook and being solely reactive to disease and healthcare issues to having a radical and disruptive approach
With healthcare being one of the oldest professions, it would be impossible to cover all the milestones in a single article; so, here, we seek to outline the major changes that have impacted the industry in the recent past.
The focus in every region during the last century, until recently, has been developing and making medicines that benefit the masses. For example, anti-infectives were developed during epidemics such as cholera, malaria, plague, typhoid and polio, and for ailments such as tuberculosis and asthma. These were, and are, prevalent in some geographies because of climate, working conditions, hereditary or socio-economic factors.
The 20th century marked the discovery of many new chemical entities that turned out to be remarkable drugs. Throughout this period, there have been major advances in terms of diversity and the efficacy of new actives.
The first key stepping stone occurred in the 19th century with the discovery and development of anti-infectives in the form of crude drugs such as quinine and other extracts. The chance discovery of penicillin by Dr Alexander Fleming in 1928 was spectacular! It was not until the late 1930s that the first commercial penicillin was available, but it provided a gateway to the discovery and commercialisation of more antibiotics and anti-bacterial drugs, including quinolone derivatives and anti-HIV drugs.
We’ve recently seen a radical evolution of medicines for many ailments. Some of the most enduring themes are chemotherapy, pain medication and anti-inflammatory drugs. Chemotherapy was a word first coined by the German scientist, Paul Ehrlich, in the early 19th century, when he was hoping to find a “magic bullet” that could target specific organs and cells for treatment.
A breakthrough then occurred for both leukaemia and Hodgkin’s disease with the discovery of plant alkaloids from Vinca rosea at Eli Lilly and the formulation of ibenzmethyzin (renamed as procarbazine) by Brunner, et al., in the 1950s and 1960s. Subsequently, in 1973, the field of medical oncology was officially established as a subspecialty of internal medicine — a spin-off that prompted the pharma industry to make oncology drugs.
Pain medication has a long tradition for human use. Regular medications for pain and fever were being developed throughout the 20th century. Amongst the oldest is morphine, which was widely used during global conflicts to treat the wounded. However, the drug had to be categorised as a controlled substance because of its addictive properties and has been largely substituted by the discovery of many other analgesics.
Ajit Kanetkar, Head, Process Technology, ACG
Along with pain medications, there’s been a steady increase in the need for anti-inflammatory drugs for both individual applications as well as a complement to oncology, autoimmune and dementia treatments. With the discovery and commercial manufacturing of cardiovascular, antipsychotic, antidepressant, sedative, anti-infectives, antiallergic and anti-inflammatory drugs, to name a few, the 20th century saw the introduction of a vast range of new chemical entities for use as actives.
Technology has advanced in large-scale manufacturing environments to deliver higher outputs. The pharma industry has witnessed the introduction of sophisticated machines and automated lines that require less human intervention whilst producing greater volumes with consistency and reliability.
Supplementary platforms have supported the production of delivery systems such as modified release forms (capsules and tablets) and layered tablets. Sterile products have benefited from novel innovations with a transition from glass containers to plastics and the evolution of technologies such as blow-fill-seal (BFS), prefilled syringe (PFS) and prefilled pens (PFP).
A growing number of oncology and other potent molecules have been enabled owing to the introduction of containment systems such as isolators, RABS (Restricted Access Barrier Systems) and PPE (Personal Protective Equipment).
Machines have become smarter with the use of PLC and PC systems with process control, data acquisition, data storage and trend analysis. The use of SCADA systems has enabled data security, recipe management and access control.
The introduction of sophisticated instruments in quality control (QC), such as high-pressure liquid chromatography (HPLC), gas chromatography, nuclear magnetic resonance (NMR) and X-ray diffraction (XRD) have helped with both precision during analysis and facilitated the discovery and development of new drugs and formulations. Throughout the last century, as new chemical entities were being discovered, the industry consolidated the large-scale production of these chemical moieties and their subsequent generics.
Until the late 1900s, there was a greater emphasis on quality control — the testing of finished products — as a measure of quality. This was followed by the comprehensive testing of raw materials and in-process QC. Advances were made in testing methods, as well as the validation of analytical methods, and the period was marked by a distinct shift to, and a growing reliance on, instrumental analysis.
However, simply testing finished formulations did not confirm that the systems, processes and specifications used were standardised to a level of expected consistency with quality, which led to the new and dominant functional space of Quality Assurance (QA).
The responsibility of QA was to ensure that all operations were systems-based rather than individual-based, thereby eliminating any aspect of subjectivity. Nudged by regulators, the pharma industry adopted the concept of validation in the 1980s.
A validation master plan (VMP) for a facility covers equipment qualification, the qualification and validation of utilities such as HVAC, water systems and other utilities, analytical method validation, process validation for all products, computer systems, etc., and also influences all aspects of operations, including the cleaning of equipment and facilities. Working concepts such as risk analysis, risk mitigation, FMEA (failure mode and effects analysis) evolved during the same period.
Regulatory guidelines for validation and quality by design have compelled the industry to study and better understand their processes, so all variables can be identified, monitored and controlled. Major agencies in the mature markets of North America and Europe, as well as the national authorities of various countries, have contributed a lot by providing guidance and direction to the industry.
The product registration procedures required for manufacturing licences (also termed product licence or market authorisation) were made extensive. Regulators such as the US FDA, EMEA, UK MHRA and other bodies now require manufacturers to provide comprehensive data on material specifications, process parameters, validation data and information on the company’s quality systems through the submission of CMC (Chemistry, Manufacturing and Controls) and the CTD (Common Technical Documents).
Along with regional regulators, the International Council for Harmonization has played a key role in the strengthening of systems and bringing about harmonisation between different regional regulations, as has the World Health Organization in terms of the good manufacturing practices (GMPs) that are adhered to, in more than 100 countries (in conjunction with other standards). The goal has consistently been to move towards improving systems and a stronger focus on the safety, efficacy and quality of medicines.
The manufacture and production of drugs with chemical entities as active pharma ingredients (APIs), both patented and generic, will continue for a long time. However, the number of patented chemical drugs is dwindling and this will lead to a reduction in generics in the future.
The pharma industry has now invested in developing biologics and biosimilars and, for the past two decades, we’ve seen remarkable growth in this area. Currently, there are more than 300 patented biologics, half of which are likely to go off-patent in the next few years, which will lead to a rise in new biosimilars.
For years, it’s been common knowledge that we need to improve the efficacy of drugs and reduce their side-effects. It is a known fact that the actual quantity of drug in the final dosage form is more than that required for action, allowing for losses during metabolism and transport to the site of action.
Therapeutics have thus seen the rise of new philosophies, such as targeted delivery and personalised medicine. Both of these disciplines can help to reduce overall dosages and side-effects while maintain the same or, in some cases, enhanced levels of efficacy.
Several new delivery platforms and concepts have evolved during the last two decades, including
Owing to the variety of products under development, there is likely to be a future need for smaller batches or shorter campaigns that will require flexible manufacturing facilities with frequent changeovers.
In fact, the biologics sector is actively exploring single-use options for many forms of equipment, including bioreactors up to 2000 L, which will eliminate the need for cleaning and thus prevent contamination of fragile biosystems. Likewise, continuous manufacturing already helps to optimise resources and eliminates many scale-up issues.
In terms of information management, the pharma industry is required to collect, compile, analyse and store huge volumes of data. Technology developments in digitisation from other sectors will have a sweeping effect on drug production.
Artificial intelligence (AI), for example, provides various platforms, such as data compilation and analysis, predictive analysis and simulation studies, augmented reality (AR), virtual reality (VR), machine learning, robotics and the Internet of Things (IoT), all of which will greatly influence and support functional areas such as market research, the development of new drugs, clinical studies and manufacturing.
Maximising resource use will improve efficiency, cost control and regulatory compliance, and provide competitive advantages.
In summary, the pharma industry has undergone a unique evolution during the past century, moving from a conservative outlook to a radical and disruptive one. The therapeutic needs of societies will always determine trends and, by default, new drug development and manufacturing.
Yet, in today’s world, the rapid advancement of technology from both within and without the industry has a greater impact on what and how we do things. Alongside the need to comply with constant global and national regulatory updates, there are many factors that now influence the development, manufacture and production of pharmaceuticals, leading us to strive for better solutions and changing the industry to the radical, future-facing perspective it holds today. The future will be exciting and challenging.