Pharmaceutical manufacturing has been performed using batch technologies for more than a century. While most other manufacturing industries use continuous operations combined with advanced process control and automation, the pharmaceutical industry has mostly relied on fixed recipes to produce batches. This practice results in very long and expensive processes that have been supported by high gross margins. In contrast, the development of novel manufacturing technologies has the potential to transform the current “batch manufacturing” process into a “novel” integrated continuous manufacturing (ICM) process.
This vision for the future of pharmaceutical manufacturing employs the concepts of continuous flow, end-to-end integration, a systems approach, and an integrated control strategy. The vision was initially validated by a team of researchers at the Novartis-MIT Center for Continuous Manufacturing, who designed and constructed a small-scale prototype system to demonstrate that pharmaceuticals can be produced continuously in a fully integrated manner with automated control. In this way, raw materials can be transformed into finished tablets without interruption (24 hours a day), with the active ingredient being synthesized in situ without isolation. This approach opens a new manufacturing paradigm for the pharmaceutical industry with drugs being delivered to patients much quicker, at significantly reduced cost, and with consistently high quality.
BATCH IS INEFFICIENT
Significant advances in science and technology have opened new avenues toward a first-principles understanding of the pharmaceutical manufacturing processes, whose efficiencies lag behind those of many other industries. A decade ago, pharma companies were challenged by U.S. Food and Drug Administration (FDA) Commissioner Mark McClellan who referred to the science of drug manufacturing as being “behind that of potato chips and soap makers.”¹ Unfortunately, there has not been a great deal of improvement so far: The pharmaceutical industry endures losses of ~$50 billion/year in manufacturing costs from inefficient processes.² In many cases, pharmaceutical processes lack advanced on-line quality control systems and rely only on numerous off-line material tests. For this reason, regulators have encouraged the industry to embrace concepts such as Quality by Design (QbD) and the use of advanced process analytical technology (PAT) to produce pharmaceuticals with a higher assurance of acceptable quality at the time and place of manufacture.³
Many of the issues related to the current inefficiency in drug manufacturing originate from the disconnected nature of the processes the industry employs. Current manufacturing practice consists of a series of lengthy and segmented batch process steps often performed in different facilities around the world including isolation, testing, storage and transportation of the various chemical intermediates, as well as the final active pharmaceutical ingredient (API). The API is then transported elsewhere to be formulated into the final dosage form, packaged and shipped to distributors. Because of this disconnect between API and drug product, there is often limited feedback from downstream operators on the desired API’s physico-chemical properties to facilitate its downstream processing. This practice typically leads to a number of “correction steps” that need to be applied to formulate the API into an acceptable dosage form, such as the many APIs that are crystallized as poorly flowable compounds and require micronization and/or granulation before being made into tablets. Also, these series of disconnected steps result in large and expensive inventories.4 Trends in inventory turns are often used as key indicators of improved performance in manufacturing processes and lean management and, unfortunately, in the last decade there have been no significant changes in inventory turns among the top drug companies.5
Batch manufacturing introduces a significant lag-time between technical operations such that the cycle time from the start of manufacture to delivery to patients can be as long as 12 months.6 This practice limits the ability of a manufacturing process to react quickly to changes in demand of a newly launched product or when a large volume of medicine is needed in a relatively short amount of time (such as for flu medicaments). In addition, a recent analysis conducted by the U.S. Government Accountability Office found that the number of critical drug shortages has more than tripled since 2006, especially among cancer drugs and nutritional products, and that these shortages were mainly caused by manufacturing problems, sometimes causing manufacturing shutdowns.7 A recent example of a manufacturing-limited shortage is doxorubicin (Adriamycin), a cancer drug for children; availability of this drug dropped due to manufacturing lacking the capacity to satisfy increased demand.8
The complexity and inefficiency of existing drug manufacturing processes find their roots in the early stages of drug manufacturing process development, where extensive scale-up batches and complex validation procedures are necessary before a new molecular entity can be commercialized, with four major scale-up exercises often being involved (bench, kilo, pilot and commercial). Consequently, clinical trial batches may not be representative of final commercial batches such as for the small molecule drug gabapentin, an anticonvulsant and analgesic, which has been subject to several recalls due to new impurities that appeared after scale-up.9
In such cases when the commercial product does not meet specifications, the entire batch must be rejected, which creates a supply problem. Furthermore, the current scenario for quality control during production, which establishes safety and efficacy of a medicament, is not ideal. Drug makers continue to rely mostly on a ‘Quality by Testing’ (QbT) approach, which involves running a large number of post-processing tests to demonstrate that products meet specifications. Although somewhat reliable, this testing protocol leaves significant opportunities for improvement, as demonstrated by the number of post-approval recalls due to quality issues. This number has not decreased in the last five years (≈ 500/year),10 with the FDA recording an increase of more than 54% compared to average between second and third quarter of 2011.11