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In September 2017, Hurricane Maria devastated the island of Puerto Rico. In addition to creating a public health and humanitarian crisis in PR, Maria’s impact was felt worldwide when it left an acute shortage of essential drugs in its wake. The island is home to forty-nine FDA approved pharmaceutical manufacturing sites and is an essential part of the global drug supply chain. Many thought that this supply disruption was a once-in-a-century event, only to find themselves amid a worldwide pandemic just thirty months later. Given the dependency of many nations on the complex and fragmented global supply chain for medicines, several countries are now concerned about their domestic supply of medicines should another disruption occur. It is clear that diversification of the drug supply chain is needed, but it is not going to be easily achieved using only the traditional manufacturing approaches.
Focus on Advanced Manufacturing Technologies (AMT)
AMT is a term used to refer to several technologies, and the most prominent of them today is Continuous Manufacturing (CM) of pharmaceuticals. In contrast to traditional batch-based manufacturing which involves large quantities of material to be handled and transformed at once, CM refers to a process in which the product is continuously harvested over time while simultaneously feeding the ingredients into the manufacturing train. While this paradigm is not new to industries such as petrochemicals, its adoption in the pharmaceutical industry is just now increasing with a handful of innovator drug products having received regulatory approval.CM is applicable to the manufacture of traditional small molecule medicines made through chemical routes as well as newer biologics produced using living cells and can be utilized separately to manufacture active pharmaceutical ingredients (APIs), finished dosage forms (FDFs),or in an end-to-end integrated manner (from raw materials to FDF with API being synthesized along the way). The key potential benefits of CM are better process insight due to real-time monitoring using sensors, advanced process control, ability to divert out-of-specification material in real time, significantly smaller facility size, lower costs of utilities, higher efficiency, and environment friendliness. On the downside, it requires new equipment such as feeders, continuous mixers, spectroscopic tools for in-line measurements as well as sophisticated control systems.
"Today the industry is speaking about Pharma 4.0, is developing digital twins of API manufacturing processes and is finding ways to leverage the success of AMT with a few branded products to expand into generics, industries such as catalyst, nutraceuticals, cosmetics, and foods"
The generics manufacturing challenge
With about 90% of prescriptions in the U.S. being generic medicines, and with that percentage being larger for some other countries—it is clear that the AMT’s largest benefit to global public health will be realized only with greater adoption by generics manufacturers. However, there are several barriers to this.
The pharmaceutical industry is highly regulated to ensure the safety and well-being of patients, and any significant change to the manufacturing process must receive regulatory approval. CM is relatively new to the block, however, as is evident by several approved cases, the current regulatory framework is sufficient to gain approval. What is lacking is a clear understanding of the technology and the associated regulatory requirements that the manufacturers must meet in order to convert from batch to CM. Adopting CM requires investments into new equipment, workforce recruitment and training, as well as the time and material required for fresh process development.
USP’s efforts to increase access to quality medications via AMT
As an independent, science-based non-profit organization working globally, USP has a unique role to play both in the developed as well as the low- and middle-income countries (LMICs).USP has identified several of it’s existing standards applicable to CM as well as explored opportunities to develop new standards for materials, characterization, models, and digital methodologies essential for successful implementation of AMT. These, alongside USP’s unique capability building initiatives for the industry, it’s advocacy for regulatory policies, and incentives constitute a well rounded and timely intervention. In collaboration with leading academic R&D centers, USP is developing a comprehensive introductory course for industry as well as the regulatory workforce worldwide with the aim of filling the knowledge gaps about CM. To demonstrate how to switch from a batch to CM approach, USP selected one of the top ten prescribed lifesaving generic medicines and, in partnership with a contract research organization developed a CM process for its manufacture. The knowledge developed from this and other similar studies will be disseminated for the benefit of the manufacturing world.
AMT and its impact on pharmaceutical manufacturing
As the manufacturing world makes big leaps forward with Industry 4.0 and the associated concepts of digital twins, machine learning, big data and analytics, the pharmaceutical industry has not been untouched. Today the industry is speaking about Pharma 4.0, is developing digital twins of API manufacturing processes and is finding ways to leverage the success of AMT with a few branded products to expand into generics, industries such as catalyst, nutraceuticals, cosmetics, and foods. It is important that regulatory and government incentives are provided to initiate adoption of AMTs. USP can convene such discussion groups and facilitate these initiatives. As advances are made in technologies for real-time sensing, automated controls, artificial intelligence, 3D printing, and hand-held material characterization technologies, we will see more robust, small-footprint factories producing high quality pharmaceutical products closer to the point of consumption. A paradigm shift is happening— in the way we manufacture, market, and consume pharmaceuticals.