May 25, 2023

닫기 The biopharmaceutical industry is pushing for continuous manufacturing (CM) due to the shift in global pharmaceutical needs from blockbuster drugs to customized rare disease drugs, and the need for creating a faster rollout of innovative treatments, especially during pandemics, according to Korea BIO's most recent economic brief report. Continuous manufacturing might be closer to happening with the convergence of guidelines in the industry providing reassurance to manufacturers. (Credit: Getty Image) CM refers to an integrated continuous system where active pharmaceutical ingredients (APIs) can be uninterruptedly fed into the equipment without the need for testing and storage after each manufacturing process. The International Council for Harmonization’s (ICH) guidelines for CM are expected to take effect from July 10, 2023. The American Society for Testing and Materials (ASTM) guidance for CM was published in November last year. Earlier in 2019, the Food and Drug Administration (FDA) also released draft CM guidelines. Nevertheless, Korean manufacturers continue to face significant challenges due to a lack of local regulatory guidance, acting as a major obstacle for domestic companies seeking to transition. The prevailing regulatory uncertainty raises concerns about potential approval delays, further discouraging companies from pursuing the change. Hurdles for achieving continuous manufacturing Notwithstanding the lack of domestic regulations, high initial investments in process analytical technology (PAT) and establishing integrated quality by design (QbD) systems have been labeled as other deterrents hindering the CM process. For CM to be conducted smoothly, automated technologies are required for monitoring the quality. In turn, this shortens the processing time from raw material to finished product. As a result, the KoreaBIO report also highlighted that CM can help bring products to market faster to guarantee pharmaceutical companies a longer period of market exclusivity. The diagram shows the difference between continuous manufacturing and batch manufacturing. (Source: FDA) Is CM feasible in Korea? However, the application of CM is not merely a theoretical aspiration for Big Pharma; it has already been implemented successfully in sectors such as petroleum refining and the food industry. Nonetheless, the biopharmaceutical industry has approached CM with greater caution, displaying a more measured adoption. The FDA published a CM audit in 2022 which proved that CM processes had faster approval times between three to eight months and made it to market four to 12 months faster than the batch processes. Among Janssen Pharmaceuticals, Lilly, Vertex Pharmaceuticals, and Pfizer, eight drugs manufactured via a CM process have already obtained approval from the FDA, European Medicines Agency (EMA), or the Pharmaceutical and Medical Device Agency (PDMA). Vertex Pharmaceuticals’ cystic fibrosis drug, Orkambi (ingredient: lumacaftor/ivacaftor) was the first in 2015. However, the report noted the APIs of these drugs were not manufactured via a CM system, suggesting a higher level of complexity to develop APIs continuously compared to the finished drug. As such, an end-to-end CM process integrating API production with the finished drug product is still under development and none are yet compliant with current good manufacturing practice (cGMP) standards. The report also pointed out that all CM-approved drugs thus far were for oral solid dosage drugs (OSDs). Particularly, the FDA guidelines are also geared towards OSD small molecule drugs but applying this same guidance to biopharmaceuticals might prove difficult. For example, vaccine manufacturing requires virus inactivation, ultrafiltration, and purification which is not easy to transfer to perform on existing equipment used for the production of small molecule drugs. Therefore, the manufacturing site has to be fit for purpose as CM processes will differ depending on the drug substance or drug product and whether it is a large or small molecule. Elaborating on the domestic situation, a company official from Daewoong Bio told Korea Biomedical Review that the company has been conducting CM research for several years and plans to conduct qualification and license production for submission to the Ministry of Food and Drug Safety (MFDS) in the third quarter of this year. However, due to the confidential nature of the business, the official could not disclose the specific drugs that would be manufactured on this platform. “We have been selected as a World Class Plus government project and will receive government support for four years to upgrade our technology for developing continuous manufacturing,” the company official said. World Class Plus is a government project carried out by the Ministry of Trade, Industry, and Energy that supports domestic world-class companies with non-R&D funds. What about the hybrid approach? Just like a hybrid approach has been suggested for decentralized clinical trials (DCT), a hybrid approach is also being mentioned as a way forward for biopharmaceutical manufacturing. Certain industry officials have already highlighted that batch manufacturing continues to perform effectively, suggesting that there is no imperative to completely abandon this approach. Especially for generic drug manufacturers where profit margins are generally low, there is a very small incentive for setting up a CM system as initial set-up costs are high. “From a business perspective, it is more effective to implement CM at the clinical stage for biopharmaceuticals than to modify the existing batch process, as it is inherently more complex and process-dependent,” said a Korea BIO official. “In order not to delay the adoption of new technologies such as CM, regulators should create specific guidelines for CM, which should be harmonized globally.”