The International Council for Harmonization (ICH) has adopted its guideline on continuous manufacturing for both drug substances and drug products. What does this mean for the industry and what are the implications for US and EU GMP?

ICH adopts guideline on continuous manufacturing
After a multi-year process, in late November (November 2022), the International Council for Harmonization (ICH) adopted its guideline on continuous manufacturing for drug substances and drug products. The guideline describes scientific and regulatory considerations for the development, implementation, operation, and lifecycle management of continuous manufacturing.

The ICH is a non-binding body that seeks to harmonize international standards for the bio/pharmaceutical industry, including on issues related to manufacturing and quality. The ICH engages regulatory authorities and the bio/pharmaceutical industry to discuss scientific and technical aspects of drug registration, including quality considerations and good manufacturing practice (GMP), as a means to harmonize pharmaceutical regulation among regulatory bodies. Its membership includes the regulatory authorities from the US (the US Food and Drug Administration [FDA]), the European Union (European Commission), and Japan (Japan’s Ministry of Health, Labor and Welfare and Japan’s Pharmaceuticals and Medical Devices Agency). Its members further include regulatory authorities from Canada, Switzerland, China, Brazil, Singapore, and the Republic of Korea as well as industry associations, the Pharmaceutical Research and Manufacturers of America, the Biotechnology Innovation Organization, the European Federation of Pharmaceutical Industries and Associations, and Japan Pharmaceutical Manufacturers Association. Once an ICH guideline is issued, its implementation depends on the adoption of the guideline by the participating regulatory agencies in the ICH.

The ICH guideline, Q13, Continuous Manufacturing of Drug Substances and Drug Products, builds on existing ICH Quality Guidelines, provides clarification on continuous manufacturing concepts, describes scientific approaches, and presents regulatory considerations specific to continuous manufacturing of drug substances and drug products. The guideline focuses on the integrated aspects of a continuous manufacturing system in which two or more unit operations are directly connected and describes scientific and regulatory considerations for the development, implementation, operation, and lifecycle management of continuous manufacturing.

FDA’s draft guidance on continuous manufacturing
For its part, the FDA issued draft guidance on continuous manufacturing for drug substances and drug products last October (October 2021). The draft guidance, which was prepared under the support of ICH, is applicable to new products (e.g., new drugs, generic drugs, biosimilars) and the conversion of existing products using batch manufacturing to continuous manufacturing. The FDA opened up feedback on its draft guidance with input received last December (December 2021), and finalization of the guidance is pending.

The FDA has long supported continuous manufacturing and has taken steps to facilitate the bio/pharmaceutical industry’s implementation of continuous manufacturing. The FDA first put forth its support for continuous manufacturing in 2002 with the agency’s initiative, Pharmaceutical Current Good Manufacturing Practices for the 21st Century, as a means to modernize pharmaceutical manufacturing and enhance product quality. This initiative included putting forth a science- and risk-based approach to pharmaceutical manufacturing and regulatory oversight through a Quality-by-Design approach as well as by encouraging new technologies, such as process analytical technology (PAT) and continuous manufacturing.

Support by the FDA and other regulatory agencies for continuous manufacturing is crucial. With the industry’s installed manufacturing base still in batch manufacturing and further investment required in equipment, analytical technology, such as process analytical technology (PAT), and technical training for continuous manufacturing, the industry has been proceeding on a measured basis in adopting continuous manufacturing. 

Continuous manufacturing involves the continuous feeding of input materials into, the transformation of in-process materials within, and the concomitant removal of output materials from a manufacturing process. While this description may apply to an individual unit operation (e.g., tableting, perfusion bioreactors), the FDA draft guidance focuses on the integrated aspects of a continuous manufacturing system in which two or more unit operations are directly connected. In this context, any changes made in a unit operation of continuous manufacturing may have a direct and often immediate impact on downstream and upstream unit operations. 

As outlined in the FDA’s draft guidance, material attributes can impact various aspects of continuous operation and performance, such as material feeding, process dynamics, and output-material quality. Understanding the impact of material attributes and their variability on process performance and product quality is important for the development of the control strategy. Input materials may require evaluation and control of attributes beyond those typically considered for a material specification used in batch manufacturing.  

The control strategy of a continuous manufacturing process is designed to ensure that output materials made over the run time are of the desired quality as highlighted in the FDA’s draft guidance. The control strategy should describe the relevant controls and approaches used during the manufacturing and the operational aspects of the continuous manufacturing process.  

Although batch manufacturing prevails in the bio/pharmaceutical industry, continuous manufacturing holds the potential for improved process control and reduced and more flexible manufacturing footprints. Key benefits for continuous manufacturing cited by the FDA in its draft guidance are: (1) eliminates manual handling and human error; (2) increases quality assurance through online monitoring and control; (3) reduces manufacturing time and increases efficiency; (4) reduces capital costs by using smaller equipment and less manufacturing space; (5) responds more nimbly in the event of a drug shortage; and (6) allows manufacturers to tailor drug production to fit the needs of precision medicines.

Drug approvals and evaluation using continuous manufacturing
To date, the FDA has approved a limited number of drugs that use a continuous manufacturing process. In 2020, the FDA approved four drugs using continuous manufacturing, which included the first regulatory application using continuous manufacturing for an active pharmaceutical ingredient, the first continuous biomanufacturing process, as well as two different marketed products using semi-continuous manufacturing processes. The first approval for a drug made using a continuous manufacturing process was in 2015 for Vertex’s Orkambi (lumacaftor/ivacaftor), a drug for treating cystic fibrosis. Since then, Vertex has had two other drugs approved using continuous manufacturing, also to treat cystic fibrosis:  Symdeco/Symkevi (tezacaftor/ivacaftor and ivacaftor) and Trikafta (elexacaftor/tezacaftor/ivacaftor and ivacaftor). Johnson & Johnson received approval for its HIV drug, Prezista (darunavir), which was the first drug that the FDA allowed to be switched from batch manufacturing to continuous manufacturing. Other FDA-approved drugs using continuous manufacturing include Pfizer’s Daurismo (glasdegib) for treating acute myeloid leukemia and Lilly’s Verzenio (abemaciclib) for treating metastatic breast cancer.

At the start of 2022, there were six FDA-approved applications that used continuous manufacturing for their finished solid oral drug products. In June (June 2022), the FDA’s Center for Drug Evaluation and  Research (CDER), Office of Pharmaceutical Quality (OPQ) issued the results of a self-audit of approved US regulatory submissions that employed continuous manufacturing versus traditional batch processes and analyzed regulatory outcomes during the product lifecycle and at approval. It analyzed the effects of continuous manufacturing versus batch operations on time to approval, market entry, as well as manufacturing process changes reported in annual reports, post-approval inspections and application supplements, and pre-approval inspections.

Based on this self-audit, the applications that used continuous manufacturing were approved in a shorter time than the comparator batch applications. Continuous applications were approved in the first cycle of review with no Complete Response letters issued. In addition, continuous applications were approved ahead of the FDA’s target review date under the Prescription Drug Use Fee Amendments (PDUFA) on average nine months faster than the batch applications that the FDA compared against. Four  of the six approved continuous applications, had been granted breakthrough therapy designation, which expedited their review timeline. But overall, the FDA said that use of continuous manufacturing did not impact its ability to review and act on applications using continuous manufacturing even when there are expedited review timelines.

With regard to market entry, the products using continuous manufacturing entered the market 12 months faster on average after regulatory submission, and three months faster after approval when compared to the batch applications. The FDA explained there are many factors in determining the time between approval and marketing that resulted in the time differential between batch and continuous products. It explained that batch manufacturers typically need to utilize new equipment, update processes, complete process performance qualification, make supply-chain considerations and manufacturing scale-up common roadblocks. In contrast, continuous manufacturing operations have fewer process and equipment considerations in reaching commercial-scale operations. For example, this could be done simply by increasing the length of time, or speed, at which the continuous manufacturing  process is run.

FDA’s OPQ manually audited post-approval application supplements for continuous manufacturing products. Approximately 30% of post-approval supplements for all applications (batch and continuous manufacturing) were related to the manufacturing process. Thus, there was not a substantial difference in the number of process changes reported in application supplements between batch and continuous applicants.

FDA’s OPQ also manually audited pre-approval inspection documents for nearly 100% of the continuous products and for the majority of batch products in its self-audit. Continuous manufacturing applications had more process-related issues observed during inspection than batch applications. These observations were primarily related to oversight of manufacturing process and controls and may indicate a difference in inspection focus between batch and continuous manufacturing processes. In contrast to facilities manufacturing batch products, many CM facilities and processes are new, and the FDA has relatively limited knowledge of the manufacturing capabilities of continuous manufacturing facilities. This difference may contribute to an increased focus on manufacturing process and controls during inspections of continuous facilities. The FDA said in its findings that the need for pre-approval inspections and the number of process-related issues observed during inspections at facilities using continuous manufacturing should lessen as FDA gains more confidence in manufacturers’ capability to implement continuous manufacturing.

The continuous manufacturing applicants in FDA’s self audit engaged with CDER’s Emerging Technology Program, which may have supported first-cycle approvals. The Emerging Technology Program seeks to promote the adoption of innovative approaches to pharmaceutical product design and manufacturing, such as continuous manufacturing, and through direct engagement with industry representatives, FDA staff and participants discuss, identify, resolve potential technical and regulatory issues regarding development and implementation of a novel technology prior to filing of a regulatory submission.