Pharma Industry Weighs in on Continuous Manufacturing
The pharma industry is providing feedback on the FDA’s draft guidance on continuous manufacturing, with GSK, Eli Lilly, AstraZeneca, J&J, the Association for Accessible Medicines, CEFIC’s Active Pharmaceutical Ingredients Committee, and IPEC-Americas among those offering input. What did they have to say?
The state of the state: continuous manufacturing
Although batch manufacturing is the dominant mode of manufacturing in the pharmaceutical industry, the industry, with support from the US Food and Drug Administration (FDA), is making some progress in investigating and using continuous manufacturing. The FDA’s encouragement for the industry to adopt manufacturing innovation and new technologies was first put forth 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.
The agency’s support for the adoption of new technologies, such as continuous manufacturing, is crucial as the industry needs regulatory support and guidance to consider the adoption of new technology. With the industry’s installed manufacturing base still in batch manufacturing and further investment required in equipment, analytical technology, such as PAT, and technical training for continuous manufacturing, the industry has been proceeding on a measured and limited basis in adopting continuous manufacturing. However, with the potential for improved process control and reduced and more flexible manufacturing footprints, pharmaceutical companies continue to evaluate continuous manufacturing for the production of both active pharmaceutical ingredients (APIs) and drug products.
To date, there are four companies manufacturing five approved products using continuous manufacturing, according to information from the FDA, with approximately 20 additional companies, both brand and generic, engaging with the FDA in their efforts to develop and implement continuous manufacturing processes.
FDA moves forward with draft guidance for continuous manufacturing
Earlier this year (February 2019), the FDA issued draft guidance, Quality Considerations for Continuous Manufacturing, to specify key quality considerations and provide recommendations for how applicants should address these considerations in new drug applications (NDAs), abbreviated new drug applications (ANDAs), and supplemental NDAs and ANDAs for small-molecule, solid oral drug products that are produced via a continuous manufacturing process. The draft guidance clarifies the FDA’s current thinking regarding continuous manufacturing approaches to help resolve potential issues some companies may have as they consider implementation, such as concerns that use of new continuous manufacturing technology might impact the time the FDA takes to assess applications for new products and what is required from a regulatory view for switching from a batch to a continuous-manufacturing process for existing products.
In issuing the draft guidance, the FDA also outlined other steps it is taking to support the adoption of continuous manufacturing, which includes proposed development of a guidance on continuous manufacturing to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), proposed funding to support company projects in continuous manufacturing, and continued support by the FDA to provide regulatory clarity for companies using continuous manufacturing processes.
Industry feedback on FDA’s draft guidance
In issuing its draft guidance, the FDA also invited public comment through May 28, 2019, and received 21 comments from pharmaceutical companies, industry associations, consulting firms, and individuals. The FDA asked for the public input in consideration of a final guidance on continuous manufacturing. The industry feedback on the draft guidance was largely positive, but stakeholders raised specific issues and questions on certain items in the draft guidance.
One larger issue addressed by the stakeholders is how the FDA guidance will fit into a proposed ICH guideline, Q13, Continuous Manufacturing of Drug Substances and Drug Products . In 2018, ICH endorsed the development of a guideline on continuous manufacturing, which it anticipates would take three years to develop with the adoption of a final guideline expected in November 2021. ICH has formed an Expert Working Group for the development of the guideline with the goal of having a draft guideline available for public consultation by June 2020. ICH is a non-binding body that engages regulatory authorities and the 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 FDA), the European Union (European Commission), and Japan (Ministry of Health, Labour and Welfare and the 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.
The new ICH guideline document on continuous manufacturing seeks to address several main issues, including capturing key technical and regulatory considerations that promote harmonization, including certain cGMP elements specific to continuous manufacturing. It also seeks to allow drug manufacturers to employ flexible approaches to develop, implement, or integrate continuous manufacturing for the manufacture of both drug substances and drug products for small molecules and therapeutic proteins for new and existing products. The ICH guideline will also provide guidance to industry and regulatory agencies regarding regulatory expectations on the development, implementation, and assessment of continuous manufacturing technologies used in the manufacture of drug substances and drug products.
In offering feedback on the FDA’s draft guidance on continuous manufacturing, the Active Pharmaceutical Ingredient Committee (APIC) of the European Chemical Industry Council (CEFIC), which represents chemical manufacturers in Europe, said that it was APIC’s expectation that the FDA document would merge into the upcoming ICH Q13 guideline and eventually be replaced by Q13 once it is adopted. GlaxoSmithKline (GSK) raised a similar point saying that it would expect the FDA to withdraw the FDA guidance and align it to the practices and recommendations in Q13 to ensure global harmonization.
GSK also commented that in general, the FDA draft guidance mixes GMP and regulatory issues and, as such, the guidance lacks clarity as to where the expectations are for submission versus GMP control. “This may result in more rigidity and could be interpreted as pulling more from inspection activities to the regulatory domain,” it said. GSK also noted that the guidance could offer more specifics of the advantages of using continuous manufacturing to simplify areas, such as validation and deviation.
Some of the comments from Eli Lilly and Company on the draft guidance related to process validation. The company says it supports the application of the validation lifecycle approach to process validation for continuous manufacturing processes overall. “However, given the unique features of continuous manufacturing relative to batch processing, we propose there is a scientific basis to provide for further flexibility and how reproducibility and reliability are demonstrated in process validation of continuous manufacturing processes,” said the company. “These features include but are not limited to additional integrated controls, increased levels of data on product and process, which can provide increased levels of monitoring and detection, and similarity in the levels of these controls and data streams across validation life cycle stages.”
Janssen, the pharmaceutical arm of Johnson & Johnson, offered its support for the draft guidance but made several specific recommendations. It said it would be beneficial to include examples that show what changes that would fall under a decreased need for post approval submissions and what changes the agency sees as requiring post approval submissions.
It also specified the need for clarification of “run-time extension” and to base the concept of full “batch” rejection on the number of disturbances. It said that the increase in run duration does not constitute a change in the manufacturing process in its opinion, and it recommends allowing for a run-time extension without the need for prior approval if an appropriate level of process control and monitoring is in place. With regard to “batch” rejection, the company said that it agrees that unexpected disturbances should be appropriately investigated, and nonconforming material shall be rejected, but it did not agree with the draft guidance that a higher than normal rate of disturbances within a single run should result in full batch rejection. It instead recommended that “when frequent or cyclical process disturbances occur within a single production run resulting in atypical low yield, the disposition of the material from the run should be based on the ability to segregate out good material and the investigation into the reason for the disturbances.”
IPEC-Americas, which represents excipient users and manufacturers, said that the FDA draft guidance “addresses key considerations for process dynamics, batch definition, control strategy, pharmaceutical quality system, scale-up, stability, and bridging of existing batch manufacturing to continuous manufacturing,” but made some recommendations to include in the guidance as it is reviewed for finalization. These include more consistency in the guidance when using the terms “batch,” “lot,” and “production run.” It also noted that the guidance should reflect the advantage of continuous manufacturing systems to make real-time adjustments to minimize or eliminate out-of-specification material.
The Association for Accessible Medicines (AAM), which represents generic drug manufacturers, raised concerns about the costs associated with continuous manufacturing. “If it is costlier for generic entrants to replicate and manufacture products because they are manufactured through continuous manufacturing rather than through a batch process, it is possible that generic competition would be diminished, with the number of generic suppliers shrinking, perhaps to zero,” said the AAM in its comments. “A diminished generic manufacturing base is less capable of acting as a market-based solution for product shortages and increasing prices. These are important issues that policy makers and industry thought leaders need to consider.”
In providing economic considerations for continuous manufacturing, the AAM offered information from a cost view for a set-up of a continuous manufacturing process. It estimated equipment and facility costs at $50 million per 1 billion units produced when employing continuous manufacturing. This breaks down into $30 million for facilities and $20 million for equipment (facilities reconfiguration, HVAC and other mechanical/electrical retrofit).
The AAM also pointed to potential drawbacks and issues: long technology integration times to switch from a batch to a continuous manufacturing process; a significant portion of batch equipment still within useful life; risk of single dedicated/integrated lines for key products; significant set-up cleaning changeover time for small batch products; requiring multiple lines of large and small capacity with modifications needed between products; reduction of endpoint testing; and significant up-front resources to establish integrated in-line testing systems.
“While there is general agreement that in many circumstances, continuous manufcturing processes lead to lower incremental manufacturing cost, it is less clear—after considering start-up costs, including the acquisition of new facilities and the potential abandonment of existing manufacturing capital— that continuous manufacturing leads to lower total manufacturing cost,” said the AAM in its comments.