Patient Centricity, Risk Communication and Regulatory Considerations for Continuous Manufacturing

Continuous manufacturing is currently a hot topic in the pharmaceutical landscape despite the concept having been around for decades. One reason is that the majority of pharmaceutical manufacturing is, at present, accomplished by traditional batch processes. The use of batch processes has several limitations, including the lack of flexibility in batch size to meet potential fluctuations in patient supply and demand. Additionally, if a batch does not meet release specifications and if reprocessing is not an option, the batch may have to be discarded. This can be very costly to the manufacturer and potentially create a drug shortage.

The appeal of continuous manufacturing is that equipment is usually highly specialized and compact with integrated manufacturing capabilities that result in fewer manufacturing steps and a smaller carbon footprint.¹ When continuous manufacturing is implemented, it is expected that the process maintains a state of control that allows the manufacturer to produce medicines based on current demand. If, for any reason, the state of control is interrupted, there is also an opportunity for material diversion allowing operators to rectify any issues by discarding only material that may be out of specification without the risk of losing the whole batch.

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By using a continuous platform, there are plenty of opportunities to utilize PAT (Process Analytical Technology) that can generate a large amount of real-time data and support Real-Time Release Testing (RTRT) which, in turn, can allow for better control of the manufacturing process of the product and while also leading to faster batch release. Models can also be used to support RTRT with some examples including multivariate models to predict dissolution for release and calibration models associated with NIR procedures that are used for content uniformity and assay release testing.²

For several years, FDA has been strongly committed to the advancement of manufacturing technology to support public health emergency preparedness and response. According to the FDA, the advancement of manufacturing will help rapidly scale manufacturing capabilities, shorten supply chains and increase manufacturing resilience, accelerate therapy development, increase the speed of emerging therapies, and provide new tools to address drug shortages.³ This commitment is present in the establishment of the FDA Emerging Technology Team (ETT),⁴ which is designed to collaboratively assist applicants in the adoption of new manufacturing technologies.

In February 2019, FDA published draft guidance titled “Quality Considerations for Continuous Manufacturing”.² The draft guidance describes quality considerations for marketing applications with a focus on small molecule, solid oral dosage forms for New Drug Applications (NDA) and Abbreviated New Drug Applications (ANDA). In the guidance, FDA states that the principles of continuous manufacturing in the guidance can be used for biotech products as well.

From a more global perspective, a significant step forward was achieved with the ICH assembly’s endorsement of ICH Q13 “Continuous Manufacturing of Drug Substances and Drug Products” in June 2018. According to the ICH Expert Working Group work plan, the draft guideline includes both small molecules and biologics, with a target for step 3 sign-off and step 4 adoption of the final guideline as November 2022.⁵

Though the global focus on continuous manufacturing is promising, applicants may still have concerns with requirements of this new technology in non-ICH regions as those regions sometimes lack the resources and can be less comfortable assessing new technologies. Manufacturers may also hesitate to switch from an approved traditional batch process to continuous manufacturing due to potential regulatory hurdles and/or burden that may cause delays. Through the establishment of the ETT, FDA proactively tried to ease industry concerns by providing opportunities for FDA/industry interactions during early stages of development, while increasing the opportunity for feedback throughout later stages of development. This was a substantial first step in encouraging companies to consider utilizing this technology for the future manufacturing of medicines.

An additional challenge that faces both industry and regulators is the inability to easily translate terminology between continuous manufacturing and a traditional batch process. For example, the definition of batch, continuous manufacturing, process validation and shelf life can all be impacted slightly differently when referencing a batch versus a continuous process.

As is typical of highly technical concepts, it can be quite challenging to tie the specific technical language and elements of continuous manufacturing to more tangible outputs. It becomes even more challenging to do so when operating within a multidisciplinary space and amongst various stakeholders with a spectrum of interests. Add in the interactions between regulators and industry in a global environment, and a highly complex dialog emerges that requires balance, levity, and above all, very clear communication across all parties.

In the case of continuous manufacturing, one can argue that the ultimate output is potential benefit to patients. However, one can also query - where exactly is that benefit and how is it measured? Is it a benefit in ultimately conserving manufacturing resources to ensure supply to patients? Is it a benefit in transitioning from a historical manufacturing batch process to a more modern and efficient continuous process? Or is it the precise linkage of certain process parameters and product attributes to the continuous-manufactured product itself? Holistically, one can also argue that all of the above can be true and do not necessarily need to be exclusive of each other. In other words, all represent potential benefits to patients.

Fortunately, this concept is outlined throughout the ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) quality guidelines, with a particular reference to ICH Q9 “Quality Risk Management”. ICH Q9 introduces the concept of risk communication as part of overall quality risk management. In this context, risk communication is captured as an ongoing element throughout a product’s lifecycle.⁶ When presented in this fashion, Q9 becomes a platform for the effective and efficient conveyance of information relating to an overall control strategy, potential product risks and fundamentally, serves as the core consideration for potential benefit/risk to patients.

In the global regulatory arena, effective risk communication is a powerful tool to support the implementation and global submission of continuous manufacturing and other advanced manufacturing technologies, as it can apply across multiple areas of consideration. In a simple and very collaborative form, effective risk communication can be viewed as an efficient and patient-centric dialog between regulators and industry, to facilitate the availability of a new product and/or new technology. A broader interpretation could designate effective risk communication as having the right conversations at the right time, both internal and external, during development and healthy authority assessment. An even more holistic perspective is one that ties directly to the amount of information contained/required in a global submission to support the approval of a product, or to support post approval variations for that same product.

In the space of continuous manufacturing, all of the elements of risk communication become highly critical both to internal technical conversations as well as pursuant conversations and interactions with key stakeholders and ultimately, with regulators. An appropriate context on risk is also important, as the word “risk” can apply to many different types of issues. From an industry standpoint, there may be identified risks for a project – perhaps related to ability to deliver set key project milestones or deliverables, while from a regulators perspective, there may be potential risks to quality that arise during a review or assessment and then may need to be mitigated and/or addressed by the industry applicant. From an ICH standpoint, risk is defined in relationship to overall product performance (i.e. quality), and despite the magnetism of highly technical debates, it is this overall context of risk that needs to be in the forefront of collaborative risk communication throughout a product’s lifecycle. When effective, this communication can be a powerful enabler to facilitate further efficiency and dialog for both regulators and industry.

Strategically, there continues to be many efforts centered around risk communication, and there are many opportunities to explore the concept of appropriate and effective risk communication in the development and commercialization of pharmaceuticals. In 2018, FDA published a White Paper “A Regulatory Perspective on the Quality Overall Summary: Putting the Pieces Together”⁷ that outlined the potential use of the Quality Overall Summary to support the risk-based “story” of a product. It is also important to note that ICH Q13 is currently being developed.⁸ This has been followed up by the ongoing revision of ICH Q9⁹ and pursuant to other efforts by global regulators to develop and use region-specific formats and streamlined content to drive efficiency in both submissions and assessment by health authorities. While certainly the importance of risk communication cannot be overstated, it is also imperative that any region-specific efforts remain compatible with the global context and enable submission efficiency on a global scale.

In the highly technical world of advanced manufacturing technologies, such as continuous manufacturing, the fundamental focus on patient expectations and effective risk communication is a fundamental focus and cannot be lost. In parallel with the intent of ICH Q8-12,¹⁰ as well as existing initiatives related to the bigger picture of overall patient expectations and need, this bigger picture remains the most prominent driver for strong collaboration, pragmatism, innovation, and creativity by all involved.

References

1. Brookings. Promoting continuous manufacturing in the pharmaceutical sector page. Available at: https://www.brookings.edu/events/promoting-continuous-manufacturingin- the-pharmaceutical-sector. Accessed March 4, 2021.
2. Food Drug Administration (FDA). FDA quality draft guidance page. Available at: https:// www.fda.gov/regulatory-information/search-fda-guidance-documents/qualityconsiderations- continuous-manufacturing. Accessed March 4, 2021. 
3. FDA advanced manufacturing page. Available at: https://www.fda.gov/emergencypreparedness- and-response/mcm-issues/advanced-manufacturing. Accessed March 4, 2021. 
4. FDA Emerging Technology Program page. Available at: https://www.fda.gov/about-fda/ center-drug-evaluation-and-research-cder/emerging-technology-program. Accessed March 4, 2021. 
5. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). ICH quality guidance page. Available at: https://database.ich.org/sites/ default/files/Q13_EWG_WorkPlan_2020_0913.pdf. Accessed March 4, 2021. 
6. ICH quality guidance page. Available at: https://database.ich.org/sites/default/files/ Q9%20Guideline.pdf. Accessed March 4, 2021. 
7. FDA drugs page. Available at: https://www.fda.gov/files/drugs/published/A-Regulatory- Perspective-on-the-Quality-Overall-Summary---Putting-the-Pieces-Together.pdf. Accessed March 4, 2021. 
8. ICH quality guidance page. Available at: https://database.ich.org/sites/default/files/ Q13%20Business%20Plan.pdf. Accessed March 4, 2021. 
9. ICH quality guidance page. Available at: https://database.ich.org/sites/default/files/Q9- R1_Concept%20Paper_2020_1113.pdf. Accessed March 4, 2021.
10. ICH quality guidance page. Available at: https://www.ich.org/page/quality-guidelines. Accessed March 4, 2021.