PROLOGUE

It's been about three years since I had written the three-part series of articles on Continuous Manufacturing (CM). Since then, a lot of water has flown under the bridge and there have been several developments in the field of CM. Now is probably the right time, to summarize all developments, from a technical perspective, from a regulatory perspective and in terms of the adoption of CM from the pharmaceutical industry perspective. 

Continuous Manufacturing, an innovation in the advanced manufacturing field has been gaining importance over the last few years, as drug products have been getting commercially approved by regulators over the world and reaching the market. This series of three articles on this topic reviews some of the recent developments for this important topic. 

The first article focuses on the recent regulatory national and international guidance and their impact on the acceptability of CM across the globe. 

The second article focuses on the challenges still open to CM after the publication of ICH Q13 Guidance document and how CM could contribute to in-shoring back to US.

The third and final part article focuses on CM in China and adoption of CM for biologic products.

DEVELOPMENTS IN CM- PART 1

ABSTRACT: This paper outlines some of the global regulatory changes that have taken place for CM, their significance and what impact this has on the global acceptance of CM as an advanced manufacturing technique. 

CHANGES IN GLOBAL REGULATORY LANDSCAPE

GUIDANCE FROM US-FDA

In March 2023, the FDA issued a final guidance¹, titled "Q13 Continuous Manufacturing of Drug Substances and Drug Products" that describes the scientific and regulatory considerations for the development, implementation, operation, and lifecycle management of CM.  The guidance applies to CM of drug substances and drug products for chemical entities and therapeutic proteins, including biosimilars, and the conversion of batch manufacturing to CM for existing products.

The guidance proposes strategies that account for scientific and regulatory considerations that impact CM. Under the scientific considerations, development of a CM should consider process dynamics, material characterization, equipment design and system integration. Regulatory considerations include input material attributes, process monitoring and control, and drug stability to ensure quality product over time. The last section of the guidance provides examples of how to implement CM of drug substances for chemical entities and therapeutic proteins and provides additional regulatory and scientific considerations and approaches for managing disturbances.

ICH GUIDELINE Q13 ON CM OF DRUG SUBSTANCES AND DRUG PRODUCTS

After two years of analysis and comments from the first draft publication, on January 6th, 2023, the final guidance document ², "ICH Q13 Continuous Manufacturing of Drug Substances and Drug Products", was published and became legally effective from July 10th, 2023.   

This guideline describes scientific and regulatory considerations for the development, implementation, operation, and lifecycle management of CM. Building on existing ICH Quality guidelines, this guideline provides clarification on CM concepts, describes scientific approaches, and presents regulatory considerations specific to CM of drug substances and drug products. This guideline applies to CM of drug substances and drug products for chemical entities and therapeutic proteins. The principles described in this guideline may also apply to other biological/biotechnological entities. It is applicable to CM for new products (e.g., new drugs, generic drugs, biosimilars) and the conversion of batch manufacturing to CM for existing products.

The European Medicines Agency (EMA) became the first regulator to adopt the International Council for Harmonization (ICH) new guideline Q13 on continuous manufacturing (CM) of drug substances and drug products, effective July 10, 2023.

Two aspects are key to this new ICH Q13 Guideline. Firstly, it has a wider scope than others, covering not only drug products and APIs, but also considers biotechnological/biological processes with non-clear boundaries of what those types of processes include.  

Secondly, CM basically has the same requirements as batch manufacturing processes, which makes sense and includes enforcing consistent good manufacturing practices, making robust quality assurance for pre- and post-production tasks, ensuring robust control strategies and warranty of stability of products.   

GUIDANCE FROM CDE, CHINA

In China, to guide the R&D of enterprises, unify the evaluation scale, and help the implementation of the guiding principles of ICH "Q13: Continuous Manufacturing of APIs and Preparations", on 20th March 2023, the Drug Evaluation Center of the State Food and Drug Administration issued "Technical Guidelines for the Continuous Manufacturing of Oral Solid Preparations for Chemical Drugs (Trial)" ³  

SIGNIFICANCE AND IMPACT OF REGULATORY GUIDANCES

While CM is a relatively new concept for the pharmaceutical industry, it is a concept that's already well-established in many other industries. This high-efficiency approach is already the standard for many industry verticals, including fossil fuel, chemicals, paper products, and more. For these diverse industries, CM is a vital and established way to maximize quality and minimize supply disruptions, while lowering manufacturing costs, expediting outputs, and simplifying scale.

Through the FDA, 2019 draft guidance, the agency presented the opportunity to the pharmaceutical industry to switch from batch manufacturing to CM to shorten processing times, enhance development approaches and boost supply chain resilience. 

There is general consensus in the industry that one of the top barrier for implementation of CM were the regulatory challenges stemming from a lack of a globally harmonized regulatory guideline on CM ^4,5,6. Harmonization is crucial, without which, the manufacturers are forced to get approval from different regulatory agencies to market their products in various countries, which can be an expensive and time consuming process to an extent that even the marketing of the product could be a question. Typically, regulatory approvals tended to suppress post-approval changes to drug products, inadvertently forcing a fixed mindset of batch processes for safety in the manufacturer's production philosophy ⁷. Furthermore, fear of regulatory delays has hindered the adoption of CM by manufacturers⁸. The situation gets even more complex for CRO's/CDMO's wanting to adopt this technique given the initial high cost of the manufacturing equipment and analytical controls, as well as the technical skillsets and experience needed to be developed for both development as well as the manufacturing stage. The regulatory uncertainty just adds another dimension to decision making for adoption of CM.  

However, regulatory support for CM has grown in recent years. FDA, EMA and PMDA have established specialized teams to promote the adoption of CM. Established in 2014, FDA Emerging Technology Program (ETP) aims to help manufacturers overcome implementation challenges.^9,10 With the implementation of ICH Q12 guideline in 2019¹¹ unnecessary post-approval applications are reduced to promote manufacturing innovations.¹² With the more wider acceptance of ICH in general for harmonization, the publication of ICH Q13 guidance document will hopefully address this global acceptability challenge from regulators that the manufacturers face. Also the FDA's forward looking statement in the news release about the guidance: "The FDA will continue taking necessary steps to facilitate the pharmaceutical industry's implementation of CM and other emerging technologies that can improve product quality and help address many of the underlying causes of drug shortages and recalls", tends to provide more reassurance to the manufacturers about the continued support from FDA on the acceptability of CM as an advanced manufacturing technique.  

Continue to read: 

Continuous Manufacturing Part 2: Challenges Open to CM

REFERENCES

1. Q13 Continuous Manufacturing of Drug Substances and Drug Products Guidance for Industry, https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs  

2. ICH guideline Q13 on continuous manufacturing of drug substances and drug product, EMA/CHMP/ICH/427817/2021 Committee for Medicinal Products for Human Use

3. Notice of the Center for Drug Evaluation of the State Food and Drug Administration on the release of the "Technical Guiding Principles for Continuous Manufacturing of Oral Solid Preparations of Chemical Drugs (Trial)" (No. 19, 2023) (cde.org.cn) 

4. Fonteyne M et al. Process analytical technology for continuous manufacturing of solid-dosage forms. TrAC Trends in Analytical Chemistry. 2015; 67:159-66

5. Vanhoorne V, et al. Recent progress in continuous manufacturing of oral solid dosage forms. Int J Pharm. 2020; 579:119194.

6.  Lee K, et al. Summary from advanced manufacturing technology workshop held at 6th Accelerating Biopharmaceutical Development Meeting. PDA J Pharm Sci Technol. 2020: pdajpst.2020.011429.

7. Plumb K. Continuous processing in the pharmaceutical industry: changing the mindset. Chem Eng Res Des. 2005;83(6):730-8.

8. Promoting continuous manufacturing in the pharmaceutical sector. Center for Health Policy at Brookings. 2015 Oct 19.

9. Martin J. Is continuous manufacturing right for your drug product? Pharmaceutical Online. 2019 May 30.

10. U.S. Food and Drug Administration. Emerging Technology Program. 2019 [homepage on the Internet]. [cited 2020 Dec 20]. Available from: https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/emerging-technology-program.

 11. International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. Technical and regulatory considerations for pharmaceutical product lifecycle management. Q12. 2019 [homepage on the Internet]. [cited 2020 Dec 20]. Available from: https://database.ich.org/sites/default/files/Q12_Guideline_Step4_2019_1119.pdf

12. U.S. Food and Drug Administration. Statement from FDA Commissioner Scott Gottlieb, M.D. on new programs to promote the adoption of innovations in drug manufacturing that can improve quality and lower drug costs. 2019 [homepage on the Internet]. [cited 2020 Dec 20]. Available from: https://www.fda.gov/news-events/press-announcements/statement-fda-commissioner-scott-gottlieb-md-new-programs-promote-adoption-innovations-drug.

ABOUT THE AUTHOR 

Deepak Hegde, Ph.D., M.F.M, is an industrial pharmacist by training. He has a been involved in development and commercialization of both innovative and generic drugs from a very early phase of development to technical transfers for commercial manufacturing sites, for the past 25 years. During his career, he has worked at Rhone Poulenc, Novartis (Sandoz), USV Ltd., WuXi AppTec, GSK & EOC Pharma. He is currently working with Shenzhen Pharmacin Co. Ltd. as Senior Vice President-Technology & Manufacturing. 

Email: deepak.hegde@hlkpharma.com