China's first continuous manufacturing guide is coming, and the pharmaceutical industry will usher in major changes!

In order to encourage innovation and pharmaceutical modernization, help the implementation of the ICH Q13 guiding principles in China, and also guide enterprise research and development, unified evaluation scale
.
On September 9, 2022, the official website of the Center for Drug Evaluation (CDE) of the State Food and Drug Administration issued a public solicitation of technical guidelines for the continuous manufacturing of oral solid preparations of chemical drugs (draft for comments), and the time limit for soliciting comments is one month from the date of issuance, which is the first technical guideline for continuous manufacturing of preparations in China, making up for the gaps
in China's continuous manufacturing technology at the regulatory level and technical level 。 This is not only the specific requirements of how to carry out continuous manufacturing of preparations, but also reflects the scientific regulatory consideration between continuous manufacturing of complex preparations and industrial innovation, which is more worthy of attention, and the implementation of continuous manufacturing technology in China can also be expected
in the future.

Regulatory background of regulatory practices for continuous manufacturing of pharmaceuticals abroad

- ICH Chapter

Continuous manufacturing is an innovative production concept, continuous manufacturing (CM), mainly refers to the production of an intermediate product in the upper process, that is, the production method of downward transfer, known as continuous manufacturing, in the manufacturing industry called assembly operation, and in chemical production called continuous manufacturing, in July 2015, the first FDA-approved continuous manufacturing drug - The treatment of cystic fibrosis (Orkambi?) developed by Vertex in the United States, a number of chemical oral solid dosage products using continuous manufacturing processes have been approved for marketing worldwide, ICH has issued strict regulatory control and quality requirements for continuous manufacturing, the author has sorted out the milestones related to continuous manufacturing, as follows:

1) In 2018, the ICH group established a new working group on the supervision of continuous manufacturing of drugs, with the main members coming from regulators and industry representatives
with sufficient background, professional knowledge and experience in the supervision of continuous manufacturing of drugs.

2) In June 2018, the Q13
: Continuous Manufacturing for Drug Substances and Drug Products issue was approved in Kobe, Japan.

3) In November 2018, the topic "Q13: Continuous Manufacturing of APIs and Formulations" was officially adopted, endorsing its concept paper and business plan
.

4) On July 27, 2021, ICH officially released the Q13 Continuous Manufacturing of APIs and Formulations, for public consultation, describing the scientific and regulatory considerations for the development, implementation, operation and lifecycle management of continuous manufacturing (CM), which has entered Phase 2 of the ICH process, during which the ICH Conference will release a draft consensus to regional regulators for internal consultation and public comment
.

Regulatory background of regulatory practices for continuous manufacturing of pharmaceuticals abroad

- America

At present, the United States is recognized as the country with the largest number of continuously manufactured drugs, and the author has sorted out the milestones related to continuous manufacturing, as follows,

1) On September 29, 2004, the FDA issued the "Guidance for Industry: PAT-A Framework for Innovative Pharmaceutical Development, Manufacturing, and Qualit Assurance", which clearly stipulates
continuous production.

2) In 2015, the FDA began to encourage the industrial application of continuous manufacturing of drugs, and established an emerging technology team to help companies implement innovative technologies, and continuous manufacturing is one of
the emerging technologies that the organization mainly focuses on and vigorously promotes.

3) On June 23, 2017, FDA released the Current Recommendations for Implementing and Developing Continuous Manufacturing of Solid Dosage Drug Products in Pharmaceutical Manufacturing
.

4) On February 26, 2019, FDA released the draft "Quality Considerations for Continuous Manufacturing Guidance for Industry", which outlines the current FDA's thinking on innovative continuous manufacturing production models, divided into six parts, namely introduction, background, quality considerations, information location in the declaration documents, definitions, references, etc
.

Regulatory background of regulatory practices in the continuous manufacturing of pharmaceuticals in China

Continuous manufacturing is a new type of production process, the current domestic relevant experience is insufficient, the foundation is relatively weak, there is currently no continuous manufacturing related guidelines in China, the author sorted out the milestones related to continuous manufacturing, as follows,

1) On October 18, 2021, the official website of CDE issued the Notice on the Public Solicitation of Opinions on the ICH Guiding Principles (Q13: Continuous Manufacturing of APIs and Preparations), clarifying that Q13: Continuous Manufacturing of APIs and Preparations is now entering the third phase of solicitation of comments, and in accordance with the requirements of the relevant ICH charter, ICH regulatory members need to collect opinions on the draft guidance of Phase 2b in the region and feedback ICH, and the deadline for solicitation is December 31, 2021
。

2) In February 2022, an expert working group on continuous manufacturing was established and research and literature translation were launched, and on the basis of fully discussing the feasibility of implementing the Q13 guiding principles in China, a transformation implementation timeline and roadmap
were formulated.

3) In July 2022, after internal discussion and solicitation of opinions from the department, the technical committee of the department reviewed and formed the first draft
.

4) In August 2022, organize industry experts, industry associations, and representatives of domestic and foreign pharmaceutical enterprises to hold expert meetings to discuss, revise according to expert opinions, and form a draft
for comments.

5) In August 2022, CDE cooperated with the China Drug Administration Research Association to hold an online training on "Concepts and Case Studies Related to Continuous Manufacturing", which will invite ICH Q13 Expert Working Group (EWG) experts from foreign regulatory agencies and enterprise experts with practical experience in continuous manufacturing as speakers to interpret the technical requirements of continuous manufacturing and share cases, the topics and trainers are excerpted as follows:

6) On August 19, 2022, CDE held an expert seminar on ICH Q13 guiding principles in a combination of online and offline mode, and the meeting discussed that the implementation of Q13 guiding principles in China is of great significance
to accelerate drug research and development, promote the high-quality development of the industry, and promote patients' faster access to new drugs.
However, there are problems such as insufficient experience and lack of personnel in professional fields in the implementation of continuous manufacturing in registration review and verification and inspection, and there is still a certain gap
with other international regulatory agencies.
In the future, we will make comprehensive preparations for the implementation of the Q13 guiding principles, further improve relevant domestic technical guidelines, inspection and verification standards, etc.
, increase training and publicity related to continuous manufacturing, and organize on-site visits in close cooperation with the industry to deepen the understanding and mastery
of advanced technology.

7) On September 9, 2022, CDE issued the "Technical Guidelines for Continuous Manufacturing of Chemical Oral Solid Preparations (Draft for Comments)", the time limit for soliciting comments is 1 month from the date of issuance, which is the first domestic technical guideline for continuous manufacturing of preparations, making up for the gaps in China's continuous manufacturing technology at the regulatory level and technical level, the drafting of this guiding principle draws on relevant foreign guiding principles and standards, and clarifies the basic considerations for continuous manufacturing of oral solid preparations of chemical drugs.
The relevant requirements are consistent with the basic principles and concepts of ICH Q13, and the main contents include: overview, overall consideration, related concepts, control strategies, process verification, stability studies, batch changes, drug quality systems, application requirements, and references
.

brief summary

At present, China's pharmaceutical enterprises have a certain degree of attention to continuous manufacturing, but the understanding is not deep enough, the motivation is insufficient, there are practical difficulties in the development of professional talents, technical reserves and instruments and equipment, etc.
, it is necessary to lay out in advance, accelerate the development of continuous manufacturing processes and equipment, and shorten the gap between China's continuous manufacturing processes and equipment and the international advanced level has become a top priority
.

References

       [1] www.
cde.
org.
cn

[2] Chinese Journal of Food and Drug Regulation, etc