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

In order to encourage innovation and pharmaceutical modernization, to help the implementation of the ICH Q13 guidelines in China, but also to guide enterprises in research and development, unified review scale
.
On September 9, 2022, the official website of the Drug Evaluation Center (CDE) of the State Food and Drug Administration released the public solicitation of the "Technical Guidelines for the Continuous Manufacturing of Oral Solid Preparations of Chemical Drugs (Draft for Comment)", and the time limit for soliciting opinions is 1 month from the date of issuance, which is the first technical guidance principle for the continuous manufacturing of preparations in China, and makes up for the gap
in China's continuous manufacturing technology at the regulatory level and technical level 。 This is by no means just the specific requirements of how to carry out the continuous manufacturing of preparations, but also reflects the scientific regulatory considerations between the 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.

1 Regulatory background of continuous manufacturing of drugs in foreign countries - ICH

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

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

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

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

4) On July 27, 2021, ICH officially released the Q13 "Continuous Manufacturing of APIs and Preparations" guide, which is open for comments, describing the scientific and regulatory considerations for the development, implementation, operation and life cycle management of continuous manufacturing (CM), which has entered Phase 2 of the ICH process, at which the ICH Assembly will issue a draft consensus to regional regulators for internal consultation and public comment
.

2 Regulatory Background of Continuous Manufacturing of Pharmaceuticals in Foreign Countries - United States

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 has clear regulations
on 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 enterprises 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, the FDA released Current Recommendations for Implementing and Developing Continuous Manufacturing of Solid Dosage Drug Products in Pharmaceutical Manufacturing
.

4) On February 26, 2019, the 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, which are divided into six parts, namely introduction, background, quality considerations, information location in the declaration document, definitions, references, etc
.

3 Regulatory background of continuous manufacturing of drugs in China

Continuous manufacturing is a new type of production process, the current domestic relevant experience is insufficient, the foundation is relatively weak, the domestic current no continuous manufacturing related guidelines issued, the author sorted out the milestone events related to continuous manufacturing, as follows,

1) On October 18, 2021, the official website of CDE published the "Notice on 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 Phase 3 for comments, and in accordance with the requirements of the relevant ICH regulations, ICH regulatory body members are required to collect the region's comments on the draft Guiding Principles of Phase 2b and feedback to ICH, and the deadline for soliciting is December 31, 2021
。

2) In February 2022, an expert working group on continuous manufacturing was established and research and literature translation were initiated, and on the basis of fully discussing the feasibility of the implementation of Q13 guidelines in China, a timetable and roadmap
for the implementation of the transformation 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 a first draft
.

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

5) In August 2022, CDE cooperated with the China Drug Supervision and 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 continuous manufacturing practice experience to serve as speakers to interpret continuous manufacturing technical requirements and share cases, and the topics and trainers are excerpted as follows:

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

7) On September 9, 2022, CDE issued a public solicitation of "Guidelines for the Continuous Manufacturing Technology of Oral Solid Preparations for Chemical Drugs (Draft for Comment)", the time limit for soliciting opinions is 1 month from the date of release, which is the first domestic technical guidelines for the continuous manufacturing of preparations, making up for the gap at the regulatory level and technical level of China's continuous manufacturing technology for preparations, the drafting of this guiding principle, drawing on relevant foreign guidelines and standards, clarifies the basic considerations for the 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 considerations, relevant concepts, control strategies, process verification, stability studies, batch changes, drug quality systems, declaration requirements, and references
.

4 Summary

At present, China's pharmaceutical enterprises have a certain degree of concern for continuous manufacturing, but the understanding is not deep enough, the power is insufficient, there are practical difficulties in the development of professional talents, technical reserves and equipment and equipment, etc.
, it is necessary to advance the layout, 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 Administration, etc