Look at the GMP development process of cell therapy products

On 2022.

The author of this article will sort out the cell therapy products based on his work experience

Although it is written as a manuscript, the author uses colloquial terms, tries not to write SOP, and does not conduct "risk" assessment

This new type of "drug" can only be understood from the perspective of a new recruit who has been in the cell industry for many years

First of all, it can be seen from the name "cell therapy product" that it is different from our traditional "drug" name

The concept of medicine is very familiar to everyone.

With the occurrence of the "Wei Zexi" incident as a symbol, the state also realized that it was a very serious problem.

Based on the author's professional experience, I would like to briefly sort out the process of the "Appendix Second Edition Draft for Comments" to today

In 2017, the author entered the industry when the "sorrow" of the "Wei Zexi" incident was not exhausted and the industry was in a cold winter

As a person who has worked in a pharmaceutical manufacturing company for many years, when I first entered the industry, the impact at that time was huge

First of all, my original knowledge system structure is not in line with the cell therapy industry, whether it is a specific technical problem or an understanding of some terms

Secondly, I am puzzled by the entire operation mode of the industry.

The understanding and implementation of the quality system in software is even less

It is under such hardware and software conditions that a large number of clinical studies initiated by researchers are being carried out in China

As the author who has been indoctrinated with GMP awareness for many years, the impact is huge

It was because of their persistence that the cold winter gradually began to feel warm

It is said that there are two lines of "cell therapy": a "pharmaceutical line" and a "medical technology line"
.

2017 "Medical Technology Line" is still a cold winter! !

01  Drug Line of "Cell Therapy"

Let's talk about the "drug line" first.
Of course, the competent authority is the Food and Drug Administration
.

On August 30, 2017, the FDA approved the listing of Novartis' Kymriah (Tisagenlecleucel), making Kymriah the world's first marketed CAR-T therapy
.

At this time, the entire industry is boiling, and the industry leaders who have persisted for so many years finally see the hope of being able to go public
.

At the same time, the "capital" market has also smelled the Chinese market
.
As a result, large and small companies engaged in cell therapy research and development have sprung up in China
.

In 2017, the first real crab-eater in China came out.
On 2017.
12.
08, Nanjing Legend applied for a clinical trial application to CDE, and it was successfully accepted on 2017.
12.
11, and the clinical trial application was approved on 2018.
03.
13
.

There was also a supplement in the middle.
The speed is so fast that I am very impressed by the person who has dealt with the Food and Drug Administration for many years! Perhaps this is the beginning of the change of the Food and Drug Administration, and the follow-up is indeed getting better and better
.

The various departments of the National Food and Drug Administration have not been idle, and a large number of follow-up guidelines have continued to be released:

2003-03-20 "Technical Guidelines for Human Cell Therapy Research and Preparation Quality Control"

In fact, there has been guidance for a long time, but no one has succeeded in the follow-up clinical and drug declaration! !

2017-12-22 "Technical Guidelines for Research and Evaluation of Cell Therapy Products (Trial)"

2018-06-05 "Key points to consider in CAR-T cell therapy product quality control testing research and non-clinical research"

2019-10-18 "Cell Therapy Product Telegram Clinical Trial Pharmacy Research Questions and Answers (Phase 1)"

2019-11-28 "GMP Appendix - Cell Therapy Products" (draft for comments)

2020-03-13 "Key points to consider when applying for clinical trial pharmaceutical research and application materials for cell therapy products"

2020-08-24 "Technical Guidelines for Clinical Trials of Human-derived Stem Cells and Their Derived Cell Therapy Products (Draft for Comment)"

2020-09-10 "Technical Guiding Principles for Pharmacy Research and Alteration of Bovine Drug Products during Clinical Trials" (Draft for online comments)

2020-09-30 "Technical Guidelines for Pharmaceutical Research and Evaluation of Gene Transduction and Modification Systems (Draft for Comment)"

2020-09-30 "Technical Guidelines for Pharmaceutical Research and Evaluation of Immune Cell Therapy Products (Draft for Comment)"

2021-02-09 "Technical Guidelines for Clinical Trials of Immune Cell Therapy Products (Trial)"

2021-08-17 "Technical Guidelines for Pharmaceutical Research and Evaluation of Human-derived Stem Cell Products" (Draft for Comment)

2021-09-18 "Technical Guidelines for Clinical Risk Management Plan for the Application of Chimeric Antigen Receptor T Cell (CAR-T) Cell Therapy Products" for Comments

2021-11-30 "Technical Guidelines for Non-clinical Research of Gene Modified Cell Therapy Products (Trial)"

2021-11-30 "Technical Guidelines for Clinical Research and Evaluation of Gene Therapy Products (Trial)"

2022-01-06 "Good Manufacturing Practice for Pharmaceuticals-Appendix for Cell Therapy Products (Draft for Comment)"

During this period, 2 drugs were also approved for marketing
.

Fosun Kate

In May 2018, report to IND

In June 2021, "Aquilence Injection" was approved for marketing

About Yikaida (Aquilence Injection)

Achilles injection is a human CD19 autologous CAR-targeted human CD19 autologous CAR-targeted human CD19 that Fosun Kite introduced from Kite (a Gilead company) in the United States for technology transfer in China in early 2017.
T cell therapy products
.

It is indicated for the treatment of adult patients with relapsed or refractory large B-cell lymphoma (including diffuse large B-cell lymphoma unspecified, primary mediastinal large B-cell lymphoma, high-grade New drug applications for B-cell lymphoma and diffuse large B-cell lymphoma transformed from follicular lymphoma) have been approved by the NMPA in June 2021
.

WuXi Junuo

In December 2017, report to IND

In September 2021, "Ruiji Orenza Injection" was approved for marketing

About Benoda (Rigiorenza Injection)

Benoda (Ruiji Orenza Injection) is a CD19-targeting drug independently developed by WuXi Ju Nuo on the basis of the CAR-T cell technology platform of Ju Nuo Medical (a company of Bristol-Myers Squibb).
Autologous CAR-T cell immunotherapy products
.

As WuXi Junuo's first product, Benoda has been approved by the China National Medical Products Administration in September 2021 for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after second-line or above systemic therapy tumor (r/r LBCL), becoming the first CAR-T product approved as a Class 1 biological product in China
.

Benoda is currently the only CAR-T cell immunotherapy product in China that has received three awards at the same time, including the "Major New Drug Creation" project, the priority review qualification for new drug marketing applications, and the breakthrough therapy drug designation
.

Also, institutional reforms, preclinical communication mechanisms, and a 60-day clinical default licensing system.
.
.

02 The medical technology line of "cell therapy"

Let's come back to talk about the "medical technology line", the competent authority is the National Health Commission
.

The medical technology line can be further divided into "clinical research line" and "clinical application line"
.

Let's list the laws first

Clinical Research IIT:

2014-10-28 "Clinical research in medical and health institutions"

2015-08-21 "Notice on Printing and Distributing Stem Cell Clinical Research Management Measures (Trial)"

2019-03-29 "Clinical Research and Translational Application of Somatic Cell Therapy (Draft for Comment)"

2021-09-09 "Administrative Measures for Medical and Health Institutions to Carry out Investigator-Initiated Clinical Research"

Clinical application:

2009-05-01 "Notice of the Ministry of Health on Printing and Distributing the Administrative Measures for the Clinical Application of Medical Technology"

2009, Notice of the General Office of the Ministry of Health on Publishing the First Class III Medical Technology Catalogue Allowed for Clinical Application

2015-06-29 "Notice of the National Health and Family Planning Commission on Cancelling the Approval of Class III Medical Technology Clinical Application Access"

2018-11-01 "Administrative Measures for Clinical Application of Medical Technology"

2019-03-29 "Clinical Research and Translational Application of Somatic Cell Therapy (Draft for Comment)"

The difference between "clinical research" and "clinical application" is similar to the concepts of "clinical trial" and "marketed drug" in medicine
.
To put it bluntly is "don't want money" and "want money"
.

As for the issue of "receiving money" for cell therapy products, the National Health and Construction Commission has not mentioned it since 2019.
According to the "2019 Transformation and Application (Draft for Comment)", even if the money is collected, "the hospital can do it by itself.
" , companies should honestly go the way of IND
.

If enterprises want to verify whether their products are effective as soon as possible, they can also consider the IIT line
.
Of course, starting from 2021, pilot IITs in some cities require national-level filing for clinical research, and the relevant requirements are much stricter than before
.

Finally, let’s talk back to the “Good Manufacturing Practice for Pharmaceuticals – Appendices for Cell Therapy Products (Draft for Comment)”.
From the low of 2019 to the beginning of 2022, the technology of cell therapy is advancing rapidly, and the variety and quantity of products are also advancing rapidly.
Therefore,22 The content of the edition is almost completely rewritten
.

The types of drugs covered are wider and the requirements for MAH are clearer.
The main differences between the two versions I summarized are as follows:

1.
A separate chapter "Chapter 5 Donor Screening and Donor Materials" is added, which is no longer together with the "Materials" chapter
.

2.
The wording is more people-oriented, with "donors" becoming "donors"

3.
Increase the requirements for retaining samples of "donor materials" and "key materials"
.

4.
Add "according to registration requirements" to make corresponding changes and implementations
.
The applicable stage that is more in line with the GMP appendix is ​​"Good Manufacturing Practice"
.
Among the corresponding requirements are the requirements and standards for inheritance and implementation "at the time of registration"
.

5.
The most important point is to close the original "conditional release" and "conditional use"
.

Biotechnology is advancing, and regulatory authorities are advancing
.
Our pharmaceutical practitioners should make progress, so that this "medical technology", which originally originated from the "health system", is more suitable for the attributes of "drugs"
.

Note: The original text has been deleted