Cell therapy is coming to a harvest, and the Pharmacopoeia Commission intends to release a rapid microbial examination strategy for cell-based products

However, there are many particularities in the quality attributes and aseptic production process of such products, its individual differences are large, the yield is small, the validity period is short, the clinical demand is urgent, and the final product needs to be released quickly.

1) In 2019, the National Pharmacopoeia Commission established the project of "Sterility Rapid Inspection Method" (Project No.
2019S11) National Drug Standard Improvement Project
.

2) Chinese Pharmacopoeia 2020 Edition, 9201 "Guidelines for the Verification of Alternative Methods for Microbiological Testing of Drugs" (Part III, page 684, Part IV, page 494) clearly provides guidance for whether the test methods used can replace the methods prescribed by the pharmacopoeia for the microbiological testing of drugs, and microbiology laboratories should verify alternative methods when using non-pharmacopoeia test methods (i.
e.
alternative methods) for various reasons, such as cost, production volume, speed and simplicity, and improving the quality of drugs.
A method
that confirms that its application is better than or equivalent to pharmacopeia.
Compared with traditional inspection methods, these methods are either simple and fast, or have the potential for real-time or near-real-time monitoring, making it possible to take corrective actions early in production and monitor and guide good production, while the use of new technologies also promotes the reduction of production costs and the improvement
of inspection levels.

3) On October 26, 2021, the official website of the National Pharmacopoeia Commission published for the first time the draft of the draft law on the microbiological examination of cell products, pointing out that the current sterility examination method (General Rule 1101) cannot guarantee the completion of the release inspection of cell products
before product use.
The use of this method for microbial release inspection of products shall be conditionally implemented after risk assessment on the basis of fully considering factors such as the production process of the product, the level of sterility assurance, the risk of microbial contamination, and the benefit/risk of the user
.

4) On May 31, 2022, CDE issued the "Technical Guidelines for Pharmaceutical Research and Evaluation of Immune Cell Therapy Products (Trial)", which also mentioned that for products with short expiration dates or small sample sizes, new detection methods
with rapid and small sample sizes can be considered.

5) On June 28, 2022, the national group information platform released the group standard "Technical Requirements for the Verification of Rapid Aseptic Examination Method for Cell and Gene Therapy Products" (T/SHPPA 012-2022), jointly drafted by Shanghai Institute of Food and Drug Inspection and Research Institute, Shanghai Drug Evaluation and Verification Center of Shanghai Food and Drug Administration and Shanghai Pharmaceutical Industry Association, which will be implemented from July 28, 2022, and the verification technical requirements for rapid sterility examination of cell and gene therapy products are suitable for short-term, Cell and gene therapy products with small batches and the use of current pharmacopeia methods can not guarantee the completion of release inspection before product use, can also be used as a reference for the implementation of rapid sterility examination method in the clinical trial stage of cell and gene therapy products, and the verification requirements of rapid sterility examination method are stipulated, which should at least include: exclusivity, detection limit, reproducibility, durability, and these rapid alternative methods will be widely used
as innovative drugs are on the market.

6) On December 1, 2022, the official website of the National Pharmacopoeia Commission once again released the public draft of the "Microbiological Inspection Law for Cell Products", the publicity period is 1 month, the "Microbiological Inspection Law for Cell Products" released this time is a rapid microbiological examination method, mainly suitable for cell products
with short validity period and small batch, and the current sterility examination method (General Rule 1101) cannot ensure that the release inspection is completed before the product is used.

Second, why is it called "Microbiological Inspection Law for Cell Products" instead of "Sterile Inspection Law for Cell Products"

Microbiology experts from the China Institute for Food and Drug Control and the Shanghai Institute of Food and Drug Inspection pointed out in the article that the cell therapy products targeted by the "Microbiological Inspection of Cell Products" have not been treated by the final sterilization process, and are also different from the varieties that use aseptic production processes and sterilization and filtration, and are not sterile products in the traditional sense, referring to foreign pharmacopoeia (EP General Principles 2.
6.
27.
"Microbiological examination of cell products", USP1071 Rapid Microbiological Testing for Sterile Short-Term Product Release - Risk-Based Approach"), named Microbiological Examination rather than Sterility Examination
.

Third, the consideration of choosing a detection method

The 2020 edition of the Chinese Pharmacopoeia, 9201 "Guidelines for the Verification of Alternative Methods for Drug Microbial Testing" mentioned that with the rapid development of microbiology, some new microbiological testing technologies have been introduced, which can be roughly divided into three categories:

(1) Testing technology based on microbial growth information, such as bioluminescence technology, electrochemical technology, turbidimetry, etc.
;

(2) Detection technology for direct determination of live microorganisms in the measured medium, such as solid-phase cell counting method, flow cytometry counting method, etc.
;

(3) Analysis technology based on specific components contained in microbial cells, such as fatty acid determination technology, nucleic acid amplification technology, gene fingerprint analysis technology, etc
.

In the selection of detection methods, the "Microbial Inspection Law for Cell Products" adopts a detection method based on commercial automatic microbial culture system, which monitors the color or fluorescence change signal of the reaction substrate in the flask caused by carbon dioxide produced by microbial growth and metabolism in real time through the instrument, or the headspace pressure change signal of the culture flask, combined with visual observation, to determine whether there is microbial growth in the test product, originally developed for clinical testing, mainly used for rapid microbial detection of blood and other body fluid samples, and also used in clinical stem cell bank detection.
This type of technology is also recommended
by the European and American pharmacopoeias.

References

[1] Official website of the Chinese Pharmacopoeia Commission, China Journal of Drug Standards, etc

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