"Guidelines for Stability Studies of Passive Implantable Medical Devices (Revised 2022)"

In order to further strengthen the management of the stability research of passive implantable medical devices, the Center for Device Review of the State Food and Drug Administration organized the formulation of the "Guidelines for the Stability Research of Passive Implantable Medical Devices (Revised 2022)", which is hereby issued .
Announce.

Attachment: Guidelines for Stability Research of Passive Implantable Medical Devices (Revised in 2022) (Download)

 

State Drug Administration

Medical Device Technology Review Center

March 15, 2022

 

Appendix

 

Guidelines for Stability Studies of Passive Implantable Medical Devices

(Revised 2022)

The purpose of this guideline is to guide registration applicants in the preparation and writing of passive implantable medical device stability research and registration application materials, and also provide reference for technical review departments.

This guideline is a general requirement for the stability study of passive implantable medical devices, and the applicant should determine whether the content is applicable based on the specific characteristics of the product. If it is not applicable, the reasons and corresponding scientific basis shall be explained in detail, and the contents of the registration application materials shall be enriched and refined according to the specific characteristics of the product.

This guideline is a guidance document for registration applicants and technical reviewers, but does not include administrative matters involved in review and approval, nor is it enforced as a regulation. The guideline should be used under the premise of complying with relevant laws and regulations. . If there are other methods that can meet the requirements of relevant regulations, they can also be used, but detailed research data and verification data should be provided. If there are other regulations and guidance documents involving specific regulations on the stability study of a certain type of medical device, it is recommended that the registration applicant use this guideline together. The stability study of the drugs in the drug-device combination medical device should also refer to the relevant guidance documents for drugs.

This guiding principle is formulated under the current system of regulations and standards and the current level of cognition. With the continuous improvement of regulations and standards, as well as the continuous development of science and technology, the relevant content of this guiding principle will also be adjusted in a timely manner.

This guideline is a revised version of the "Guidelines for the Application Materials for Shelf Validity Registration of Passive Implantable Medical Devices" (2017 revision) issued by the former State Food and Drug Administration.

1. Scope of application

This guideline is mainly applicable to the stability study of passive implantable medical devices and the preparation of relevant registration application materials. Stability studies generally include shelf life, in-use stability, and shipping stability. Passive non-implantable medical devices shall be implemented with reference to the applicable part according to the actual product situation and risk analysis results.

The shelf life and transportation stability studies include both the performance stability of the device itself and the stability of the packaging performance. When the medical device material is relatively stable, the verification of the packaging stability should be mainly considered. If the product properties and packaging properties of a medical device do not change significantly over time, shelf life verification may not be required.

2. Key points of registration review

(1) Study on shelf life

1. Influencing factors of shelf life

There are many factors that affect the shelf life of medical devices. Some of the factors that are closely related to passive implantable medical devices are listed here, but they are not limited to the following:

External influencing factors mainly include:

- Storage conditions, such as temperature, humidity, light, ventilation, air pressure, pollution, etc.;

- Transportation conditions, such as vibration, shock during transportation.

Internal influencing factors mainly include:

- The characteristics of each raw material/component in a medical device deteriorating over time, such as some polymer materials, drug components in some combination products of medicine and equipment, etc.;

- possible interactions between raw materials/components in the medical device;

- possible interactions between raw materials/components and packaging materials (including preservation media) in medical devices;

- The impact of raw materials/components and packaging materials in medical devices due to the production process, such as the irradiation sterilization process used in the production process;

- Influence of radioactive substances contained in medical devices and their by-products after radioactive decay on raw materials/components and packaging materials in medical devices;

- Retention of microbial barriers in aseptically packaged products.

Both internal and external factors can affect the technical performance indicators of medical device products to varying degrees, and when the expected performance cannot be achieved, the device may fail. The registration applicant should try to effectively control each factor to minimize the impact on the technical performance indicators of the medical device.

In addition, the impact of the following factors on the shelf life setting should also be considered during product design and development:

- Influence of raw and auxiliary materials, such as suppliers, quality standards, stability, etc.;

- Production method, the same medical device product produced by different methods may have different shelf life;

- Production environment, such as cleanliness, temperature and humidity, microbial and suspended particle load of sterile medical device production sites;

- Packaging, e.g. liquid products in containers of different sizes may have different shelf lives due to different specific surface areas in contact with the container;

- Other influencing factors, such as the influence of changes in production equipment and the influence of cleaning agents and mold release agents used in the equipment.

When the above factors change, it may lead to changes in shelf life, and re-verification is necessary.

2. The shelf life verification process

The registration applicant needs to study the shelf life to prove that the product meets the requirements for use within the shelf life under the specified storage and transportation conditions.

The verification of the shelf life of medical devices runs through the entire process of the device's research and development, and is continuously confirmed during the product verification and improvement process.

The registration applicant needs to reasonably design the medical device shelf validity verification scheme, and carry out the verification according to the scheme. When the verification result does not support the set shelf validity period, the product can be improved or the shelf validity period can be reset according to the existing verification results.

3. Shelf validity period verification content

3.1 Type of verification test

The verification test of shelf life of medical devices can usually be divided into two categories: accelerated stability test and real-time stability test.

3.1.1 Accelerated stability test

Accelerated stability testing is a test in which samples are stored at a higher temperature to shorten the time to simulate real-time aging.

The accelerated stability experimental design is based on the assumption that the chemical reactions involved in material modification follow the Arrhenius reaction rate function. The function is based on collision theory, which confirms that the rate of increase or decrease in the reaction that produces a change in a chemical reaction proceeds according to the following formula:

r: The reaction rate; A: The constant (frequency factor) of the material; φ: Apparent activation energy (eV); k: Boltzmann constant (0.8617×10-4eV/K); t: Absolute temperature.

It is important to note that not all materials/components age according to the thermodynamic ageing properties of this function. Registration applicants need to consider its applicability before using this function for accelerated stability test design.

A large number of chemical reaction studies have shown that a 10°C increase or decrease in temperature can result in a doubling or halving of the rate of chemical reactions. Then a simplified formula of accelerated aging can be established according to the Arrhenius reaction rate function:

 

AAT: accelerated aging time; RT: real-time aging time; Q10: aging coefficient of temperature increase or decrease by 10℃; TAA: accelerated aging temperature; TRT: preset actual storage temperature.

The above formula reflects the relationship between the accelerated aging time and the corresponding real-time aging time in the accelerated stability test.

Among them, Q10 is generally set to 2, but can also be conservatively set to 1.8. If the Q10 set by the registration applicant in the accelerated stability test is greater than 2, detailed relevant research data must be provided at the same time.

Setting a higher accelerated aging temperature TAA can reduce the time of accelerated stability test. However, higher temperatures (eg, above the glass transition temperature of polymers) may cause changes in the properties of medical device raw materials, components, and/or packaging materials or induce multi-stage or multiple chemical reactions, resulting in biased test results. Therefore, the accelerated aging temperature should generally not exceed 60 °C. If the registration applicant sets a higher accelerated aging temperature in the accelerated stability test, detailed relevant research data should also be provided.

The TRT should be able to represent the temperature under the actual storage conditions of the product. The TRT can be set in combination with the expected storage temperature range, existing historical data of similar products, and stability data of equipment and/or packaging materials, and provide a basis for formulation. If the product has a special standard or guidance document that stipulates TRT, it should be used first.

Some products are not suitable for the above-mentioned accelerated stability test design, and real-time stability test is required, such as the drug ingredients in some combination medical device products.

3.1.2 Real-time stability test

The real-time stability test is a test performed by storing the samples under the specified actual storage conditions. In the real-time stability test, the registration applicant should determine the appropriate temperature, humidity, light and other conditions according to the actual production, transportation and storage conditions of the product, and test the product at the set observation time point.

The applicant can set the real-time aging temperature in combination with the expected storage temperature range, existing historical data of similar products, and stability data of equipment and/or packaging materials. If the product has a special standard or guidance document that specifies the real-time aging temperature, it should be used first.

The real-time stability test results are direct evidence to verify the shelf life of the product. When the accelerated stability test results are inconsistent with them, the real-time stability test results shall prevail.

3.1.3 Consideration of other test conditions

In accelerated and real-time stability studies, the applicant should evaluate and select the appropriate relative humidity according to the product characteristics and expected storage conditions, and provide the reasons and basis for the selection. The relative humidity of 60%±10% is generally recommended. If humidity has a significant impact on product performance within the validity period, it is recommended that the applicant set high humidity and/or low humidity and other conditions to verify the performance of the product under the most unfavorable conditions. If the relative humidity has little effect on the product within the validity period, no special requirements for relative humidity are required.

If other factors significantly affect the stability of the product, it is recommended to set appropriate test conditions for verification, such as illumination.

3.2 Validation test test/evaluation items

Regardless of the accelerated stability test or the real-time stability test, the registration applicant needs to set the test items, test methods and judgment standards in the test plan. When there is no criterion, the zero-point time performance data can be used as the reference index of the test item.

The test project only needs to evaluate the relevant performance of the product over time, including the performance test of the device itself and the performance test of the packaging system. The main purpose of the packaging system performance test is to verify the barrier performance of the packaging system to microorganisms, that is, the maintenance of sterile state/microbial limit requirements. If the biocompatibility of the product involved may change over time, a biological evaluation is also required.

3.3 Products subject to verification tests

The shelf life verification test of medical devices should be carried out with the same final product as in conventional production, and suitable items (such as packaging system performance) can be verified using packaging without product or simulated product.

The registration applicant may conduct verification tests under worst-case conditions on the test product to ensure that the test product can represent the worst production conditions, such as a standard sterilization cycle followed by one or more additional sterilization cycles, or the use of several sterilization cycles. different sterilization methods.

3.4 Reference Standards

It is recommended that applicants for medical device registration use the methods/measures specified in national standards, industry standards and recognized international standards to verify the shelf life of their medical device products as much as possible, so as to reduce the deviation of verification results and improve the accuracy of verification conclusions. The appendix lists some of the standards that may be involved in the shelf life verification process, but is not limited to the listed content.

3.5 Requirements for research data on shelf life

When registering passive implantable medical devices, registration applicants need to provide detailed shelf life research materials, generally including test conditions (temperature/humidity, transportation conditions), test items, judgment standards, accelerated aging parameters (if applicable), tests Time point, sample type and specification, batch and sample size, test data results and analysis, test conclusions, etc.

If the registration applicant uses the shelf life research data of other medical device products it produces instead of the application product research data, it is necessary to demonstrate the suitability.

(2) Use stability

In-use stability should be distinguished from shelf life studies. The product shall maintain its safety and efficacy during its life cycle under normal use, maintenance (if applicable) conditions. The implantation site and intended use are different, and the factors affecting the stability of its use are also different, and the impact of the implantation operation should be considered when applicable. For passive implantable medical devices, in-use stability can generally be verified in performance studies.

(3) Transportation stability

Transportation stability is usually carried out through simulated transportation tests. By simulating changes in the environment (temperature, humidity, air pressure, etc.), drop, collision, vibration, acceleration, etc. during transportation, the product will not change in performance and function, and the packaging system has the ability to protect the product. ability. After the simulation test, observe whether there are unacceptable abnormalities in the appearance of the package, test whether the product performance function meets the requirements, and prove that the environmental conditions during transportation will not adversely affect the characteristics and performance of the medical device (including integrity and cleanliness) influence. For medical devices containing liquids, low temperature or freeze-thaw conditions also need to be considered.

The shelf life may be affected by the shipping process. If affected, simulated shipping can be combined with shelf life. Simulated shipping can be performed before or after aging. Before or after aging, depending on whether to simulate transport to a hospital for storage, or to simulate storage at the manufacturer and then transport two different scenarios.

3. References

[1] "Regulations on the Supervision and Administration of Medical Devices" (Order No. 739 of the State Council of the People's Republic of China) [Z].

[2] "Administrative Measures for Registration and Filing of Medical Devices" (Order No. 47 of the State Administration for Market Regulation) [Z].

[3] "Announcement on the Announcement of Medical Device Registration Application Materials Requirements and Approval Document Format" (State Drug Administration No. 121 in 2021) [Z].

[4] Basic principles of medical device safety and performance. (State Drug Administration No. 18 in 2020) [Z].

[5] Shelf Life of Medical Devices[Z], FDA Guidance, 1991

[6] Container and Closure System Integrity Testing in Lieu of Sterility Testing as a Component of the Stability Protocol for Sterile Products[Z], FDA, 2008.

[7] Guidance Technical Files and Design Dossiers for Non Active Medical Devices [Z]. TuV SuD, 2008.

[8] "USE-BY" DATE[Z]. MEDDEV 2.2/3 rev.3.1998.

[9] ASTM F 1980(07), Standard Guide for Accelerated Aging of Sterile Barrier Systems for Medical Devices[S].

[10] "Technical Guiding Principles for Chemical Drug Stability Research" [Z], State Drug Administration, 2005.

[11] Wang Chunren. The basic principle and method of determining the validity period of medical device accelerated aging experiment [J]. China Medical Device Information. 2008,14(5):67-70.

 

Appendix

Some of the standards involved in the shelf life verification process

 

1. Basic requirements and quality system standards

1. ISO 11607-1 "Packaging for terminally sterilized medical devices - Part 1: Requirements for materials, sterile barrier systems and packaging systems"

2. ISO 11607-2 "Packaging of Terminally Sterilized Medical Devices Part 2 Qualification Requirements for Forming, Sealing and Assembly Processes"

Two, packaging system test method standard

1. YY/T 0681 series of standards

6. ASTM D 4169 "Transportation Container and System Performance Testing"

7. ASTM F 1608 "Breathable Packaging Materials Resistance to Microbial Penetration Grade Test"

3. Packaging material standards

YY/T 0698 series of standards