On June 10, 2021, the NMPA issued the “Guideline of Shelf-life for Passive Implantable Medical Device”, directing type testing and regulatory submission for wide range of non-active implantable devices.
Batch-to-Batch Variability
The guideline is the revised version of “Guideline of Shelf-life for Passive Implantable Medical Device” issued in May 2017. Compared with last one, this edition pays more attention on batch-to-batch variability:
- The shelf validity test should be carried out using the same final product as that of regular production., and items (e.g. packaging) shall be verified in packages without products. If batch-to-batch variability may affect the results, the reason for choosing certain batches shall be given.
- If real-time stability test is used to verify the shelf-life, the test plan and test report should be submitted. At the same time, the test conditions, test items, test judgment standards, test time points, test batch, and sample size determination basis and related research data in the test plan should be provided.
- After analysis, if accelerated stability could be used, the test plan and test report for accelerated stability tests and the experimental plan for real-time stability experiments shall be provided. At the same time, it provides the basis for determination of test conditions, test items, test criteria, accelerated aging parameters, test time points, test batches and sample sizes and related research data in the test plan.
What the Guideline Says:
The outline of the Guideline is as follows:
a. Factors affecting Shelf-life
External Factors:
1) Storage conditions, such as temperature, humidity, light, ventilation, air pressure, pollution, etc;
2) Transport condition, such as shaking and shock
3) Production method. Same medical device with different production method may have different shelf-life.
4) Production environment, such as the cleanliness, temperature, humidity, microbial, air-borne particles of sterile medical device production site.
5) Packaging, for example, product packaged in different sized containers may have different shelf-life
6) Changes in the source of raw and auxiliary materials, such as changes in supplier, purchase batch numbers,
7) Other factors, such as impact of changes in production equipment and cleaning agents, residual in cleaning the molds the equipment.
Internal factors:
1) The performance of the raw materials / components in the medical device, the degradation of the raw materials / components over time, leading to changes in their chemical properties, physical properties or expected functions, thereby affecting the overall performance of the medical device. Such as certain macromolecular materials and combinations of drugs, bioactive factors.
2) The possible interaction between the raw materials / components in the medical device.
3) The possible interaction between the raw materials / components in the medical device and the packaging material
4) The impact of production process on the raw materials / components, packaging materials, such as sterilization process.
5) The impact of radioactive substances contained in medical devices and their byproducts after radiation decay on raw materials / components and packaging materials in medical devices.
6) Retention of anti-microbial barriers in sterile packaging products.
Both internal factors and external factors can affect the technical performance of medical devices. When they exceeded the tolerance specification, they can cause equipment failure.
It is important to note that not all medical devices are required to have a definite shelf-life. When the performance of a medical device and the performance of the packaging material do not have significant change over time, it may not be necessary to determine a strict shelf-life. Additionally, when a medical device has poor stability or high-risk clinical use, the shelf-life is required to be strictly verified. For a passive implantable medical device supplied in a sterile status, the applicant should designate a validated shelf-life.
b. The Verification Process of Shelf-life
1) The registration applicant should set shelf-life for medical devices to ensure transportation, storage and expected effectiveness.
2) The registration applicant is required to conduct a comprehensive assessment of the materials, components and associated production processes used in the production and packaging, as well as the involved reference materials.
3) The registration applicant is required to set up a strict quality system document to ensure that the product is stored, transported and sold during the shelf-life.
c. The content of shelf-life verification
Verification test type:
1) Accelerated stability test
Accelerated stability test refers to a test that can infer products’ degradation in normal storage condition by placing the products in external stressed state by correlating the accelerated known degradation factors with the rate of the degradation.
2) Real-time stability test
A real-time stability test refers to placing products under predetermined storage conditions until it is noticed that its performance does not meet the specified requirements.
The real-time stability test and accelerated stability test of passive implantable medical devices should be carried out simultaneously. The results of the real-time stability test are direct evidence of the shelf-life. When the acceleration stability test results are inconsistent with them, the results should be based on real-time stability test.
Verification test detection/ evaluation items:
The applicant should set test items, test methods and determine standards in both accelerated stability test and real-time test methods. Testing items include product performance testing and packaging system performance testing.
• Product performance testing: physical and chemical testing that is related to shelf-life; biological testing if needed.
• Packaging performance testing: packaging integrity, packaging strength and microbial barrier performance testing.
Registration applicant is suggested to set up multiple detection time points (usually no less than 3) during the test of passive implantable medical device.
The products in verification test:
End products that are same with the products in conventional production should be used in medical device shelf validity verification test. At least 3 representative consecutive batches of products should be included.
Statistical methods in verification test:
Applicants should set the number of test samples for each test item in the verification test plan to ensure that the test results are statistically significant and provide relevant information in the test report.
d. The reference standards
• Basic requirements and quality system standards
ISO 11607-1; ISO 11607-2
• Standards of packaging system testing methods
YY/T 0681.1; YY/T 0681.2; YY/T 0681.3; YY/T 0681.4; YY/T 0681.5; ASTM D 4169; ASTM F 1608
• Packaging material standards
YY/T 0698.2; YY/T 0698.3; YY/T 0698.4; YY/T 0698.5; YY/T 0698.6; YY/T 0698.7; YY/T 0698.8; YY/T 0698.9; YY/T 0698.10
e. The technical documents required in registration submission
1) Basic information related to the shelf-life of the product, including the raw materials / components, packaging materials, production technology, sterilization methods (if involved), shelf validity, storage and transportation conditions;
2) An assessment report of the relevant influencing factors in the verification process of medical device shelf-life;
3) The test plan and test report of the real-time stability test.
4) If applicable, provide the test protocols and test reports for accelerated stability tests.
5) Packing process verification report and packaging, sealing equipment details;
6) Other relevant supporting information
