The PMDA has issued a Q&A document providing practical guidance on the implementation of the Standards for Biological Raw Materials to ensure the quality and safety of pharmaceuticals, medical devices, and related products. The updated guidance addresses topics such as ensuring the reliability of donor screening and testing, the evaluation of prion clearance values, and considerations related to BSE risk status designations, thereby clarifying the latest operational approach to the Standards for Biological Raw Materials.

Q&A

Question 1

What specific means should be used to demonstrate that "the qualifications of facilities and personnel for infectious disease testing, as well as the reliability of testing data, are sufficiently ensured" as stated in Section 3(6) and (7) of the "Operation of the Standards for Biological Materials" (Notification No. 1002-1 / No. 1002-5, dated October 2, 2014; hereinafter referred to as the "Operation Notification")?

➜ Answer 1

To demonstrate that "the qualifications of facilities and personnel for infectious disease testing, as well as the reliability of testing data, are sufficiently ensured," all of the following requirements must be met:

1. If it is possible to appropriately perform the intended testing based on the latest scientific knowledge by using medical devices or in vitro diagnostics (IVD) that have received marketing approval in Japan according to the instructions in the package insert, such devices or IVDs must be used according to those instructions. Alternatively, testing equipment or reagents validated to have specificity and sensitivity equal to or higher than these must be used according to the validated method. If the intended testing cannot be appropriately performed using approved medical devices or IVDs according to their package inserts, testing equipment or reagents validated to have appropriate specificity and sensitivity in light of the latest knowledge must be used according to the validated method.
2. The intended testing must be conducted by entities (hospitals, etc., parties commissioned for specimen testing, or health laboratories) that fall under Item 1, 2, or 4 of Part 1 of the "Notification on the Enforcement of the Ministerial Ordinance Concerning the Development of Relevant Ministerial Ordinances of the Ministry of Health, Labour and Welfare Accompanying the Enforcement of Part of the Act to Partially Amend the Medical Care Act, etc." (Notification No. 0810-1 of the Health Policy Bureau, MHLW, dated August 10, 2018; hereinafter "Ordinance Enforcement Notification"). Regarding health laboratories, in principle, they must be registered by the governor of the prefecture where they are located in accordance with the "Guiding Principles for Health Laboratories" (Attachment 1 to Notification No. 0329-24 of the Health Policy Bureau, MHLW, dated March 29, 2021).
3. In accordance with the Ordinance Enforcement Notification, a quality management system for the intended testing must be established at the testing institution. Furthermore, "third-party accreditation of testing facilities such as ISO 15189," which is a recommended item in the Ordinance Enforcement Notification, must be obtained. "ISO 15189, etc." referred to here includes, for example, CLIA (Clinical Laboratory Improvement Amendments) and CAP-LAP (the Laboratory Accreditation Program by the College of American Pathologists) in addition to ISO 15189.
4. Implementation of internal quality control and participation in external quality assessment surveys, which are categorized as a "duty of effort" for hospitals and other institutions under the Ordinance Enforcement Notification, must be carried out for the intended testing. These external quality assessment surveys must be led by a third-party organization that has obtained accreditation as a proficiency testing provider (e.g., CLIA program, CAP surveys, or other inter-laboratory comparison programs consistent with relevant requirements of ISO/IEC 17043).

Question 2

Operational Notification 5(2)(i) states that "the safety of the product can be considered ensured based on the clearance value of prions that may be present in the raw materials, calculated from simulations of dilution factors during the manufacturing process and prion reduction factors during the purification process." Could you please clarify how it should be determined that the product safety has been adequately ensured? What specific criteria or evidence would be considered acceptable for such an evaluation?

➜ Answer 2

Currently, there are no specific indicators for prion clearance values that allow for the evaluation that product safety is ensured. Section 5(2)(b) of the Operation Notification was included in consideration of the possibility that such indicators or methods may be established in the future.

Question 3

There have been cases in which approval was granted on the condition that the raw materials be switched from those originating in the United States to those sourced from countries designated as acceptable for use. However, if the United States becomes an acceptable country of origin, it would appear that, from a safety perspective, there would no longer be a need to switch the raw materials. In such cases, may it be understood that implementation of the switch required as a condition of approval is no longer necessary? In addition, if the timing of the raw material switch is described in the marketing authorization application, please advise on the appropriate procedure for deleting or revising such statements. Furthermore, if information regarding the switch has been provided through the package insert or on the Ministry of Health, Labour and Welfare website, please advise on the appropriate procedure for deleting or revising those descriptions.

➜ Answer 3

The United States was recognized by the World Organisation for Animal Health (OIE) as a country with a negligible risk for bovine spongiform encephalopathy (BSE) on May 29, 2013. Therefore, U.S.-origin bovine-derived raw materials manufactured from materials collected before the date of recognition must still be replaced. However, U.S.-origin bovine-derived raw materials manufactured from materials collected on or after the date of recognition comply with the Standards for Biological Raw Materials, and therefore replacement is no longer required. As the circumstances differ depending on the individual product, the appropriate method for deleting or revising descriptions in the marketing authorization application and related documents (such as the timing of the replacement) should be discussed on a case-by-case basis with the Pharmaceuticals and Medical Devices Agency (PMDA).

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Reference

Partial Revision of the Q&A on the Implementation of the Standards for Biological Ingredients