Circular No. 10/2020/TT-BYT on Bioequivalence Testing of Medicines

CIRCULAR

Regulations on Bioequivalence Testing of Medicines

Pursuant to Law No. 105/2016/QH13 dated April 6, 2016 on pharmaceuticals;

Pursuant to Decree No. 75/2017/NĐ-CP dated June 20, 2017 of the Government stipulating the functions, tasks, powers, and organizational structure of the Ministry of Health;

At the proposal of the Director of the Department of Science, Technology and Training;

The Minister of Health issues this Circular regulating bioequivalence testing of medicines.

Article 1. Scope of Regulation and Applicability

1. This Circular regulates the assessment of qualifications for bioequivalence testing facilities of medicines; guides bioequivalence testing of medicines and the dossier, procedures for bioequivalence testing of medicines.

2. This Circular applies to bioequivalence testing facilities of medicines and organizations and individuals related to bioequivalence testing activities of medicines.

3. Bioequivalence testing facilities of medicines subject to this Circular are facilities meeting the conditions regarding infrastructure, technology, and personnel as stipulated in Point g Clause 1 Article 33 of the Medicine Law, including:

a) Facilities complying with Good Laboratory Practice (GLP) principles and standards as prescribed in Circular No. 04/2018/TT-BYT dated February 9, 2018 of the Minister of Health on Good Laboratory Practice (hereinafter referred to as Circular No. 04/2018/TT-BYT) and complying with Good Clinical Practice (GCP) principles and standards for Phase 1 as prescribed in Circular No. 29/2018/TT-BYT dated October 29, 2018 of the Minister of Health (hereinafter referred to as Circular No. 29/2018/TT-BYT).

b) Facilities complying with GLP as prescribed in Circular No. 04/2018/TT-BYT, without accommodation areas for monitoring drug users for bioequivalence evaluation purposes, and having a contractual agreement with clinical trial facilities that comply with GCP for Phase 1 of clinical trials as prescribed in Circular No. 29/2018/TT-BYT;

c) Facilities complying with GLP as prescribed in Circular No. 04/2018/TT-BYT, with accommodation areas for monitoring drug users for bioequivalence evaluation purposes that meet the standards and principles of Good Clinical Practice as prescribed in the Appendix attached hereto, and having a contractual agreement with clinical trial facilities that comply with GCP as prescribed in Circular No. 29/2018/TT-BYT to conduct the clinical research phase in bioequivalence testing.

Article 2. Dossier for assessing qualification of bioequivalence testing facilities

1. Facilities falling under the provisions of Point a Clause 3 Article 1 of this Circular shall submit one set of dossier as follows:

a) Dossier as prescribed in Article 5 of Circular No. 04/2018/TT-BYT for evaluating compliance with GLP and dossier as prescribed in Article 8 of Circular No. 29/2018/TT-BYT for evaluating compliance with GCP. In case the facility has been issued a GLP Certificate or a Report concluding that the facility complies with GLP, the facility shall submit the dossier as prescribed in Article 8 of Circular No. 29/2018/TT-BYT to request evaluation of compliance with GCP.

b) In case the facility has been issued a GLP Certificate, GCP Certificate, or a Report concluding that the facility complies with GLP and GCP, the facility only needs to submit an Application for Issuance of a Certificate of Qualification for Pharmaceutical Business Operations according to the Model prescribed in Clause 1 Article 32 of Decree No. 54/2017/NĐ-CP dated May 8, 2017 of the Government detailing certain provisions and implementation measures of the Medicine Law (for facilities engaged in bioequivalence testing services), clearly stating that it has been issued a GLP Certificate, GCP Certificate, or a Report concluding that the facility complies with GLP and GCP. For non-commercial bioequivalence testing facilities, they only need to submit an Application for Conducting Bioequivalence Testing according to Form No. 01 attached hereto.

2. Facilities falling under the provisions of Point b Clause 3 Article 1 of this Circular shall submit one set of dossier as prescribed in Article 5 of Circular No. 04/2018/TT-BYT (for facilities requesting evaluation of compliance with GLP) or Application as prescribed in Point b Clause 1 of this Article (for facilities that have been issued a GLP Certificate) and the following technical documents:

a) Contractual agreement with healthcare facilities complying with GCP for Phase 1 of clinical trials;

b) Copy of GCP Certificate for Phase 1 of the associated facility or Report concluding that the associated facility complies with GCP for Phase 1.

3. Facilities falling under the provisions of Point c Clause 3 Article 1 of this Circular shall submit one set of dossier as prescribed in Article 5 of Circular No. 04/2018/TT-BYT (for facilities requesting evaluation of compliance with GLP) or Application as prescribed in Point b Clause 1 of this Article (for facilities that have been issued a GLP Certificate) and the following technical documents:

a) List of infrastructure, technology, and emergency equipment of the bioequivalence testing facility;

b) Contractual agreement with healthcare facilities complying with GCP;

c) Copy of GCP Certificate of the associated facility or Report concluding that the associated facility complies with GCP.

Article 3. Procedure and process for evaluating facilities meeting the conditions for conducting bioequivalence testing of drugs

1. Facilities conducting bioequivalence testing of drugs submit one set of application files corresponding to the cases of evaluation of conditions as prescribed in Article 2 of this Circular, along with the review fee as stipulated, to the Department of Medicine Management, Ministry of Health.

2. Facilities falling under the provisions of point a, Clause 3, Article 1 of this Circular:

a) The Department of Medicine Management shall cooperate with the Department of Science, Technology and Training to simultaneously assess compliance with GLP and GCP according to the procedures and processes specified in Circular No. 04/2018/TT-BYT and/or Circular No. 29/2018/TT-BYT.

b) In cases where the facility conducting bioequivalence testing of drugs already has a GLP Certificate or a report concluding that the facility meets GLP requirements, the Department of Medicine Management shall cooperate with the Department of Science, Technology and Training to assess GCP according to the procedures and processes specified in Circular No. 29/2018/TT-BYT.

c) In cases where the facility conducting bioequivalence testing of drugs already has a GLP and GCP Certificate or a report concluding that the facility meets GLP and GCP requirements: The Department of Medicine Management shall cooperate with the Department of Science, Technology and Training to accept and evaluate the application file of the facility.

3. Facilities falling under the provisions of point b, Clause 3, Article 1 of this Circular:

a) For facilities without a GLP Certificate or a report concluding that the facility meets GLP requirements, the Department of Medicine Management shall cooperate with the Department of Science, Technology and Training to assess compliance with GLP according to the procedures and processes specified in Circular No. 04/2018/TT-BYT.

b) For facilities that have been issued a GLP Certificate or a report concluding that the facility meets GLP requirements, the Department of Medicine Management shall cooperate with the Department of Science, Technology and Training to accept and evaluate the application file of the facility.

4. Facilities falling under the provisions of point c, Clause 3, Article 1 of this Circular:

a) For facilities without a GLP Certificate or a report concluding that the facility meets GLP requirements, the Department of Medicine Management shall cooperate with the Department of Science, Technology and Training to assess compliance with GLP and the accommodation area for monitoring drug users for bioequivalence testing according to the procedures and processes specified in Circular No. 04/2018/TT-BYT.

b) For facilities that have been issued a GLP Certificate or a report concluding that the facility meets GLP requirements, the Department of Medicine Management shall cooperate with the Department of Science, Technology and Training to assess the accommodation area for monitoring drug users for bioequivalence testing of drugs and emergency equipment at the facility within 15 days from the date of receiving complete valid files.

Article 4. Handling the results of evaluating facilities meeting the conditions for conducting bioequivalence testing of drugs

1. Facilities falling under the provisions of point a, Clause 3, Article 1 of this Circular:

a) The handling of assessment results and issuance of a Drug Business License with the scope of bioequivalence testing of drugs (for facilities providing bioequivalence testing services), GLP and GCP Certificates or not issuing these certificates for facilities meeting the conditions for conducting bioequivalence testing of drugs shall be carried out according to the provisions of Article 8 of Circular No. 04/2018/TT-BYT or Article 11 of Circular No. 29/2018/TT-BYT.

b) For facilities conducting bioequivalence testing of drugs that are not eligible for a Drug Business License, the GLP and GCP Certificate or report concluding that the facility meets GLP and GCP requirements serve as certification documents for the facility to conduct bioequivalence testing of drugs.

c) In cases where the facility conducting bioequivalence testing of drugs already has a GLP and GCP Certificate or a report concluding that the facility meets GLP and GCP requirements: After reviewing and assessing the files, the Department of Medicine Management, Ministry of Health shall submit to the Minister of Health for issuance of a Drug Business License with the scope of bioequivalence testing of drugs (for facilities providing bioequivalence testing services) or issue a notification confirming that the facility meets the conditions for conducting bioequivalence testing of drugs according to Model No. 02 attached to this Circular within 15 days from the date of receiving complete valid files.

2. Facilities falling under the provisions of point b, Clause 3, Article 1 of this Circular:

a) For facilities without a GLP Certificate or a report concluding that the facility meets GLP requirements, the handling of assessment results and issuance of a Drug Business License with the scope of bioequivalence testing of drugs (for facilities providing bioequivalence testing services), GLP Certificate or not issuing these certificates for facilities meeting the conditions for conducting bioequivalence testing of drugs shall be carried out according to the provisions of Article 8 of Circular No. 04/2018/TT-BYT. For facilities conducting bioequivalence testing of drugs that are not eligible for a Drug Business License, when issuing a GLP Certificate, the Department of Medicine Management, Ministry of Health must simultaneously issue a notification confirming that the facility meets the conditions for conducting bioequivalence testing of drugs according to Model No. 02 attached to this Circular.

b) For facilities that have been issued a GLP Certificate or a report concluding that the facility meets GLP requirements, after reviewing and assessing the files, the Department of Medicine Management, Ministry of Health shall submit to the Minister of Health for issuance of a Drug Business License with the scope of bioequivalence testing of drugs (for facilities providing bioequivalence testing services) or issue a notification confirming that the facility meets the conditions for conducting bioequivalence testing of drugs according to Model No. 02 attached to this Circular within 15 days from the date of receiving complete valid files.

3. Facilities falling under the provisions of point c, Clause 3, Article 1 of this Circular:

a) For facilities without a GLP Certificate or a report concluding that the facility meets GLP requirements, the handling of assessment results shall be carried out according to the provisions of point a, Clause 2 of this Article.

b) For facilities that have been issued a GLP Certificate or a report concluding that the facility meets GLP requirements:

- In case the report on the assessment of the conditions for the bioequivalence testing facility concludes that the bioequivalence testing facility meets the requirements regarding the living area, monitoring of drug users for bioequivalence testing purposes, along with emergency equipment as prescribed in the Appendix attached to this Circular, the Department of Medicines Management, Ministry of Health shall submit to the Minister of Health for issuance of a Certificate of Compliance with Conditions for Drug Business with the scope of bioequivalence testing of drugs (for bioequivalence testing service business facilities) or issue a notification document stating that the facility meets the conditions for conducting bioequivalence testing of drugs according to Model No. 02 issued together with this Circular within ten days from the date of signing the evaluation record.

- In case the report on the assessment of the conditions for the bioequivalence testing facility concludes that the bioequivalence testing facility needs to rectify and repair: within five working days from the date of completion of the actual assessment at the bioequivalence testing facility and signing the evaluation record, the Department of Medicines Management shall send a document requesting the bioequivalence testing facility to carry out rectification and repair of the deficiencies recorded in the Assessment Report.

After completing the rectification and repair, the bioequivalence testing facility must submit a written report accompanied by evidence (document files, images, videos, certificates) proving that it has completed the rectification and repair of the deficiencies recorded in the Assessment Report.

Within twenty days from the date of receipt of the rectification report, the Department of Medicines Management, in conjunction with the Department of Science, Technology and Training, shall evaluate the results of the rectification of the bioequivalence testing facility and conclude on the status of compliance with the conditions of the bioequivalence testing facility.

In case the rectification of the bioequivalence testing facility meets the requirements: the Department of Medicines Management, Ministry of Health shall submit to the Minister of Health for issuance of a Certificate of Compliance with Conditions for Drug Business with the scope of bioequivalence testing of drugs (for bioequivalence testing service business facilities) or issue a notification document stating that the facility meets the conditions for conducting bioequivalence testing of drugs according to Model No. 02 issued together with this Circular.

In case the rectification of the bioequivalence testing facility does not meet the requirements, the Department of Medicines Management shall issue a reply document specifying the reasons and send it to the facility.

Within six months from the date the Department of Medicines Management issues a document requesting amendments and supplements, the bioequivalence testing facility must submit the amended and supplemented application dossier as required. If the facility fails to amend and supplement within the above period or if the supplementary dossier submitted within twelve months from the date of the initial application does not meet the requirements, the submitted dossier will lose its validity.

- In case the report on the assessment of the conditions for the bioequivalence testing facility concludes that the bioequivalence testing facility does not meet the requirements regarding the living area, monitoring of drug users for bioequivalence testing purposes, along with emergency equipment as prescribed in the Appendix attached to this Circular: within five days from the date of completion of the actual assessment at the bioequivalence testing facility and signing the evaluation record, the Department of Medicines Management shall issue a notification document stating non-compliance with the conditions, accompanied by the Assessment Report on the Conditions for Bioequivalence Testing Facilities, and send it to the facility.

4. Within five working days from the date of issuance of a Certificate of Compliance with Conditions for Drug Business with the scope of bioequivalence testing of drugs or a Good Laboratory Practice (GLP) Certificate, a Good Clinical Practice (GCP) Certificate, or a notification document stating that the facility meets the conditions for conducting bioequivalence testing of drugs, the Department of Medicines Management shall publish on the Ministry of Health's Electronic Information Portal and the Department of Medicines Management's Electronic Information Website the following information:

a) Name and address of the bioequivalence testing facility;

b) Name of the person responsible for pharmaceutical expertise and their Pharmaceutical Practitioner License number;

c) Number of the Certificate of Compliance with Conditions for Drug Business and the GLP, GCP Certificates (if applicable);

d) Expiry date of the bioequivalence testing condition assessment and the date of the next periodic assessment;

đ) Scope of activities of the bioequivalence testing facility.

Article 5. Evaluation of the maintenance of compliance with conditions for biological equivalence testing facilities of drugs.

The periodic evaluation, handling of periodic evaluation results, change control, and sudden evaluation of the maintenance of compliance with conditions for biological equivalence testing of drugs shall be carried out in accordance with the provisions of Chapter IV of Circular No. 04/2018/TT-BYT and Chapter V of Circular No. 29/2018/TT-BYT.

Article 6. Guidelines for Biological Equivalence Testing of Drugs

The implementation of research on biological equivalence testing of drugs must comply with the guidelines stipulated in Appendix 1 of Circular No. 32/2018/TT-BYT dated November 12, 2018, which regulates the registration for circulation of drugs and drug ingredients, and Circular No. 08/2010/TT-BYT dated April 26, 2010 issued by the Minister of Health guiding the reporting of bioavailability/biological equivalence study data in drug registration and the list of reference drugs issued by the Minister of Health.

Article 7. Documentation for Biological Equivalence Testing of Drugs

The documentation for biological equivalence testing of drugs is technical documentation including the application for registration of biological equivalence testing research of drugs; the application for approval of biological equivalence testing research of drugs; the application for approval of the results of biological equivalence testing of drugs, specifically defined as follows:

1. The application for registration of biological equivalence testing research of drugs includes:

a) A request form to conduct biological equivalence testing research of drugs according to Model No. 03 issued together with this Circular;

b) Documentation containing information about the drug to be tested for biological equivalence: name of the drug, active ingredient name, composition, concentration/content, dosage form, and other related information (if applicable).

2. The application for approval of biological equivalence testing research of drugs includes:

a) A request form from the biological equivalence testing facility to approve the biological equivalence testing research of drugs submitted to the Institutional Ethics Committee in Biomedical Research according to Model No. 04 issued together with this Circular;

b) Documentation containing information about the drug to be tested for biological equivalence, including research materials on the drug: formula components, raw material source, production scheme/process summary, drug quality standards, drug test report (manufacturer's test report meeting Good Manufacturing Practice (GMP) requirements or drug testing facility's test report meeting Good Laboratory Practice (GLP) requirements), pharmacological development documentation/file of the drug to be tested for biological equivalence;

c) Legal documentation of the drug to be tested for biological equivalence, including: - The approved drug usage guide of the reference drug used in the study and the drug to be tested for biological equivalence (if applicable); - Cooperation research agreement for biological equivalence testing of drugs between the entity having the drug to be tested for biological equivalence and the biological equivalence testing facility; cooperation agreement between the organization or individual having the drug and the research support organization (if applicable).

d) Research outline for biological equivalence testing of drugs, including: - Description of the research outline for biological equivalence testing of drugs; - Data collection form or Clinical Research Case Report Form (CRF);

đ) Scientific curriculum vitae and a copy of the certificate of completion of Good Clinical Practice (GCP) training course and safety reporting training for the principal investigator issued by the Ministry of Health or by training institutions authorized to provide GCP training;

e) Information provision form and consent form for participants in the biological equivalence testing of drugs;

g) Drug label including information: drug name, active ingredient name, concentration/content, dosage form, batch number, expiration date, manufacturer's name and address. In cases where the drug has already been granted a Registration Circulation Permit, the drug label shall comply with the provisions of Circular No. 01/2018/TT-BYT dated January 18, 2018, issued by the Minister of Health regarding drug labeling and drug ingredient labeling.

3. The application for approval of the results of biological equivalence testing of drugs includes:

a) A request form to approve the results of biological equivalence testing of drugs according to Model No. 05 issued together with this Circular;

b) Report on the results of biological equivalence testing research of drugs.

Article 8. Biological equivalence testing procedure for drugs

The biological equivalence testing procedure for drugs shall be carried out in accordance with the provisions of Articles 100 and 101 of the Drug Law, specifically as follows:

1. Registration for research on biological equivalence testing of drugs:

a) The entity having the drug that needs to undergo biological equivalence testing shall submit one set of registration dossier for research on biological equivalence testing of drugs in accordance with Clause 1, Article 7 of this Circular to the entity conducting biological equivalence testing of drugs.

b) The entity conducting biological equivalence testing of drugs shall consider approving the research proposal for biological equivalence testing of drugs and enter into a biological equivalence testing contract with the entity having the drug that needs to undergo biological equivalence testing.

2. Approval of research on biological equivalence testing of drugs:

a) The entity conducting biological equivalence testing of drugs shall prepare one set of dossier in accordance with Clause 2, Article 7 of this Circular and send it to the Institutional Ethics Committee in Biomedical Research.

b) The Institutional Ethics Committee in Biomedical Research shall convene a meeting to review the research outline for biological equivalence testing of drugs within ten days from the date of receipt of complete valid dossiers and issue a review report on the research outline for biological equivalence testing of drugs.

c) Within five days from the date of issuance of the review report by the Institutional Ethics Committee in Biomedical Research, the person responsible for the professional work at the entity conducting biological equivalence testing of drugs shall decide to approve the research outline for biological equivalence testing of drugs if the research outline meets the requirements.

d) In case the research outline for biological equivalence testing of drugs requires revision, the entity conducting biological equivalence testing of drugs shall have the responsibility to perfect the dossier within a maximum period of twenty days from the date of receipt of the review report issued by the Institutional Ethics Committee in Biomedical Research requesting revisions and supplements. Beyond this deadline, the approval process for the research outline must be restarted from the beginning.

đ) Within five days from the date of receipt of the completed research outline, the person responsible for the professional work at the entity conducting biological equivalence testing of drugs shall approve the research outline for biological equivalence testing of drugs.

3. Implementation of biological equivalence testing of drugs: The entity conducting biological equivalence testing of drugs shall carry out the stages of equivalent biological research at the entity conducting biological equivalence testing or related units in accordance with the approved research outline.

4. Acceptance and approval of results of biological equivalence testing of drugs.

a) The principal researcher responsible for the study shall directly submit one set of dossier requesting acceptance of the results of biological equivalence testing of drugs in accordance with Clause 3, Article 7 of this Circular to the Institutional Ethics Committee in Biomedical Research.

b) Within ten days from the date of receipt of complete valid dossiers, the Institutional Ethics Committee in Biomedical Research shall convene a meeting and issue an acceptance report on the results of biological equivalence testing of drugs, which must include conclusions such as meeting the requirements, meeting but requiring revisions and supplements, or not meeting the requirements.

c) Within five days from the date of issuance of the acceptance report meeting safety and efficacy requirements by the Institutional Ethics Committee in Biomedical Research, the person responsible for the professional work at the entity conducting biological equivalence testing of drugs shall approve the equivalent biological research report.

d) In case the acceptance report meets the requirements but requires revisions and supplements, the entity conducting biological equivalence testing of drugs shall perfect the dossier within a maximum period of twenty-five days from the date of receipt of the notification letter. Beyond this deadline, the approval process for the results of biological equivalence testing of drugs must be restarted from the beginning.

đ) Within five days from the date of receipt of the completed dossier in accordance with the notification letter, the person responsible for the professional work at the entity conducting biological equivalence testing of drugs shall decide to approve the equivalent biological research report.

Article 9. Amending and supplementing Appendix I of Circular No. 29/2018/TT-BYT

Amending and supplementing Appendix I on Good Clinical Practice for drug clinical trials of Circular No. 29/2018/TT-BYT as set out in the Appendix attached to this Circular.

Article 10. Effective Date

This Circular takes effect from August 10, 2020. Appendix I on Good Clinical Practice (GCP) for drug clinical trials issued together with Circular No. 29/2018/TT-BYT shall be abolished from the date this Circular takes effect.

Article 11. Cross-Reference Provisions

In cases where the referenced documents in this Circular are replaced, amended, or supplemented, they shall be implemented according to the replacing document or the amended or supplemented document.

Article 12. Responsibility for Implementation

1. The Department of Science, Technology and Training:

a) Coordinate with the Drug Administration and relevant units under the Ministry to guide and organize the implementation of this Circular;

b) Participate in evaluating whether facilities meet the conditions for conducting bioequivalence testing of drugs;

c) Publish updated GCP materials for bioequivalence testing of drugs on the Ministry of Health's website and the Department of Science, Technology and Training's website;

d) Coordinate with the Ministry of Health Inspectorate and relevant units under the Ministry of Health to conduct inspections and audits to ensure compliance with GCP requirements for bioequivalence testing facilities, and handle violations within their authority or recommend competent authorities to handle them;

e) Coordinate with the Drug Administration to publish updates on integrated administrative procedures in current procedures to facilitate agencies, organizations, and individuals in handling administrative procedures.

2. Drug Administration:

a) Coordinate with the Department of Science, Technology and Training in guiding the implementation of this Circular.

b) Coordinate with the Department of Science, Technology and Training to accept applications and implement evaluations for bioequivalence testing facilities in accordance with this Circular.

3. Bioequivalence Testing Facilities of Drugs:

a) Conduct bioequivalence testing activities within the scope permitted in compliance with legal regulations;

b) Comply with the evaluation of meeting the conditions for bioequivalence testing of drugs as stipulated in this Circular;

c) Conduct bioequivalence testing activities in accordance with the files and procedures specified in this Circular;

d) Prepare files in compliance with the provisions of this Circular for submission to the Institutional Ethics Committee for review and approval, and store files in accordance with legal regulations.

e) Be subject to surprise inspections, audits, and assessments by competent state authorities to maintain GCP compliance in accordance with legal regulations.

During the implementation process, if there are difficulties or obstacles, agencies, organizations, and individuals should promptly report to the Ministry of Health (Drug Administration or Department of Science, Technology and Training) for consideration and resolution./.