Circular No. 07/2022/TT-BYT stipulates drugs that must undergo bioequivalence testing and requirements for bioequivalence study data reports in drug registration for circulation in Vietnam.

CIRCULAR

Regulations on drugs that must undergo bioequivalence testing and requirements for the dossier reporting bioequivalence research data in drug registration for circulation in Vietnamreport on bioequivalence study data for drug registration and circulation in Vietnamthuốc tại Việt Nam

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Pursuant to the Medicine Law dated April 6, 2016;

Pursuant to Decree No. 54/2017/NĐ-CP dated May 8, 2017 of the Government detailing certain provisions and implementation measures of the Law on Medicines;7 Government Decree detailing certain provisions and measures to implement the Drug Law;

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 Drug Administration Department,

The Minister of Health issues this Circular regulating drugs that must undergo bioequivalence testing and requirements for the dossier reporting bioequivalence research data in drug registration for circulation in Vietnam.

PART I

GENERAL PROVISIONS

Article 1. Scope of Regulation

1. This Circular provides for:

a) Generic drugs containing active ingredients or having a particular dosage form must report bioequivalence research data when registering for circulation in Vietnam;

b) Dossier on reporting bioequivalence research data of generic drugs.

2. This Circular applies to generic drugs with systemic therapeutic effects after absorption into the general circulation.

Article 2. Interpretation of Terms

In this Circular, the following terms are understood as follows:

1. Test drug: Is a generic drug used to prove the same efficacy (both in terms of effectiveness and safety of the drug) when administered at the same dose via the same route of administration under the specified conditions on the label (if any) compared to the reference drug through bioequivalence test data (in vivo) or dissolution equivalence test (in vitro) compared to the reference drug. Reference drug

2. (Comparator product/Reference product): Is the drug that the generic drug will replace in treatment. Typically, the reference drug is an innovator drug or a drug that has been registered for circulation with established data on efficacy, safety, and quality. Innovator drug

3. (Innovator pharmaceutical product): Is the first drug approved for circulation worldwide based on complete data on quality, safety, and efficacy, including drugs approved or not yet approved for circulation in Vietnam. Pharmaceutical equivalence

4. (Pharmaceutical equivalence): Are drugs containing the same active ingredient (for single-ingredient drugs) or the same set of active ingredients (for multi-ingredient drugs), where the active ingredients in the drugs are identical and have the same molar concentration, while the drugs have the same dosage form, drug release mechanism, the same route of administration, and equivalent quality standards. Pharmaceutical alternatives

5. (Pharmaceutical alternatives): Are drugs containing the same active ingredient but differing in chemical form (salts, esters, ethers, isomers, mixtures of isomers, complexes, or derivatives) of each active ingredient or in active ingredient concentration or dosage form. Investigational drug

6. : Is a generic drug submitting a registration dossier for circulation which includes a dossier reporting bioequivalence research data.Bioequivalence study (in vivo

7. Bioequivalence study): Is a clinical trial on volunteers designed to compare the bioavailability of the generic drug with the reference drug with the aim of proving the substitutability of the generic drug for the reference drug. Dissolution equivalence test

8. (Equivalence dissolution): Is a comparative study of dissolution profiles between drugs in different dissolution media. The dissolution equivalence test is also known as an in vitro equivalence study. In vitro-in vivo correlation

9. (In vitro - in vivo correlation): Is a mathematical model describing the correlation between in vitro characteristics (dissolution characteristics or drug release characteristics) and in vivo responses (drug concentration or total amount of drug absorbed into biological fluids) of a drug. Research institution : Is an organization participating in part or all of the bioequivalence testing or dissolution equivalence testing process of the investigational drug. Immediate-release dosage form (Immediate release dosage form): Is a dosage form using traditional excipients and manufacturing techniques without the intention to change the rate of drug release from the dosage form - including conventional dosage forms such as tablets, capsules, suspensions, oral solutions, injectable solutions, suspensions, emulsions, and unconventional dosage forms or special dosage forms such as solid dispersions, chewable tablets, effervescent tablets, buccal tablets, sublingual tablets. Modified-release dosage form

10. (Modified release dosage form): Is a dosage form using some excipients and/or manufacturing techniques different from immediate-release dosage forms to create a different rate and/or location of drug release compared to immediate-release dosage forms when used via the same route of administration. Common modified-release dosage forms include delayed-release dosage forms, prolonged-release dosage forms, multiphasic-release dosage forms, intramuscular/subcutaneous depot formulations, transdermal drug delivery systems.Fixed-dose combination finished pharmaceutical product

11. (Fixed-dose combination finished pharmaceutical product): Is a finished pharmaceutical product in a formula combining two or more active ingredients in a fixed ratio. Single-ingredient drugs packaged together in the same unit for simultaneous use do not fall into this category. Biopharmaceutics Classification System (BCS)

12. (Biopharmaceutics Classification System abbreviated as BCS): Is a system classifying drugs based on their solubility in water and permeability through gastrointestinal epithelium. Biowaiver

13. (Biowaiver): Is the approval of a generic drug's ability to substitute for a reference drug without requiring the submission of bioequivalence research data of the generic drug itself.

14. Drug study in fasting state: (Biopharmaceutics Classification System abbreviated as BCS): Is a drug substance classification system based on the drug substance's solubility in water and its permeability through the gastrointestinal mucosa.

15. No requirement for bioequivalence testing (Biowaiver): Approval of a generic drug that can replace a reference drug without requiring a report on bioequivalence study data of that reference drug. (Immediate release dosage form): Is a dosage form using traditional excipients and manufacturing techniques without the intention to change the rate of drug release from the dosage form - including conventional dosage forms such as tablets, capsules, suspensions, oral solutions, injectable solutions, suspensions, emulsions, and unconventional dosage forms or special dosage forms such as solid dispersions, chewable tablets, effervescent tablets, buccal tablets, sublingual tablets. của chính loại thuốc đó.

16. Drug study under fasting conditions: Biological equivalence study where the volunteer participant takes the medication in a fasting state and without consuming alcoholic and xanthine-containing beverages for at least 8 hours.

17. Postprandial drug administration study: Biological equivalence study where the volunteer participant takes the medication immediately after eating or according to the guidance on the timing of medication intake relative to meals as specified in the summary of product characteristics.

18. Single-dose design study: Biological equivalence study in which biological samples used for analysis are collected after a single dose of the medication is administered at each study stage.

19. Multiple-dose design study: Biological equivalence study in which biological samples used for analysis are collected after multiple doses of the medication are taken to achieve steady-state blood concentrations.

20. Polar approach: The process of analyzing and selecting two concentrations among various concentrations of the same drug (with the same formulation, produced by the same manufacturer) that are determined to be most different such that any differences between the remaining concentrations fall within the range of difference of the two selected concentrations to conduct the study and extrapolate the study results to the remaining concentrations.

21. ASEAN: An acronym for the English phrase "Association of Southeast Asian Nations," translated into Vietnamese as the Association of Southeast Asian Nations.

22. ICH: An acronym for the English phrase "International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use," translated into Vietnamese as the International Conference on Harmonization of Technical Requirements for the Registration of Pharmaceuticals for Human Use.

23. ASEAN Bioequivalence Study Data Report Template: The report template prescribed in Appendix IV of the ASEAN Implementation Guidelines for Bioequivalence Studies issued together with Circular No. 32/2018/TT-BYT dated November 12, 2018, of the Minister of Health on the registration and circulation of drugs and raw materials for drug production (hereinafter referred to as Circular No. 32/2018/TT-BYT).

24. ICH Bioequivalence Study Data Report Template: The report template according to the structure and content of clinical study reports (Structure and Content of Clinical Study Reports - E3 Guideline) of ICH.

Chapter II

DRUGS CONTAINING ACTIVE INGREDIENTS AND FORMULATIONS MUST HAVE BIOEQUIVALENCE STUDY DATA REPORT

Article 3. Drugs containing active ingredients must submit bioequivalence study data when registering for circulation

1. Criteria for selecting active ingredients contained in generic drugs that require submission of bioequivalence study data upon registration for circulation shall be prioritized in the following order:

a) Narrow therapeutic window;

b) Low bioavailability and/or significant inter-individual variability;

c) Included in prescription drugs belonging to one of the pharmacological groups including cardiovascular drugs, antidiabetic drugs, antibiotics, antipsychotics/anticonvulsants, antivirals;

d) Included in the list of drugs used in national programs including: HIV/AIDS Prevention Project; Mental Health Protection Community Project; Tuberculosis Prevention Project; Malaria Prevention Project.

2. The list of active ingredients contained in generic drugs that require submission of bioequivalence study data when registering for circulation is stipulated in Appendix I attached hereto.

Article 4. Generic drugs according to their pharmaceutical form must have a report on bioequivalence study data when registering for circulation.

Generic drugs according to their pharmaceutical form must have a report on bioequivalence study data when registering for circulation including:

1. Drugs with an immediate-release pharmaceutical form, having systemic effects, containing active substances specified in Clause 2, Article 3 of this Circular and not falling under the cases stipulated in Article 5 of this Circular.

2. Drugs with a modified-release pharmaceutical form, having systemic effects, and not falling under the cases stipulated in Article 5 of this Circular.

Article 5. Generic drugs that do not undergo bioequivalence testing due to inherent bioequivalence characteristics with the reference drug.

Generic drugs that do not undergo bioequivalence testing due to inherent bioequivalence characteristics with the reference drug include:

1. Injectable generic drugs administered intravenously as aqueous solutions, containing the same active substances at the same molar concentrations as the reference drug and not containing excipients that interact with the active substances or affect their distribution as in the reference drug. In cases where such excipients must be used in the formulation, their components must be similar to those in the reference drug with equivalent quantities or if there are differences in quantity, it must be proven that these differences do not affect the pharmacokinetics of the active substance.

2. Generic drugs administered by injection other than intravenous injection, in the form of aqueous or oil solutions, containing the same active substances at the same molar concentrations and the same excipients at similar concentrations compared to the reference drug. For injectable drugs in aqueous solution, the excipients in the formulation may differ but must be of the same type (having the same function) with similar concentrations as those in the reference drug, and any differences in excipients must be proven not to affect the viscosity of the solution.

3. Oral liquid generic drugs (including solid drugs that are directed to be dissolved in water before use) must have the same pharmaceutical equivalence as the reference drug and not contain excipients that can affect the transport, absorption, or stability of the active substance in the body as in the reference drug. In cases where the formulation must use excipients that can affect the transport, absorption, or stability of the active substance in the body, the types and quantities of these excipients in the generic drug must be similar to those in the reference drug.

4. Generic drugs in gaseous form at the time of use must have the same pharmaceutical equivalence as the reference drug.

Chapter III

PROVISIONS ON REFERENCE DRUGS AND REQUIREMENTS FOR BIOEQUIVALENCE TESTING BIOEQUIVALENCE TESTING

Article 6. Reference drugs used in bioequivalence testing.

1. The criteria for selecting reference drugs used in bioequivalence testing for registration purposes are prescribed in the following order of priority:

a) Drugs listed in the list of original brand-name drugs published by the Ministry of Health or drugs that have been granted a registration certificate by the Ministry of Health with complete quality, safety, and clinical efficacy data;

b) Reference drugs are new chemical entities that have not yet been granted a Registration Certificate in Vietnam but have been approved by one of the stringent regulatory authorities specified in Clause 10, Article 2 of Circular No. 32/2018/TT-BYT and are currently circulating in the markets of these countries;

c) In cases where it is impossible to determine a reference drug meeting the requirements of points a and b of this clause, the selection of reference drugs should prioritize the following:

- Drugs that have been approved by one of the stringent regulatory authorities specified in Clause 10, Article 2 of Circular No. 32/2018/TT-BYT and are currently circulating in the markets of these countries.

- Drugs that have been prequalified by the World Health Organization.

Among these drugs, priority should be given to those with valid registration certificates issued by the Ministry of Health of Vietnam.

2. In addition to complying with the provisions of Clause 1 of this Article, reference drugs used in bioequivalence testing for immediate-release formulations, modified-release formulations, and fixed-dose combination drugs must also comply with the following requirements:

a) In cases where the drug under consideration is a single-component immediate-release formulation, the reference drug is a single-component immediate-release formulation;

b) In cases where the drug under consideration is a modified-release formulation, the reference drug is a modified-release formulation with the same release mechanism;

c) For fixed-dose combination drugs:

- In cases where the drug under consideration is intended to replace a fixed-dose combination drug that has been approved with full safety and efficacy data (original brand-name drug or new chemical entity), this fixed-dose combination drug should be selected as the reference drug.

- In cases where the drug under consideration is being developed to replace a regimen of single-component drugs and this regimen has full safety and efficacy data, the corresponding single-component drugs should be selected as the reference drugs.

3. Reference drugs used in bioequivalence testing must have clear origins and sources. Documentation proving the origin and source of the reference drugs is specified in Point c, Clause 1, Article 8 of this Circular.

4. Based on the criteria for selecting reference drugs stipulated in Clause 1 of this Article, based on other regulations concerning reference drugs stipulated in Clauses 2 and 3 of this Article, and taking into account practical circumstances, the Drug Administration Department will establish a list of reference drugs, seek opinions from the Advisory Council for Granting Drug Registration Certificates, and issue a Decision on the List of Reference Drugs Used in Bioequivalence Testing. The List of Reference Drugs Used in Bioequivalence Testing will be announced on the Drug Administration Department's website at https://dav.gov.vn by the Drug Administration Department of the Ministry of Health.

Article 7. Provisions for bioequivalence research in the dossier of the bioequivalence study data report

1. The research must meet the following requirements:

a) It must be designed and conducted in accordance with the guidelines for conducting ASEAN bioequivalence testing or other reference guidelines specified in Appendix VI issued together with this Circular;

b) For modified-release dosage forms that release active ingredients orally and have systemic effects, studies must be conducted under fasting conditions and fed conditions;

c) For immediate-release dosage forms that have systemic effects and do not fall within the cases stipulated in Article 5 of this Circular, studies must be conducted under fasting conditions. In cases where the pharmacokinetic characteristics of the comparator drug are known to be affected by food or the comparator drug has instructions for use after meals, studies may be conducted under fed conditions instead of fasting conditions;

d) For fixed-dose combination drugs, bioequivalence studies must be conducted for all active ingredients contained in the drug;

đ) Apply bioequivalence test designs for each drug according to the recommendations of the United States Food and Drug Administration (US FDA) or the European Medicines Agency (EMA);

2. The research must be conducted at testing units evaluated and recognized by the competent authority of the country concerned and must comply with Good Clinical Practice (GCP) principles as stipulated in Clause 1, Article 4 of Circular No. 29/2018/TT-BYT dated October 29, 2018, issued by the Minister of Health on clinical drug trials and Good Laboratory Practice (GLP) as stipulated in Clause 1, Article 3 of Circular No. 04/2018/TT-BYT dated February 9, 2018, issued by the Minister of Health on laboratory practices;

3. In cases where the comparator drug being considered for use in bioequivalence research is an innovator drug but is not produced at the same manufacturing facility as the innovator drug registered for circulation in Vietnam, the registration entity must demonstrate the interchangeability between the comparator drug used in the research and the innovator drug registered for circulation in Vietnam according to the ASEAN Bioavailability/Bioequivalence Research Guidelines;

4. The model report of bioequivalence study data for the drug is prescribed in Point a, Clause 1, Article 8 of this Circular. Specific requirements for the report of bioequivalence study data for the drug being considered are prescribed in Appendix III issued together with this Circular;

5. Bioequivalence testing is not required for the drug being considered in the following cases:

a) The drug being considered has a formulation ratio equivalent to the test drug in the bioequivalence study and complies with the provisions in Section I of Appendix II issued together with this Circular;

b) The drug being considered has the same dosage form, formulation, production process but a different active ingredient content from the test drugs in the bioequivalence study and complies with the provisions in Section II of Appendix II issued together with this Circular;

c) The drug being considered is an oral solid immediate-release dosage form that is bioequivalent to the comparator drug and belongs to the fast-dissolving, fast-absorbing group according to the biopharmaceutics classification system and complies with the provisions in Section III of Appendix II issued together with this Circular;

d) The drug being considered is manufactured at a different production site than the test drug in the bioequivalence study and complies with the conditions stipulated in Section IV of Appendix II issued together with this Circular;

Chapter IV

Dossier of the Bioequivalence Study Data Report

Article 8. Documents for reporting bioequivalence study data in cases where the drug under consideration is being tested for bioequivalence with a reference drug.

1. The contents of the documents include the following materials:

a) A report on bioequivalence study data (in vivo) of the drug according to the ASEAN Bioequivalence Data Report Form current version or the ICH Bioequivalence Data Report Form, wherein the commitment regarding similarity between the test drug used in the study and the drug under consideration must be prepared according to Form 01/BE stipulated in Appendix VII issued together with this Circular;

b) Research institution's documents and information as prescribed in Article 12 of this Circular;

c) Documents proving the origin and source of the reference drug used in the research including:

- A copy of the purchase invoice for the reference drug from the supplier clearly showing the name and address of the supplier;

- A copy of the drug label confirmed by the registration entity/manufacturing entity clearly showing all relevant information: drug name, name and address of the drug manufacturer, production batch number, expiration date;

- A signed commitment by the director of the registration entity/manufacturer regarding the authenticity of the provided documents, committing that the reference drug was purchased from the correct market where the drug is authorized for circulation, stored under the correct storage conditions indicated on the label from the time of purchase until the start of the research.

2. In cases where the drug under consideration is being tested for bioequivalence while the volunteer uses the drug in different states (fasted, fed, single dose, multiple doses), the documents for reporting bioequivalence study data shall include multiple bioequivalence study reports and each report corresponding to each state of drug use must contain all or sufficiently explain the documents prescribed in Clause 1 of this Article.

Article 9. Documents for reporting bioequivalence study data for drugs specified in point a, point b, Clause 5, Article 7 of this Circular.

The documents for reporting bioequivalence study data for drugs specified in point a, point b, Clause 5, Article 7 of this Circular include the following materials:

1. A request form for not conducting bioequivalence testing (Biowaiver) for the drug under consideration according to Form 02/BE stipulated in Appendix VII issued together with this Circular.

2. Bioequivalence documents of the selected dosage forms or dosages tested for bioequivalence with the reference drug in accordance with the provisions of Article 8 of this Circular.

3. An explanation of the selection of dosages for reporting bioequivalence study data and using the results of bioequivalence testing of these dosages to request not to conduct bioequivalence testing for the remaining dosages, including the dosage of the drug under consideration.

4. A comparison table of the formulations of the dosages proposed not to conduct bioequivalence testing, including the dosage of the drug under consideration, with the formulations of the dosages with reported bioequivalence study data.

5. A comparison table of the manufacturing processes of the dosages proposed not to conduct bioequivalence testing, including the dosage of the drug under consideration, with the manufacturing processes of the dosages with reported bioequivalence study data.

6. A report on the dissolution equivalence test between the dosages proposed not to conduct bioequivalence testing, including the dosage of the drug under consideration, and the dosages with reported bioequivalence study data. Requirements for the dissolution equivalence test report are specifically stipulated in Appendix IV issued together with this Circular.

7. A commitment regarding the similarity between the drug under consideration and the test drug used in the dissolution equivalence test according to Form 01/BE stipulated in Appendix VII issued together with this Circular.

8. Information on the linear pharmacokinetics of the drug under consideration (if applicable).

Article 10. The dossier for reporting biological equivalence study data for the drug under consideration as stipulated in point c, Clause 5, Article 7 of this Circular

The dossier for reporting biological equivalence study data for the drug under consideration as stipulated in point c, Clause 5, Article 7 of this Circular shall include the following documents:

1. A request form for not conducting bioequivalence testing (Biowaiver) for the drug under consideration according to Form 02/BE stipulated in Appendix VII issued together with this Circular.

2. Documents of the research institution as prescribed in Article 12 of this Circular.

3. Documents proving that the active substance(s) in the drug under consideration have good solubility and permeability characteristics in accordance with the guidance provided in Appendix III. Bioequivalence testing based on BCS guidelines set forth in the ASEAN Biological Equivalence Study Implementation Guidelines issued together with Circular No. 32/2018/TT-BYT is exempted.

4. Data proving that the excipients in the drug under consideration meet the requirements to be considered for exemption from bioequivalence testing, including:

a) A comparison table of excipient components in the formula between the drug under consideration and the reference drug or another non-reference drug but with equivalent formulation to the drug under consideration and has been designated as a reference drug by one of the stringent regulatory authorities specified in Clause 10, Article 2 of Circular No. 32/2018/TT-BYT, accompanied by information on the sources of excipient component data in the reference drug or reference drug formula, including the Drug Information Manual approved by the Drug Administration Department, the Summary of Product Characteristics already approved, or the Drug Assessment Report published on the European Medicines Agency (EMA) and the Stricter Regulatory Authority (SRA) websites specified in Clause 10, Article 2 of Circular No. 32/2018/TT-BYT, or on reputable pharmaceutical information websites such as eMC (Electronic Medicines Compendium). In cases where information about the excipient components in the reference drug or reference drug formula cannot be found, qualitative results of the excipient components in the reference drug or reference drug formula must be provided to prove that the drug under consideration has the same excipient components in its formula as one of these drugs;

b) In cases where the drug formula contains excipient components that affect drug bioavailability: Qualitative and quantitative results of these excipient components in the formula of the drug under consideration and the reference drug to demonstrate that the drug under consideration and the reference drug have the same amount of these excipient components;

c) An evaluation report of the qualitative and quantitative analytical procedures used in the above tests.

5. A solubility characteristic assessment report of the drug (for drugs with very fast dissolution characteristics) or a dissolution equivalence test report between the drug under consideration and the reference drug (in cases of drugs with fast dissolution characteristics). Requirements for the dissolution equivalence test report are specifically defined in Appendix IV issued together with this Circular.

6. A commitment statement regarding the similarity between the drug under consideration and the test drug used in the dissolution or dissolution equivalence test according to Form 01/BE specified in Appendix VII issued together with this Circular.

7. Documents related to the reference drug as prescribed in point c, Clause 1, Article 8 of this Circular.

7. Documents related to the reference drug as specified in Point c Clause 1 Article 8 of this Circular.

Article 11. The dossier for reporting data on bioequivalence studies for the drug under consideration as prescribed in Point d Clause 5 Article 7 of this Circular

The dossier for reporting data on bioequivalence studies for the drug under consideration as prescribed in Point d Clause 5 Article 7 of this Circular shall include the following documents:

1. A request form for not conducting bioequivalence testing (Biowaiver) for the drug under consideration according to Form 02/BE stipulated in Appendix VII issued together with this Circular.

2. In case of changing the production site due to a change from the original manufacturer of the drug owner to another manufacturer under contract with the drug owner, or between different manufacturers under contract with the drug owner: The document of the drug owner designating the drug under consideration as a contracted manufacturer and the document accepting participation in manufacturing the drug under contract of the designated contracted manufacturer. In case the difference in the production site is due to a change from one contracted manufacturer to another contracted manufacturer of the drug owner, additional documentation explaining the reasons for this change by the drug owner shall be supplemented.

3. In case of changing the production site of the drug due to a change between different manufacturers of the same drug owner or between different production sites of the same manufacturer: Documentation from the drug owner or the registration entity explaining the reasons for changing the production site.

4. The quality dossier of the test drug in bioequivalence studies includes:

- Section S. Active Ingredient: Summary of the synthesis process of the active ingredient accompanied by a flowchart; Solvents used during the process; Properties of the active ingredient; Impurity characteristics; Quality standards for the active ingredient; Data on analysis of batches of the active ingredient;

- Section P. Finished Product: Formulation; Production process; Quality standards for excipients; Quality standards and analytical procedures for finished products; Data on analysis of at least three batches of finished product, minimum at the pilot batch size specified in Appendix V of this Circular - including the batch used in bioequivalence testing; Stability data of the finished product (in cases where there is insufficient long-term stability data for the drug under consideration up to its expiry date); Bioequivalence dossier meeting the provisions of Article 8 of this Circular.

5. Documents stipulated in Clauses 3, 4, 5, 6, 7, and 8 of Article 9 of this Circular in cases where the drug produced at the old production site has been implemented according to the provisions of Point a or Point b Clause 5 Article 7 of this Circular.

6. A list of changes related to the formulation, batch size, production process, and active ingredient manufacturer during circulation (if any) of the drug produced at the old production site.

7. Approval documents for these changes issued by the local drug regulatory authority.

8. Dossier for each change item listed, complying with the provisions set out in Appendix II promulgated together with Circular No. 32/2018/TT-BYT, excluding administrative documents.

9. Scientific rationale and experimental data proving that the test drug in bioequivalence studies still represents the drug under consideration. The scientific rationale must include the following minimum contents:

a) Similarity in the production formula between the drug under consideration and the test drug in bioequivalence studies or correlation in the formulation between the drug under consideration and the test drug in bioequivalence studies meeting the conditions specified in Sections I and II - Appendix II promulgated together with this Circular in cases where the drug produced at the old production site was approved without requiring bioequivalence testing as stipulated in Point a or Point b Clause 5 Article 7 of this Circular;

b) Similarity in the quality standards of the active ingredient, including known properties affecting the bioavailability of the finished product, quality standards of excipients, production processes and standard operating procedures, equipment used in production, environmental control during production, and quality standards of the finished product;

c) Characteristics of excipients affecting the bioavailability of the active ingredient in the formulation;

d) Comparison of data from the analysis of at least three batches, minimum at the pilot batch size specified in Appendix V of this Circular, between batches of the test drug used in bioequivalence studies and batches of the drug under consideration.

10. Report on dissolution equivalence testing between the drug produced at the old production site and the drug under consideration proving similarity in the dissolution profile between the two drugs. Requirements for the report on dissolution equivalence testing are specifically provided in Appendix IV promulgated together with this Circular. This document is not required if the change in the production site only relates to one or several steps including primary packaging without accompanying dosage distribution, quality control, release of batches, and secondary packaging.

11. Report on data from research proving in vitro-in vivo correlation established in cases where the drug has a modified-release dosage form. If the change in the production site only relates to one or several steps including primary packaging after dosage distribution, quality control, release of batches, and secondary packaging, then this document is not required.

12. In cases where the change in the production site is due to a change in the manufacturer and the drug produced at the old production site has been granted a marketing authorization in Vietnam based on the ASEAN Common Technical Document (ACTD) but has not been announced as a bioequivalent drug, the dossier for reporting data on bioequivalence studies for the drug produced at the old production site must comply with the provisions of Article 8, and the dossier for reporting data on bioequivalence studies for the drug under consideration must comply with the provisions of Clauses 1, 2, 3, 5, 6, 7, 8, 9, 10, and 11 of this Article.

13. In cases where the change in the production site is due to a change in the manufacturer and the drug produced at the old production site has been announced as a bioequivalent drug in Vietnam, the dossier for reporting data on bioequivalence studies for the drug under consideration must comply with the provisions of Clauses 1, 2, 3, 5, 6, 7, 8, 9, 10, and 11 of this Article.

14. In case of changes between different production sites of the same manufacturer and the drug produced at the old production site has already been granted a registration certificate for circulation in Vietnam: Apply according to the form of change and supplement for chemical drugs that have been registered for circulation as stipulated in Appendix II issued together with Circular No. 32/2018/TT-BYT.

Article 12. Documents and information of research facilities

1. No requirement for documents from research facilities for bioequivalence testing facilities in Vietnam that have been evaluated and announced by the Ministry of Health of Vietnam in the list of facilities meeting the conditions for conducting bioequivalence testing of drugs on the Ministry of Health's Electronic Information Portal and the Drug Administration's Electronic Information Portal, or facilities permitted in writing by the Ministry of Health to conduct bioequivalence testing of drugs.

2. Documents for research facilities certified and listed by the World Health Organization in the prequalified laboratories list with a scope of bioequivalence testing, or facilities evaluated and certified by one of the drug regulatory authorities specified in Clause 10, Article 2 of Circular No. 32/2018/TT-BYT with a scope of bioequivalence testing, or facilities certified by the competent authority of one of the ICH countries regarding bioequivalence testing, or facilities listed in the ASEAN recognized research facility list for bioequivalence study reports (published on the ASEAN website), and other facilities in countries where Vietnam has mutual recognition agreements are required to provide one of the following two types of documents:

a) Original or copy of the Certificate confirming that the facility complies with GCP and GLP principles or ISO/IEC 17025 or a permit/certificate/confirmation/notification issued by the competent authority of the host country for facilities with functions of bioequivalence testing or a certificate/confirmation/notification issued by the competent authority of the host country agreeing to the facility conducting bioequivalence testing;

b) The result of self-searching the legal documents specified in point a of this clause from the English-language website of the issuing authority, accompanied by a document providing the search link to the Drug Administration in cases where the legal documents are electronic versions, including cases where there are insufficient signatures, signatories' names, and stamps of the competent national management authority of the issuing country.

3. Documents to be submitted for research facilities not covered by the provisions of Clause 1 and Clause 2 of this Article are one of the following types of documents:

a) Original or copy of a permit/certificate/confirmation/notification issued by the competent authority of the host country for facilities with functions of bioequivalence testing or a certificate/confirmation/notification issued by the competent authority of the host country agreeing to the facility conducting bioequivalence testing of the drug under consideration;

b) Original or copy of a GLP certificate or ISO/IEC 17025 certificate with a scope of biological sample analysis issued by the host country's management authority for facilities involved in the analytical phase and a GCP certificate issued by the host country's management authority for facilities involved in the clinical phase;

c) In cases where facilities cannot provide the documents specified in points a or b of this clause due to laws of the host country not requiring such issuance for research facilities, the drug registration applicant must provide documents to prove compliance with GCP and/or GLP as follows:

- Documents proving compliance with GLP:

+ Quality manual or overall file of the bioequivalence research facility. These documents must demonstrate the capability and scope of testing;

+ Original or copy of the contract between the bioequivalence research facility and the sponsor and any subcontracts of the bioequivalence research facility;

+ List of inspections conducted by the management authority or certification body in the last three years and the most recent inspection report of the local management authority.

- Documents proving compliance with GCP:

+ Overall file of the clinical bioequivalence research facility fully demonstrating the testing capability for bioequivalence testing of drugs;

+ Original or copy of the contract between the bioequivalence research facility and the sponsor and any subcontracts of the bioequivalence research facility;

+ Original or copy of the inspection report of the national drug administration or WHO conducted within the last three years;

+ Original or copy of the monitoring report of the research by the sponsor or research organization for the ongoing research.

4. The documents specified in Clause 2 and points a and b of Clause 3 of this Article must comply with the following requirements:

a) Must remain valid during the research period. If the documents do not specify the validity period, they are considered valid for three years from the date of issue;

b) In cases where GLP certificates or GCP certificates do not meet the requirements of point a of this clause, accept the GLP/GCP assessment conclusion in the latest inspection record/report of the competent authority within three years after the assessment was conducted.

5. The documents specified in this Article must be stamped and confirmed by the registering entity. The registering entity shall bear legal responsibility for the results of self-searching by the facility at point b of Clause 2 of this Article and the legality and accuracy of the documents and information specified in this Article.

Chapter V

IMPLEMENTING PROVISIONS

Article 13. Effective Date

1. This Circular takes effect from November 1, 2022.

2. Circular No. 08/2010/TT-BYT dated April 26, 2010, guiding the reporting of bioavailability/bioequivalence study data in drug registration, shall cease to be effective from the date this Circular takes effect.

Article 14. Implementation timeline

1. From the date this Circular takes effect, establishments registering the following drugs must submit a dossier reporting bioequivalence study data when submitting a dossier requesting issuance of a drug circulation registration certificate, specifically as follows:

a) Generic drugs formulated in immediate release form and modified release enteric-coated form, either single-component or with a fixed-dose combination formula containing active ingredients listed in the Catalogue of Active Ingredients Required to Report Bioequivalence Study Data for Drug Circulation Registration;

b) Generic drugs formulated in modified release enteric-coated form, except for those not covered by the provisions of point a of this clause;

2. After 36 months from the date this Circular takes effect, drug registration establishments must submit the bioequivalence test dossier when submitting a dossier requesting issuance of a drug circulation registration certificate for all generic drugs formulated in modified release enteric-coated form, except for those subject to the provisions of Clause 1 of this Article.

3. After 48 months from the date this Circular takes effect, drug registration establishments that have been issued a drug circulation registration certificate for drugs containing active ingredients or formulations required to undergo bioequivalence testing under this Circular must publish the drug with bioequivalence evidence documentation. The procedures and formalities for publishing drugs with bioequivalence evidence documentation are stipulated in the Circular on drug circulation registration and raw materials.

Article 15. Transitional Provisions

1. Reports of bioequivalence research data submitted in dossiers requesting issuance, modification, or supplementation of a drug circulation registration certificate before the date this Circular takes effect shall continue to be implemented according to the provisions of Circular No. 08/2010/TT-BYT dated April 26, 2010, guiding the reporting of bioavailability/bioequivalence research data in drug registration, except where the registration establishment voluntarily implements the provisions of this Circular.

2. For drugs that have submitted a registration dossier before the date this Circular takes effect: There is no requirement to supplement a report of bioequivalence research data prior to issuance of a drug circulation registration certificate; the registration establishment must implement the provisions of Clause 3 of Article 14 after the drug has been issued a circulation registration certificate.

3. For bioequivalence studies and dissolution equivalence tests conducted before the date this Circular takes effect, if it is not possible to provide documentation proving the origin and source of the reference drug used in the study according to point c of Clause 1 of Article 8 of this Circular, the enterprise's declaration regarding the origin and source of the reference drug used in the study according to Form 03/BE attached hereto will be accepted.

4. For bioequivalence studies conducted before the date this Circular takes effect, the research establishment, reference drug, and study design will be accepted in cases where the drug under consideration has been approved by one of the strict pharmaceutical regulatory authorities specified in Clause 10 of Article 2 of Circular No. 32/2018/TT-BYT and is currently circulating in the markets of these countries.

5. For bioequivalence studies conducted before the date this Circular takes effect, except for the case provided for in Clause 3 of this Article, the selection of the reference drug in the study will be accepted if it falls within one of the following cases:

a) Listed in the list of original brand-name drugs issued by the Ministry of Health at the time of conducting the study;

b) Has been accepted in writing by the Department of Medicines Administration - Ministry of Health;

c) Has been approved and marketed in the national market by one of the European Medicines Agency (EMA) and strict regulatory authority (SRA) specified in Clause 10 of Article 2 of Circular No. 32/2018/TT-BYT.

Article 16. Reference Provisions

In cases where the legal regulatory documents and provisions cited in this Circular are amended, supplemented, or replaced, they shall be implemented according to the new cited legal regulatory documents or provisions.

The technical guidance provisions specified in Appendix VI attached hereto shall be applied as a basis for reviewing and evaluating biological equivalence test files. In cases where these guidelines are updated or changed, the basis for applying new versions is permitted.

Article 17. Responsibility for Implementation

1. The Drug Administration Department shall be responsible for:

a) Organize and implement the provisions of this Circular;

b) Update and publish the List of reference drugs used in biological equivalence tests issued by the Ministry of Health;

c) Update and publish the list of biological equivalence testing facilities evaluated and recognized by the Ministry of Health of Vietnam.

2. The Director of the Ministry's Office; the Director of the Drug Administration Bureau; the Inspector General of the Ministry; the Heads of units under and affiliated with the Ministry of Health; the Directors of Provincial Health Departments; the Heads of health sector institutions; the directors of biological equivalence testing facilities for drugs; organizations and individuals engaged in drug registration activities are responsible for implementing this Circular.

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