Circular 07/2022/TT-BYT drugs subject to in vivo bioequivalence study

CIRCULAR

Providing for regulations on drugs subject to in vivo bioequivalence study and requirements for dossiers on bioequivalence study data reporting upon marketing authorization of the drugs in Vietnam

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Pursuant to the Law on Pharmacy dated April 06, 2016;

Pursuant to the Government’s Decree No. 54/2017/ND-CP dated May 08, 2017 detailing a number of articles of and providing measures for implementing the Law on Pharmacy;

Pursuant to the Government's Decree No. 75/2017/ND-CP dated June 20, 2017 on defining the functions, tasks, powers and organizational structure of the Ministry of Health;

At the proposal of the Director of Drug Administration of Vietnam;

The Minister of Health promulgates the Circular providing for regulations on drugs subject to in vivo bioequivalence study and requirements for dossiers on bioequivalence study data reporting upon marketing authorization of the drugs in Vietnam.

Chapter I

GENERAL PROVISIONS

              Article 1. Scope of regulation

1. This Circular defines:

a) Generic drugs containing pharmaceutical ingredient(s) and having a dosage form of which reports on bioequivalence study data are required upon marketing authorization in Vietnam;

b) Dossiers on bioequivalence study data reporting of generic drugs.

2. This Circular applies to generic drugs that have systemic pharmacological effects after being absorbed into the general circulation.

Article 2. Interpretation of terms

In this Circular, the terms below are construed as follows:

1. A test product  means a generic drug used to demonstrate that it has the same therapeutic effect (in terms of both efficacy and safety) when patients administer the same dose level following the same route of administration with specific conditions defined on the label (if any) as the comparator product through comparison of data on (in vivo) bioequivalence study or (in vitro) equivalence dissolution between the drug and the comparator product.

2. Comparator product/Reference product means a drug that will be replaced by a generic drug for use in therapy. Normally, comparator products are innovator pharmaceutical products or drugs for which a marketing authorization has been granted, with sufficient data on their effectiveness, safety, and quality which has been established.

3. Innovator pharmaceutical product means a drug licensed for the first circulation in the world, on the basis of sufficient data on its quality, safety, and efficiency, that has or has not been licensed for circulation in Vietnam.

4. Pharmaceutical equivalence means the drugs containing the same pharmaceutical ingredient (for single active ingredient drugs) or the same pharmaceutical ingredients (for multiple active ingredient drugs) with the same molar contents, which are in the same dosage form, with the same pharmaceutical ingredient release mechanism, and are intended to be administered by the same route and meet comparable standards.

5. Pharmaceutical alternatives means drugs that contain the same pharmaceutical ingredient(s) but are different from chemical form or physicochemical form (salts, esters, ethers, isomers, mixtures of isomers, complexes or derivatives) of an pharmaceutical ingredient or different from pharmaceutical ingredient content or dosage form.

6. Drug under consideration: means a generic drug for which the submitted dossier of marketing authorization has a dossier on bioequivalence study data reporting.

7. In vivo bioequivalence study: Means the clinical study for that is designed for volunteers to compare the bioavailability between a generic drug and its comparator product for the purpose of demonstrating the generic drug’s ability to replace its comparator product.

8. Equivalence dissolution means study of comparison of dissolution profiles of drugs in different dissolution media. Equivalence dissolution is also known as the in vitro equivalence study.

9. In vitro - in vivo correlation means a mathematical model describing the relationship between the in vitro property (the property of dissolution or pharmaceutical ingredient release) of a drug and its relevant in vivo response (the drug concentration or amount absorbed in biological fluid).

10. Research establishment means an organization partly or wholly participating in the in vivo bioequivalence study or equivalence dissolution of the drug under consideration.

11. Immediate release dosage form Means a dosage form using conventional excipients and techniques, without intentionally changing the rate of pharmaceutical ingredient release, including conventional dosage forms such as tablets, capsules, suspensions, solutions for oral administration, solutions, suspensions and emulsions for injection, and unconventional dosage forms also known as specific dosage form such as solid dispersion systems, lozenges, chewable tablets, orodispersible tablets, sublingual tablets.

12. Modified release dosage form Means a dosage form using a number of excipients and/or technique other than that of the immediate release dosage form in order to create the rate and/or site of release of the pharmaceutical ingredient(s) different from that of the immediate release dosage form administered by the same route. Common modified release dosage forms include dosage forms of delayed release, prolonged release, multiphasic release, intramuscular/subcutaneous depot, transdermal drug delivery system.

13. Fixed-dose combination finished pharmaceutical product means a drug containing 2 or more pharmaceutical ingredients in a fixed ratio of doses. Single active ingredient drugs packaged together in the same packing unit for simultaneous use do not fall into this category.

14. Biopharmaceutics classification system (BCS) is a scientific framework for classifying pharmaceutical ingredients based upon their aqueous solubility and intestinal permeability.

15. Bio-waiver means the approval of a generic drug to be interchangeable with a comparator product without in vivo bioequivalence study data reports of such drug.

16. Study on drug administration in the fasted state: means a bioequivalence study that is conducted after volunteers administer drugs following a fast without alcohol and xanthine of at least 8 hours.

17. Study on drug administration in the fed state: means a bioequivalence study that is conducted when volunteers administer drugs right after a meal or under the instruction on drug administration time after meal stated in the summary of drug properties.

18. Single-dose study means a bioequivalence study in which biological samples used in the analysis are collected after administration of a single dose of the drug at each study period.

19. Multiple-dose study means a bioequivalence study in which biological samples used in the analysis are collected after administration of multiple doses for achievement of steady-state concentration of the drug in the blood.

20. The polarization approach: means the analysis and selection of 02 contents in many different contents of a drug (with the same dosage form, manufactured by a manufacturer) that are determined to have the most differences so that any difference between the remaining contents is within the difference between the two selected contents to conduct the study and extrapolate the research results for the remaining contents.

21. ASEAN refers to “Association of Southeast Asian Nations”.

22. ICH refers to “International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use”.

23. Form of ASEAN report on their bioequivalence study data means the report form specified in Appendix IV of the ASEAN Guideline for the conduct of bioequivalence studies issued together with the Minister of Health’s Circular No. 32/2018/TT-BYT dated November 12, 2018 defining marketing authorization of drugs and drug materials (hereinafter referred to as Circular No. 32/2018/TT-BYT).

24. Form of ICH report on their bioequivalence study data means the report form specified in ICH Structure and Content of Clinical Study Reports- E3 Guideline.

Chapter II

GENERIC DRUGS CONTAINING PHARMACEUTICAL INGREDIENTS OR HAVING DOSAGE FORMS SUBJECT TO BIOEQUIVALENCE STUDY DATA REPORTING

              Article 3. Generic drugs containing pharmaceutical ingredients of which reports on bioequivalence study data are required upon marketing authorization

1. Criteria for selection of pharmaceutical ingredients in generic drugs of which reports on bioequivalence study data are required upon marketing authorization shall be according to the order of priority as follows:

a) Having a narrow therapeutic index;

b) Having low bioavailability and/or varying widely among individuals;

c) Being in prescription drugs, belonging to one of groups of cardiovascular drugs, hypoglycemic drugs, antibiotic drugs, antipsychotic/anti-epileptic drugs, antiviral drugs;

d) Being drugs on the list of drugs used in national programs, including: HIV/AIDS prevention project; Community mental health project; Tuberculosis prevention and control project; Malaria prevention and control project.

2. The list of pharmaceutical ingredients in generic drugs of which reports on bioequivalence study data are required upon marketing authorization is specified in Appendix I to this Circular.

Article 4. Generic drugs having dosage forms of which reports on bioequivalence study data are required upon marketing authorization

Generic drugs having dosage forms of which reports on bioequivalence study data are required upon marketing authorization include:

1. Drugs that have immediate release dosage forms, systemic effect, contain pharmaceutical ingredients specified in Clause 2 Article 3 of this Circular and are not the cases specified in Article 5 of this Circular.

2. Drugs that have modified release dosage forms, systemic effect and are not the cases specified in Article 5 of this Circular.

Article 5. Generic drugs eligible for bio-waiver due to the availability of bioequivalence between the drugs and their comparator products

Generic drugs eligible for bio-waiver due to the availability of bioequivalence between the drugs and their comparator products include:

1. Intravenous generic drugs that are solutions in water at the time of injection, contain the same pharmaceutical ingredients at the same molar concentrations upon use as their comparator products and do not contain excipients that interact with pharmaceutical ingredients or affect the distribution of pharmaceutical ingredients similarly to their comparator products. In case these excipients must be used in their formulas, the composition of these excipients must be similar to the composition of the excipients in the comparator products with the amount equivalent to that used in the comparator products or if there is a difference in the quantity, it must be demonstrated that such difference does not affect the pharmacokinetics of their pharmaceutical ingredients.

2. Generic drugs for parenteral administration other than intravenous injection, in the form of solutions in water or in oil for injection, that contain the same pharmaceutical ingredients in the same molar concentrations and the same excipients in similar concentrations as their comparator products. For the injectable drugs being solutions in water, excipients in their formulas may be different but must be the same of type (with the same function) with the same concentrations as the excipients of their comparator products and the difference in excipients must be demonstrated not to affect the viscosity of the solution.

3. Generic drugs are oral solutions at time of administration (including drugs in solid dosage form with instructions of mixing them with water for administration) that have the pharmaceutical equivalence with their comparator products and do not contain excipients which may affect the transport, absorption or in vivo stability of the pharmaceutical ingredients similarly to their comparator products.  In case it is compulsory for their formulas to use excipients which may affect the transport, absorption or in vivo stability of the pharmaceutical ingredients, the types and quantity of these excipients of the generic drugs must be similar to those of their comparator products.

4. Generic drugs in gaseous form at time of administration with pharmaceutical equivalence to their comparator products.

Chapter III

REGULATIONS ON COMPARATOR PRODUCTS AND REQUIREMENTS FOR IN VIVO BIOEQUIVALENCE STUDY

              Article 6. Comparator products used for in vivo bioequivalence study

1. Criteria for selection of comparator products used for in vivo bioequivalence study for marketing authorization shall be according to the order of priority as follows:

a) Comparator products being in the list of brand name drugs announced by the Ministry of Health and drugs for which a marketing authorization is granted, with sufficient data on their quality, safety and clinical efficacy;

b) Comparator products being innovator pharmaceutical products for which a marketing authorization in Vietnam has not been granted but that are approved by one of stringent regulatory authorities specified in Clause 10 Article 2 of Circular No. 32/2018/TT-BYT and are marketing in such countries’ market;

c) In case it is not possible to identify comparator products satisfying regulations at Points a and b of this Clause, the selection of comparator products shall be prioritized as follows:

- Drugs that are approved by one of stringent regulatory authorities specified in Clause 10 Article 2 of Circular No. 32/2018/TT-BYT and are marketing in such countries’ market.

- Drugs that are prequalified by World Health Organization (WHO).

Among the products meeting such condition, priority is given to those with a valid marketing authorization issued by the Ministry of Health of Vietnam.

2. In addition to Clause 1 of this Article, comparator products used for in vivo bioequivalence study being those having immediate release dosage form or modified release dosage form and fixed-dose combination finished pharmaceutical products must satisfy the following regulations:

a) If drugs under consideration are single active ingredient drugs with immediate release dosage form, comparator products shall be single active ingredient drugs with immediate release dosage form;

b) If drugs under consideration are drugs with modified release dosage form, comparator products shall be the drugs having modified release dosage form with the same pharmaceutical ingredient release mechanism;

c) For fixed-dose combination finished pharmaceutical products:

- In case a drug under consideration expected to replace an approved fixed-dose combination finished pharmaceutical product with sufficient data on its clinical efficacy and safety (being brand name drug or innovator pharmaceutical product), such fixed-dose combination finished pharmaceutical product shall be selected as comparator product.

- In case a drug under consideration is developed to replace a regime of dose combination of single active ingredient drugs and such dose combination regime has sufficient data on its clinical efficacy and safety, the comparator products shall be the corresponding single active ingredient drugs.

3. Comparator products used for in vivo bioequivalence study must be of clear origin. Documents proving the origin of comparator products are defined at Point c Clause 1 Article 8 of this Circular.

4. Based on the criteria for selection of comparator products specified in Clause 1 of this Article, other regulations on comparator products defined in Clauses 2 and 3 of this Article, and practical situation, the Drug Administration of Vietnam shall make a list of comparator products, collect opinions of the advisory council for grant of marketing authorizations of drugs and drug materials for promulgation of Decision on issuing the list of comparator products used for in vivo bioequivalence study. The list of comparator products used for in vivo bioequivalence study is announced in the website of Drug Administration of Vietnam - the Ministry of Health: https://dav.gov.vn/.

Article 7. Regulations on bioequivalence study in dossiers on bioequivalence study data reporting

1. A study must satisfy the following requirements:

a) The study must be designed and conducted in accordance with ASEAN Guideline for the conduct of bioequivalence studies or other organizations’ reference guidance in Appendix VI to this Circular;

b) For an oral drug having modified release dosage form with systemic effect, the study on drug administration in fasted and fed states is required;

c) For a drug having immediate release dosage form with systemic effect and not being the cases specified in Article 5 of this Circular, the study on drug administration in fasted state is required. In cases a known pharmacokinetic property of a comparator product is that food affects its bioavailability or the comparator product must be administered in fed state under its instruction of use, the study on drug administration in fed state may be conducted instead of study on drug administration in fasted state;

d) For a fixed-dose combination finished pharmaceutical product, bioequivalence assessment studies of all pharmaceutical ingredients are required;

dd) Apply design of in vivo bioequivalence study for each drug in accordance with recommendations of U.S. Food and Drug Administration (US FDA) or European Medicines Agency (EMA).

2. A study must be conducted in a testing establishment that has been evaluated and recognized by the competent agency of the host country and must comply with principles on good clinical practice (GCP) of drugs specified in Clause 1 Article 4 of the Minister of Health’s Circular No. 29/2018/TT-BYT dated October 29, 2018 providing for regulations on clinical trial of drugs and those on good laboratory practices (GLP) defined in Clause 1 Article 3 of the Minister of Health’s Circular No. 04/2018/TT-BYT dated February 09, 2018 providing for regulations on good laboratory practices.

3. If in the bioequivalence study of a drug under consideration, a comparator product being an innovator pharmaceutical product is used but it is not manufactured at the same manufacturing facility as the innovator pharmaceutical product for which a marketing authorization in Vietnam is granted, the registering establishment must demonstrate the interchangeability between the comparator product used in the study and the innovator pharmaceutical product licensed for marketing authorization in Vietnam in accordance with the ASEAN Guidelines for the Conduct of Bioavailability and Bioequivalence Studies.

4. Form of report on drug bioequivalence study data is specified at Point a Clause 1 Article 8 of this Circular. Specific requirements for reports on bioequivalence study data for drugs under consideration are defined in Appendix III to this Circular.

5. Bio-waiver for the drugs under consideration shall apply in the following cases:

a) Drugs under consideration that have a formula in proportion to their test products in bioequivalence study and satisfy regulations in Section I, Appendix II to this Circular;

b) Drugs under consideration that have the same dosage form, formula and manufacturing process as their test products in bioequivalence study, but have different content of pharmaceutical ingredients, and satisfy regulations in Section II, Appendix II to this Circular;

c) Drugs under consideration that have immediate-release oral solid dosage form with pharmaceutical equivalence to their comparator products and have pharmaceutical ingredients with high solubility and high permeability under biopharmaceutics classification system, and satisfy regulations in Section III, Appendix II to this Circular;

d) Drugs under consideration that are manufactured at a site different from the production site of their test products in the bioequivalence study and satisfy conditions defined in Section IV, Appendix II to this Circular.

Chapter IV

DOSSIERS ON BIOEQUIVALENCE STUDY DATA REPORTING

Article 8. Dossiers on bioequivalence study data reporting in cases of in vivo bioequivalence study between drugs under consideration and their comparator products

1. A dossier must comprise the following documents:

a) Report on (in vivo) bioequivalence study data of the drug, made using current version of form of ASEAN report on bioequivalence study data or form of ICH report on bioequivalence study data, in which the written commitment on similarity between the test product used in the study and the drug under consideration must be made using Form 01/BE in Appendix VII to this Circular;

b) Documents and information of research establishment specified in Article 12 of this Circular;

c) Documents proving the origin of the comparator product used in the study, including:

- A copy of the purchase invoice for the comparator product from the supplier, clearly showing the name and address of the supplier;

- A copy of the drug label certified by the registering establishment/manufacturing facility, showing fully and clearly the following information: drug name, the drug manufacturer’s name and address, manufacture batch number, expiry date;

- A written commitment signed by the director of the registering establishment/manufacturer about the authenticity of the above-mentioned documents, with a commitment that the comparator product was purchased from the market of the country where the drug is licensed for marketing authorization and preserved in accordance with the preservation conditions indicated on the drug label from the time of purchase to the time of starting the study.

2. In case of in vivo bioequivalence study of a drug under consideration and the volunteers administer the drug in different conditions (drug administration in fasted and fed states, single-dose administration, multiple-dose administration), the dossier of bioequivalence study data reporting includes many bioequivalence study reports and each report corresponding to each state of drug administration must be attached sufficiently or have explanations on sufficiency of documents specified in Clause 1 of this Article.

Article 9. Dossiers on bioequivalence study data reporting applicable to drugs under consideration specified at Points a and b Clause 5 Article 7 of this Circular

A dossier on bioequivalence study data reporting applicable to a drug under consideration specified at Point a or b Clause 5 Article 7 of this Circular includes the following documents:

1. An application of biowaiver for drug under consideration, made according to Form 02/BE in Appendix VII to this Circular.

2. Bioequivalence dossier(s) of content(s) selected for conducting in vivo bioequivalence study between the drug under consideration and the comparator product that satisfies regulations in Article 8 of this Circular.

3. Explanation of the selection of contents for report on bioequivalence study data and use of in vivo bioequivalence study results of these contents to propose bio-waiver for the remaining concentrations, including the content of the drug under consideration.

4. Comparison table of formulas of contents proposed to apply bio-waiver, including the content of the drug under consideration and formulas of contents with reports on bioequivalence study data.

5. A comparison table of manufacturing process of contents proposed to apply bio-waiver, including the content of the drug under consideration and manufacturing process of contents with reports on bioequivalence study data.

6. Report on equivalence dissolution between contents proposed to apply bio-waiver, including the content of the drug under consideration and contents with reports on bioequivalence study data. Requirements for equivalence dissolution report are detailed in Appendix IV to this Circular.

7. Written commitment on similarity between the drug under consideration and the test product used in the equivalence dissolution testing, made according to Form 01/BE in Appendix VII to this Circular.

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

Article 10. Dossiers on bioequivalence study data reporting applicable to drugs under consideration specified at Point c Clause 5 Article 7 of this Circular

A dossier on bioequivalence study data reporting applicable to a drug under consideration specified at Point c Clause 5 Article 7 of this Circular includes the following documents:

1. An application of biowaiver for drug under consideration, made according to Form 02/BE in Appendix VII to this Circular.

2. Documents of research establishment specified in Article 12 of this Circular.

3. Documents proving that pharmaceutical ingredient(s) of the drug under consideration has high solubility and high permeability in accordance with the guidance in Appendix III. BCS-based biowaiver of the ASEAN Guideline for the conduct of bioequivalence studies issued together with Circular No. 32/2018/TT-BYT.

4. Data proving that the drug under consideration have excipients satisfying regulations for consideration of biowaiver:

a) Comparison table of excipients in formulas between the drug under consideration and its comparator product or a drug not being comparator product that has pharmaceutical equivalence with the drug under consideration and is selected by one of stringent regulatory authorities specified in Clause 10 Article 2 of Circular No. 32/2018/TT-BYT as the reference medicinal product, and accompanied information on search sources of excipients in formula of such comparator product or reference medicinal product.

Accepted search sources include: Instructions for drug use approved by the Drug Administration of Vietnam, approved summaries of drug properties or drug assessment reports published on websites of European Medicines Agency (EMA) and stringent regulatory authorities (SRA) specified in Clause 10 Article 2 of Circular No. 32/2018/TT-BYT or on official drug information websites such as eMC (electronic Medicines Compendium). In case it is not possible to look up the information on the composition of excipients in the formula of the comparator product or the reference medicinal product, the qualitative results of the excipients in the formula of the comparator product or the reference medicinal product are required to demonstrate that the drug under consideration’s formula has the same excipients as one of these drugs;

b) In case the drug formula contains excipients that affect the bioavailability of the drug: Qualitative and quantitative results of these excipients in the formula of the drug under consideration and that of the comparator product for the purpose of demonstrating that the drug under consideration and the comparator product have the same content of these excipients;

c) Report on appraisal of the qualitative and quantitative analysis procedures used in the above-mentioned testings.

5. Report on assessment of drug dissolution (for drugs with very rapid dissolution) or report on equivalence dissolution of the drug under consideration and its comparator product (in cases of drugs with rapid dissolution). Requirements for equivalence dissolution reports are detailed in Appendix IV to this Circular.

6. Written commitment on similarity between the drug under consideration and the test product used in the testing of dissolution or equivalence dissolution, made according to Form 01/BE in Appendix VII to this Circular.

7. Documents relating to the comparator product specified at Point c Clause 1 Article 8 of this Circular.

Article 11. Dossiers on bioequivalence study data reporting applicable to drugs under consideration specified at Point d Clause 5 Article 7 of this Circular

A dossier on bioequivalence study data reporting applicable to a drug under consideration specified at Point d Clause 5 Article 7 includes the following documents:

1. An application of biowaiver for drug under consideration, made according to Form 02/BE in Appendix VII to this Circular.

2. In case of change of production site due to change from manufacturer of the drug owner to manufacturer under contract with drug owner or change between manufacturers under contract with drug owner: The drug owner's document designating the manufacturer of drug under consideration as the manufacturer under contract with the drug owner and the designated contractual manufacturer's acceptance letter to participate in the drug manufacturing under the contract. In case of difference in production site due to a change from one contractual manufacturer to another by the owner, the owner’s written explanation of reason for such change is required.

3. In case of change in production site due to the change between manufacturers of the same drug owner or change between production sites of the same manufacturer: A written explanation of the drug owner or the registering establishment of reason for the change of production site is required.

4. The quality dossier of a test product in bioequivalence study includes:

- Part S. Pharmaceutical ingredients: Summary of pharmaceutical ingredient synthesis process together with process diagram; Solvents used in the process; Pharmacological properties; Characteristics of impurities; Quality standards of pharmaceutical ingredients; Data on analysis of pharmaceutical ingredient batches;

- Part P. Finished products: Formula; Manufacturing process; Quality standards of excipients; Quality standards and analytical procedures for the finished product; Data on analysis of finished product batches of at least 03 batches at pilot scale or more specified in Appendix V to this Circular - including the batch used for in vivo bioequivalence study; Stability of the finished product (in case there is not sufficient data on the long-term stability of the drug under consideration until the expiry date of the registration); Bioequivalence dossier satisfying regulations on Article 8 of this Circular.

5. The documents specified in Clauses 3, 4, 5, 6, 7 and 8 Article 9 of this Circular, in case drugs manufactured at the old production site comply with Points a or b Clause 5 Article 7 of this Circular.

6. The lists of changes related to the formulation, batch size, manufacturing process, pharmaceutical ingredient manufacturer during circulation (if any) of the drug manufactured at the old production site.

7. Written approval of these changes by the pharmaceutical regulatory agency of the host country.

8. Dossiers to be changed or supplemented for each listed change that are satisfied Appendix II to the Circular No. 32/2018/TT-BYT, except for administrative documents.

9. The statement of scientific bases together with experimental data proving that the test product used in the bioequivalence study is still representative of the drug under consideration. A statement of scientific bases must contain at least the following contents:

a) The similarity in manufacture formula between the drug under consideration and the test product used in the bioequivalence study or the correlation in the formula between the drug under consideration and the test product in the bioequivalence study meeting the conditions specified in Sections I, II - Appendix II to this Circular in case the drug manufactured at the old production site of which bio-waiver is approved as specified at Point a or Point b Clause 5 Article 7 of this Circular;

b) The similarity in quality standards for pharmaceutical ingredients including pharmaceutical ingredient properties known to affect the bioavailability of the finished drug product, quality standards for excipients, manufacturing processes and standard operating procedures, equipment used in production, environmental control during production, quality standards of the finished product;

c) Properties of excipients affecting the bioavailability of pharmaceutical ingredients in formula;

d) Comparison of batch analysis data of at least 03 batches at pilot scale or more specified in Appendix V to this Circular between batches of test product used in bioequivalence study and batches of drug under consideration.

10. Report of equivalence dissolution between the drug manufactured at the old production site and the drug under consideration to demonstrate the similarity in dissolution chart between the two drugs. Requirements for equivalence dissolution reports are detailed in Appendix IV to this Circular. This document is not required if the change of production site involves only one or several stages including primary packaging but excluding drug dosing, quality control, batch delivery and secondary packaging.

11. In vitro - in vivo correlation data report made for drugs in a modified release dosage form. This document is not required if the change of production site involves only one or several stages including primary packaging after drug dosing, quality control, batch delivery and secondary packaging.

12. In case there is a change in production site due to change of manufacturer, and the drug manufactured at the old production site has a marketing authorization in Vietnam according to the ASEAN Common Technical Dossier (ACTD) but has not yet been announced to be the drug with proven bioequivalence, the dossier on bioequivalence study data reporting applicable to the drug manufactured at the old production site must comply with Article 8 and the dossier on bioequivalence study data reporting applicable to the drug under consideration must meet Clauses 1, 2, 3, 5, 6, 7, 8, 9, 10 and 11 of this Article.

13. In case there is a change in production site due to change of manufacturer, and the drug manufactured at the old production site has been been announced to be the drug with proven bioequivalence in Vietnam, thte dossier on bioequivalence study data reporting applicable to the drug under consideration must satisfy Clauses 1, 2, 3, 5, 6, 7, 8, 9, 10 and 11 of this Article.

14. In case there is a change between production sites of the same manufacturer and the drug manufactured at the old production site has a marketing authorization in Vietnam: To apply in the method of changes and supplements for pharmacochemical drugs having a marketing authorization as prescribed in Appendix II to the Circular No. 32/2018/TT-BYT.

Article 12. Documents and information of research establishments

1. Documents of research establishments are not required for in vivo bioequivalence study establishments in Vietnam that have been assessed by the Ministry of Health of Vietnam and announced in the list of establishments eligible for in vivo bioequivalence study of drugs on portal of the Ministry of Health and website of the Drug Administration of Vietnam, or of establishments that are permitted in writing to conduct in vivo bioequivalence study of drug by the Ministry of Health.

2. Document applicable to research establishments certified and announced in the list of prequalified laboratories with in vivo bioequivalence study activity by WHO or establishments with bioequivalence study activity assessed and certified by one of stringent regulatory authorities specified in Clause 10 Article 2 of Circular No. 32/2018/TT-BYT or establishments certified by competent management agency of one of counties of ICH for in vivo bioequivalence study or establishments in the list of bioequivalence study establishments recognized under ASEAN mutual recognition arrangement for bioequivalence study reports for generic medicinal products (posted on the ASEAN’s website) and other establishments belonging to countries with which Vietnam has an recognition agreement shall be one of the two documents as follows:

a) The original or a copy of Certificate on GCP and GLP or ISO/IEC 17025 compliance or license/certificate/certification/notice issued by the competent agency of the host country to the establishment with in vivo bioequivalence study function or certificate/certification/notice issued by the competent agency of the host country with the content of approval for  the establishment’s in vivo bioequivalence study;

b) Search results of legal document specified at Point a of this Clause from the English website of the legal document-issuing agency, enclosed with a document providing information on the search link to the Drug Administration of Vietnam in case the granted legal document is an electronic version, including cases where signature, the signer’s name and seal of the competent state management agency of the country where the legal document is granted are inadequate.

3. Document to be submitted applicable to research establishments other than those specified in Clauses 1 and 2 of this Article shall be one of the following documents:

a) The original or a copy of license/certificate/certification/notice issued by the competent agency of the host country to the establishment with bioequivalence study function or certificate/certification/notice issued by the competent agency of the host country with the content of approval for the research establishment’s in vivo bioequivalence study for the drug under consideration;

b) The original or a copy of GLP certificate or ISO/IEC 17025 accreditation with the scope of biological fluid analysis issued by the management agency of the host country for establishments participating in the analysis phase and a GCP certificate issued by the management agency of the host country for establishments participating in the clinical phase;

c) In case the establishment fails to provide the document specified at Point a or b of this Clause because the host country’s law does not provide for the grant of such document to the research establishments, the unit registering the drug under consideration must provide documents proving GCP and/or GLP compliance as follows:

- Documents proving GLP compliance:

+Quality manual or master dossier of bioequivalence study establishment. These documents shall demonstrate the competence and scope of testing;

+ The original or a copy of contracts between the bioequivalence study establishment and sponsors, and subcontracts of the bioequivalence study establishment;

+ A list of inspections by the management agencies or accreditation body in the past 3 years and the local management agency’s most recent inspection report.

- Documents proving GCP compliance:

+ The overall profile of the clinical bioequivalence study establishment that fully demonstrates the testing capacity for bioequivalence study of the drug;

+ The original or a copy of contracts between the bioequivalence study establishment and sponsors, and subcontracts of the bioequivalence study establishment;

+ The original or a copy of the inspection report issued by the pharmaceutical regulatory agency of the country or WHO within no more than 3 years;

+ The original or copy of the research supervision report by the sponsor or research organization for the study under consideration.

4. The documents specified in Clause 2 and Points a and b Clause 3 of this Article must satisfy the following regulations:

a) Be valid for during the conduct of the study. If the documents do not specify the validity period, they are considered to be valid for 03 years from the date of issuance;

b) In case the GLP Certificate or GCP Certificate does not meet the requirements at Point a of this Clause, the GLP/GCP assessment conclusion in the competent management agency’s latest inspection minutes/report within 03 years after the date of assessment shall be accepted.

5. The documents specified in this Article must be stamped and certified by the registering establishments. Registering establishments shall take responsibility before law for their search results specified at Point b Clause 2 of this Article and the legality and accuracy of the documents and information specified in this Article.

Chapter V

IMPLEMENTATION PROVISIONS

              Article 13. Effect

1. This Circular takes effect on November 01, 2022.

2. The Minister of Health’s Circular No. 08/2010/TT-BYT dated April 26, 2010 defining guidance on bioavailability/bioequivalence study data reporting in drug registration ceases to be effective from the effective date of this Circular.

              Article 14. Application roadmap

              1. From the effective date of this Circular, establishments registering the following drugs must submit a dossier on bioequivalence study data reporting when submitting a application dossiers for marketing authorization of drugs:

a) Generic drugs in immediate release dosage form and delayed release dosage form, with single active ingredient or fixed-dose combination formula, containing pharmaceutical ingredients in the List of pharmaceutical ingredients subject to bioequivalence study data reporting upon marketing authorization of drugs;

b) Generic drugs in modified release dosage forms, except for drugs in delayed release dosage form other than those specified at Point a of this Clause.

2. After 36 months from the effective date of this Circular, drug registering establishments must submit part of in vivo bioequivalence study dossier when submitting the application dossiers for marketing authorizations for all generic drugs in delayed release dosage form, except for drugs that must comply with Clause 1 of this Article.

3. After 48 months from the effective date of this Circular, drug registering establishments that have been granted marketing authorizations for drugs containing pharmaceutical ingredient(s) or in dosage forms subject to in vivo bioequivalence study as specified in this Circular must announce their drugs with documents proving bioequivalence. The order and procedures for announcing drugs with documents proving bioequivalence are specified in the Circular defining the registration of marketing authorization of drugs and drug materials.

Article 15. Transitional provisions

1. Reports on bioequivalence study data in application dossiers of grant, amendment or supplementation of marketing authorizations that are submitted before the effective date of this Circular shall continue to comply with the Minister of Health’s Circular No. 08/2010/TT-BYT dated April 26, 2010 defining guidance on bioavailability/bioequivalence study data reporting in drug registration, except for cases where registering establishments voluntarily comply with this Circular.

2. For drugs for which application dossiers for marketing authorization have been submitted before the effective date of this Circular: Reports on bioequivalence study data are not required to be submitted before grant of marketing authorizations; registering establishments shall comply with Clause 3 Article 14 after the marketing authorizations are granted.

3. For bioequivalence studies and equivalence dissolutions that have been conducted before the effective date of this Circular, if enterprises may not provide their documents proving the origin of comparator products specified at Point c Clause 1 Article 8 of this Circular, their written commitments on the origin of comparator products used in study made using the Form 03/BE in Appendix VII to this Circular are accepted.

4. For bioequivalence studies that have been conducted before the effective date of this Circular, research establishments, comparator products, and study designs shall be accepted in cases the drugs under consideration have been approved by one of stringent regulatory authorities specified in Clause 10 Article 2 of Circular No. 32/2018/TT-BYT and are marketing in such countries’ market.

5. For a bioequivalence study conducted before the effective date of this Circular, except for the cases specified in Clause 3 of this Article, a comparator product selected in the study shall be accepted if it falls into one of the following cases:

a) The comparator product is in the list of brand name drugs promulgated by the Ministry of Health at the time of study;

b) The comparator product is approved in writing by the Drug Administration of Vietnam of the Ministry of Health;

c) The comparator product is approved by European Medicines Agency (EMA) or one of stringent regulatory authorities (SRA) specified in Clause 10 Article 2 of Circular No. 32/2018/TT-BYT and is marketing in such country’s market.

Article 16. Terms of reference

In case legal documents and regulations referred to in this Circular are amended, supplemented or superseded, the amending, supplementing, superseding documents or regulations shall be applied.

The reference technical instructions specified in Appendix VI to this Circular shall apply as a basis for consideration and assessment of in vivo bioequivalence study dossiers. In case such instructions are changed or updated, establishments are allowed to apply the new version.

Article 17. Implementation responsibility

1. The Drug Administration of Vietnam shall:

a) Organize the guidance and implementation of this Circular;

b) Update and publicize the List of comparator products used for in vivo bioequivalence study issued by the Ministry of Health;

c) Update and publicize the List of in vivo bioequivalence study establishments assessed and recognized by the Ministry of Health of Vietnam.

2. Chief of Ministry Office; Director of the Drug Administration of Vietnam; Chief of Ministry Inspectorate; Heads of units under the Ministry of Health; Directors of Departments of Health of provinces and centrally-run cities; Heads of sectoral health establishments; directors of in vivo bioequivalence study establishments; organizations and individuals engaged in drug registration shall be responsible for implementing this Circular.

3. Any problem arising in the course of implementation shall be promptly reported to the Ministry of Health (Drug Administration of Vietnam) for consideration and settlement./.

* All Appendices are not translated herein.