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MINISTRY OF HEALTH OF VIETNAM |
SOCIALIST REPUBLIC OF VIETNAM |
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No. 07/2022/TT-BYT |
Hanoi, September 05, 2022 |
Pursuant to the Law on Pharmacy dated April 06, 2016;
Pursuant to Decree No. 54/2017/ND-CP dated May 08, 2017 of the Government of Vietnam providing detailed regulations on some Articles and measures for implementation of the Law on Pharmacy;
Pursuant to Decree No. 75/2017/ND-CP dated June 20, 2017 of the Government on function, tasks, powers and organizational structures of the Ministry of Health of Vietnam;
At the request of the Director General of Drug Administration of Vietnam,
The Minister of Health promulgates a Circular on pharmaceutical products for which in vivo bioequivalence studies are required and requirements for documentation of bioequivalence study reporting during application for marketing authorization of these pharmaceutical products in Vietnam.
1. This Circular provides for:
a) Generic drugs whose active pharmaceutical ingredients (APIs) or dosage forms are subject to bioequivalence study reporting during application for marketing authorization in Vietnam;
b) Documentation of bioequivalence study reporting of generic drugs.
2. This Circular applies to generic drugs which have systemic actions after these drugs are absorbed into the general circulation.
For the purposes of this Circular, the terms below shall be construed as follows:
1. “reagent" is a generic drug which is used for proving that it is therapeutically equivalent (with respect to both efficacy and safety of the drug) to a comparator product when being administered to patients in the same dose by the same route under the specific conditions specified in the labeling (if any) via data of in vivo bioequivalence studies or in vitro bioequivalence studies.
2. “comparator product/reference product” is a pharmaceutical product with which the generic drug is intended to be interchangeable in clinical practice. The comparator products will normally be innovator pharmaceutical products or products granted marketing authorizations for which efficacy, safety and quality have been established.
3. “innovator pharmaceutical product” is that which was first authorized for marketing in the world, on the basis of complete documentation of quality, safety and efficacy and may be a product granted or not granted marketing authorization in Vietnam.
4. “pharmaceutical equivalence” means products containing the same molar amount of the same API (for single ingredient drugs) or the same APIs (for multi-ingredient drugs) in the same dosage form, having the same drug release mechanism, the same route of administration and the equivalent quality standards.
5. “Pharmaceutical alternatives” are products which contain the same active pharmaceutical moiety or moieties but differ in chemical form (e.g. different salts, esters, ethers, isomers, mixtures of isomers, complexes or derivatives) of each API or differ in drug content or dosage form.
6. “drug under consideration" is a generic drug for which a marketing authorisation application which includes documentation of bioequivalence study reporting has been submitted.
7. “In vivo bioequivalence study” means a clinical study undertaken on a volunteer and designed to compare the bioavailability of a generic drug with a comparator product with the aim of demonstrating the interchangeability of generic drugs to replace comparator products.
8. “equivalence dissolution” means a study that includes comparison of dissolution profile between drugs/pharmaceutical products in different dissolution media. Equivalence dissolution is also known as an in vitro equivalence study.
9. “In vitro - in vivo correlation” means a predictive mathematical model describing the relationship between the in vitro property (drug dissolution or release) and relevant in vivo response (drug concentration or amount absorbed in biological fluids) of a drug/pharmaceutical product.
10. “research facility” is an organization partly or wholly participating in the in vivo bioequivalence study or in vitro equivalence study of the drug under consideration.
11. “immediate release dosage form” means a dosage form using classic excipients and preparation techniques, without intentionally changing the drug release rate from the dosage form- including conventional dosage forms such as tablets, capsules, suspensions, solutions for oral administration, solutions, suspensions, emulsions for injection and unconventional dosage forms which are also known as special dosage forms such as solid dispersion systems, lozenges, chewable tablets, oral dispersible tablets and sublingual tablets.
12. “Modified release dosage form” means a dosage form using some excipients and/or preparation techniques different from those of the immediate release dosage form in order to produce a rate and/or site of drug release different than those of the immediate release dosage form when being administered by the same route. The most common modified release dosage forms include delayed release, prolonged release, multiphasic release, drug, intramuscular/subcutaneous depot and transdermal drug delivery system.
13. “Fixed-dose combination finished pharmaceutical product” is a pharmaceutical product of which there is a combination of two or more APIs in a fixed ratio of doses. Single ingredient drugs that are packaged together in the same packaging unit for use together do not fall into this category.
14. “Biopharmaceutics classification system (BCS)” means a system of classifying APIs based upon their aqueous solubility and intestinal permeability.
15. “bio-waiver” means the approval for a generic drug, based on evidence of equivalence between the generic drug and its comparator product other than in vivo bioequivalence study reporting.
16. “study under fasted condition” is a bioequivalence study that a volunteer participating in the study did not eat and drink alcohol or xanthine for at least 8 hours before taking the drug.
17. “study under fed condition” is a bioequivalence study that a volunteer participating in the study takes the drug immediately after eating or according to the instructions on time for taking the drug compared to the time for eating as mentioned in the drug property summary.
18. “single-dose study” means a bioequivalence study that biological samples used for analysis are collected after taking a single dose of drug at each study period.
19. “multi-dose study” means a bioequivalence study that biological samples used for analysis are collected after taking multiple doses of a drug to achieve a stable drug concentration in the blood.
20. “Polarized approach” means the analysis and selection of 02 strengths in many different strengths of the same drug (with the same dosage form, manufactured by the same manufacturer) that are determined as having the most significant differences so that any difference between the remaining strengths is within the difference of these two selected strengths to conduct a research and extrapolate the research results to the remaining strengths.
21. “ASEAN" is an abbreviation of the English phrase “Association of Southeast Asian Nations”, translated into Vietnamese as “Hiệp hội các nước Đông Nam Á”.
22. “ICH” is an abbreviation of the English phrase “International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use”, translated into Vietnamese as “Hội nghị quốc tế về hài hòa các thủ tục đăng ký dược phẩm sử dụng cho con người”.
23. “Form of ASEAN bioequivalence study reports" means a reporting form prescribed in Appendix IV of the Guideline on conducting ASEAN bioequivalence studies issued together with Circular No. 32/2018/TT-BYT dated November 12, 2018 of the Minister of Health on application for marketing authorization of pharmaceutical products and medicinal ingredients (hereinafter referred to as “Circular No. 32/2018/TT-BYT”).
24. “Form of ICH bioequivalence study reports" means a reporting form according to the Guideline on the Structure and Content of Clinical Study Reports (E3 Guideline) of ICH.
1. Criteria for selection of an API contained in a generic drug subject to a bioequivalence study report upon applying for marketing authorization are sorted according to the following priority:
a) Possessing a narrow therapeutic index;
b) Having a bioavailability that is low and/or very different between individuals;
c) Being presented in prescription drugs, belonging to one of the drug classes including cardiovascular drugs, hypoglycemic drugs, antibiotics, antipsychotic/antiepileptic drugs, antivirals;
d) Being contained in drugs in the list of drugs used in National Programs, including: HIV-AIDS prevention project; Community mental health protection project; Tuberculosis prevention project; Malaria Prevention Project.
2. The list of APIs contained in the generic drug for which a bioequivalence study report is required during application for marketing authorization of the generic drug is prescribed in Appendix I issued together with this Circular.
Generic drugs in dosage form for which reports on bioequivalence study data are required upon applying for marketing authorization include:
1. Immediate release pharmaceutical products with systemic action, which contain APIs specified in Clause 2, Article 3 of this Circular and do not fall into the cases specified in Article 5 of this Circular.
2. Modified release pharmaceutical products with systemic action, except for cases specified in Article 5 of this Circular.
Generic drugs for which in vivo bioequivalence studies are waived due to the available bioequivalence between these drugs and comparator products include:
1. Generic drugs which are used for intravenous (IV) injection in the form of aqueous solutions, contain the same APIs at the same molar concentrations when being used as comparator drugs and do not contain excipients that interact with APIs or have the same effect on the distribution of the APIs as that of the comparator products. In case these excipients must be used in the formulation, these excipients and excipients contained in the comparator products must have the same qualitative and quantitative composition or if there is a difference in quantity, it must be demonstrated that this difference does not affect the pharmacokinetics of the APIs.
2. Generic drugs which are used for other routes of administration other than IV injection in the form of aqueous or oil-based solutions, contain the same APIs at the same molar concentrations and contain the same excipients with the similar concentrations when being compared with their comparator products. For an injecting drug which is an aqueous solution, excipients in the formulation may be different but they must have the same class (same effect) and concentration as those contained in the comparator product and different excipients must not affect the viscosity of the aqueous solution according to evidence.
3. Generic drugs which are oral solutions (including solid dosage-form drugs with instructions for dissolving into oral solutions before use), are equivalent in pharmaceutical formulation to their comparator products and both generic drugs and comparator products do not contain excipients which may affect the in vivo delivery, absorption or stability of APIs as those in their comparator products. In case there must have excipients that may affect the in vivo delivery, absorption or stability of APIs in the pharmaceutical formulation of the generic drugs, categories and quantities of these excipients of the generic drugs must be equivalent to those of their comparator products.
4. Generic drugs in gaseous form which are equivalent in pharmaceutical formulation to their comparator products.
REQUIREMENTS FOR COMPARATOR PRODUCTS AND IN VIVO BIOEQUIVALENCE STUDIES
Article 6. Comparator products used in in vivo bioequivalence studies
1. Criteria for selection of a comparator product for an in vivo bioequivalence study serving the application for marketing authorisation are prescribed in the priority as follows:
a) Being a drug/pharmaceutical product on the list of proprietary drugs published by the Ministry of Health or a pharmaceutical product granted a marketing authorization with adequate data on clinical efficacy, safety and quality;
b) Being an innovator pharmaceutical product which is not granted a Marketing Authorization Approval certificate in Vietnam but is approved and marketed in a country by a stringent pharmaceutical regulatory authority prescribed in clause 10 Article 2 of Circular No. 32/2018/TT-BYT of the country;
c) In case it is unable to determine any comparator product meeting regulations in point a and point b of this clause, the comparator product will be selected in the priority as follows:
- Being a pharmaceutical product which is approved and marketed in a country by a stringent pharmaceutical regulatory authority prescribed in clause 10 Article2 of Circular No. 32/2018/TT-BYT of the country.
- Being a pharmaceutical product which has been prequalified by the World Health Organization (WHO).
Pharmaceutical products which meet this requirement and have unexpired marketing authorizations by the Ministry of Health of Vietnam will be given priority.
2. In addition to the requirements mentioned in clause 1 of this Article, if the comparator product used in the in vivo bioequivalence study is a an immediate release pharmaceutical product, modified release pharmaceutical product or fixed-dose combination finished pharmaceutical product, it must meet the following requirements as well:
a) In case a pharmaceutical product which is under consideration is a single ingredient drug in immediate release dosage form, the comparator product must be a single ingredient drug in immediate release dosage form as well;
b) In case the pharmaceutical product which is under consideration is a modified release pharmaceutical product, the comparator product must also be a modified release product with the same drug release mechanism as the pharmaceutical product;
c) For a fixed-dose combination finished pharmaceutical product:
- In case the pharmaceutical product is under consideration to intendedly replace a fixed-dose combination finished pharmaceutical product approved with complete documentation of safety and efficacy in clinical practice (which is a proprietary drug or an innovator pharmaceutical product), the fixed-dose combination finished pharmaceutical product will be selected to be the comparator product.
- In case the pharmaceutical product which is under consideration is developed for the purpose of replacing the fixed-dose combination of single ingredient drugs with complete documentation of safety and efficacy in clinical practice, the comparator product will be a corresponding single-ingredient drug.
3. The comparator product used in the in vivo bioequivalence study must have clear origin. Documentary evidence of origin of the comparator product is prescribed in point c clause 1 Article 8 hereof.
4. On the basis of criteria for selection of comparator products prescribed in clause 1 of this Article, other requirements for them prescribed in clause 2 and clause 3 of this Article and actual conditions, the Drug Administration of Vietnam shall make a list of comparator products and ask the Consulting Council for issuance of marketing authorizations of pharmaceutical products and medicinal ingredients for promulgation of a Decision on issuing the List of comparator products used in in vivo bioequivalence studies. The List of comparator products used in in vivo bioequivalence studies is published on the website of the Drug Administration of Vietnam at https://dav.gov.vn/.
1. Each study must meet the following requirements:
a) must be designed and conducted according to the Guideline on conducting ASEAN bioequivalence studies or reference guidelines of other organizations prescribed in Appendix VI enclosed herewith.
b) For oral, modified release pharmaceutical products with systemic action, must conduct the study under fasted condition and fed condition;
c) For immediate release pharmaceutical products with systemic action, except for cases specified in Article 5 of this Circular, must conduct the study under fasted condition. On the basis of pharmacokinetics of the comparator product, it is known that food can affect bioavailability or the comparator product must be used after meal as specified in instructions for use, may conduct the study under fed condition instead of fasted condition;
d) For a fixed-dose combination finished pharmaceutical product, must conduct the study on bioequivalence evaluation of active pharmaceutical moieties contained in the product;
dd) Apply in vivo bioequivalence study design for each pharmaceutical product according to recommendations of US Food and Drug Administration (US FDA) or European Medicines Agency (EMA).
2. The study must be conducted at testing centers that are evaluated and approved by competent authorities in the hosting country and must comply with regulations on good clinical practice (GCP) as prescribed in clause 1 Article 4 of Circular No. 29/2018/TT-BYT dated October 29, 2018 of the Ministry of Health on clinical trials and good laboratory practice (GLP) as prescribed in clause 1 Article 3 of Circular No. 04/2018/TT-BYT dated February 09, 2018 of the Ministry of Health on Good Laboratory Practice.
3. In case a bioequivalence study of a pharmaceutical product which is under consideration uses a comparator product which is an innovator pharmaceutical product but is not produced in the same manufacturer as the innovator pharmaceutical product granted a marketing authorization in Vietnam of the product, the applying facility needs to prove the mutual interchangeability between the comparator product used in the study and the innovator product granted the marketing authorization in Vietnam of the product according to the ASEAN Guideline for the conduct of Bioavailability/Bioequivalence studies.
4. Form of documentation of bioequivalence study reporting of pharmaceutical products is prescribed in point a clause 1 Article 8 hereof. Specific requirements for the documentation of bioequivalence study reporting of pharmaceutical products under consideration are prescribed in Appendix III enclosed herewith.
5. Bio-waiver is claimed for pharmaceutical products under consideration if they meet the following requirements:
a) Pharmaceutical products under consideration whose pharmaceutical formulations are proportionally similar with those of reagents in a bioequivalence study meet regulations in section I Appendix II enclosed herewith;
b) Pharmaceutical products under consideration which have the same dosage form, pharmaceutical formulation and manufacturing process as reagents in the bioequivalence studies but differ in strengths of APIs meet regulations in section II Appendix II enclosed herewith;
c) Oral, solid and immediate-release pharmaceutical products under consideration which have pharmaceutical equivalence upon being compare with comparator products and APIs classified into the class of high solubility and high permeability according to the biopharmaceutics classification system meet regulations in section III Appendix II enclosed herewith;
d) Pharmaceutical products under consideration which are manufactured a manufacturing site different from it of reagents in a bioequivalence study meet requirements in section IV Appendix II enclosed herewith.
DOCUMENTATION OF BIOEQUIVALENCE STUDY REPORTING
1. The documentation shall include:
a) A report on in vivo bioequivalence study data based on the current form of ASEAN bioequivalence study reports or form of ICH bioequivalence study reports, from which a written commitment on the equivalence between the reagent in the study and the pharmaceutical product under consideration must be prepared according to Schedule 01/BE prescribed in Appendix VII enclosed herewith;
b) Documents and information of the research facility as prescribed in Article 12 hereof;
c) Documentary evidence of origins of the comparator product used in the study including:
- A copy of an invoice of comparator product with clear name and address of the manufacturer;
- A copy of the product label with confirmation of the applying facility/manufacturer with full and clear information about name of the comparator product, name and address of the manufacturer, batch number and expiry date;
- The written commitment with signature of the Director of the applying facility/manufacturer on the purchase of the comparator product from the right country where the product is granted its marketing authorisation approval certificate and preservation under the reasonable condition labeled from the time of purchase to the time of beginning conducting the study in order to confirm the authentication of the documents provided above.
2. In case a volunteer takes the pharmaceutical product under consideration in different conditions (fed, fasted, single-dose or multi-dose), the documentation of bioequivalence study reporting including various reports on bioequivalence studies and each of them will specify each condition of taking the product must be adequate or documented to have adequate documents prescribed in clause 1 hereof.
The documentation of bioequivalence study reporting of a pharmaceutical product under consideration prescribed in point a point b clause 5 Article 7 hereof includes:
1. A petition for bio-waiver for the pharmaceutical product under consideration according to Schedule 02/BE prescribed in Appendix VII enclosed herewith.
2. A dossier on bioequivalence of a strength or strengths selected to conduct an in vivo bioequivalence study for the comparator product meeting regulations in Article 8 hereof.
3. Documentation of the selection of strengths for bioequivalence study reporting and use of the result of bioequivalence study of these strengths to apply bio-waiver for other strengths, including strength of the pharmaceutical product under consideration.
4. A comparison table for pharmaceutical formulation with strengths for which the bio-waiver is applied, including strength of the pharmaceutical product under consideration and that of strengths of which there are bioequivalence study reports.
5. A comparison table for manufacturing process with strengths for which the bio-waiver is applied, including strength of the pharmaceutical product under consideration and that of strengths of which there are bioequivalence study reports.
6. An in vitro bioequivalence study report between strengths for which the bio-waiver is applied, including strength of the pharmaceutical product under consideration and strengths of which there are reports on bioequivalence study data. Requirements for the in vitro bioequivalence study report are prescribed specifically in Appendix IV enclosed with this Circular.
7. A commitment to the equivalence between the pharmaceutical product under consideration and the reagent used in in vitro bioequivalence study according to schedule 01/BE prescribed in Appendix VII enclosed herewith.
8. Information about linear pharmacokinetics of the pharmaceutical product under consideration (if applicable).
The documentation of bioequivalence study reporting of a pharmaceutical product under consideration prescribed in point c clause 5 Article 7 hereof shall include:
1. A written petition for bio-waiver for the pharmaceutical product under consideration according to schedule 02/BE prescribed in Appendix VII enclosed herewith.
2. Documents of the research facility prescribed in Article 12 hereof.
3. Documentary evidence of the good solubility and permeability of the API/APIs contained in the product under consideration according to the guideline in Appendix III. The bio-waiver is based on the BCS of the ASEAN Guideline on conduct of bioequivalence studies issued together with Circular No. 32/2018/TT-BYT .
4. Data proving that the product under consideration contains excipients meeting requirements for being taken into consideration for bio-waiver includes:
a) A comparison table for excipients used in the formulation between the product under consideration and the comparator product or a pharmaceutical product that is not a comparator product but has the pharmaceutical equivalence between it and the product under consideration and has been used as a reference product by one of the stringent pharmaceutical regulatory authorities specified in Clause 10 Article 2 of Circular No. 32/2018/TT-BYT with information on reference sources for excipients in the formulation of the comparator product or reference product..
Some official approved reference sources include: the approved Guideline on use of pharmaceutical products by the Drug Administration of Vietnam, overview of properties of authorized pharmaceutical products or report on evaluation of pharmaceutical products posted on the website of the European Medicines Agencies (EMA) and the stringent regulatory authority (SRA) prescribed in clause 10 Article 2 of Circular No. 32/2018/TT-BYT or on official sites for drug and medication information such as eMC (electronic Medicines Compendium). In case information on the excipients used in the formulation of the comparator product or reference product can not be found, qualitative results of the excipients in the formulation of the comparator product or the reference product must be provided to demonstrate that the product under consideration has the same excipients in the formulation as one of these products;
b) In case excipients used in the formulation of the product under consideration affect bioavailability of it, qualitative and quantities results of the excipients used in the formulation of the product under consideration and that of the comparator product must be provided to demonstrate that the product under consideration has the same excipients as the comparator product;
c) A report on validation of qualitative and quantitative analytical procedures used in the above-mentioned studies.
5. A report on evaluation of the solubility of the product under consideration (for products with the very rapid solubility) or a report on in vitro bioequivalence study between the product under consideration and the comparator product (for products with the rapid solubility). Requirements for the report on in vitro bioequivalence study are prescribed specifically in Appendix IV enclosed with this Circular.
6. A commitment of the equivalence between the product under consideration and the reagent used in the in vitro study or in vitro bioequivalence study according to schedule 01/BE prescribed in Appendix VII enclosed herewith.
7. Related documents concerning the comparator product in accordance with regulations in point c clause 1 Article 8 hereof.
The documentation of bioequivalence study reporting of a pharmaceutical product under consideration prescribed in point d clause 5 Article 7 hereof includes:
1. A written petition for bio-waiver for the pharmaceutical product under consideration according to Schedule 02/BE prescribed in Appendix VII enclosed herewith.
2. In case of change of manufacturing site due to the change from the manufacturer of the product owner to a contract manufacturer of the product owner or change between contract manufacturers of the product owner: a product owner's document about the manufacturer of the product under consideration designated as the contract manufacturer of the product owner, and a written agreement on participation in manufacture of the product under contract of the designated contract manufacturer. In case the manufacturing site is changed due to the change from one contract manufacturer to another of the product owner, a product owner's written explanation of reasons for this change shall be added.
3. In case of change of manufacturing site due to the change between different manufacturers of the same product owner or between different manufacturing sites of the same manufacturer: a written explanation of the product owner or applying facility of reasons for the change of manufacturing site.
4. A document about quality of the reagent used in the bioequivalence study includes:
- Part S. APIs: an overview of API integration process attached to a process mapping; Solvents used in the process; API properties; Impurity properties; Quality standards of APIs; Analytical data on batches of APIs;
- Part P. Finished pharmaceutical products (FPPs): Pharmaceutical formulation; Manufacturing process; Quality standards of excipients; Quality standards and analytical procedures for FPPs; Analytical data on at least 03 pilot-scale batches of FPPs as specified in Appendix V hereof - including batches used in in vivo bioequivalence study; Stability of FPPs (in case there is not enough data on the long-term stability of the product under consideration until its registered expiry date); Bioequivalence dossiers satisfying the regulations in Article 8 hereof.
5. Documents prescribed in clauses 3, 4, 5, 6, 7, and 8 Article 9 hereof in case the product under consideration has been manufactured according to regulations in point a or b clause 5 Article 7 hereof at the old manufacturing site.
6. A table listing changes related to the pharmaceutical formulation, production batch size, manufacturing process, manufacturer of APIs during marketing (if any) of the pharmaceutical product under consideration manufactured at the old manufacturing site.
7. A written approval for these changes of the pharmacy authority of the host country.
8. A dossier on changes and addition to each listed change meeting regulations in Appendix II enclosed with Circular No. 32/2018/TT-BYT , except for administrative documents.
9. The documentation of scientific bases attached to experimental data proving that the reagent used in the bioequivalence study are still representative of the product under consideration. The documentation of scientific bases must include the following contents at the minimum:
a) The equivalence of manufacturing formulation between the product under consideration and the reagent used in the bioequivalence study or that of pharmaceutical formulation between them meeting requirements prescribed in sections I and II of Appendix II enclosed herewith in case the product under consideration manufactured at the old manufacturing site is approved for bio-waiver according to regulations in point a or point b clause 5 Article 7 hereof;
b) The equivalence of quality standards of APIs including API properties known as having effects on bioavailability of FPPs, quality standards of excipients, manufacturing process and standard operating procedures, equipment used in manufacture and environmental control in the manufacturing process, quality standards of FPPs;
c) Properties of excipients effecting bioavailability of APIs used in the formulation;
d) Comparison of analytical data of at least 03 pilot-scale batches as prescribed in Appendix V hereof including batches of reagents used in the bioequivalence study and batches of products under consideration.
10. The documentation of in vitro bioequivalence between the pharmaceutical product manufactured at the old manufacturing site and the product under consideration. Requirements for the report on in vitro bioequivalence study are prescribed specifically in Appendix IV enclosed with this Circular. This documentation is not required if the change of manufacturing site only relates to one or a number of stages including primary packaging without dosing, quality control, batch release and secondary packaging.
11. The data documentation of in vitro - in vivo correlation which has been established in case of modified release pharmaceutical products. In case the change of manufacturing site only affects one or a number of stages including primary packaging after dosing, quality control, batch release and secondary packaging, this documentation is not required.
12. In case manufacturing site changes due to the change of the manufacturer and the product manufactured at the old manufacturing site which has been granted the marketing authorization in Vietnam according to ASEAN common technical dossier (ACTD) but has not been released as a documented bioequivalent product: the documentation of bioequivalence study reporting of the product manufactured at the old manufacturing site which must meet regulations in Article 8 and the documentation of bioequivalence study reporting of the product under consideration which must meet regulations in clauses 1, 2, 3, 5, 6, 7, 8, 9, 10 and 11 of this Article.
13. In case manufacturing site changes due to the change of the manufacturer and the product manufactured at the old manufacturing site which has been released as a documented bioequivalent product: the documentation of bioequivalence study reporting of the product under consideration which must meet regulations in clauses 1, 2, 3, 5, 6, 7, 8, 9, 10 and 11 of this Article.
14. In case there is a change in different manufacturing sites of the same manufacturer and product manufactured at the old manufacturing site which has been granted the marketing authorisation in Vietnam: based on the changes and addition of pharmaco-chemical products already granted marketing authorizations specified in Appendix II issued with Circular No. 32/2018/TT-BYT .
Article 12. Documents and information of research facilities
1. Documents of the research facilities are not mandatorily required for facilities performing in vivo bioequivalence study in Vietnam which have been assessed by the Ministry of Health and published on the list of facilities meeting requirements for conducting in vivo bioequivalence studies of pharmaceutical products on the web portal of the Ministry of Health and website of the Drug Administration of Vietnam or facilities permitted in writing to conduct in vivo bioequivalence studies of pharmaceutical products by the Ministry of Health.
2. Documentation for a research facility certified by the World Health Organization and published on the list of prequalified laboratories allowed to conduct in vivo bioequivalence studies or a facility assessed and certified as being allowed to conduct in vivo bioequivalence studies by one of pharmaceutical regulatory authorities prescribed in clause 10 Article 2 of Circular No. 32/2018/TT-BYT or a facility certified by a competent regulatory authority of one of the countries of the ICH to conduct in vivo bioequivalence study or a facility named in the list of facilities performing bioequivalence studies approved under the ASEAN mutual recognition arrangements (MRAs) for bioequivalence study reports of pharmaceutical products (posted on the ASEAN website) and other facilities belonging to countries with which Vietnam has a recognition arrangement is one of the following two types of:
a) An original or a copy of a certificate of a facility meeting GCP and GLP or ISO/IEC 17025 or a license/certificate/confirmation/notification granted to a facility performing in vivo bioequivalence study by a competent authority of the host country or a certificate/confirmation/notification of approval for conducting in vivo bioequivalence study by a facility from a competent authority of the host country;
b) A result after self-searching a legal document prescribed in point a of this clause from the English website of the agency granting the legal document attached to a document providing information on reference links to the Drug Administration of Vietnam in case of an electronic legal document, or lack of signature, name of signatory or certificate seal of a competent state regulatory authority of the country granting the legal document.
3. Documentation which must be submitted of a research facility which is not prescribed in clause 1 and clause 2 of this Article is one of the following documents:
a) An original or a copy of a license/certificate/confirmation/notification granted to a facility performing in vivo bioequivalence study by a competent authority of the host country or a certificate/confirmation/notification of approval for trial conduct of in vivo bioequivalence study of a pharmaceutical product under consideration by a facility from a competent authority of the host country;
b) An original or a copy of a certificate of meeting GLP or certificate of meeting ISO/IEC 17025 to perform an analysis of biological fluids granted to a facility participating in the analytical stage by a regulatory authority of the host country and a certificate of meeting GCP granted to a facility participating in the clinical stage by a regulatory authority of the host country;
c) In case a research facility cannot provide documents prescribed in point a or b of this clause due to law of the host country which not provides for issuing these documents to the research facility, the unit which applies for marketing authorization of the product under consideration is required to provide documentary evidence of the compliance with GCP and/or GLP including:
- Documentary evidence of the compliance with GLP:
+ A quality manual or an overall profile of the bioequivalence research facility. These documents must address capacity and scope of conducting the study;
+ An original or a copy of a contract between the bioequivalence research facility and its donor and subcontractors;
+ A list of inspections by regulatory authorities or accreditation bodies over the last 3 years and the most recent inspection report of the local regulatory authority.
- Documentary evidence of the compliance with GCP:
+ An overall profile of a center for bioequivalence studies and clinical research (CBSCR) demonstrating full testing capacity for conducting bioequivalence studies of pharmaceutical products;
+ An original or a copy of a contract between the bioequivalence research facility and its donor and subcontractors;
+ An original or a copy of an inspection report of a national pharmaceutical regulatory authority or WHO which has been made within 3 years;
+ An original or a copy of a research supervision report by a donor or research organization for studies under consideration.
4. Documents prescribed in clause 2, points a and b clause 3 of this Article must satisfy the following requirements:
a) Documents must be valid during the study period. A document shall be effective for 03 years from the date on which it is issued if the effective period is not clarified on the document;
b) In case the certificate of meeting GLP and the certificate of meeting GCP do not satisfy the regulations in point a of this clause, conclusion of GLP/GCP assessment in the inspection report of the competent regulatory authority of the latest inspection in 03 years after the date on which the assessment is carried out.
5. Documents prescribed in this Article must be given seals of approval by the applying facility. The applying facility must be responsible before the law for the result after self-searching of the facility specified in point b clause 2 of this Article and the legitimacy and accuracy of the documents and information specified in this Article.
1. This Circular comes into force from November 01, 2022.
2. Circular No. 08/2010/TT-BYT dated April 26, 2010 of the Minister of Health providing for Guideline on reports on bioavailability/bioequivalence study data in applying for marketing authorisation of pharmaceutical products is null and void from the date on which this Circular comes into force.
1. From the date on which this Circular comes into force, each facility applying for marketing authorization of the following pharmaceutical products must submit the documentation of bioequivalence study reporting when the facility submits an application for issuance of marketing authorization of the pharmaceutical products including:
a) Generic drugs which are prepared in the immediate release dosage form and delayed release dosage form, are single active ingredient or fixed-dose combination drugs, contain APIs on the List of APIs in the formulation for which bioequivalence study reports are required when applying for marketing authorization of these drugs;
b) Generic drugs which are prepared in the modified release dosage form, except for delayed release drugs which are not prescribed in point a of this clause;
2. After 36 months from the date on which this Circular comes into force, each applying facility must submit a dossier on in vivo bioequivalence study when submitting the application for issuance of marketing authorization of all delayed release generic drugs, except for generic drugs prescribed in clause 1 of this Article.
3. After 48 months from the date on which this Circular comes into force, each applying facility granted marketing authorization of pharmaceutical products containing APIs or being in dosage forms required of in vivo bioequivalence studies according to regulations herein must be certified publically to have pharmaceutical products which are bioequivalent after being documented. Procedures for public certification of pharmaceutical products which are bioequivalent after being documented are prescribed in the Circular on the application for marketing authorization of drugs and medicinal materials.
Article 15. Transitional regulations
1. Bioequivalence study reports in applications for issuance, change or addition of marketing authorizations submitted before the date on which this Circular comes into force shall continuously comply with regulations in Circular No. 08/2010/TT-BYT dated April 26, 2010 of the Minister of Health providing for guideline on reports on bioavailability/bioequivalence study data in applying for marketing authorization of pharmaceutical products, except for the case that facilities voluntarily comply with regulations herein.
2. For pharmaceutical products of which marketing authorization applications are submitted before the date on which this Circular comes into force: bioequivalence study reports are not required of additional submission before the dates on which marketing authorizations are granted; facilities applying for marketing authorization must comply with regulations in clause 3 Article 14 after marketing authorizations of pharmaceutical products are granted.
3. In case in vivo bioequivalence studies or in vitro bioequivalence studies are conducted before the date on which this Circlular comes into force, commitments of enterprises to origins of comparator products used in these studies shall be approved according to schedule 03/BE prescribed in Appendix VII enclosed herewith if documentary evidence of origins of these comparator products cannot be provided according to regulations in point c clause 1 Article 8 hereof.
4. In case in vivo bioequivalence studies are conducted before the date on which this Circular comes into force, research facilities, comparator products and study designs shall be approved if pharmaceutical products under consideration have been approved and marketed in countries by their stringent regulatory authorities prescribed in clause 10 Article 2 of Circular No. 32/2018/TT-BYT .
5. In case in vivo bioequivalence studies are conducted before the date on which this Circular comes into force, except for cases prescribed in clause 3 of this Article, comparator products that are selected in these studies shall be approved in one of the following cases:
a) Comparator products are prescribed in the lists of proprietary drugs issued by the Ministry of Health in the study periods;
b) Comparator products are approved in writing by the Drug Administration of Vietnam of the Ministry of Health;
c) Comparator products are approved and marketed in countries by their EMAs and SRAs prescribed in clause 10 Article 2 of Circular No. 32/2018/TT-BYT .
Article 16. Reference regulations
In case legislative documents and regulations cited in this Circular are changed, added or replaced, new legislative documents or cited regulations shall be applied.
Reference technical guidelines prescribed in Appendix VI enclosed herewith shall be applied as bases for consideration and assessment of dossiers on in vivo bioequivalence studies. In case these guidelines have changes or updates, research facilities are permitted to apply new versions of them.
Article 17. Responsibility for implementation
1. Drug Administration of Vietnam is responsible for:
a) organizing guidance and implementing regulations herein;
b) updating and publishing the List of comparator products used in in vivo bioequivalence studies issued by the Ministry of Health;
c) updating and publishing the list of facilities conducting bioequivalence studies assessed and approved by the Ministry of Health of Vietnam;
2. Chief of the Ministry Office, Director General of the Drug Administration of Vietnam, Chief Inspector of the Ministry, Heads of units affiliated to the Ministry of Health, Directors of Departments of Health of provinces or central-affiliated cities; Heads of healthcare facilities of health sectors, directors of facilities conducting in vivo bioequivalence studies of pharmaceutical products; organizations and individuals operating in the field of marketing authorization of pharmaceutical products are responsible for implementation of this Circular.
3. Agencies, organizations and individuals should report difficulties that arise during the period of implementation of this Circular to the Ministry of Health (via the Drug Administration of Vietnam) for consideration and settlement./.
|
|
PP. MINISTER |
list of APIs
contained in generic drugs for which
bioequivalence study reports are required while applying for marketing authorization
of pharmaceutical products
(enclosed with Circular No. 07/2022/TT-BYT dated September 05, 2022 of the
Ministry of Health of Vietnam)
|
No. |
Name of API |
|
1 |
Amlodipin |
|
2 |
Azithromycin |
|
3 |
Carbamazepin |
|
4 |
Cefixim |
|
5 |
Cefuroxim Axetil |
|
6 |
Clarithromycin |
|
7 |
Glibenclamid |
|
8 |
Gliclazid |
|
9 |
Metformin |
|
10 |
Metoprolol |
|
11 |
Nifedipin |
|
12 |
Rifampicin |
|
13 |
Amoxicilin and acid clavulanic |
|
14 |
Carvedilol |
|
15 |
Cefpodoxim |
|
16 |
Ezetimibe |
|
17 |
Irbesartan |
|
18 |
Itraconazol |
|
19 |
Risperidon |
|
20 |
Rosuvastatin |
|
21 |
Simvastatin |
|
22 |
Sulpirid |
|
23 |
Sultamicillin |
|
24 |
Telmisartan |
|
25 |
Valproat natri |
|
26 |
Fenofibrat |
REQUIREMENTS FOR
BEING GRANTED APPROVAL FOR PHARMACEUTICAL PRODUCTS FOR WHICH IN VIVO
BIOEQUIVALENCE STUDIES MAY BE WAIVED
(enclosed with Circular No. 07/2022/TT-BYT dated September 05, 2022 of the
Ministry of Health of Vietnam)
1. Proportional formulations mean pharmaceutical formulations of different strengths of the same pharmaceutical product (the same dosage form, the same manufacturer) that meet the following requirements:
a) Regarding an immediate release product: when pharmaceutical formulations of the product have the same APIs and excipients (excluding coating components, capsule shells, colour agents, flavours and preservatives not capable of altering the bioavailability of the product) in the different strengths in the same proportions of all the APIs and excipients or where the amount of an API in the dosage form is either less than or equal to 5% of the weight of the dosage form, the total weight of the dosage form remains similar for all strengths or only the amount of filler is changed to account for the change in amount of API and the amounts of other core excipients in the dosage form should be the same for the strengths concerned. If the product is an encapsulated tablet, the weight of the dosage form is calculated as that of the solid product covered by a film coating. If the product is a capsule, the weight of the dosage form is calculated as that of the pharmaceutical product covered by a capsule shell.
b) Regarding an enteric-coated product:
- Regarding an enteric-coated tablet: when pharmaceutical formulations of the tablet have the same APIs and excipients (excluding colour agents, flavours and preservatives not capable of altering the bioavailability of the product) in the different strengths in the same proportions of all the APIs and excipients or where an API is either less than or equal to 5% of the weight of the dosage form, the total weight of the dosage form remains the similar for all strengths or only the amount of filler is changed to account for the change in amount of API and the amounts of other core excipients in the dosage form should be the same for the strengths concerned, and the ratio of acid resistant coating weight/volume to tablet surface area between tablets with different strengths (mg/cm2) must be the same).
- Regarding a pharmaceutical product which is a capsule containing enteric-coated beads: enteric-coated beads are in the same type for all different strengths (manufactured with the same manufacturing process) and the different strengths have been achieved solely by means of adjusting the number (or weight) of beads containing the API.
c) Regarding a prolonged-release product:
- When there is a series of strengths of a product that have the same API release mechanism and pharmaceutical formulations of the product have the same APIs and excipients in the different strengths in the same proportions of all the APIs and excipients or where the amount of an API in the dosage form is either less than or equal to 5% of the weight of the dosage form, only the amount of filler is changed to account for the change in amount of API and the amounts of other core excipients in the dosage form should be the same for the strengths concerned. If the product is an encapsulated tablet, the weight of the dosage form is calculated as that of the solid product covered by a film coating. If the product is a capsule, the weight of the dosage form is calculated as that of the pharmaceutical product covered by a capsule shell.
- Regarding a pharmaceutical product which is a capsule containing prolonged-release beads: prolonged-release beads are in the same type for all different strengths (manufactured with the same manufacturing process) and the different strengths have been achieved solely by means of adjusting the number (or weight) of beads containing the API.
d) For a transdermal product, APIs and excipients are the same for all different strengths, the strengths are proportional to the effective surface area of the patch, and the lower dose strengths can be considered as partial areas of the highest dose strength.
dd) Regarding a fixed-dose combination finished pharmaceutical product, all the APIs contained in the product must meet requirements for a series of strengths that can be considered to be proportionally formulated. If an API is considered, the remaining APIs are considered as excipients in the pharmaceutical formulation unless scientific evidence can be provided to show that differences in combination ratios for the remaining APIs are acceptable. For a bilayer tablet, each layer can be considered independently.
2. If a pharmaceutical product under consideration has a series of strengths that is proportionally formulated according to regulations in clause 1 of this section, a bioequivalence study report of one or both strength(s) that is (are) considered to carry the greatest risk of not reaching bioequivalence in accordance with regulations in clause 3 of this section can be applied for consideration for biowaiver for the remaining strengths if the strengths above meet both requirements below-mentioned:
a) Strengths in the series of the pharmaceutical product for which a proposal for submission of bioequivalence study reports are not involved are used in the same manufacturing process as that of the strengths applied in the in vivo bioequivalence study.
b) Dissolution profile of the strengths proposed for biowaiver must be similar to dissolution profile of one of any strengths applied in the in vivo bioequivalence study (based on the percentage of strengths of APIs released in comparison with those labeled over time).
3. Strengths in the series of the pharmaceutical product for which a bioequivalence study report is required to be able to consider for biowaiver for the remaining strengths are selected for the study as follows:
a) For a pharmaceutical product exhibiting linear pharmacokinetics (proportional increase in extent of absorption): a bioequivalence study report is required at a strength, usually the highest strength (except for cases that a study with the highest strength cannot be conducted for safety or tolerability reasons).
b) For a pharmaceutical product exhibiting non-linear pharmacokinetics:
- For a pharmaceutical product with a less-than-dose-proportional increase in extent of absorption with increasing dose over the therapeutic dose range, a bioequivalence study should be conducted on at least the highest strength.
- For a pharmaceutical product with a less-than-dose-proportional increase in extent of absorption with increasing dose over the therapeutic dose range not caused by limited solubility of the API but due to saturation of uptake transporters and both its test product and comparator product do not contain any excipients that may affect gastrointestinal (GI) motility or transport proteins, a bioequivalence study should be conducted on the lowest strength or a strength in the linear range.
- For a pharmaceutical product with a less-than-dose-proportional increase in extent of absorption with increasing dose due to limited solubility of the API, a bioequivalence study should be conducted on both the highest strength and the lowest strength or a strength in the linear range.
The lasted edition of the ASEAN Guideline for the conduct of bioequivalence studies, section 3.1.6. Strength to be evaluated is a reference source to consider other exceptions applicable to the selection of strengths for which a bioequivalence study report is required to be able to consider for biowaiver for the other strengths in each one of the above cases.
c) Special cases:
- For depot-injection pharmaceutical products administered via intramuscular/subcutaneous injection: if different strengths are only achieved due to the difference in the total volume of these products contained in a dosage unit (total volume of these products injected), an in vivo bioequivalence study may be conducted at any strength. In cases where it is unable to use doses over the therapeutic dose range for conduct of studies in healthy volunteers for safety reasons, a report on an in vivo bioequivalence study at a dose lower than the therapeutic dose.
- For an enteric-coated product containing multiple subunits which are homogeneous pellets: the product contains the same type of enteric coated beads in different strengths (manufactured with the same manufacturing process) and it has a proportional formulation: a report on an in vivo bioequivalence study at the highest strength or a strength that is considered to carry the greatest risk of not reaching the bioequivalence may be required.
- For an prolonged-release product containing multiple subunits which are homogeneous pellets: the product contains the same type of prolonged-release pellets in different strengths (manufactured with the same manufacturing process) and it has a proportional formulation: a report on an in vivo bioequivalence study at the highest strength or a strength that is considered to carry the greatest risk of not reaching the bioequivalence may be required.
- For pharmaceutical products for which reports on in vivo bioequivalence studies under both fasted and fed conditions are required (the same regulations with those for oral prolonged-release products) and their pharmacokinetics are non-linear resulting in the conduct of in vivo bioequivalence studies in 02 different strengths to apply for biowaiver for the remaining strengths, only reports on in vivo bioequivalence studies under both fasted and fed conditions in a strength and applications for biowaiver are necessary or reports on in vivo bioequivalence studies under fasted condition or fed condition in the remaining strengths, based on which condition is considered to be less sensitive for detecting the inequivalence between test products and comparator products. Regulations in clause 3 section II of this Appendix are reference sources for selection of which condition is considered to be less sensitive and application for biowaiver under this condition for the remaining strengths.
4. The similarity of the dissolution profile of pharmaceutical products under consideration between strengths proposed for biowaiver with those for which in vivo bioequivalence study reports are involved is prescribed in regulations of Appendix I. Dissolution testing and similarity of dissolution profiles - ASEAN Guideline for the conduct of bioequivalence studies.
1. If a pharmaceutical product with different strengths (the same dosage form and manufacturer) does not meet requirements for applying biowaiver for proportional formulations prescribed in clause 1 and clause 2 section I of this Appendix due to one of two following reasons:
- The product has the same API and excipient compositions in its pharmaceutical formulations for the different strengths but the combination ratio between these compositions does not meet regulations in clause 1 section I of this Appendix;
- The dissolution profiles of the pharmaceutical product between strengths for which a biowaiver is considered and strengths used in the in vivo bioequivalence study is not similar to each other, a report on in vivo bioequivalence studies for 02 strengths selected on the basis of polarized approaches to apply biowaiver for the remaining strengths of the product.
2. For a prolonged-release or enteric-coated pharmaceutical product under consideration, upon applying polarized approaches, a biowaiver is only considered when the product has the same API release mechanism for all the different strengths and the same excipients playing a role of controlling the API release of the dosage form (for the prolonged-release pharmaceutical product) or has the same API controlled-release coatings (for the enteric-coated pharmaceutical product).
3. For pharmaceutical products for which in vivo bioequivalence studies performed under both fasted and fed conditions are required (the same regulations with that for an oral modified-release product), if a biowaiver based on polarized approaches is applied, in vivo bioequivalence studies under fasted or fed condition at only one of the two strengths selected for the studies, depending on the condition which is considered to be less sensitive for detection of the inequivalence between test products and comparator products, may be waived. To be specific:
a) In case where the summary of characteristics recommends intake of comparator products only in a fasted state or even in a fed state (or in both fasted and fed states): a waiver of the fed study at only one of the strengths is considered.
b) In case where the summary of characteristics recommends intake of comparator products only in a fed state: a biowaiver of the fasted study at only one of the strengths is considered.
1. Oral, solid and immediate-release generic products, which are pharmaceutically equivalent to their comparator products which are products that are dispersed/dissolved in the oral cavity but not absorbed in the oral cavity, are pharmaceutically equivalent to their comparator products, contain APIs proved to have good solubility and permeability (BCS class I), which are not among those with a narrow therapeutic range, will be considered not to require in vivo bioequivalence studies when applying for marketing authorization or when requesting to declare a product that has been granted a marketing authorization as a product with proven bioequivalence if the following proofs are provided:
a) The products under consideration are very rapidly dissolving (more than 85% of APIs presented in a single dosage unit are dissolved in environments in a pH between 1 and 6.8 in 15 minutes), or the products under consideration are rapidly dissolving (more than 85% of APIs presented in a single dosage unit are dissolved in environments in a pH between 1 and 6.8 in 30 minutes) and the dissolution profiles of the products under consideration are similar to those of the comparator products in the tried environments.
b) For excipients known to affect drug bioavailability (manitol, sorbitol, surfactants, etc.): The qualitative and quantitative composition of these excipients in the products under consideration must be similar to that of the comparator products.
c) Other excipients in formulations of the products under consideration are qualitatively similar to those of products pharmaceutically equivalent to the products under consideration approved in any of reference countries, or common excipients known to have properties with amounts used in the formulations should be within the normal range suitable for dosage forms of the products under consideration.
2. Requirements for consideration of a biowaiver based on the BCS specified in clause 1 of this section may also, in lieu of the requirements for having pharmaceutical equivalence, apply to the cases that both products under consideration and comparator products are pharmaceutical alternatives but differ only in salt forms of APIs that are highly soluble and permeable (BCS class I). A BCS-based biowaiver is not applied when APIs used between the products under consideration and comparator products differ in form of ester, ether, isomer or mixture of isomers, complexes or other derivatives.
3. For fixed-dose combination pharmaceutical products, a biowaiver may be considered based on the BCS if all APIs in the formulations are highly soluble and permeable (BCS class I), the excipients in the formulations of the products under consideration meet the regulations mentioned at points b and c clause 1 of this section and the solubility of the products under consideration, for each API in the products, all meet the requirements specified at Point a, Clause 1 of this Section.
4. Sublingual pharmaceutical products, buccal troches and modified-release pharmaceutical products are products for which a BCS-based biowaiver is not considered.
5. Criteria for evaluating an API that are highly soluble and permeable are prescribed in section III. APIs - Appendix III. BCS-based biowaiver - The lasted edition of the ASEAN Guideline for the conduct of bioequivalence studies.
6. Methods for evaluation of solubility of the products under consideration and establishment of an in vitro bioequivalence between the products under consideration and the comparator products are prescribed in section IV. Finished pharmaceutical products (FPPs) - Appendix III. BCS-based biowaiver - The lasted edition of the ASEAN Guideline for the conduct of bioequivalence studies.
1. These differences in manufacturing sites are due to:
- Change from manufacturers of the product owners to new contract manufacturers of the product owners or change from these contract manufacturers of the product owners to other contract manufacturers of the product owners, or
- Change between different manufacturing sites of the same manufacturer.
2. For pharmaceutical products manufactured abroad: both products manufactured in the old manufacturing sites and products under consideration must be authorized for marketing in their host countries by one of pharmacy authorities belonging to the stringent regulatory authorities (SRAs).
3. Pharmaceutical products under consideration must be similar to those manufactured in the old manufacturing sites in terms of:
- Dosage forms;
- Quality standards of APIs, including qualitative properties of APIs known to affect bioavailability of FPPs;
- Quality standards of excipients;
- Manufacturing processes and standard operating procedures (SOPs);
- Equipment employed in the manufacture of pharmaceutical products;
- Environmental conditions in the manufacturing processes;
- Quality standards of FPPs.
4. Dissolution profiles of pharmaceutical products under consideration must be similar to those of pharmaceutical products manufactured in the old manufacturing sites. Methods for establishment of similarity of the dissolution profiles between pharmaceutical products under consideration and pharmaceutical products manufactured in the old manufacturing sites are prescribed in Appendix I. Dissolution testing and similarity of dissolution profiles - ASEAN Guideline for the conduct of bioequivalence studies.
5. Besides the above requirements, modified-release pharmaceutical products must be products for which an in vivo-in vitro correlation is able to be established.
6. Requirements 4 and 5 shall be exempted where the difference in manufacturing sites only affects one or a number of stages including primary packaging without drug dosing (for example: primary packaging of tablet and capsule dosage forms), quality control, batch release and secondary packaging.
Specific
requirements in BIOEQUIVALENCE STUDY REPORTS according to API release and route
of administration
(enclosed with Circular No. 07/2022/TT-BYT dated September 05, 2022 of the
Ministry of Health of Vietnam)
I. Regarding immediate-release products
1. Bioequivalence study reports must be in accordance with the latest edition of the ASEAN Guideline for the conduct of bioequivalence studies or other equivalent technical guidelines of EMA or US-FDA.
2. Regarding oral pharmaceutical products:
2.1. If the summary of characteristics clearly recommends intake of comparator products only in a fasted state or does not recommend the intake in a fed state or even in a fed state, in vivo bioequivalence study reports of fasted studies are required.
2.2. If the summary of characteristics clearly recommends intake of comparator products only in a fasted state or does not recommend the intake in a fed state or even in a fed state, in vivo bioequivalence study reports of fasted state studies are required.
2.3. For pharmaceutical products with specific formulations characteristics such as solid dispersions, micro-emulsions, if the summary of characteristics does not recommends intake of comparator products in a fasted state or a fed state (both fasted and fed conditions may be recommended), reports on in vivo bioequivalence studies performed under both fasted and fed conditions are required.
3. For pharmaceutical products dispersed/dissolved in the oral cavity:
3.1. Regarding pharmaceutical products under consideration which are pharmaceutically equivalent to comparator products:
a) When comparator products may be administered both with water and without water, reports on in vivo bioequivalence studies performed between test products and comparator products administered without water (that is a dosing condition carrying greater risks of not achieving bioequivalence) are required.
b) When comparator products are only administered with water or without water, reports on in vivo bioequivalence studies performed between test products administered following their usages or registered usages and comparator products administered following their right usages (pharmaceutical products under consideration will be able to register more usages than comparator products if the products under consideration are proved to be bioequivalent to the comparator products when being administered following the registered usages).
3.2. Regarding products under consideration which are intended for replacing orally immediate-release comparator products (if the products under consideration are pharmaceutical alternatives of the comparator products):
Reports on in vivo bioequivalence studies performed between test products administered both with water and without water and comparator products administered with water or reports on in vivo bioequivalence studies performed between test products administered without water and comparator products administered with water are required.
II. For modified-release pharmaceutical products
1. Regarding modified-release pharmaceutical products under consideration which are designed for a purpose of achieving API release rates similar to those of the comparator products:
1.1. In vivo bioequivalence study reports must be suitable for the latest edition of the Guideline on the pharmacokinetic and clinical evaluation of modified release dosage form of EMA - Abridged application for modified release forms reffering to a marketed modified release form.
1.2. Other specific notes:
a) Except for enteric-coated products, in addition to single-dose studies, multiple-dose studies may be considered for modified-release dosage forms with a tendency to accumulate (e.g. after a single dose of the highest strength the AUC for the dosing interval covers < 90% of AUC extrapolated to infinity/ rate of AUC (0-ԏ)/AUC (0-ꝏ) < 90%).
b) For modified-release products based on a multiphase release mechanism (two-phase release, rhythmic release): in vivo bioequivalence study reports must prove that the test products are bioequivalent to the comparator products in all phases.
c) For oral, modified-release products: in vivo bioequivalence study reports must prove that test products are bioequivalent to comparator products even when these products are taken in a fasted or fed state.
d) For modified-release products under transdermal system: In addition to reports on in vivo bioequivalence studies performed between test products and comparator products, reports on study data of comparing skin adhesion, local irritation and sensitisation between test products and comparator products to demonstrate that the test products have comparable or better skin adhesion to the comparator products and have comparable or lower local irritation and sensitisation to the comparator products. Appendix I. Sensitisation and irritation tets for transdermal products and Appendix II. In vivo skin adhesion in the Guideline on the pharmacokinetic and clinical evaluation of modified release dosage form of EMA in the may be used as reference documents for making designs and performing these comparison studies.
2. Regarding modified-release products under consideration with API release rates different from those of comparator products:
- Since bioequivalence between the products under consideration and the comparator products cannot be established due to differences in the API release rates, in lieu of in vivo bioequivalence study reports, reports on pharmacokinetic studies of the products under consideration, enclosed with reports on clinical safety and efficacy comparison studies performed between the immediate-release products under consideration and the immediate-release comparator products.
- The reports on pharmacokinetic studies of the products under consideration and reports on safety and efficacy comparison studies performed between the immediate-release products under consideration and the immediate-release comparator products should be in accordance with the latest edition of the Guideline on the pharmacokinetic and clinical evaluation of modified release dosage form of EMA - Application for modified release formulation of a drug that is authorized in a formulation with a different release rate.
GENERAL REQUIREMENTS FOR IN VITRO BIOEQUIVALENCE STUDy reports
(enclosed with Circular No. 07/2022/TT-BYT dated September 05, 2022 of the
Ministry of Health of Vietnam)
1. In vitro equivalence study reports must demonstrate the similarity of the dissolution profiles between test products and comparator products, under defined test conditions, typically in at least three solvents: pH 1,2; pH 4,5 and pH 6,8. In case of not providing enough test data in all 03 of these solvents or providing test data at other pHs of solvents, there must be an explanation of the appropriateness of omitting any solvent or using a solvent with a different pH in the test.
2. Profile compositions of an in vitro bioequivalence study report include:
a) Test outline;
b) Report on study data of test results, including:
- Information on test samples, test conditions, test methods, test periods and performing locations.
- Data tables,
- Dissolution profiles,
- Statistical analysis,
- Resulting discussion.
c) Report on study data of validation of the analytical procedure used in the test (enclosed with original monitoring data representing the validation results).
Regulations on
pilot batch sizes
(enclosed with Circular No. 07/2022/TT-BYT dated September 05, 2022 of the
Ministry of Health of Vietnam)
Pilot batch sizes are particularly determined as follows:
1. For immediate-release tablets/capsules or modified-release tablets/capsules: At least 1/10 of registered batch size or 100.000 dosage units, whichever is greater. In case the registered batch size is less than 100.000 dosage units, the pilot batch size must be equal to the registered batch size.
2. For powders, solutions, suspensions: At least 1/10 of the largest registered batch size.
3. For injectable drugs including solutions, powders/ lyophilized powders for injection, suspensions, emulsions: At least 1/10 of the largest registered batch size or 50 liters (for liquid drugs with a volume of 01 smallest packing unit which is greater than 2ml) and 30 liters (for liquid drugs with a volume of 01 smallest packing unit which is equal to or less than 2ml), whichever is greater. In case of registering multiple packing specifications with different volumes in 01 packing unit: the minimum or 1/10 of the largest registered batch size or 50 liters, whichever is greater.
4. Transdermal Therapy System: At least 1/10 of registered batch size or 25.000 units, whichever is greater.
Reference
Technical Guidelines (*)
(issued together with Circular No. 07/2022/TT-BYT dated September 05, 2022
of the Ministry of Health of Vietnam)
1. ASEAN Guideline for the conduct of bioequivalence studies - 2015 Edition
2. ASEAN Variation Guideline for Pharmaceutical Products – 2014.
3. Structure and Content of Clinical Study Reports- ICH E3 Guideline, CPMP/ICH/137/95
4. General Considerations for Clinical Trials- ICH Topic E8, CPMP/ICH/291/95
5. Guideline for Good Clinical Practice- (ICH E6 (R1), CPMP/ICH/135/95
6. Statistical Principles for Clinical Trials- ICH E9, CPMP/ICH/363/96
7. Guideline on Bioanalytical Method Validation- EMEA/CHPM/EWP/192217/2009
8. Guideline on the Pharmacokinetic and Clinical Evaluation of Modified Release Dosage Forms (EMA/CPMP/EWP/280/96 Corr1).
9. Multisource (generic) pharmaceutical products: Guidelines on registration requirements to establish interchangeability -WHO Technical Reports Series, No. 992, Annex 7 (2015). 10. USFDA: Product-Specific Guidances for Generic Drug Development
11. USFDA: Guidance for Industry: Food-Effect Bioavailability and Fed Bioequivalence Studies
12. USFDA: Guidance for industry: Statistical Approaches to Establishing Bioequivalence
13. USFDA: Guidance for industry: Immediate-Release Solid Oral Dosage Forms: Scale-Up and Post-Approval Changes: Chemistry, Manufacturing and Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation (SUPAC-IR).
14. USFDA: Guidance for industry: Modified-Release Solid Oral Dosage Forms: Scale-Up and Post-Approval Changes: Chemistry, Manufacturing and Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation (SUPAC-MR).
15. EMA: Guideline on the investigation of bioequivalence (European Medicines Agency, London, 20 January 2010, CPMP/EWWP/QWP/1401/98 Rev 1).
16. EMA: Guidance on classification of minor changes of class IA, class IB and big changes of class II.
17. ICH HARMONISED GUIDELINE: BIOPHARMACEUTICS CLASSIFICATION SYSTEM-BASED BIOWAIVERS, Topic M9, 2019
(*) Latest editions of the above-mentioned Guidelines/Guidance will be updated for replacing the existing editions mentioned in this Appendix.
FORMS
(issued together with Circular No. 07/2022/TT-BYT dated September 05, 2022
of the Ministry of Health of Vietnam)
To: Drug Administration of Vietnam – Ministry of Health of Vietnam
We are:
Authorization holder………(full name as presented in the establishment license)
Address…………. (full address as presented in the establishment license).
And manufacturer……….. (full name as presented in legal documents enclosed with the application)
Address............(full address as presented in legal documents enclosed with the application)
We are together responsible for the test product used in the in vivo bioequivalence study/in vitro bioequivalence study No……(Study code/testing code) which is performed in..... (full name and address of the facility at which the study/ testing method employed) in the period from ….[date]… to ……[date]….. to be applicable to replace registered pharmaceutical product/product proposed for publication of proven bioequivalence with the name ……… (pharmaceutical product’s name/strength), with the following specific information:
|
Comparison content |
Similarity (1) |
Difference (1) |
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- Manufacturing site |
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- A pharmaceutical formulation for 01 dosage unit: |
||
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Ingredients |
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Amount of ingredients |
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Quality standards of ingredients |
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- Manufacturing process, including equipment employed in the manufacture of pharmaceutical products. |
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- Batch size |
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Detailed table of differences between the test product used in the study and the pharmaceutical product under consideration/ registered product/ product proposed for publication of proven bioequivalence (2)
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Other contents |
Test product used in the study |
Registered product/ product proposed for publication of proven bioequivalence |
Attached documents (3) |
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Manufacturing site |
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A pharmaceutical formulation for 01 dosage unit: - Ingredients - Amount of ingredients - Quality standards of ingredients |
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Manufacturing process (including equipment employed in the manufacture of pharmaceutical products) |
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Batch size (4) |
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(1) Give a cross mark “X” in the suitable checkbox
(2) Apply when there is a difference between two products
(3) List attached documents proving the differences between the test product used in the study and the registered product that do not affect the replacement for the registered product of the test product.
(4) Do not require attached documents when batch size of the test product used in the in vivo bioequivalence study in comparison with batch size of the product under consideration meets the regulations in Appendix V of this Circular.
(*) In case of application for point d clause 5 Article 7 of this Circular, the registered product may be replaced by the product granted Certificate of pharmaceutical product (CPP).
We will be responsible for the reliability of such information.
|
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,
date….month…year….. |
A. detailed information about the authorization holder and manufacturer
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Authorization holder: Address: |
Manufacturer (1): Address: |
B. Content:
An application for the biowaiver (in vivo) is eligible for: (give a cross mark in the responding checkbox)
|
a) Pharmaceutical product eligible for biowaiver (in vivo) for proportional formulations |
|
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b) Pharmaceutical product eligible for biowaiver (in vivo) based on a polarized approach |
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c) Pharmaceutical product eligible for BCS-based biowaiver (in vivo) |
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d) Pharmaceutical product eligible for biowaiver (in vivo) when a product under consideration manufactured in a manufacturing site other than that of the test product used in an in vivo bioequivalence study. |
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In order to submit the application for grant of a marketing authorization/ application for publication about the product granted a marketing authorization to be a product with proven bioequivalence:
- Name:…… (trade name of the product)
- Number of the marketing authorization: (if it is a product granted a marketing authorization)
- Dosage form:
- API/API strength contained in 01 usage unit:
C. Information about the test product used in the in vivo bioequivalence study (when having a request for applying cases a, b and d)
- Name:…… (trade name of the product)
- Number of the marketing authorization (2):
- Manufacturer (listing manufacturers participating in the manufacturing process)
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Name |
Address |
Position |
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D. List of Attached documents:
(attached to a copy of the Official Dispatch presenting the consent of the Drug Administration of Vietnam for the product granted the marketing authorization)
DD. COMMITMENT:
We are, including an authorization holder and a manufacturer, together responsible for the inspection and seal in terms of related parts in the documents enclosed with this application and the reliability of such documents. We will wholly be responsible for any falsification which is detected and penalized according to regulations of law.
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date….month…year….. |
(1) clarify name of the manufacturer/manufacturer participating in the manufacturing process of dosage forms of non-sterile drugs; or manufacturer creating dosage forms and their secondary packaging for sterile drugs.
(2): apply in case the test product used in the in vivo bioequivalence study publicized to be a product with proven bioequivalence.
Commitment on origin of the comparator product used in the in vivo bioequivalence study
To: Drug Administration of Vietnam – Ministry of Health of Vietnam
We are:
Authorization holder………(full name as presented in its establishment license)
Address…………. (full address as presented in its establishment license).
And manufacturer ………..(full name as presented in legal documents enclosed with the application)
Address…………. (full address as presented in legal documents enclosed with the application)
We are together responsible for the authentication of the following information related to the comparator product used in the in vivo bioequivalence study/in vitro bioequivalence study No……(Study code/testing code) which is performed in..... (full name and address of the facility at which the study/ testing method employed) in the period from ….[date]… to ……[date]….. :
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Content |
Information |
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Name |
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Manufacturer (manufacturing address) |
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Country of purchase |
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Batch number |
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Expiry date |
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Attached documentation (if any) |
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Attached documentation (if any) (*): …………………………….
(*) oblige to be involved for studies performed before the effective date of this Circular.
We are, including an authorization holder and a manufacturer, together responsible for the commitment:
The above-mentioned comparator product transferred and preserved under product’s preservation conditions labeled from the date of purchase to the date of beginning of performing the study.
We will be responsible for the reliability of such information. We will wholly be responsible for any falsification which is detected and penalized according to regulations of law.
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date….month…year….. |
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This translation is made by THƯ VIỆN PHÁP LUẬT, Ho Chi Minh City, Vietnam and
for reference purposes only. Its copyright is owned by THƯ VIỆN PHÁP LUẬT
and protected under Clause 2, Article 14 of the Law on Intellectual Property.Your comments are always welcomed
