Resolution - RDC nº 139 of 29 May 2003(*)
Republished in the D.O.U of 08/05/2003

Regulates the registration and exemption of registration of industrialized homeopathic drug products.

The Collegiate Board of Directors of the National Sanitary Surveillance Agency, in the use of the attributions vested in it under Article 11, item IV of the ANVISA Regulation approved by Decree Nº 3.029 dated 16 April 1999, c/c Article 111, item I, letter “b”,

Paragraph 1 of the Internal Regulation approved by Presidential Decree nº 593 dated 25 August 2000, republished on 22 December 2000 in meeting held on 6 March 2003,
Whereas the need to implement actions that contribute to improve healthcare services;

Whereas it is up to the National Sanitary Surveillance Agency to set guidelines for the productive sector, in compliance with that disposed in Law nº 6.360, dated 23 September 1976, and in Decree n.° 57.477, dated 28 December 1965, and in this Regulation;

Whereas Article 41 of Law n.º 9.782 dated 26 January 1999 that gives ANVISA power to debureaucratize and hasten the registration of drug products;

Whereas established in the Technical Regulation on substances and drug products subject to special control;

Whereas disposed in article 61 of Presidential Decree SVS/MS nº 344, dated 12 May 1998 and its updates;

Whereas the definitions in the GLOSSARY OF LEGAL DEFINITIONS;

Whereas drug products classified as exempt of registration are actually registered in order to monitor the market and control their quality even though they do not receive a registration number;

Whereas item II of Article 23 of Law nº 6.360 of 1976 that allows industrialized homeopathic drug products to be exempt of registration;

Whereas articles 33 and 34 of Decree nº 79.094, dated 5 January 1977 that allows the registration of industrialized homeopathic drug products having a therapeutic indication;

Whereas resolution CFM n° 1000 of 1980 that recognizes Homeopathy as a medical specialty in the country and resolution CFF n° 232 of 1992, updated by resolution CFF n.º 335 of 1998 that recognizes Homeopathic Pharmacy as being a special training of traditional pharmacy as well as the existence of a particular pharmacopoeia in accordance with Decree Law n.º 78.841 of 1976, and resolution n° 625of the CFMV, of 1995, that recognizes Homeopathic Veterinary as a medical specialty of veterinary;

Whereas the Brazilian Homeopathic Pharmacy and the Manual of Technical Norms for Homeopathic Pharmacies, editions in force, recognize the existence of “homeopathic formulations” with two or more liquid or solid active inputs;

Whereas the peculiar sanitary risk submitted by industrialized homeopathic drug products, evidences by their pharmacotechnical characteristics;

Whereas the need to update the norms for the registration and exemption of registration of industrialized homeopathic drug products included in Presidential Decree SNFMF/MS nº 17 of 1966, and other subsequent ones.

Adopts the following resolution and I, the Chairman, determine its publication.

Article 1 This resolution encompasses the registration of industrialized homeopathic drug products, the exemption of registration of industrialized homeopathic drug products, their dispensation and their classification in the sales category of homeopathic drug products.

Sole Paragraph. The present regulation does not affect the application of stricter regulations to narcotics, psychotropic substances and chemical precursors or any type of product subject to special control.

Article 2 The following definitions are used in this Regulation:
Industrialized homeopathic drug product exempt of registration: simple drug product (with a single active ingredient in the established homeopathic drug product literature) in its derivate pharmaceutical forms, without trademark or brand, of any potency prepared in the decimal or centesimal dilution whose manufacturing obeys the official methods described in the Brazilian Homeopathic Pharmacopoeia, edition in force, or in its absence, in official compendia recognized by ANVISA.

Industrialized homeopathic drug product that classifies for registration: simple (single ingredient) or compound (two or more ingredients) drug product having a brand or trademark, whose manufacturing obeys the official methods described in the Brazilian Homeopathic Pharmacopoeia, edition in force and official compendia recognized by ANVISA, and whose formulation is composed of substances of verified therapeutic action described in the homeopathic drug product literature, official compendia, clinical studies or indexed journals.

Article 3 The drug products regulated herein are dispensed in pharmacy under the supervision of a pharmacist. The Over the Counter Drugs regulated herein can also be dispensed in special drug product dispensing establishments, in compliance with the legislation in force.

Article 4 Industrialized homeopathic drug products exempt of registration shall be inscribed at ANVISA in accordance with Annex I and II of this resolution and shall revalidate their inscription every five years.

Article 5 Industrialized homeopathic drug products that classify for registration having one or more active ingredients that do not have a specific therapeutic indication shall be registered at ANVISA in accordance with Annex I and II of this resolution and shall revalidate their registration every five years.

Article 6 Injected industrialized homeopathic drug products shall submit risk/benefit studies compared to the oral presentation of the same product.

Article 7 Industrialized homeopathic drug products already inscribed as exempt of registration at ANVISA shall request an update of their inscription within 3 years after the date of the last inscription concession. On this occasion they shall submit the documentation established in the Regulation excepting the copy of the protocol of the pilot-batch production.

Paragraph 1 Products already exempt of registration whose inscription update deadline ends up to 30 days after the publication of this resolution will have an extension of up to 180 days in the deadline in order to adapt to this resolution.

Paragraph 2 Products that do not comply with the caput of this article will have any previously granted exemptions cancelled.

Article 8 Upon the first renewal after the publication of this resolution, holders of industrialized homeopathic drug product registrations shall comply with Annex III of this resolution, excepting the copy of the protocol of the pilot-batch production notification.

Article 9 Industrialized homeopathic drug products of topical or systemic use that classify for or are exempt of registration shall be marketed as follows:

Paragraph 1° With prescription only:
I – for injected pharmaceutical forms;
II – whenever their composition contains at least one of the active ingredients in a dynamization equal to or less than that described in the Table of Relative Toxicity of Substances Used in Homeopathy - Annex V

Paragraph 2° With or without prescription:
I – drug products with dynamizations greater than those described in the Table of

Relative Toxicity of Substances Used in Homeopathy - Annex V and up to 6CH or 20DH, inclusive.
II – topical use pharmaceutical form,

Paragraph 3° In case of substance not included in the Table of Relative Toxicity of Substances Used in Homeopathy - Annex V, it the responsibility of the manufacturer to establish and prove the safety of its use in the intended concentration through clinical and non-clinical toxicological studies adequate to the profile of the substance.

Article 10 Associations based on synthetic, semi-synthetic and biologic drug products, herbal drug products, vitamins/minerals/aminoacids, opotherapics with homeopathic drug products in fixed doses in one and the same formulation or two or more presentations in one same packaging for concomitant or sequential are forbidden.

Article 11 – Homeopathic preparations are object of the resolution that regulates the registration of specific drug products.

Article 12 Any cases not foreseen in this resolution will be judged by ANVISA.

Article 13 This resolution enters into force on the day of its publication. Articles 12, 16, 18, 19 and 20 of Presidential Decree nº 17, dated 22 August 1966, and item IV of Article 1 of resolution RDC n.º 23, dated 6 December 1999 are hereby revoked.

CLAUDIO MAIEROVITCH PESSANHA HENRIQUES

ANNEXES

REGISTRATION AND EXEMPTION OF INDUSTRIALIZED HOMEOPATHIC MEDICINES

ANNEX I

PRE REGISTRATION AND EXEMPTION OF REGISTRATION MEASURES OF INDUSTRIALIZED HOMEOPATHIC MEDICINES

1. Notify the production of pilot-batches in accordance to the GUIDE FOR THE NOTIFICATION OF PILOT BATCHES OF MEDICINES, excepting imported products.

ANNEX II
REGISTRATION EXEMPTION OF INDUSTRIALIZED HOMEOPATHIC MEDICINES
1. To apply for registration exemption of industrialized homeopathic drug products, the applicant shall submit the following documentation:

a) Registration exemption petition forms;
b) Proof of payment of Sanitary Surveillance Inspection Fee or proof of exemption (original);
c) Up-to-date copy of the company’s Operation License (Sanitary Permit);
d) Up-to-date Technical Responsibility Certificate emitted by the Regional Pharmacy Council;
e) Copy of the notification protocol of pilot batch production;

2. General data that will appear in the package insert, draft label and packaging “lay-out”, in compliance with the legislation in force. Industrialized homeopathic drug products exempt of registration shall not be required to submit an insert package, provided that the general data is included in the labeling. Industrialized homeopathic drug products exempt of registration shall be named according to the official homeopathic nomenclature; the adoption of a fantasy name or brand name is forbidden.

3. For exemption of registration of industrialized homeopathic drug products, only the decimal and centesimal scales shall be admitted.

4. Industrialized homeopathic drug products exempt of registration shall not display the specific therapeutic indication in the packaging, package insert or promotional materials.

5. Technical Report containing the following information:

a) Expiration date and conservation: give details on how the expiration date and conservation of the pharmaceutical form were determined concerning the microbiological physical and chemical integrity of the product.

b) Complete production reports: pharmaceutical form, detailed description of the complete formula indicating the scale, dynamization of each component and preparation method, naming them according to the official nomenclature; minimum and maximum size of the industrial batches to produced, description of all the stages of the production process, including the equipment used; control methodology of the productive process; and description of the identification criteria of the industrial batch.

c) Quality control of all the raw materials used in the finished product: submit the specification, the bibliographic reference of the consulted Pharmacopoeia recognized by ANVISA, in compliance with the legislation in force.

6. Good Manufacturing and Control Practices certificate (GMP) emitted by ANVISA for the production line in which the product classified as homeopathic drug product will be manufactured, or copy of the inspection petition protocol for the emission of GMP certificate. This protocol will be valid as long as the intended production line was considered satisfactory in the last inspection for compliance with GMP.

7. All documents shall be submitted in a printed copy of which each paper is initialized and the last paper is signed by the company’s chief technician. A copy of all technical reports shall be attached in disk or CD-ROM with files in the file.doc format or any other accepted by ANVISA.

8. Besides the above, manufacturers and their representatives who wish to commercialize industrialized homeopathic drug products exempt of registration produced abroad and imported in bulk, in their primary packaging or as finished products shall submit:

a) Authorization of the manufacturing company for the registration, commercial representation and use of the brand in Brazil.

b) Up-to-date copy of the GMP emitted by ANVISA for each production line of the manufacturing company.

b.1 In case ANVISA has not yet inspected the manufacturing company, the receipt of the ANVISA sanitary inspection petition together with the Certificate of Good Manufacturing Practices of pharmaceutical products per production line emitted by the organization in charge of Sanitary Surveillance of the manufacturing country will be accepted.

b.2 ANVISA may, in compliance with specific legislation, inspect the manufacturing company in the country or block of origin.
c) Submit the physicochemical, chemical, microbiological and biological quality control methodology to be used by the importer according to the pharmaceutical form – in bulk, primary packaging or finished product. If the method used is not pharmacopoeic, submit the validation of the analytic methodology.
d) For pharmaceutical products imported in bulk, Certificate of Good Manufacturing Practices emitted by ANVISA for the packaging line used in the country.
e) For imported pharmaceutical products – in bulk, primary packaging or finished products - give details on how the expiration date and conservation of the pharmaceutical form were determined concerning the physical, physicochemical and microbiological integrity of the product. If there is a need to import samples, an import permit emitted by ANVISA is mandatory.
f) The expiration date of imported bulk products shall be counted from the manufacturing date of the product abroad, not from the date of packaging here in Brazil. The expiration date registered at ANVISA shall be respected.
g) Any materials that make up the product’s dossier such as production and quality control reports, information contained in labels, package insert and packaging shall be in the Portuguese language, in compliance with the legislation in force. Any official documents emitted by sanitary authorities in a foreign language that are used in the registration shall be accompanied by a legal translation.

ANNEX III

REGISTRATION OF INDUSTRIALIZED HOMEOPATHIC MEDICINES
1. For the registration of an industrialized homeopathic drug product the company shall protocol a single process with separate reports (specified in item II of this ANNEX) for each pharmaceutical form. The company shall have complied with all the pre-registration demands and submit the following documentation:

a) Registration petition forms.
b) Proof of payment of Sanitary Surveillance Inspection Fee or proof of exemption (original);
c) Up-to-date copy of the company’s Operation License (Sanitary Permit);
d) Copy of the notification protocol of pilot batch production;
e) Up-to-date Technical Responsibility Certificate emitted by the Regional Pharmacy Council, in compliance with the legislation in force;
f) Registered industrialized homeopathic drug products shall adopt a trademark or brand name in accordance with the labeling legislation.

2. In the act of protocol of a petition to register an industrialized homeopathic drug product, the applicant shall submit a technical report containing the following information:
a) General data that will be included in the package insert;

b) Label and packaging "lay-out" draft in compliance with the legislation in force;

c) The suggested dosage shall be included in the package insert and can be modified only with medical orientation.

d) Expiration date and conservation: give details on how the expiration date and conservation of the pharmaceutical form were determined concerning the physical, physicochemical and microbiological integrity of the product.

e) Complete production reports: pharmaceutical form, detailed description of the complete formula indicating the scale, dynamization of each component and preparation method, naming them according to the official nomenclature; minimum and maximum size of the industrial batches to produced, description of all the stages of the production process, including the equipment used; control methodology of the productive process; and description of the identification criteria of the industrial batch.

f) Quality control of all the raw materials used in the finished product: submit the specification, the bibliographic reference of the consulted Pharmacopoeia recognized by ANVISA, in compliance with the legislation in force.

g) Good Manufacturing and Control Practices certificate (GMP) emitted by ANVISA for the production line in which the product classified as homeopathic drug product will be manufactured, or copy of the inspection petition protocol for the emission of GMP certificate. This protocol will be valid as long as the intended production line was considered satisfactory in the last inspection for compliance with GMP.

4. Registered industrialized homeopathic drug products shall submit therapeutic indication based on the homeopathic drug product literature, official compendia or clinical studies. The alleged therapeutic indication of the compound drug product shall be listed in the homeopathic literature foe each ingredient in isolation, respecting the incompatibility between the ingredients. Products containing in their formulas substances that are not described in homeopathic literature and compendia shall submit proof of the therapeutic indication through pathogenesis or clinical experience upon applying for registration.

5. For the registration of industrialized homeopathic drug products only the decimal and centesimal scales shall be admitted.

6. All documents shall be submitted in a printed copy of which each paper is initialized and the last paper is signed by the company’s chief technician. A copy of all technical reports shall be attached in disk or CD-ROM with files in the file.doc format or any other accepted by ANVISA.

7. Besides the items listed above, manufacturers and their representatives that commercialize industrialized homeopathic drug products produced abroad and imported in their primary packaging, in bulk or as finished product shall submit:

a) Authorization of the manufacturing company for the registration, commercial representation and use of the brand in Brazil, when fitting.
b) Up-to-date copy of the GMP emitted by ANVISA for each production line of the manufacturing company;

b.1 In case ANVISA has not yet inspected the manufacturing company, the receipt of the ANVISA sanitary inspection petition together with the Certificate of Good Manufacturing Practices of pharmaceutical products per production line emitted by the organization in charge of Sanitary Surveillance of the manufacturing country will be accepted.

b.2 ANVISA may, in compliance with specific legislation, inspect the manufacturing company in the country or block of origin.

c) Submit a registration receipt of the drug product emitted by the sanitary authority of the country of origin. If this is not possible, submit a receipt of the registration in force emitted by the sanitary authority of the country where the drug product is commercialized or by the international sanitary authority.

d) Submit the physicochemical, chemical, microbiological and biological quality control methodology to be used by the importer according to the pharmaceutical form – primary packaging, in bulk or finished product. If the method used is not pharmacopoeic, submit the validation of the analytic methodology.

e) For pharmaceutical products imported in bulk, Certificate of Good Manufacturing Practices emitted by ANVISA for the packaging line used in the country.

f) For imported pharmaceutical products – primary packaging, in bulk or finished products - give details on the expiration date and conservation of the pharmaceutical form concerning the physical, physicochemical and microbiological integrity of the product. If there is a need to import samples, an import permit emitted by ANVISA is mandatory.

g) The expiration date of products imported in bulk shall be counted from the manufacturing date of the product abroad, not from the date of packaging here in Brazil. The expiration date registered at ANVISA shall be respected.

h) Any materials that make up the product’s dossier such as production and quality control reports, information contained in labels, package insert and packaging shall be in the Portuguese language, in compliance with the legislation in force. Any official documents emitted by sanitary authorities in a foreign language that are used in the registration shall be accompanied by a legal translation.

ANNEX IV

POST REGISTRATION EXEMPTION AND POST REGISTRATION MEASURES OF INDUSTRIALIZED HOMEOPATHIC MEDICINES

1. The manufacturer of industrialized homeopathic drug products that classify for or are exempt of registration shall protocol a petition at ANVISA informing the intended alteration and/or inclusion with the due technical justifications up to 90 days before it becomes effective. ANVISA reserves the right not to publish these updates in the DOU provided the alteration/inclusion does not result in a rejected registration or in a new registration/inscription number. The alteration/inclusion shall become effective 90 days after the protocol of the petition as long as there is no objection from ANVISA. In this case the company shall present the technical reports described in annex II, item 5 or annex III, item 2 of this regulation.

2. ANVISA may undertake control analyses of the commercialized batches in official laboratories to monitor the quality of drug products and their conformity with the registered drug product.

3. For the renewal of the registration/inscription of industrialized homeopathic drug products, companies shall submit the following documentation to ANVISA during the first semester of the last year of the five years of validity of the already conceded registration/inscription:

a) Duly filled-in petition form;
b) Proof of payment of Sanitary Surveillance Inspection Fee or proof of exemption, when fitting;
c) Up-to-date Certificate of Technical Responsibility emitted by the Regional Pharmacy Council;
d) Submit invoices of proving that the product was marketed in a maximum of 3 (three) receipts per pharmaceutical form. A declaration concerning commercial presentations that were not marketed but whose registration the company is interested in keeping may be submitted, provided at least one presentation of that form has been marketed.
e) A list that includes all the post-registration alterations and/or inclusions that took place during the product’s last valid period of registration accompanied by a copy of the D.O.U. or in its absence, a copy of the protocol of the corresponding petition(s);
f) For imported products, submit the respective technical reports of physicochemical, chemical, microbiological and biological quality control according to the pharmaceutical form made by the importer in Brazil of three batches imported in the last three years.

ANNEX V

RELATIVE TOXICITY TABLE OF SUBSTANCES USED IN HOMEOPATHY
Guide
Name: Homeopathic name of the drug product.
Scale: The table refers to dynamizations in the decimal scale. To apply the centesimal scale consider the corresponding concentration of the drug product.
Reference: The Homoeopathic Pharmacopoeia of the United States, 9th ed.