resolution rdc nº 315, of 10/26/05 brazilian official gazette of 10 · pdf...

RESOLUTION RDC Nº 315, OF 10/26/05 BRAZILIAN OFFICIAL GAZETTE OF 10/31/05

Addresses the Technical Rules for Registration, Post-Registration Changes and Registration Renewal of Finished Biological Products.

The Collegiate Board of Directors of the National Sanitary Surveillance Agency, in use of its attributions granted by art. 11, item IV, of Anvisa Bylaws, approved by the Decree # 3,029, of April 16th, 1999, c/c art. 111, item I, letter "b", 1st Paragraph of the Bylaws approved by the Administrative Rule # 593, of August 25th, 2000, republished in December 22nd, 2000, in a meeting occurred in October 24th, 2005.

whereas the provisions of Law # 6,360, of September 23rd, 1976, in its article 12 and of the Decree # 79,094, of January 5th, 1977, changed by Decree # 3,961, of October 10th, 2001, art. 14, ruling Law # 6,360/76;

whereas art.10, item IV, of Law # 6,437, of August 20th, 1977, which determines the requirement of products registration issued by a competent agency, and establishes the specific requirements for drugs, medicines and pharmaceutical inputs registration;

whereas the need to rule procedures for registration, post-registration changes and inclusions, and registration renewal of Finished Biological Products.

has adopted the following Resolution by the Collegiate Board of Directors, and I, as the Director-President, determine its publication:

1st Art. To approve the Technical Rules for Registration, Post-registration Changes and Registration Renewal of Finished Biological Products, according to document attached to the Resolution herein.

2nd Art. The RDC 80, of March 18th, 2002 is hereby revoked.

3rd Art. The Resolution herein by the Collegiate Board of Directors shall be in force from the date it is published on.

DIRCEU RAPOSO DE MELLO

ANNEX

TECHNICAL RULES FOR REGISTRATION, POST-REGISTRATION CHANGES AND REGISTRATION RENEWAL PROCEDURES OF FINISHED BIOLOGICAL PRODUCTS.

The procedures for finished biological products Registration, in the National Sanitary Surveillance Agency of the Ministry of Health (ANVISA/MS), are determined by the biological source of the active substance and by employed manufacturing technologies.

Biological drugs considered herein are:

1. Vaccines;

2. Hyperimmune serum;

3. Hemoderivatives;

4. Biomedicines;

4.1 – Drugs obtained from biological fluids or animal-source tissues.

4.2 – Drugs obtained by Biotechnological procedures.

5 – Monoclonal antibodies;

6.- Drugs containing live, attenuated or dead microorganisms;

7.- Probiotics;

8.- Allergens.

These Rules do not include semi-synthetic conjugated antibiotics and estrogens (Anovulatory).

These Rules establish the criteria for registration, post-registration changes, and registration renewals of finished biological products.

Chapter I: GLOSSARY

The definitions given below apply to the terms used herein. They can have different meanings in other contexts.

1.- Monoclonal Antibodies:

Immunoglobulins derived from a same B-lymphocyte clone, which cloning and propagation occur in continuous cell lines.

2.- Allergens:

Substances (antigens) able to trigger hypersensitivity processes.

3.- Good Manufacturing Practices Certificate

A legal document, issued by the competent Sanitary Authority of the manufacturing country, certifying that a particular manufacturing line of a company complies with the requirements of the Good Manufacturing Practices (GMP) established by law in force. In the case of finished biological products, GMP Certificate refers to a biological product manufacturing line (active substance, bulk biologic product, and finished biological product).

4.- Registration Holder (Registration Owner)

Legal entity that owns the registration of a biological product, holding the rights upon that product and responsible for it until it reaches the end consumer.

5.- Blood-derived products

Biological drugs obtained from human plasma, submitted to processes of industrialization, normalization and quality control, assuring them quality, stability, activity, and specificity.

6.- Secondary package

A package that makes contact to the primary package, constituting wrapping or any other kind of protection, whether removable or not, and may contain one or more primary packages.

7.- Primary package

Container making contact with the product.

8.- Manufacturing

All operations including the acquisition of materials, all production phases, quality control, release, storage, shipping and related controls.

9.- Manufacturer

Holder of the Business License, issued by the Competent Sanitary Authority of the country in which the manufacturing plant is established, according to the provisions of the sanitary law in force in the manufacturing country.

9.1.- Manufacturer of Active Substance

Responsible for all required materials acquisition operations for producing the Active Substance (manufacturing and purification), for the lot release for use according to pre-established specifications by internal, national or international rules, for the storage, shipping of the active substance lot and for related quality controls.

9.2.- Manufacturer of the Bulk Biological Product

Responsible for all required materials acquisition operations for producing the Bulk Biological Product (formulation and packaging in a single container), for the lot release for use according to pre-established specifications by internal, national or international rules, for the storage, shipping of the Bulk Biological Product and for related quality controls.

9.3.- Manufacturer of the Biological Product in its Primary Package

Responsible for all required materials acquisition operations for producing the Biological Product in its primary package (formulation and packaging in a primary container), for the lot release for use according to pre-established specifications by internal, national or international rules, for the storage, shipping of the Biological Product in its primary package and for related quality control.

9.4.- Manufacturer of the Finished Biological Product

Responsible for all required materials acquisition operations for producing the Finished Biological Product (labeled and packed in a secondary package), for the lot release for use according to the pre-established specifications by internal, national or international rules, for the storage, shipping of the Finished Biological Product and for related quality controls.

10.- Formulation

Technological process consisting of formulating active substance(s) in its end pharmaceutical form, according to the specifications registered and authorized by the Competent Sanitary Authority of the manufacturing country.

11.- Importer

Legal entity, responsible for the entrance of the active substance or biological product in its primary package or a finished biological product in the country, originated by foreign countries.

12. Manufacturing country of the active substance

Location where the active substance(s) of a Bulk Biological Product and/or Finished Biological Product is (are) produced or obtained.

13.- Manufacturing country of the bulk biological product

Location where the Bulk Biological Product in its end pharmaceutical form (formulation) is produced, according to the specifications authorized by the Competent Sanitary Authority of the manufacturing country.

14.- Manufacturing country of a biological product in its primary package

Location where the primary package of the Bulk Biological Product is performed, according to the specifications authorized by the Competent Sanitary Authority of the manufacturing country.

15.- Manufacturing country of a finished biological product

Location where the Finished Biological Product is produced, in its end pharmaceutical form, according to the specifications authorized by the Competent Sanitary Authority of the manufacturing country.

16. Active substance

A substance with major pharmacological effect for the intended therapeutic activity, used in the manufacturing of a particular biological product.

17.- Probiotics

Finished biological products having living or inactivated microorganisms for preventing or treating human diseases through the interaction with the microbiota or with intestinal epithelium or associated immune cells or other mechanism of action.

18. Finished Biological Product

Pharmaceutical product, of biological source, technically obtained or prepared, with prophylactic, curative, palliative or diagnostic purposes “in vivo”.

18.1.- New Biological Drug

Biological Drug containing a molecule with known biological activity, not yet registered in Brazil, which has been submitted to all manufacturing phases (formulation, filling, lyophilization, labeling, packaging, storage, quality control and lot release of a new biological drug for use).

18.2.- Biological Drug

Biological drug containing a molecule with known biological activity, already registered in Brazil having been submitted to all manufacturing phases

(formulation, filling, lyophilization, labeling, packaging, storage, quality control and lot release of biological product for use).

19.- Biological product in its primary package

Biological product that has completed all manufacturing phases, formulated in its end pharmaceutical form, comprised in its final container (primary package), sterile (if applicable), not including labeling and packaging process, and released by manufacturer quality control.

20. Bulk biological product

Biological product that has completed all manufacturing phases, formulated in its end pharmaceutical form, in bulk, comprised in a single container, sterile (if applicable), and released by manufacturer quality control.

21.- Lot registration

Set of documents related to the manufacturing of a particular lot of active substance, bulk biological product, biological product in its primary package, and finished biological product. Such documents describe the manufacturing procedures and record all operations related to lot quality, including the Lot Release Certification.

22.- Hyperimmune serum:

Finished biological product having specific immunoglobulins of heterologous, purified sources, which, when inoculated, are able to neutralize its specific antigens.

23.- Vaccines:

Biological products having one or more antigenic substances which, when inoculated, are able to induce active specific immunity and protect against the disease caused by the infectious agent that originated the antigen.

Chapter II: General.

1.- Only Finished Biological Products, registered at ANVISA/MS, manufactured or imported by legal entities, duly authorized by federal government and licensed by state government, may be marketed and distributed in the country.

2.- At the moment of filing the registration request, the requesting company shall pay the corresponding sanitary surveillance fee.

2.1.- For Biological Drugs, the value charged as sanitary surveillance fee is the same as for similar products.

3.- All Registration, Registration Change or Registration renewal requests for Finished Biological Products, due to the biological source of their active substances and to the diversity of technological processes used for obtaining them, shall be analyzed according to the requirements established at Chapter III (Documents required to build processes of Finished Biological Products Registration) Hereof.

4.-The registered Biological Drug requesting a new therapeutic indication in the country shall be reclassified as a New Biological Drug.

5.- When documenting the Finished Biological Product registration, the requester shall indicate the name of the manufacturer and the manufacturing country of the active substance(s), bulk biological product, biological product in its primary package, and finished biological product, list all quality control tests performed to the active substance lot, bulk biological product lot and finished biological product lot, inform the place where the corresponding quality control tests are performed, and indicate the ruling documentation where specifications are established.

6.- All documents delivered to Anvisa, as well as any existent information on labels, package inserts, cartridges, and all printed material shall be written in Portuguese, according to the law in force. Official documents in foreign language presented for Registration purposes shall be accompanied of sworn-in translation, in compliance with law.

7.- The Registration of a New Biological Drug not registered in the manufacturing country shall only be granted in Brazil upon delivery of registration proof issued by the competent Sanitary Authority (other country) and recognized by ANVISA.

8.- The Registration of Biological Drugs manufactured abroad may only be granted in Brazil if it is registered and authorized for use in its manufacturing country, according to the law in force.

8.1.- In exceptional cases, Biological Drugs not registered in their manufacturing countries, but registered in another country due to epidemiologic need, after an analysis of the documentation presented by the requester, and provided the epidemiologic impact of its use is proven, may be registered in Brazil.

8.2.- Biological Drugs registered in their manufacturing countries but not authorized for use in the country that has granted the registration shall not be registered in Brazil.

9.- In case the requester, at the moment of filing the Finished Biological Product Registration request, is not able to deliver all the documents listed below, it will be given a maximum term of one hundred eighty (180) days to present them to ANVISA:

9.1.-Document proving the Registration of the product in the manufacturing country, according to the law in force, accompanied by a corresponding original

package insert text, approved by the Sanitary Authority of the manufacturing country which has granted the registration (according to item 7, Chapter II hereof).

9.2.-Certificate of Good Manufacturing Practices, or similar document, issued by the Sanitary Authority of the manufacturing country of the active substance(s), bulk biological product and finished biological product and the legal rules adopted for GMP Certification.

10.- In case the holder of a Finished Biological Product registration is not the manufacturer of the active substance, the Finished Biological Product Registration requester shall inform, at the moment of Registration request, the name of the manufacturer of the active substance.

10.1.- The registration of a Finished Biological Product is directly related to the source of the Active Substance(s) described at the registration request, therefore, the holder of a Finished Biological Product registration cannot change the manufacturer of the Active Substance, except in cases of blood-derived products (plasma).

10.2.- When filing the registration request of a New Biological Drug, the requesting company shall deliver the documentation related to the manufacturing and quality control of at least one (01) lot of the Active Substance of the product to be registered.

10.3.- When filing the registration request of a Biological Drug, the requesting company shall deliver the documents related to the manufacturing and quality control of three (03) consecutive lots of the Active Substance of the product to be registered.

10.4.- If the holder of a Finished Biological Product registration changes the company manufacturing the Active Substance, it shall request a new biological product registration and will not be allowed to use the brand name of the finished biological product previously registered.

11.- If the holder of a Finished Biological Product registration is not the manufacturer of the Bulk Biological Product, the company requesting the Registration must state, at the moment of Registration request, the name of the company manufacturing the bulk biological product.

11.1.- If the holder of a Finished Biological Product registration changes the company manufacturing the Bulk Biological Product, it shall request a new finished biological product registration and will not be allowed to use the brand name of the finished biological product previously registered, unless:

11.1.1.- there is a technology transfer to the new company, which should be duly proven by presenting a technology transfer agreement among the involved companies;

11.1.2.- it proves, upon comparative studies, that the properties of the finished bulk biological product (safety and activity) remain unchanged, even after switching the manufacturing company.

12.- In case the holder of a Finished Biological Product registration is not the manufacturer of the Biological Product in its primary package, the company requesting Registration shall inform, at the moment of Registration request, the name of the company manufacturing the biological product in its primary package.

12.1.- If the holder of the Finished Biological Product registration switch the company manufacturing the Biological Product in its primary package, it must request a new product registration, unless:

12.1.1.- it proves, upon comparative studies, that the properties of the finished biological product (safety and activity) remain unchanged, even after switching the manufacturing company.

13.- All therapeutic activities requested for the Finished Biological Product to be registered shall be proven by clinical trials documents, which must be comprised in the dossier for product registration. The performed clinical trials must have been approved by the sanitary authority of the country in which the study was conducted. Clinical trials presented must have been performed with the Finished Biological Product as it was presented for registration purposes.

14.- The Good Manufacturing Practices (GMP) Certificate issued by the Competent Sanitary Authority of the country in which a manufacturing plant is located (item 2.13 of Chapter III Hereof), presented at the moment of filing the registration request, either can be accepted or not by ANVISA at the moment of technical analysis. In case it is not accepted, the General Management of Drugs Inspection in ANVISA shall perform an inspection at the plant, for UPBIH/GGMED to be able to grant the registration request or not.

15.- The Registration or Registration Renewal requester for Blood-derived products, when filing the request, shall present a document issued by the manufacturer of the blood-derived product informing the origin country of the plasma used as raw material, a list of the centers that collected that plasma with a correspondent number of registration and name of the competent Sanitary Authority responsible for surveillance.

16.- The Registration or Registration Renewal requester for Blood-derived products, when filing its request, shall present a manufacturer’s certificate stating

that the employed raw material is originated from units of whole blood and/ or plasmapheresis obtained and controlled according to the Brazilian law in force.

16.1.- The Registration or Registration Renewal requester for Blood-derived products, when filing its request, shall present documentation about the serological tests performed in each plasma unit or plasmapheresis units in each plasma minipool (indicating the amount of plasma or plasmapheresis units constituting the minipool), and in the fractioning lot (indicating the average volume of the fractioning lot).

16.2.- The Registration or Registration Renewal requester for Blood-derived products, when filing its request, shall present documentation about the PCR (NAT) tests performed in each plasma or plamapheresis unit, in each plasma minipool (indicating the amount of plasma or plamapheresis units constituting the minipool) and in the fractioning lot (indicating the average volume or the fractioning lot).

16.3.- The Registration or Registration Renewal requester for Blood-derived products, when filing its request, shall present documentation about the validation of serological methods and used PCR (NAT).

17.- The Registration or Registration Renewal requester for Blood-derived products, when filing its request, shall present documentation about viral inactivation procedures and their respective validations performed with the blood-derived product to be registered.

18.- In case the Finished Biological Product to be registered contains any blood-derived product in its formulation, the Registration requester shall present documentation proving that the blood-derived product is registered in Brazil, otherwise, it shall present all documents established on items # 15, 16 and 17 of Chapter II Hereof.

19.- In case the manufacturing process of a Finished biological product includes the use of ruminant animals-derived products, the Registration requester must present a manufacturer’s statement, saying that the ruminant animals-derived product employed in the manufacturing process is in compliance with the Law in force addressing the use of ruminant animals-derived products.

20.- The Finished Biological Product Registration requester, when filing its request, shall deliver documentation related to the manufacturing and quality control of three (03) consecutive lots of the Finished Biological Product to be registered.

21.- At the moment of initiating the analysis of the registration process documentation, UPBIH shall determine whether to submit three (03) consecutive lots of the finished biological product, of which documentation was delivered

together with the Registration request (item 20, Chapter II Hereof) to the analytical control of the National Institute of Quality Control on Health - INCQS, or not.

22.- In case the Active Substance, or Bulk Biological Product or Biological Product in its primary package or Finished Biological Product is manufactured by a company having more than one manufacturing site, the registration requester shall deliver documentation regarding the production and quality control of three (03) consecutive lots of the bulk biological product, biological product in its primary package, finished biological product and at least one (01) lot, in case of active substance, sourced from each manufacturing site. The requester shall inform the manufacturing site of each product on the documents for registration.

22.1.- In case the manufacturing company of the Finished Biological Product already registered in the country informs the registration holder in Brazil that the Active Substance or Bulk Biological Product or Finished Biological Product shall be manufactured in another site, which was previously stated on the registration request, the registration holder shall submit a registration Change request to ANVISA.

23.- In case the manufacturing company of the Finished Biological Product already registered in the country informs the registration holder in Brazil that the supplier of the active substance or bulk finished product is being switched by another manufacturer, the registration holder in Brazil must request a new registration and will not be allowed to use the product name approved in the previous registration.

24.- In case the Finished Biological Product is registered, the registration holder shall submit to ANVISA a registration change request for the active substance, for the bulk biological product, for the biological product in its primary package or for a finished biological product if the manufacturing process is changed.

25.- The registration holder of a Finished Biological Product importing an Active Substance or Bulk Biological Product for manufacturing the Finished Biological Product in the country shall have a business license as a manufacturer and count on a Quality Control structure that enables all quality control tests to be performed in order to release the lot, according to national or international law in force, and informed at the registration request.

26.- The Biological and Blood-therapeutic Products Unit (UPBIH), according to an approved and granted Registration Change, may require the registration holder to submit the first three (03) manufactured lots to the Quality Control of the National Institute of Quality Control on Health (INCQS).

27.- In case of a Registration Change due to Ownership Transfer, the requester shall inform, at the moment of filing the request, if the manufacturing sites of the Active Substance, Bulk Biological Product, Biological Product in its primary package and Finished Biological Product will remain the same as on previous

registration, otherwise, it shall request a Manufacturing site Change or a new Registration.

28.- A Finished Biological Product’s Registration expires in five (5) years. The holder of a Biological Product Registration shall request its renewal within six (6) months prior to the expiry date, also proving by documents that during the period of its Registration validity, the product has been marketed in the country according to the law in force.

29.- A Finished Biological Product which request is not filed at ANVISA/MS within the terms determined by the law in force, shall have its registration expired by ANVISA/MS after its expiry date.

30.- The holder of a product registration that has been cancelled may only obtain a new Registration for the same product if the processes required to obtain a Finished Biological Product Registration are followed again, according to the law in force.

31.- After all documentation set forth on Chapter III hereof is filed, the terms for issuing a final report by ANVISA/MS are:

31.1. Registration of a New Biological Drug: 180 days (06 months)

31.2. Registration of Biological Drug: 120 days (04 months).

31.3. Registration Change: 90 days (03 months).

31.4. Registration Renewal: 60 days (02 months).

31.5. Other change requests, such as: I) Registration Cancellation; II) Temporary Manufacturing Cessation or Reactivation; III) Processes Retrieval, and; IV) Adjustment of Registration Publication: 30 days.

32.- The terms allowed for the requester to comply with the requirements, as well as the extended terms requested by the Registration requester shall be added to the term set forth for ANVISA/MS to issue a final report.

33.- The terms required for National Institute of Quality Control on Health (INCQS) to perform the analytical tests of quality control and/or analysis of delivered documentation, and to issue the corresponding opinions shall be added to the term set forth for ANVISA/MS to issue a final report, which shall not exceed 60 days.

34.- A Finished Biological Product Registration, Registration Change and Registration Renewal shall only be valid after their granting is published, according to the law in force.

35.- The notification of changes on Package inserts text and on labels shall only be valid after such notification is accepted by UPBIH/GGMED.

36.- Exceptionally, in case of a New Biological Drug used to treat or prevent severe and/or highly life-threatening diseases, with completed Phase II clinical trials and ongoing Phase-III clinical trials, demonstrating a high therapeutic or preventive efficiency and/or if there is no other comparable alternative therapy or drug for that stage of the disease, the requester may request the product registration to ANVISA/MS. If ANVISA grants the registration, its safety and efficiency shall be monitored and continuously evaluated in Brazil by the Pharmaceutical Surveillance system.

37.- When filing the registration request of a Finished Biological Product, the requesting company shall deliver documentation regarding the validation of transportation procedure for the product to be registered.

38.- The National Sanitary Surveillance Agency - ANVISA/MS may grant the first registration in the world for a national or imported New Biological Drug provided the manufacturer of the product, in addition to the documents required on Chapter III hereof, delivers the following documents to ANVISA/MS.

38.1.- For ANVISA’s approval:

38.1.1.-All Protocols of phase-I, phase-II and phase-III clinical trials.

38.2.- For ANVISA’s evaluation:

38.2.1.- All documentation about the technological development of the product.

38.2.2. All documentation about the results of pre-clinical trials.

38.2.3.- All documentation about the development of quality control tests

38.2.4.- All documentation about the results of clinical trials performed with the product.

Chapter III: DOCUMENTS REQUIRED TO FORM FINISHED BIOLOGICAL PRODUCTS REGISTRATION PROCESSES

1.- GENERAL

1.1.- Documents

1.1.1.- The requesting company, when filing the Registration request, its Changes, and Renewal shall present one (1) copy of each required document and one (1) CD-ROM with the same information saved in an electronic language such as pdf (the serial number of the CD shall be exhibited on the documentation).

1.1.2.- Documents shall be sequentially numbered by the company and shall be signed by a legal representative and by the technical responsible of the company, who shall also sign his/ her initials on every page of the technical portion of the documentation.

1.1.3.- The requesting company, when filing its Registration request, shall sort the documentation presented according to the numbering as determined by item 2.- (Required documents) on Chapter III hereof.

1.1.4.- The requesting company, when filing its Registration request, shall inform about the employed International, National or Internal Rules of the company when determining the specifications of a Finished Biological Product.

1.1.5.- The requesting company, when filing its Registration request, shall inform the name and address of the active substance manufacturer, of the bulk biological product manufacturer, of the manufacturer of a biological product in its primary package and of the Finished Biological Product manufacturer. It shall also inform the name and address of the Lot Release Certificate issuer for the Finished Biological Product.

1.1.6- The requesting company, when filing its Registration request, shall present documentation of manufacturing and quality control for at least one (1) active substance lot of the New Biological Drug or three (3) active substance lots of a Biological Drug and the documents regarding manufacturing and quality control of three (3) consecutive lots of a New Biological Drug.

1.1.7.- In case the documents presented to ANVISA/MS by the requester are considered as incomplete after analysis by technical area, the following measures shall be taken by UPBIH:

1.1.7.1.- UPBIH shall require the supplementation of the documents to the requester, which has a maximum term of thirty (30) days counting from the date it is informed about to send the documentation. This term, upon requester’s request, may be extended for sixty (60) additional days.

1.1.7.2.- If, by the end of the allowed term, the required documents have not been received by UPBIH, the request shall be dismissed due to the lack of required documentation.

1.2.- Quality Control

1.2.1.- UPBIH, according to the analysis of the received documentation, to the available background of the product to be registered and/or of the manufacturer, and the possibility of having quality control technologies established and validated by Institute of Quality Control on Health - INCQS, shall determine if the three (3) lots of the Finished Biological Product shall be submitted to analytical quality control, of which documentation is delivered upon Registration request. In this

case, UPBIH shall inform INCQS about this decision and shall ask the Registration requester to send the required samples to INCQS within a maximum term of 30 days.

1.2.2.- The Registration requester has a term of thirty (30) days to deliver the samples to INCQS and may request, in written, up to two (02) extensions for this term. In case the requester does not deliver those samples to INCQS until the last allowed term, the latter shall immediately inform the fact to UPBIH, and the request shall be dismissed due to the failure to send the required samples within the established terms.

1.2.3.- In case the manufacturer does not have samples of the three (3) lots mentioned on the Registration request, the manufacturer shall inform UPBIH and INCQS that it is sending samples and documentation of other three (3) consecutive lots of the Finished Biological Product. This new documentation shall also be sent to UPBIH in order to be included in the registration process.

1.2.4.- INCQS may request on any of the activities for which it is responsible to the Registration requester, which is allowed to deliver the information or document requested within a term of thirty (30) days. If the requester is not able to comply with the requirement within the term set forth, it can officially request (in written) up to two (2) extensions for that term. If, by the end of the term granted, the information and/or requested documents have not been received, INCQS shall immediately inform UPBIH, which will dismiss the Registration request due to the lack of information and/or required documents.

2.- Required documents:

Registration of a New Biological Drug

Registration of a Biological Drug

2.1.- Document 01:

Petition Forms - FP.1 and FP.2, filled in, wherever applicable.

2.2.- Document 02:

Original copy of the payment voucher for the Sanitary Surveillance fee, duly validated and/or stamped by the bank, as well as a statement of company classification, whenever applicable.

2.3.- Document 03:

Copy of the Business License and/or Sanitary License of the Company; a copy of the Business License Certificate or its publication on the Brazilian Official Gazette (DOU).

2.4.- Document 04:

A copy of the updated Technical Responsibility Certificate, issued by the Regional Council of Pharmacy proving that the requesting company and/or manufacturer counts on the assistance of a responsible pharmacist duly qualified to that purpose.

2.5.- Document 05:

Proof of Registration in the manufacturing country of the Finished Biological Product or in the country that registered the product, according to item 7, Chapter II hereof, accompanied by its respective package inserts, approved by the Competent Sanitary Authority of the country where the registration was granted.

2.6.- Document 06:

Background information about the Registration status in other countries, whenever applicable.

2.7.- Document 07:

Whenever applicable, to present an updated Pharmaceutical Surveillance Report, according to the law in force, with data obtained from clinical trials and from product marketing.

2.8.- Document 08:

Document exhibiting:

-Name and address of the active substance manufacturer.

-Name and address of the bulk biological product manufacturer.

-Name and address of the manufacturer of the biological product in its primary package.

-Name and address of the finished biological product manufacturer.

-Name and address of the Lots Release Certificate issuer for a Finished Biological Product.

2.9.- Document 09

A copy of the company’s International, National or Internal ruling document, determining the specifications of a Finished Biological Product.

2.10.--Document 10:

Technical report for the product, exhibiting:

2.10.1.- General Data:

a) Pharmaceutical form and how supplied;

b) Composition formula, indicating the basic components per dose to be given or, if possible, per gram, milliliter, international standard unit, salt/base ratio and employed excesses;

c) Administration routes;

d) Directions for use, whenever applicable;

e) Indications, purpose or intended use;

f) Contraindications;

g) Side effects;

h) Adverse reactions;

i) Restrictions or care to be considered;

j) Precautions and warnings;

k) Drug and food interaction;

l) Changes on laboratory tests, whenever existent;

m) Overdose: signs, symptoms and approaches;

n) Expiry date;

o) Maintenance care.

p) Room temperature

q) Transportation temperature

2.10.2.- Pharmacodynamics:

a) Mechanism(s) of action;

b) Regimen and how to use;

c) Justifications for prescribed dosages;

d) Therapeutic rate, whenever applicable.

2.10.3.- Pharmacokinetics (Biomedicines)

a) Absorption;

b) Distribution;

c) Biotransformation;

d) Excretion/Elimination.

2.10.4.- Manufacturing and Quality Control:

a) Full composition of the formula with all specified components by their corresponding technical names and synonyms, according to the Brazilian Common Nomenclature - DBC (if existent), or ICN, or, if absent, CAS nomenclature. The amounts of each substance shall be expressed in a decimal measurement system or standard unit, also informing the substances used as vehicle or excipient;

b) Roles played by substances in the formula;

c) Description of all manufacturing process phases of the active substance;

d) Description of all manufacturing process phases of the bulk biological product;

e) Descriptive report on quality control, including physicochemical, biological and microbiological proofs performed with the active substance(s) and with the finished biological product;

f) The analytical methods and reference standards employed by the manufacturer shall be described in detail, as well as the analysis methodology to be adopted by the importer;

g) Tolerability limits for performed assays;

h) Code or convention used by the company to identify lots of the finished biological product;

i). Storage care and procedures employed during the transportation of the active substance, bulk biological product, biological product in its primary package, and finished biological product, whenever applicable, as well as packaging forms and conditions to be maintained in order to assure the quality of the product.

j) Documentation of transportation procedures validation for a biological product in its primary package and for a finished biological product.

k) In case of a thermolabile product, a statement shall be attached by the company that the storage and transportation meet the requirements of cold chain.

l) Report of the Viral Inactivation Process and the respective validation documents (blood-derived products).

m) Report of the quality control processes (serology and PCR) performed with the raw material (plasma) and its respective validation documents (blood-derived products).

2.10.5.- Stability Studies

Description of the stability studies with the finished biological product, compatible with the expiry date requested, performed with at least three (03) consecutive lots of the product in the strength, pharmaceutical form, primary packaging and environmental conditions in which such studies have been conducted. Stability studies data shall be presented by means of tables in order to make their analysis easier. In the stability studies, the analyses regarding physicochemical, biological and microbiological characteristics, as well as manufacturing date and identification code of product lots shall be comprised, according to the criteria described in the law in force about the matter.

Tests performed according to the criteria internationally established by MERCOSUL and WHO shall also be accepted. As supplementary references, the criteria established by EMEA, ICH and FDA shall be considered in a subsidiary basis.

2.10.6.- Supplementary Data:

a) To mention the subscription of the substance or basic components of the formula in the pharmacopoeia, official forms or publications of pharmaceutical standardization or scientific journals;

b) To attach references and pertinent literature about the product. The National Sanitary Surveillance Agency may request studies that may be considered as required for the evaluation of scientific documentation, with a copy for file purposes;

c) To present the advantages of the proposed formula, with a justification from a clinical point of view;

d) Products constituted by an association of two or more active substances must provide scientific evidence proving the efficiency and safety of the association and showing the benefits justifying it;

e) Other related or necessary elements, including those designed to judge cause and effect, so as to enable sanitary authorities to come to correct conclusions.

2.11.- Document 11:

Package inserts texts and primary and secondary packages, in two copies, according to the law in force.

2.12.- Document 12:

Therapeutic Experiment Report, prepared and presented according to the provisions of law in force. Data must be organized within the following sections:

2.12.1.- Pre-clinical studies (except for blood-derived products):

a) Acute toxicity;

b) Sub-acute toxicity;

c) Chronic toxicity;

d) Reproductive toxicity;

e) Mutagenic activity;

f) Oncogenic potential.

2.12.2.- Clinical Trials

a) Phase-I Clinical Trials;

b) Phase-II Clinical Trials;

c) Phase-III Clinical Trials;

d) Phase-IV Clinical Trials – Post-marketing, if existent;

e) Studies conducted in Brazil, in any of the phases, shall be presented together with a statement of the current phase of the trial by the responsible team, whenever existent.

f) In case of a Biological Drug, the registration requester may present Comparable Clinical trials (showing non-inferiority) as a demonstration of therapeutic activity and safety.

2.13.- Document 13:

a) A copy of the Good Manufacturing Practices (GMP) Certificate issued by the National Sanitary Surveillance Agency, in cases of products manufactured in Brazil.

b) A copy of the Good Manufacturing Practices (GMP) Certificate issued by the Competent Sanitary Authority of the country where the manufacturing plant of the Bulk Biological Product or Biological Product in its primary package or of the Finished Biological Product is located.

c) Proof of registration and marketing of the Biological Drug in the manufacturing country, according to the law in force. In case of a New Biological Drug not registered in the manufacturing country, a proof of Product Registration issued by the competent Sanitary Authority where registration exists, which must be recognized by ANVISA.

2.14.-Document 14

Bar code (GTIN), for all supplies.

2.15.- Document 15

a). Documentation of manufacturing and quality control of three (03) consecutive lots of the active substance at the moment of Biological Drug registration request, and, for a New Biological Drug, at least one (01) lot.

b). Documentation of manufacturing and quality control of three (03) consecutive lots of the Finished Biological Product.

2.16.- Document 16 (for blood-derived products).

a). Statement of plasma origin issued by the Competent Sanitary Authority of the manufacturing country of the blood-derived product.

b). Statement of pastes origin used in the manufacture of blood-derived products.

c). Statement of Plasma Origin used for manufacturing pastes, issued by the Competent Sanitary Authority of the country in which they are produced.

2.17.- Document 17 (for blood-derived products)

List of the Plasma Collection Centers authorized by the competent Sanitary Authority of the manufacturing country of the blood-derived product.

2.18.-Document 18 (for blood-derived products)

Validation Reports of the Viral Inactivation procedures.

3.- BIOLOGICAL PRODUCT REGISTRATION CHANGE

3.1.- The Biological Product Registration Change can be:

a) A change in the manufacturing process of active substance(s) of the biological product

b) A change in the manufacturing process of a bulk biological product

c) A change in the manufacturing process of a biological product in its primary package

d) A change in the manufacturing process of a finished biological product

e) A change of the manufacturing site of the active substance(s), whenever the new manufacturing site of the active substance(s) belongs to the same company.

f) A change of the manufacturing site of the bulk biological product.

g) A change of the manufacturing site of the biological product in its primary package

h) A change of the manufacturing site of the finished biological product

i) A change of the expiry date

j) A change of maintenance care

k) A change of excipient

l) A change of packaging

m) A change of regimen

n) A change of the administration route

o) A change of the external package

p) Inclusion of manufacturing site of the bulk biological product

q) Inclusion of manufacturing site of the biological product in its primary package

r) Inclusion of manufacturing site of the finished biological product

s) Inclusion of a new therapeutic indication already approved in the country

t) Inclusion of a new therapeutic indication in the country

u) Inclusion of a new pharmaceutical form

v) Inclusion of a new strength

w) Inclusion of a new commercial supply

x) Inclusion of a new packaging

y) Inclusion of a new administration route

z) Updating of production strains for influenza vaccines

aa) Enlargement of use

bb) Notification of labeling change

cc) Notification of package insert text change

3.2.- Required documents:

3.2.1.- Document 01:


3.2.2.- Document 02 (except notifications):



Copy of the Business License and/or Sanitary License of the Company; a copy of the Business License Certificate or its publication on the Brazilian Official Gazette (DOU).


Technical Responsibility Certificate, issued by the Regional Council of Pharmacy proving that the requesting company and/or manufacturer counts on the assistance of a responsible pharmacist duly qualified to that purpose.


Copy of the evidence document of Product Registration (Registration certificate in force or publication on the Brazilian Official Gazette – DOU) and a copy of the protocol of the last product Registration renewal (whenever applicable).


Technical justification for the intended request.


Certificate of compliance with the Good Manufacturing Practices (GMP), issued by the Competent Sanitary Authority of the manufacturing country of the product.

3.2.8.- SUPPLEMENTARY DOCUMENTS:

In addition to the documents mentioned above and, according to the intended change, the following documents shall be presented:

3.2.8.1.- Document A

Technical Report of the product, according to the provisions of items 2.10.4 and 2.10.5, Chapter III hereof, in case the requested change is:

A change of the manufacturing process of the active substance(s) in a biological product

A change of the manufacturing process of the bulk biological product

A change of the manufacturing process of the biological product in its primary package

A change of the manufacturing process of the finished biological product

A change of the manufacturing site of the active substance(s), whenever the new manufacturing site of the active substance(s) belongs to the same company.

A change of the manufacturing site of the bulk biological product.

A change of the manufacturing site of the biological product in its primary package

A change of the manufacturing site of the finished biological product

Inclusion of manufacturing site of the bulk biological product

Inclusion of manufacturing site of the biological product in its primary package

Inclusion of manufacturing site of the finished biological product

Inclusion of a new pharmaceutical form

Inclusion of a new strength

Inclusion of a new commercial supply

Inclusion of a new packaging

Updating of production strains for influenza vaccines

3.2.8.2.- Document B

Labels, package inserts, and packages models, in two copies, in cases of:

A change of the manufacturing site of the active substance(s), whenever the new manufacturing site of the active substance(s) belongs to the same company.

A change of the manufacturing site of the bulk biological product.

A change of the manufacturing site of the biological product in its primary package

A change of the manufacturing site of the finished biological product

A change of expiry date

A change of maintenance care

A change of excipient

A change of packaging

A change of regimen

A change of administration route

A change of external package

Inclusion of manufacturing site of the bulk biological product

Inclusion of manufacturing site of the biological product in its primary package

Inclusion of manufacturing site of the finished biological product

Inclusion of a new therapeutic indication already approved in the country

Inclusion of a new therapeutic indication in the country



Inclusion of a new commercial supply


Inclusion of a new administration route

Updating of production strains for influenza vaccines

Enlargement of use

Notification of labeling change

Notification of package inserts text change

3.2.8.3.- Document C

Descriptive Report of stability study, in cases of:

A change of the manufacturing process of a finished biological product

A change of the manufacturing site of the bulk biological product

A change of expiry date

A change of maintenance care

A change of excipient

A change of packaging




3.2.8.4.- Document D

Report of clinical trials according to item 2.12.2, Chapter III hereof

Inclusion of a new therapeutic indication already approved in the country

Inclusion of a new therapeutic indication in the country

A change of regimen



Inclusion of a new administration route

Enlargement of use

3.3.- OTHER REGISTRATION CHANGE REQUESTS

3.3.1.- Temporary Manufacturing Cessation upon request:

The requester shall wait for the approval by ANVISA to interrupt the manufacturing.

3.3.1.1.- Required documents:

3.3.1.1.1.- Document 01:


3.3.1.1.2.- Document 02:


3.3.1.1.3.- Document 03:

Justification for the intended request, informing the expiry date and number of the last produced lot, whenever applicable.

3.3.1.1.4.- Document 04:

Copy of the document proving Product Registration (Registration certificate in force or publication on the Brazilian Official Gazette – DOU) and a copy of the protocol of the last renewal (whenever applicable).

3.3.2. Cancellation of Drug Supply Registration upon request:

The requester shall wait for the approval by ANVISA in order to interrupt the manufacturing of the drug supply.

3.3.2.1.- Required Documents:

3.3.2.1.1.- Document 01:


3.3.2.1.2.- Document 02:

Justification for the intended request, informing the expiry date and number of the last produced lot, whenever applicable.

3.3.2.1.3.- Document 03:

Copy of the document proving Product Registration (Registration certificate in force or publication on the Brazilian Official Gazette – DOU) and a copy of the protocol of the last product Registration renewal (whenever applicable).

3.3.3. Cancellation of Drug Registration upon request:


3.3.3.1.1.- Document 01:


3.3.3.1.2.- Document 02:

Justification for cancellation.

3.3.3.1.3.- Document 03:


3.3.4. Processes retrieval:

3.3.4.1- Required Documents:

3.3.4.1.1.- Document 01:


3.3.4.1.2.- Document 02:


3.3.4.1.3.- Document 03:

Justification for the intended request.

3.3.5. Adjustment of Publication


3.3.5.1.1.- Document 01:


3.3.5.1.2.- Document 02:


3.3.5.1.3.- Document 03:

Explicative notice.

3.3.6. Reactivation of Product Manufacturing and Notification of Finished Biological Product Introduction

3.3.6.1- Required Documents

3.3.6.1.1. Document 01


3.3.6.1.2. Document 02


3.3.6.1.3. Document 03

Explicative notice.

3.3.7. Manufacturing License for Drugs Exportation purposes only

3.3.7.1. Required Documents.

3.3.7.1.1. Document 01:

Explicative notice.

3.3.8. Registration Certificate for drugs exportation

3.3.8.1. Required Documents:

3.3.8.1.1. Document 01:

Petition Forms - FP.1 and FP.2, filled in, wherever applicable. (in two copies).

3.3.8.1.2. Document 02:


3.3.8.1.3. Document 03:

Document proving the need of a registration certificate.

4. Registration Ownership Transfer (due to merge, incorporation, succession, or scission of Companies).

4.1.- Required Documents:






Copies of legal documents, proving the company name change due to merge, scission, succession or incorporation of company, duly legalized.


Copy of the Business License and/or Sanitary License of the Company; a copy of the Business License Certificate or its publication on the Brazilian Official Gazette (DOU) for the assignee company.


A copy of the updated Technical Responsibility Certificate, issued by the Regional Council of Pharmacy proving that the assignee company counts on the assistance of a responsible pharmacist duly qualified to that purpose.




Communication of the assignee company about the product manufacturing cessation, in case it has been manufactured and marketed, indicating the number of the last manufactured lot, whenever applicable.


List of product(s) to be transferred, informing the numbers of process, product Registration(s) and their corresponding supplies.


Copies of the package insert, and primary and secondary packages texts.

4.1.10.- Document 10:

Copy of the Good Manufacturing Practices Certificate for the new manufacturer of the product, issued or accepted by the National Sanitary Surveillance Agency, in cases of Products Manufactured in Brazil or Imported Products.

4.1.11.- Notes:

- The Registration Ownership Transfer request may be performed as a single step for the total amount of intended products, i.e., all products may be transferred to a new owner upon a single request made only once to this Agency.

- The assignor company shall proceed, simultaneously to the process of Ownership Transfer, to the cancellation of the Registrations being transferred.

5. FINISHED BIOLOGICAL PRODUCT REGISTRATION RENEWAL

New Biological Drug

Biological Drug

5.1.- Required Documents:








A copy of the updated Technical Responsibility Certificate, issued by the Regional Council of Pharmacy proving that the requesting company and/or manufacturer counts on the assistance of a responsible pharmacist duly qualified to that purpose


Document proving that the product has been manufactured or marketed (this could be a document proving that the company takes part in biddings).


Technical Report according to items 2.10.1 and 2.10.4, and package insert text according to item 2.11, Chapter III hereof.


Copy of the Good Manufacturing Practices Certificate issued or accepted by the National Sanitary Surveillance Agency, in cases of Products Manufactured in Brazil or Imported Products