Legislation
Resolution

Resolution - RE nº 480, of March 19, 2002
(Official Journal of 20/03/2002)

The Director of the Collegiate Board of Directors of the National Sanitary Surveillance Agency, in the use of the attributions vested in him under Administrative Rule 724, issued by the Director-Chairman, on October 10, 2000,

WHEREAS

paragraph 3 of article 111, of the Bylaws approved by Administrative Rule 593, of August 25, 2000, re-published in the Official Journal of the Union of December 22, 2000;
that the matter was submitted to the examination of the Collegiate Board of Directors, which approved the matter in a meeting held on March 13, 2002, decides:

Article 1 - To determine the publication of the "Guide for Production of Pilot Batches", attached.

Article 2 - This Resolution enters into force on the date of its publication.

GONZALO VECINA NETO

GUIDE FOR PRODUCTION OF PILOT BATCHES - 1/2002

1. CHARACTERISTICS

The production of pilot batches is essential for a more detailed assessment of the characteristics and quality of a product. With this production it is possible to undertake verification of the productive capacity of companies, testing of the fundamental characteristics of a product before clearing it for consumption, as well as enable the execution of any necessary biopharmacokinetic trials. Thus, the production of these batches should attempt to mimic, as far as possible, the technical and operational conditions, in addition to the conditions of the manufacturing processes, of the proposed industrial batch of the product to be assessed for later clearance of its registration by ANVISA;

For the purpose of clearance of production authorization for these pilot batches, the company must present a specific project describing clearly and precisely all the production stages with their respective experts in charge, the processes and respective controls, machinery, staff involved for each stage and the product assessment proposal, and work plan for the undertaking of bioavailability, relative bioavailability and/or bioequivalence, pharmaceutical equivalence, pharmacopeial tests or clinical trials.

The pilot batch production project must contemplate an assessment proposal for validation of the productive process, as well as the analytical methodologies involved. Thus, it is necessary to take into consideration the perspective of projection of the results obtained with the production of pilot batches quantitatively smaller than the industrial batches, in a proportion no lower than 10% between one and the other.

2. PROCEDURES

2.1 National drug without registration at ANVISA

The company must manufacture three batches of the proposed drug. The number of units produced in each batch must be close to the maximum intended for the industrial batch to be registered. In case this is impossible, the following variations shall be accepted:
- A minimum of 100,000 units for the solid oral pharmaceutical forms;
- For drugs with high added value, the manufacturing of a minimum of 30,000 units will be required;
- For the other pharmaceutical forms, batches not inferior to 10% of the industrial batch will be required;
- For products whose concentration of the active is expressed in micrograms or nanograms, or any other dosage below milligrams, pilot batches with different quantities from the industrial batches will not be allowed.
Any production of pilot batches smaller in size than those mentioned above must be accompanied by the proper technical justification in order to allow the most detailed assessment possible.
The authorization request for manufacturing the pilot batches must contain the following information:

a) standard formula,

b) process and equipment used in the manufacturing of the drug, describing the maximum capacity of each one of them;

c) analytical methods employed, in compliance with the GUIDE FOR VALIDATION OF ANALYTICAL METHODS;

d) detailed protocol of stability study, in compliance with GUIDE FOR UNDERTAKING STABILITY STUDIES;

e) protocol of pharmaceutical equivalence study, indicating the reference drug, with description of tests to be undertaken, in compliance with GUIDE FOR UNDERTAKING OF STUDY AND PREPARATION OF REPORT OF PHARMACEUTICAL EQUIVALENCE;

f) protocol of bioavailability, relative bioavailability and bioequivalence study, and/or clinical trials, in two copies, presented in compliance with GUIDE FOR PROTOCOL AND TECHNICAL REPORT OF BIOEQUIVALENCE STUDY in which the undertaking of such studies is not applicable, when indicated in the GUIDE FOR EXEMPTION AND SUBSTITUTION OF RELATIVE BIOAVAILABILITY an/or BIOEQUIVALENCE STUDY, present technical justification for the exemption.

2.2. Drug with bioavailability, bioequivalence and/or relative bioavailability test, undertaken or to be undertaken in the Country
For registration of national or imported drugs whose bioavailability, bioequivalence and/or relative bioavailability tests have been or will be undertaken in the Country, the process of this stage should contain the following documents and information:

a) standard formula,

b) process and equipment used in the manufacturing of the drug, describing the maximum capacity of each one of them;

c) detailed protocol of stability study, in compliance with the GUIDE FOR UNDERTAKING OF STABILITY STUDIES ;

d) protocol of pharmaceutical equivalence study, indicating the reference drug, with description of tests to be undertaken, in compliance with GUIDE FOR UNDERTAKING OF STUDY AND PREPARATION OF REPORT OF PHARMACEUTICAL EQUIVALENCE;

e) protocol of bioavailability, relative bioavailability and bioequivalence study, and/or clinical trials (two copies), presented in compliance with GUIDE FOR PROTOCOL AND TECHNICAL REPORT OF BIOEQUIVALENCE and/or RELATIVE BIOAVAILABILITY STUDY. For cases in which the undertaking of such studies is not applicable, when indicated in the GUIDE FOR EXEMPTION AND SUBSTITUTION OF BIOEQUIVALENCE and/or RELATIVE BIOAVAILABILITY STUDY, present technical justification for the exemption.

Obs.1: National or imported drugs that are already registered and that are intended to be registered and commercialized as generic drugs, may comply with the requirements above, using retrospective data of industrial batches already produced, provided that:

a) the validation of the analytical methods is proven in compliance with the GUIDE FOR VALIDATION OF ANALYTICAL METHODS, in the case of pharmacopeial methodology, present data pertaining to precision, accuracy and linearity;

b) the manufacturing process and the cleaning process are validated;

c) copies of complete production and quality control dossiers are presented, referring to three batches produced in the last three years;

d) stability studies of three batches are presented, contemplating the established date of expiry.

Obs. 2: for importation of samples for undertaking in vitro - in vivo tests, the company must have an Importation License, in compliance with legislation in force.
Obs. 3: bioavailability, bioequivalence and/or relative bioavailability studies that do not employ adequate design for the statistical treatment used and that have not obtained prior approval of the protocol by ANVISA will not be accepted, even if the acceptance criteria meet the recommendations.

2.3 Drug with bioavailability, bioequivalence and/or relative bioavailability test, undertaken or to be undertaken abroad
For drugs manufactured abroad, whose bioavailability, bioequivalence and/or relative bioavailability studies have already been undertaken in compliance with the guidelines set forth in this Resolution, the following must be presented:

a) standard formula,

b) process and equipment used in the manufacturing of the drug, describing the maximum capacity of each one of them;

c) copy of the complete production and quality control dossiers, referring to three batches manufactured in the last three years;

d) stability data of three batches, contemplating the established date of expiry;

e) proof of validation of the analytical method, in compliance with the GUIDE FOR VALIDATION OF ANALYTICAL METHODS, in the case of pharmacopeial methodology, present precision, accuracy and linearity data;

f) validation of the manufacturing process and the cleaning process;

g) protocol of pharmaceutical equivalence study, undertaken in compliance with GUIDE FOR UNDERTAKING OF STUDY AND PREPARATION OF REPORT OF PHARMACEUTICAL EQUIVALENCE ;

h) two copies of the bioequivalence study in compliance with the GUIDE FOR BIOAVAILABILITY, BIOEQUIVALENCE and/or RELATIVE BIOAVAILABILITY STUDIES OF DRUGS. For the cases in which the undertaking of such studies is not applicable, present technical justification for the exemption;

i) copy of comparative dissolution test dossier between the three drugs: test, international reference employed in the bioequivalence study and national reference in compliance with the GUIDE FOR DISSOLUTION TESTING OF ORAL SOLID IMMEDIATE RELEASE PHARMACEUTICAL FORMS and technical report of the in vitro- in vivo correlation studies, as described in the GUIDE FOR IN VITRO - IN VIVO CORRELATION STUDIES. In case the international and national reference profiles are not similar, it will be necessary to present a new bioequivalence study undertaken with the national reference;

j) copy of the documents that prove the origin of the reference drug used in the bioequivalence study (international reference), through information about the manufacturer (same company, licensing, etc.).

Obs. 1. The company may use retrospective data to comply with the requirements above.
Obs. 2: For importation of samples for undertaking in vitro - in vivo tests, the company must have an Importation License, in compliance with legislation in force.

Obs. 3: After the registration is published, at the discretion of ANVISA, a new bioequivalence study may be requested. The study should preferably be undertaken in Brazil, with the drug indicated by ANVISA as a reference. The non-compliance of the request will imply in cancellation of the registration.

Obs. 4: Bioavailability, bioequivalence and/or relative bioavailability studies that do not employ adequate design for the statistical treatment used and that have not obtained prior approval of the protocol by ANVISA will not be accepted, even if the acceptance criteria meet the recommendations.

3. DESTINATION OF THE PILOT BATCHES

3.1. For pilot batches approved in all phases whose quantitaty is equal to or very close to that of the industrial batch, the company may request that these products be made available for the market, after registration is granted;

3.2. For all the other options, even if they are approved in all phases, the products must be destroyed, upon communication to the competent organs, except the bio batch (the one chosen for the undertaking of bioavailability, bioequivalence and/or relative bioavailability studies).

4. DOCUMENTATION PERTAINING TO THE PILOT BATCHES

4.1 All the documentation pertaining to the production of the pilot batches must be kept on file;

4.2 For the pilot batches not approved, this documentation must be kept for at least two years, including the documentation relative to the destination given to these products. In case the company is inspected and has this documentation, it may present the documentation to the inspection team, which will verify the data in order to clear the company from the requirement of keeping the documentation for the minimum term established;

4.3 For the batches approved, this documentation must be filed together with all the documentation pertaining to the registration and kept throughout its life;

4.4 All the documentation (copy) pertaining to the production of the pilot batches must be forwarded to ANVISA upon request of its registration.