Hotsite - Genéricos - Legislação - Resolution

Legislation
Resolution

Resolution - RE nº 477, 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 Making Post-Registration Alterations and Inclusions of Drug Products", attached.

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

GONZALO VECINA NETO

GUIDE FOR MAKING POST-REGISTRATION ALTERATIONS AND INCLUSIONS OF DRUG PRODUCTS - 1/2002

1. GENERAL CONSIDERATIONS

The purpose of this guide is to classify drug post-registration alterations and inclusions and establish the documentation and the trials that shall be required by ANVISA for this stage.
In the cases of alterations and inclusions not included in this guide, or those that do not comply with one or more of the established criteria, or whenever more than one alteration is requested, the necessary tests and documentation shall be established at the discretion of ANVISA.
1.1. Post-registration alterations

1.1.1. Type I

Type I alterations are those in which:
a) Concentration, pharmaceutical form, packing, quantity and volume remain unaltered;
b) The same equipment and operational principles are used;
c) The same Standard Operational Procedures and Controls are employed, without alteration in formulation and manufacturing process.
Type I alterations are subdivided into:
a) Alteration of Labeling;
b) Alteration of Directions for Use;
c) Alteration of Date of Expiry;
d) Alteration of Preservation conditions.

1.1.2. Type II

1.1.2.1. Criteria adopted for subdivision of Type II alterations
Within each one of Type II alterations, the pharmaceutical form of the drug was considered, as well as the requirement for undertaking relative bioequivalence and/or bioavailability trial for the original registration. Thus, the following categories are defined:

a) Products exempt from relative bioequivalence and/or bioavailability
Refers to injectable pharmaceutical forms, oral, othological and ophthalmic solutions, creams, ointments, solid oral pharmaceutical forms whose active substances are not absorbed by the GIT, and other products that, according to the GUIDE FOR EXEMPTION AND SUBSTITUTION OF BIOEQUIVALENCE STUDIES, have been exempted from presentation of relative bioequivalence and/or bioavailability trials.

b) Products not exempt from relative bioequivalence and/or bioavailability
Refers only to solid oral immediate release pharmaceutical forms and suspensions which presented relative bioequivalence and/or bioavailability trials for the original registration.

Type II alterations are subdivided into:

a) Alteration of the Synthesis Path of the Active Substance;
b) Substitution of the Active Substance Manufacturer;
c) Alteration of the Manufacture Site/Manufacturer;
d) Alteration of Registration due to Excipient Change;
e) Alteration of the Drug Manufacturing Process;
f) Alteration of the Size of the Batch;
g) Change of Equipment Used.

1.2. Post-registration Inclusions
Post-registration inclusions are subdivided into:
a) Registration of New Commercial Presentation;
b) Registration of New Packing;
c) Registration of New Concentration.

2. DEFINITIONS

a) Specification: Document that describes in detail the requirements that products or materials used during the manufacturing process must comply with. The specifications are a basis for quality assessment;

b) Manufacturing: All the necessary operations for obtaining the products comprehended by this Regulation;

c) Batch: Quantity of a product obtained in a production cycle of continuous stages, and characterized by its homogeneity;

d) Raw material: Active or inactive substances employed in the manufacturing of drugs and other products comprehended by this Regulation, even when they remain unaltered, undergo changes or are completely eliminated during the manufacturing process;

e) Standard Operational Procedure (SOP): Written and authorized procedure that provides instructions that are not necessarily specific, regarding the performance of operations related to a given product or material, of a general nature (that is, operation of equipment, maintenance and cleaning; validation; cleaning of facilities and environmental control; sampling and inspection). Certain SOPs may be used to complement documentation related to the production of the batches;

f) Process: All the operations involved in preparation of a certain pharmaceutical product, from receiving the materials, processing and packaging, to conclusion of the finished product;

g) Validation: Documented deed that certifies that any procedure, process, equipment, material, activity or system is in fact leading to the expected results;

h) Equipment: Automated or mechanical machines used to produce the drug, including those used for packaging the product;

i) Pilot scale: Production of active substance or drug using representative procedures that simulate those of the industrial scale. For solid oral pharmaceutical forms, it is, generally, at least 1/10 of the industrial scale, or 100.000 units, whatever is larger;

j) Limit: Amounts with acceptable existing variation;

3. POST-REGISTRATION: TYPE I - TECHNICAL AND LEGAL ASPECTS

3.1. ALTERATION OF LABELING
Alterations on the label and/or container must be accompanied by the following documentation:

3.1.1. Legal Aspects

3.1.2. Technical Aspects

a) FP1 and FP2 properly filled out;
b) Technical Justification referring to the request;
c) Model of label and/or container, in compliance with legislation in force.

3.2. ALTERATION OF THE TEXT OF DIRECTIONS FOR USE

Alterations and/or updates in the text of the directions for use must be accompanied by the following documentation:

3.2.1. Legal Aspects
a) Original proof of bank deposit and legalized copy;
b) Copy of the Operation License of the company and/or updated Sanitary Permit;
c) Updated Certificate of Technical Responsibility, issued by the Pharmacy Regional Council;
d) Updated Certificate of Good Manufacturing and Control Practices issued by ANVISA for the line of production in which the drug has been manufactured.

3.2.2. Technical Aspects
a) FP1 and FP2 properly filled out;
b) Technical Justification referring to the request;
c) Model of Directions for Use, equivalent to that of the reference drug and in compliance with legislation in force.

3.3. ALTERATION OF THE DATE OF EXPIRY

Alterations of the date of expiry of a product must be accompanied by the following documentation:

3.3.1. Legal Aspects
a) Original proof of bank deposit and legalized copy;
b) Copy of the Operation License of the company and/or updated Sanitary Permit;
c) Updated Certificate of Technical Responsibility, issued by the Pharmacy Regional Council;
d) Updated Certificate of Good Manufacturing and Control Practices issued by ANVISA for the line of production in which the drug has been manufactured.

3.3.2. Technical Aspects
a) FP1 and FP2 properly filled out;
b) Technical Justification referring to the request;
c) Technical report containing the results and final assessment of the long term stability study of three batches produced, justifying the new date of expiry;
d) Models of secondary and primary package and directions for use, adapted to the new date of expiry.

3.4. ALTERATION OF PRESERVATION CONDITIONS
Alterations of preservation conditions must be accompanied by the following documentation:

3.4.1. Legal Aspects

a) Original proof of bank deposit and legalized copy;
b) Copy of the Operation License of the company and/or updated Sanitary Permit;
c) Updated Certificate of Technical Responsibility, issued by the Pharmacy Regional Council;
d) Updated Certificate of Good Manufacturing and Control Practices issued by ANVISA for the line of production in which the drug has been manufactured.

3.4.2. Technical Aspects
a) FP1 and FP2 properly filled out;
b) Technical Justification referring to the request;
c) Technical report containing the results and final assessment of the long term stability study of three batches produced. The stability test must be adjusted according to the requested alterations of preservation conditions;
d) Models of secondary and primary package and directions for use, adapted to the new preservation conditions.

4. POST-REGISTRATION ALTERATIONS: TYPE II - TECHNICAL AND LEGAL ASPECTS

4.1. ALTERATION OF THE SYNTHESIS PATH OF THE ACTIVE SUBSTANCE
Alterations of the synthesis path of the active substance must be accompanied by the documentation listed below:

4.1.1. Legal Aspects
a) Original proof of bank deposit and legalized copy;
b) Copy of the Operation License of the company and/or updated Sanitary Permit;
c) Certificate of Technical Responsibility, issued by the Pharmacy Regional Council;
d) Certificate of Good Manufacturing and Control Practices issued by ANVISA for the line of production in which the drug undergoing registration will be manufactured.

4.1.2. Technical Aspects

4.1.2.1. FP1 and FP2 properly filled out;

4.1.2.2.Technical Justification referring to the request;

4.1.2.3.Technical report

4.1.2.3.1. Products exempt from relative bioequivalence and/or bioavailability

a) Documentation issued by the manufacturer of the active substance:
- New synthesis path;
- Quantification and limits of the main contaminants, according to the synthesis path of the active substance;
- List of solvents used in the process.
For the active substances presenting chirality, and whose proportion of stereoisomers may compromise the effectiveness and safety of the drug: data about the proportion of stereoisomers, whenever the analytical methodology is available.
For the active substances presenting polymorphism: information about probable polymorphs and whenever possible, the analytical methodology for its determination.

b) Dossier of production and quality control of three batches of each concentration of the product;

c) Reproducibility of the analytical results between one registered batch and three batches with proposed alteration, for each concentration of the product;

d) Technical report containing the results and assessment of the accelerated stability test and the long term stability test presented annually, for each concentration of the product;

e) proof of pharmaceutical equivalence in relation to the reference drug, using, when appropriate, updated monograph of the Brazilian Pharmacopoeia or, for lack of it, of other authorized codes. The results must be presented in compliance with legislation in force.

4.1.2.3.2. Products not exempt from relative bioequivalence and/or bioavailability - solid oral immediate release pharmaceutical forms and suspensions

a) Comply with provisions under item 4.1.2.3.1;

b) Technical report containing the results and assessment of a new bioequivalence and/or bioavailability study in compliance with legislation in force, unless an in vitro/in vivo correlation has been properly established.

4.2. SUBSTITUTION AND INCLUSION OF THE ACTIVE SUBSTANCE MANUFACTURER
Substitution or inclusion of active substance manufacturer will be allowed up to the maximum number of three manufacturers, considering those already defined in the original registration. The documentation required in this case shall include:

4.2.1. Legal Aspects

a) Original proof of bank deposit and legalized copy;
b) Copy of the Operation License of the company and/or updated Sanitary Permit;
c) Certificate of Technical Responsibility, issued by the Pharmacy Regional Council;
d) Certificate of Good Manufacturing and Control Practices issued by ANVISA for the line of production in which the drug undergoing registration will be manufactured.

4.2.2. Technical Aspects
4.2.2.1. FP1 and FP2 properly filled out;
4.2.2.2.Technical Justification referring to the request;
4.2.2.3.Technical report
4.2.2.3.1. Products exempt from relative bioequivalence and/or bioavailability

a) Documentation issued by the manufacturer of the active substance:
- Manufacturing company and synthesis path;
- Quantification and limits of the main contaminants, according to the synthesis path of the active substance;
- List of solvents used in the process.
For the active substances presenting chirality, and whose proportion of stereoisomers may compromise the effectiveness and safety of the drug: data about the proportion of stereoisomers, whenever the analytical methodology is available.
For the active substances presenting polymorphism: information about probable polymorphs and whenever possible, the analytical methodology for its determination.

b) Dossier of production and quality control of three batches of each concentration of the product;

c) Reproducibility of the analytical results between one registered batch and three batches with proposed alteration, for each concentration of the product;

d) Technical report containing the results and assessment of the accelerated stability test and the long term stability test presented annually, for each concentration of the product;

e) proof of pharmaceutical equivalence in relation to the reference drug, using, when appropriate, updated monograph of the Brazilian Pharmacopoeia or, for lack of it, of other authorized codes. The results must be presented in compliance with legislation in force.

4.2.2.3.2. . Products not exempt from relative bioequivalence and/or bioavailability - solid oral immediate release pharmaceutical forms and suspensions

a) Comply with provisions under item 4.2.2.3.1;
b) Technical report containing the results and assessment of a new bioequivalence and/or bioavailability study in compliance with legislation in force, unless an in vitro/in vivo correlation has been properly established.

4.3. ALTERATION OF THE MANUFACTURE SITE

This item includes change of the manufacture site due to change of address, property transfer, third party contracting and internalization of production.

4.3.1. Legal Aspects

a) Copy of the Operation License of the new company published in the Official Journal of the Union;
b) Original proof of bank deposit and legalized copy;
c) Copy of the Operation License of the company and/or updated Sanitary Permit;
d) Certificate of Technical Responsibility, issued by the Pharmacy Regional Council;
e) Updated Certificate of Good Manufacturing and Control Practices of the new manufacture site, issued by ANVISA for the line of production in which the drug will be manufactured.

4.3.2. Technical Aspects
4.3.2.1. FP1 and FP2 properly filled out;
4.3.2.2.Technical Justification referring to the request;
4.3.2.3.Technical report
4.3.2.3.1. Products exempt from relative bioequivalence and/or bioavailability

a) Place of new facility;

b) Dossier of production and quality control of three batches of each concentration of the product;

c) Reproducibility of the analytical results between one registered batch and three batches with proposed alteration, for each concentration of the product;

d) Validation of the analytical methods employed;

e) Validation of the manufacturing process of the product, contemplating also the validation of cleanliness of the equipment. As proof, the company must present validation protocol and conclusive report;

f) Technical report containing the results and assessment of the accelerated stability test and the long term stability test presented annually, for each concentration of the product;

g) Proof of pharmaceutical equivalence in relation to the reference drug, using, when appropriate, updated monograph of the Brazilian Pharmacopoeia or, for lack of it, of other authorized codes. The results must be presented in compliance with legislation in force.

4.3.2.3.2. Products not exempt from relative bioequivalence and/or bioavailability - solid oral immediate release pharmaceutical forms and suspensions

a) Comply with provisions under item 4.3.2.3.1;
b) Technical report containing the results and assessment of a new bioequivalence and/or bioavailability study in compliance with legislation in force, unless an in vitro/in vivo correlation has been properly established.

4.4. ALTERATION OF REGISTRATION DUE TO EXCIPIENT CHANGE
Alterations of registration due to excipient change must be accompanied by the following documentation:

4.4.1. Legal Aspects

a) Original proof of bank deposit and legalized copy;
b) Copy of the Operation License of the company and/or updated Sanitary Permit;
c) Updated Certificate of Technical Responsibility, issued by the Pharmacy Regional Council;
d) Updated Certificate of Good Manufacturing and Control Practices issued by ANVISA for the line of production in which the drug has been manufactured.

4.4.2. Technical Aspects

4.4.2.1. FP1 and FP2 properly filled out;
4.4.2.2. Technical Justification referring to the request;
4.4.2.3. Technical Report:
4.4.2.3.1. Products exempt from relative bioequivalence and/or bioavailability

a) Complete description of the master formulation designating the components as per CBD, INN or a denomination described in the Chemical Abstract Substance (CAS), observing the order of priority;

Table I

Excipient	% Excipient (p/p)
Dilutant	± 5,0
Desintegrator	Starch	± 3,0
	Others	±1,0
Agglutinator	± 0,5
Lubricant	Calcium ester / Magnesium	± 0,25
	Others	± 1,0
Smoothener	Talc	± 1,0
	Others	± 0,1
Coating Film	± 1,0

The percentages mentioned in Table I refer to formulations in which the active substance presents 100% strength and the sum of alterations must not exceed 5%. Any alteration must be based on the initial approved formulation.

The required technical documentation is the following:

a) Complete description of the master formulation designating the components as per CBD, INN or a denomination described in the Chemical Abstract Substance (CAS), observing the order of priority;

Table II

Excipient	% Excipient (p/p)
Dilutant	± 10,0
Desintegrator	Starch	± 6,0
	Others	± 2,0
Agglutinator	± 1,0
Lubricant	Calcium ester / Magnesium	± 0,5
	Others	± 2,0
Smoothener	Talc	± 2,0
	Others	± 0,2
Coating Film	± 2,0

The percentages mentioned in Table II refer to the formulations in which the active substance presents 100% strength and the sum of the alterations does not exceed 10%.
Any alteration must be based on the initial approved formulation.
The required technical documentation is the following:

a) Complete description of the master formulation designating the components as per CBD, INN or a denomination described in the Chemical Abstract Substance (CAS), observing the order of priority;

b) Description of the quantity of each substance, expressed in the decimal metric system or standard unit, indicating its function in the formulation and respective reference of quality specification described in the Brazilian Pharmacopoeia or, for lack of it, in other official codes authorized by the legislation in force;

c) Dossier of production and quality control of three batches of each concentration of the product;

d) Reproducibility of the analytical results between one registered batch and three batches with proposed alteration, for each concentration of the product;

e) Technical report containing the results and assessment of the accelerated stability test and the long term stability test presented annually, for each concentration of the product;

f) Proof of pharmaceutical equivalence in relation to the reference drug, using, when appropriate, updated monograph of the Brazilian Pharmacopoeia or, for lack of it, of other authorized codes. The results must be presented in compliance with legislation in force.

g) Technical report and assessment of the results of the dissolution test carried out according to the solubility and permeability of the active substance, as described below:

Active substances with high permeability and high solubility: Case A
Active substances with low permeability and high solubility: Case B
Active substances with high permeability and low solubility: Case C

DEFINITIONS:

SOLUBILITY
Solubility is defined as high or low and is calculated based on the smallest concentration of the active substance in milligrams per milliliter (mg/ml), using the presentation containing the largest dosage, determined by physiological pH (1 to 8) and at the temperature of 37 ± 0,5°C.
Active substances are considered highly soluble when the result, in volume, of the ratio dose/solubility is less than or equal to 250 ml.
Ex: Active substance whose solubility is equal to 1.0 mg/ml (37 ± 0,5°C) and is available in pharmaceutical forms with dosages of 100, 200, 400 mg:
400 mg ¸ 1.0 mg/ml = 400 ml (active substance classified as of low solubility).

PERMEABILITY
Permeability is defined as the effective permeability of the active substance in the human at the wall of the human jejunum and includes apparent resistance to the transport of mass at the intestinal membrane. Active substances of high permeability are, generally, those that remain stable in the gastrointestinal tract and that present absolute bioavailability greater than 90%, or those for which this parameter has been experimentally determined.

Case A: high solubility (HS) and high permeability (HP)
The required documentation must include the undertaking of the technical report and assessment of the results of the dissolution test, carried out as described in the Brazilian Pharmacopoeia and, in its absence, other codes authorized by the legislation in force. There must be a dissolution of at least 85% of the active substance in up to 15 minutes, using 900ml of HCl 0,1 M. In case this criteria is not complied with, the tests described for Cases B or C must be carried out.

Case B: high solubility (HS) and low permeability (LP)
The required documentation must include the undertaking of the technical report and assessment of the results of the dissolution profile employing Pharmacopeial conditions and removing samples from the medium at appropriate time points until the plateau is reached. The dissolution profile obtained must be similar to the profile of the unaltered formulation (the similarity must be assessed according to the description in the Guide for dissolution of solid oral immediate release pharmaceutical forms).

Case C: low solubility (LS) and high permeability (HP)
The required documentation must include the undertaking of the technical report and assessment of the results of the dissolution profile in five different conditions: distilled water, HCl 0,1M and phosphate buffer pH 4,5, 6,5 and 7,5 for the proposed formulation and the previous formulation, without change. Samples of the dissolution medium must be removed at appropriate time points until 90% of the active substance is dissolved or the plateau is reached. A tensoactive may be used only when appropriately justified. The profile obtained must be similar to the profile of the unaltered formulation (the similarity must be assessed according to the description in the Guide for dissolution of solid oral immediate release pharmaceutical forms).

In the absence of Pharmacopeial methodology, other analytical methods may be used, provided they are properly validated, in compliance with legislation in force.
a) When the proposed alterations match one of the situations described in cases A, B, C, a new bioequivalence study will not be required. If not, the recommendations for level 3 must be followed.

4.4.2.3.2.1.3. Level 3 Alterations
These are alterations that generally cause significant impact on the quality and performance of the drug.
The required documentation varies according to three factors: therapeutic band, solubility and permeability of the active substance.
Level 3 alterations are:

a) The qualitative and quantitative alterations related to the excipients of a formulation containing an active substance with a low therapeutic index that exceed the percentages described for Level 1;

b) All the active substances that do not comply with the criteria described for Level 2;

c) Alterations of the excipients of a formulation containing an active substance of low solubility and low permeability, which exceed the percentages described for Level 1;
Alterations of excipients of a formulation that contains any type of active substance, which exceed the percentages described for Level 2.

a) Complete description of the master formulation designating the components as per CBD, INN or a denomination described in the Chemical Abstract Substance (CAS), observing the order of priority;

Case B
The required documentation must include the undertaking of the technical report and assessment of the results of the dissolution profile employing Pharmacopeial conditions and removing samples from the medium at appropriate time points until the plateau is reached. The profile obtained must be similar to the profile of the unaltered formulation, as described in the Guide for dissolution of solid oral immediate release pharmaceutical forms.

h) Technical report containing the results and assessment of a new bioequivalence and/or bioavailability study in compliance with legislation in force, unless an in vitro/in vivo correlation has been properly established.

4.5. ALTERATION OF THE DRUG MANUFACTURING PROCESS
Alterations of the drug manufacturing process must be accompanied by the following documentation:

4.5.1 Legal Aspects

a) Original proof of bank deposit and legalized copy;
b) Copy of the Operation License of the company and/or updated Sanitary Permit;
c) Updated Certificate of Technical Responsibility, issued by the Pharmacy Regional Council;
d) Updated Certificate of Good Manufacturing and Control Practices issued by ANVISA for the line of production in which the drug has been manufactured.

4.5.2. Technical Aspects
4.5.2.1. FP1 and FP2 properly filled out;
4.5.2.2.Technical Justification referring to the request;
4.5.2.3.Technical report
4.5.2.3.1. Products exempt from relative bioequivalence and/or bioavailability

a) Description of proposed manufacturing methods for each concentration of the product;

b) Dossier of production and quality control of three batches of each concentration of the product;

c) Reproducibility of the analytical results between one registered batch and three batches with proposed alteration, for each concentration of the product;

d) Proof of pharmaceutical equivalence in relation to the reference drug, using, when appropriate, updated monograph of the Brazilian Pharmacopoeia or, for lack of it, of other authorized codes. The results must be presented in compliance with legislation in force;

e) Technical report containing the results and assessment of the accelerated stability test and the long term stability test presented annually, for each concentration of the product;

f) Validation report of the proposed manufacturing method;

4.5.2.3.2. Products not exempt from relative bioequivalence and/or bioavailability
4.5.2.3.2.1. Solid oral immediate release pharmaceutical forms
4.5.2.3.2.1.1. Level 1 Alterations

Level 1 alterations are:
a) alterations of the mixing time and operation speed within the validated bands.
The required documentation in this case must include:

a) Description of proposed manufacturing methods for each concentration of the product;

b) Dossier of production and quality control of three batches of each concentration of the product;

c) Reproducibility of the analytical results between one registered batch and three batches with proposed alteration, for each concentration of the product;

d) Proof of pharmaceutical equivalence in relation to the reference drug, using, when appropriate, updated monograph of the Brazilian Pharmacopoeia or, for lack of it, of other authorized codes. The results must be presented in compliance with legislation in force;

e) Technical report and assessment of the results of the dissolution test according to Pharmacopeial specifications.

In the absence of Pharmacopeial methodology, other analytical methods may be used, provided they are properly validated, in compliance with legislation in force.

4.5.2.3.2.1.2. Level 2 Alterations

Level 2 alterations are:
a) alterations of processes such as the mixing time and operation speed outside the validated limits.
The required documentation in this case must include:
a) Description of proposed manufacturing methods for each concentration of the product;
b) Dossier of production and quality control of three batches of each concentration of the product;
c) Reproducibility of the analytical results between one registered batch and three batches with proposed alteration, for each concentration of the product;
d) Validation of the manufacturing process of the product, contemplating also the validation of cleanliness of the equipment. As proof, the company must present validation protocol and conclusive report;
e) Technical report containing the results and assessment of the accelerated stability test and the long term stability test presented annually, for each concentration of the product;
f) Proof of pharmaceutical equivalence in relation to the reference drug, using, when appropriate, updated monograph of the Brazilian Pharmacopoeia or, for lack of it, of other authorized codes. The results must be presented in compliance with legislation in force;

g) Technical report and evaluation of the results of the dissolution test, as described in Case B, below:

Case B:
The required documentation must include the undertaking of the technical report and assessment of the results of the dissolution profile employing Pharmacopeial conditions and removing samples from the medium at appropriate time points until the plateau is reached. The dissolution profile obtained must be similar to the profile of the unaltered formulation, as described in the Guide for dissolution of solid oral immediate release pharmaceutical forms.
In the absence of Pharmacopeial methodology, other analytical methods may be used, provided they are properly validated, in compliance with legislation in force.

4.5.2.3.2.1.3. Level 3 Alterations

These are alterations of the type of process employed in the manufacturing of the drug, such as the use of direct compression or dry means instead of granulation by wet means.
The required documentation in this case must include:
a) Description of proposed manufacturing methods for each concentration of the product;
b) Dossier of production and quality control of three batches of each concentration of the product;
c) Reproducibility of the analytical results between one registered batch and three batches with proposed alteration, for each concentration of the product;
d) Validation report of the proposed manufacturing method;
e) Technical report containing the results and assessment of the accelerated stability test and the long term stability test presented annually, for each concentration of the product;
f) Proof of pharmaceutical equivalence in relation to the reference drug, using, when appropriate, updated monograph of the Brazilian Pharmacopoeia or, for lack of it, of other authorized codes. The results must be presented in compliance with legislation in force;
g) Technical report and evaluation of the results of the dissolution test, as described in Case B, below:

Case B:
The required documentation must include the undertaking of the technical report and assessment of the results of the dissolution profile employing Pharmacopeial conditions and removing samples from the medium at appropriate times until the plateau is reached. The dissolution profile obtained must be similar to the profile of the unaltered formulation, as described in the Guide for dissolution of solid oral immediate release pharmaceutical forms.

h) Technical report containing the results and assessment of a new bioequivalence and/or bioavailability study in compliance with legislation in force, unless an in vitro/in vivo correlation has been properly established.
In the absence of Pharmacopeial methodology, other analytical methods may be used, as long as properly validated in compliance with legislation in force.

4.5.2.3.2.2 Suspensions

a) Comply with provisions under item 4.5.2.3.1.

4.6. ALTERATION OF THE BATCH SIZE

Refers to the increase of the batch size that has already been registered, contemplating change only of the capacity of the equipment used.
The required legal documentation will be the same for all cases.
4.6.1. Legal Aspects
a) Original proof of bank deposit and legalized copy;
b) Copy of the Operation License of the company and/or updated Sanitary Permit;
c) Updated Certificate of Technical Responsibility, issued by the Pharmacy Regional Council;
d) Updated Certificate of Good Manufacturing and Control Practices issued by ANVISA for the line of production in which the drug has been manufactured.
4.6.2. Technical Aspects
4.6.2.1. Level 1 Alterations
These are alterations in which the batch size is changed up to 10 times in the relation to the batch already registered;
The required documentation in these cases must include:
4.6.2.1.1. FP1 and FP2 properly filled out;
4.6.2.1.2.Technical Justification referring to the request;
4.6.2.1.3.Technical report
4.6.2.1.3.1. Products exempt from relative bioequivalence and/or bioavailability
a) Description of the quantity of each substance, expressed in the decimal metric system or standard unit;
b) Dossier of production and quality control of three batches of each concentration of the product;
c) Reproducibility of the analytical results between one registered batch and three batches with proposed alteration, for each concentration of the product;
d) Technical report containing the results and assessment of the long term stability test presented annually, for each concentration of the product;
e) Proof of pharmaceutical equivalence in relation to the reference drug, using, when appropriate, updated monograph of the Brazilian Pharmacopoeia or, for lack of it, of other authorized codes. The results must be presented in compliance with legislation in force.

4.6.2.1.3.2. Products not exempt from relative bioequivalence and/or bioavailability

4.6.2.1.3.2.1. Solid Oral Immediate Release Pharmaceutical Forms

a) Description of the quantity of each substance, expressed in the decimal metric system or standard unit;
b) Dossier of production and quality control of three batches of each concentration of the product;
c) Reproducibility of the analytical results between one registered batch and three batches with proposed alteration, for each concentration of the product;
d) Technical report containing the results and assessment of the long term stability test presented annually, for each concentration of the product;
e) Proof of pharmaceutical equivalence in relation to the reference drug, using, when appropriate, updated monograph of the Brazilian Pharmacopoeia or, for lack of it, of other authorized codes. The results must be presented in compliance with legislation in force.
f) Technical report and assessment of the results of the dissolution test according to Pharmacopeial specifications.
In the absence of Pharmacopeial methodology, other analytical methods may be used, as long as properly validated in compliance with legislation in force.

4.6.2.1.3.2.2. Suspensions

a) Comply with provisions described in item 4.6.2.1.3.1.

4.6.2.2. Level 2 Alterations

These are alterations in which the batch size is changed more than 10 times in the relation to the batch already registered;
The required documentation in these cases must include:

4.6.2.2.1. FP1 and FP2 properly filled out;

4.6.2.2.2.Technical Justification referring to the request;

4.6.2.2.3.Technical report

4.6.2.2.3.1. Products exempt from relative bioequivalence and/or bioavailability

a) Description of the quantity of each substance, expressed in the decimal metric system or standard unit;
b) Dossier of production and quality control of three batches of each concentration of the product;
c) Reproducibility of the analytical results between one registered batch and three batches with proposed alteration, for each concentration of the product;
d) Technical report containing the results and assessment of the accelerated stability test and long term stability test presented annually, for each concentration of the product;
e) Proof of pharmaceutical equivalence in relation to the reference drug, using, when appropriate, updated monograph of the Brazilian Pharmacopoeia or, for lack of it, of other authorized codes. The results must be presented in compliance with legislation in force.

4.6.2.1.3.2. Products not exempt from relative bioequivalence and/or bioavailability

4.6.2.2.3.2.1. Solid Oral Immediate Release Pharmaceutical Forms

a) Comply with provisions described in item 4.6.2.2.3.1;
b) Technical report and assessment of results of the dissolution test, as described in Case B, below:

Case B:
The required documentation must include the undertaking of the technical report and assessment of the results of the dissolution profile employing Pharmacopeial conditions and removing samples from the medium at appropriate time points until the plateau is reached. The profile obtained must be similar to the profile of the unaltered formulation, as described in the Guide for dissolution of solid oral immediate release pharmaceutical forms. In the absence of Pharmacopeial methodology, other analytical methods may be used, provided they are properly validated, in compliance with legislation in force;

4.6.2.2.3.2.2. Suspensions

a) Comply with provisions described in item 4.6.2.2.3.1;

4.7. CHANGE OF EQUIPMENT USED

Refers to changes of equipment employed in manufacturing the product.
The required legal documentation will be the same for all cases.

4.7.1. Legal Aspects
a) Original proof of bank deposit and legalized copy;
b) Copy of the Operation License of the company and/or updated Sanitary Permit;
c) Updated Certificate of Technical Responsibility, issued by the Pharmacy Regional Council;
d) Updated Certificate of Good Manufacturing and Control Practices issued by ANVISA for the line of production in which the drug has been manufactured.

4.7.2. Technical Aspects

4.7.2.1. Level 1 Alterations

Level 1 alterations are:
a) Substitution of non-automated or non-mechanical equipment for automated or mechanical equipment;

b) Substitution for alternative equipment that presents the same characteristics and operational principles, but not necessarily the same capacity.

The required documentation in this case must include:

4.7.2.1.1. FP1 and FP2 properly filled out;

4.7.2.1.2.Technical Justification referring to the request;

4.7.2.1.3.Technical report

4.7.2.1.3.1. Products exempt from relative bioequivalence and/or bioavailability

a) Description of the manufacturing methods of each concentration of the product, with the requested change of equipment;
b) Dossier of production and quality control of three batches of each concentration of the product;
c) Reproducibility of the analytical results between one registered batch and three batches with proposed alteration, for each concentration of the product;
d) Validation of the manufacturing process with the requested change of equipment, contemplating also the validation of cleanliness of the equipment. As proof, the company must present validation protocol and conclusive report;
e) Proof of pharmaceutical equivalence in relation to the reference drug, using, when appropriate, updated monograph of the Brazilian Pharmacopoeia or, for lack of it, of other authorized codes. The results must be presented in compliance with legislation in force.

4.7.2.1.3.2. Products not exempt from relative bioequivalence and/or bioavailability

4.7.2.1.3.2.1. Solid Oral Immediate Release Pharmaceutical Forms

a) Comply with provisions described in item 4.7.2.1.3.1;
b) Technical report and assessment of the results of the dissolution test according to Pharmacopeial specifications.
In the absence of Pharmacopeial methodology, other analytical methods may be used, as long as properly validated in compliance with legislation in force.

4.7.2.1.3.2.2. Suspensions
a) Comply with provisions described in item 4.7.2.1.3.1;

4.7.2.2. Level 2 Alterations
Level 2 alterations are those related to different characteristics and operational principles of the equipment.

The required documentation in this case is the following:

4.7.2.2.1. FP1 and FP2 properly filled out;

4.7.2.2.2.Technical Justification referring to the request;

4.7.2.2.3.Technical report

4.7.2.2.3.1. Products exempt from relative bioequivalence and/or bioavailability

a) Description of the manufacturing methods of each concentration of the product, with the requested change of equipment;
b) Dossier of production and quality control of three batches of each concentration of the product;
c) Validation of the manufacturing process with the requested change of equipment, contemplating also the validation of cleanliness of the equipment. As proof, the company must present validation protocol and conclusive report;
d) Reproducibility of the analytical results between one registered batch and three batches with proposed alteration, for each concentration of the product;
e) Proof of pharmaceutical equivalence in relation to the reference drug, using, when appropriate, updated monograph of the Brazilian Pharmacopoeia or, for lack of it, of other authorized codes. The results must be presented in compliance with legislation in force.
f) Technical report containing the results and assessment of the long term stability test presented annually;

4.7.2.2.3.2. Products not exempt from relative bioequivalence and/or bioavailability

4.7.2.2.3.2.1. Solid Oral Immediate Release Pharmaceutical Forms

a) Comply with provisions described in item 4.7.2.2.3.1;
b) Technical report and assessment of the results of the dissolution test, as described in Case C, below:

Case C:
The required documentation must include the undertaking of the technical report and assessment of the results of the dissolution profile in five different conditions: distilled water, HCl 0,1M and phosphate buffers H 4,5, 6,5 and 7,5 for the proposed formulation and the previous formulation, without change. Samples of the dissolution medium must be removed at appropriate time points until 90% of the active substance is dissolved or the plateau is reached. A tensoactive may be used only when appropriately justified. The profile obtained must be similar to the profile of the unaltered formulation, as described in the Guide for dissolution of solid oral immediate release pharmaceutical forms.

4.7.2.2.3.2.2. Suspensions
a) Comply with provisions described in item 4.7.2.2.3.1.;

5. POST-REGISTRATION INCLUSIONS
5.1. REGISTRATION OF NEW COMMERCIAL PRESENTATION

Refers to the registration of a new presentation of an already registered product, in which:
- There is only alteration in quantity or volume;

- Concentration, pharmaceutical form, packing, quantity and volume remain unaltered;
- The same equipment is used;
- The same Standard Operational Procedures and Controls are employed, and the same formulation and manufacturing process are maintained.

Obs:
a)The new registration does not cancel the registration of the previous presentation. In case the company is not interested in the old presentation, it should request cancellation of the registration;
b) The justification for registration of the new presentation must correspond to the recommended dose of the product.
The required documentation in this case must include:

5.1.1. Legal Aspects
a) Original proof of bank deposit and legalized copy;
b) Copy of the Operation License of the company and/or updated Sanitary Permit;
c) Updated Certificate of Technical Responsibility, issued by the Pharmacy Regional Council;
d) Updated Certificate of Good Manufacturing and Control Practices issued by ANVISA for the line of production in which the drug undergoing registration will be manufactured.

5.1.2. Technical Aspects
a) FP1 and FP2 properly filled out;
b) Technical Justification referring to the request;
c) Models of secondary and primary package and directions for use referring to the new presentation. The text must be equivalent to that of the reference drug and comply with legislation in force.

5.2. REGISTRATION OF NEW PACKING
Refers to the registration of a new packing of an already registered product, in which:
- Concentration, pharmaceutical form, labbeling, quantity and volume remain unaltered;
- The same equipment is used;
- The same Standard Operational Procedures and Controls are employed, and the same formulation and manufacturing process are maintained.

Obs:
a)The new registration does not cancel the registration of the previous presentation. In case the company is not interested in the old presentation, it should request cancellation of the registration.
The required documentation in this case must include:

5.2.1. Legal Aspects
a) Original proof of bank deposit and legalized copy;
b) Copy of the Operation License of the company and/or updated Sanitary Permit;
c) Updated Certificate of Technical Responsibility, issued by the Pharmacy Regional Council;
d) Updated Certificate of Good Manufacturing and Control Practices issued by ANVISA for the line of production in which the drug undergoing registration will be manufactured.

5.2.2. Technical Aspects
a) FP1 and FP2 properly filled out;
b) Technical Justification referring to the request;
c) Results and assessment of the study of accelerated stability of three batches produced, contemplating the established date of expiry;
d) Technical report containing the results and assessment of the long term stability test of the three batches produced, at the end of the established date of expiry;
e) Describe the specifications and analytical methods used in the analysis of the packing and packaging material;
f) Models of secondary and primary package and directions for use referring to the new presentation. The text must be equivalent to that of the reference drug and comply with legislation in force. Send copy on diskette in MS-Word and two printed copies.

5.3. REGISTRATION OF NEW CONCENTRATION
Refers to the registration of a new concentration for an already registered product.
The required documentation in this case must include:

5.3.1. Legal Aspects
a) Original proof of bank deposit and legalized copy;
b) Copy of the Operation License of the company and/or updated Sanitary Permit;
c) Updated Certificate of Technical Responsibility, issued by the Pharmacy Regional Council;
d) Updated Certificate of Good Manufacturing and Control Practices issued by ANVISA for the line of production in which the drug undergoing registration will be manufactured.
Obs.: for imported drugs, it is necessary to present a registration certificate from the country of origin, stating the manufacturing place, which must necessarily be the same as that of the drug undergoing registration in Brazil.
5.3.2. Technical Aspects
5.3.2.1. FP1 and FP2 properly filled out.
5.3.2.2. Technical Report:
5.3.2.2.1. Production and quality control report
5.3.2.2.1.1. Production report
Present technical report containing:

a) Complete description of the master formulation designating the components as per CBD, INN or a denomination described in the Chemical Abstract Substance (CAS), observing the order of priority;