RESOLUTION OF THE BOARD OF DIRECTORS - RDC nº 359/2020

TITLE I

PRELIMINARY PROVISIONS

Art. 1º This Resolution institutes the Active Pharmaceutial Ingredient Dossier (DIFA) and the Letter of Suitability of the Active Pharmaceutical Ingredient (CADIFA).

CHAPTER I

SCOPE

Art. 2º This Resolution applies to active pharmaceutical ingredients (API) used in the manufacture of new, innovator, generic and similar drug products.

§ 1º This Resolution does not apply to APIs used in the formulation of notified pharmaceutical products, biological products, herbal drug preparations and drug products classified as specific, homeopathic, antihomotoxic and anthroposophic.

§ 2º This Resolution does not apply, in addition, to APIs listed in § 1º used in fixed dose combination with synthetic or semisynthetic APIs in drug products classified as new, innovator, generic or similar.

CHAPTER II

DEFINITIONS

Art. 3º In the context of this Resolution, the following definitions are adopted:

I - Letter of Suitability of the Active Pharmaceutical Ingredient (CADIFA): administrative instrument that attests the compliance of the API with the requirements of this Resolution.;

II - CADIFA holder: DIFA holder, after the granting of the CADIFA;

III - DIFA holder: company that possesses the knowledge about the entire manufacturing process of the API and under whose oversight the manufacture of the API is conducted, from the introduction of the starting material;

IV - Active Pharmaceutical Ingredient Dossier (DIFA): collection of administrative and technical documents of an active pharmaceutical ingredient;

V - active pharmaceutical ingredient (API): any substance used in the formulation of a dosage form that, when administered to a patient, acts as an active ingredient. Such substances are intended to exert pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure and function of the body.

VI - expression of interest: procedure through which the DIFA holder states its interest in applying for a CADIFA through a standalone CADIFA application (i.e., not associated with a drug product marketing authorization or variation);

VII - new chemical entity: API used in the formulation of a new drug product.

Single clause. In addition, the definitions of ICH guidelines referenced in this Resolution as well as those from other ANVISA Resolutions are adopted.

TITLE II

ACTIVE PHARMACEUTICAL INGREDIENT DOSSIER (DIFA) AND LETTER OF SUITABILITY OF THE ACTIVE PHARMACEUTICAL INGREDIENT (CADIFA)

CHAPTER I

SUBMISSION OF THE ACTIVE PHARMACEUTICAL INGREDIENT DOSSIER (DIFA)

Art. 4º The Active Pharmaceutical Ingredient Dossier (DIFA) as well as changes to the DIFA should be submitted to ANVISA by its holder.

Single clause. ANVISA may, at its discretion, request the submission of the DIFA in the following circumstances:

I - after an expression of interest submitted by the DIFA holder; or

II - after an invitation by the Board of Directors.

Art. 5º After the submission of the DIFA according to art. 4º, a reference number will be generated.

CHAPTER II

ACTIVE PHARMACEUTICAL INGREDIENT DOSSIER (DIFA)

Art. 6º The DIFA should contain a version number and table of contents. Its documents should be organized in the order described in Chapter III (Administrative Documents of the Active Pharmaceutical Ingredient Dossier) and Chapter IV (Quality Documents of the Active Pharmaceutical Ingredient Dossier) of this Resolution.

Art. 7º The assessment of the Active Pharmaceutical Ingredient Dossier (DIFA) and its changes is comprised of the evaluation of administrative and quality documents.

Art. 8º Deficiency letters and communications of approval or rejection will be sent directly to the DIFA holder.

Single clause. If the DIFA or its changes are rejected, a reconsideration request may be submitted, according to RDC 266/2019.

CHAPTER III

ADMINISTRATIVE DOCUMENTS OF THE ACTIVE PHARMACEUTICAL INGREDIENT DOSSIER (DIFA)

Art. 9º. The Active Pharmaceutical Ingredient Dossier (DIFA) should contain the following administrative documents:

I - filled in application form and declarations stating the responsibilities of the DIFA holder with ANVISA and with the marketing authorization applicant/holder; and

II - evaluation of the DIFA holder regarding the risk of transmission of spongiform encephalopathy or, when applicable, declaration that raw materials from human or animal origin are not used.

CHAPTER IV

QUALITY DOCUMENTS OF THE ACTIVE PHARMACEUTICAL INGREDIENT DOSSIER (DIFA)

Art. 10. The quality sections of the DIFA should be organized according to the quality module of the active pharmaceutical ingredient (3.2.S) of Guia 24/2019, Annex 2 (or ICH M4Q).

§ 1º When there are confidentiality restrictions between the DIFA holder and the marketing authorization applicant/holder, the quality documents should be divided into applicant's and restricted parts, according to Annex III of this Resolution.

§ 2º The applicant's part should contain sufficient information to allow the marketing authorization applicant/holder to evaluate the quality of the API and its suitability for the manufacture of the drug product.

Art. 11. The Active Pharmaceutical Ingredient Dossier (DIFA) should comply with the requirements for APIs of the following ICH guidelines and supplementary documents:

I - ICH Q1A - Stability Testing of New Drug Substances and Products;

II - ICH Q1B - Stability Testing: Photostability Testing of New Drug Substances and Products;

III - ICH Q1D - Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products;

IV - ICH Q1E - Evaluation for Stability Data;

V - ICH Q2(R1) - Validation of Analytical Procedures: Text and Methodology;

VI - ICH Q3A(R2) - Impurities in New Drug Substances;

VII - ICH Q3C(R6) - Impurities: Guideline for Residual Solvents;

VIII - ICH Q3D(R1) - Guideline for Elemental Impurities, according to ANNEX I of this Resolution;

IX - ICH Q6A - Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances;

X - ICH Q11 - Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities); and

XI - ICH M7(R1) - Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk;.

Art. 12. ANVISA may request studies and documents not listed in this Resolution, provided that the request is justified by issues related to the safety and quality of the API and in accordance with international guidelines.

Art. 13. Alternative approaches to this Resolution should be justified and supported by a technical/scientific rationale .

Section I

General Information (3.2.S.1)

Subsection I

Nomenclature (3.2.S.1.1)

Art. 14. The Brazilian Nonproprietary Name (DCB) or International Nonproprietary Name (INN), chemical name, CAS registry number, compendial name and, if relevant, other names should be provided.

Subsection II

Structure (3.2.S.1.2)

Art. 15. The structural formula, including stereochemical configuration, molecular formula and relative molecular mass should be provided.

Subsection III

General Properties (3.2.S.1.3)

Art. 16. A list of physicochemical properties and other relevant properties should be provided, in particular those that affect the efficacy and safety of the drug product, such as solubility, pKa, polymorphism, isomerism, partition coefficient (logP), permeability and hygroscopicity.

Section II

Manufacture (3.2.S.2)

Subsection I

Manufacturer(s) (3.2.S.2.1)

Art. 17. The name, address and responsibility of the units that perform manufacturing steps of intermediates and API and quality control of the API, from the introduction of the starting material(s), should be provided.

Single clause. When physical steps (e.g., milling, micronization, lyophilization) or sterilization are performed by the DIFA holder of under its oversight, the unit(s) should be included, as well as contractors.

Subsection II

Description of Manufacturing Process and Process Controls (3.2.S.2.2)

Art. 18. The synthetic scheme, from the introduction of the starting material(s), should be provided.

§ 1º The molecular formula, relative molecular mass and structural formula, including stereochemical configuration, of starting materials, intermediates and the API should be indicated .

§ 2º Non-isolated intermediates should be depicted between brackets.

§ 3º Solvents, reagents, catalysts and other raw materials used in the manufacturing process should be described and the steps at which they are used should be indicated.

Art. 19. A sequential procedural narrative should be provided, including:

I - Process parameters, including quantities or ranges of raw materials, starting materials, intermediates, solvents, catalysts and reagents used in the manufacture of industrial-scale batches, as well as operating conditions (e.g., temperature, pressure, pH, time, flux, etc.), should be provided;

II - identification of critical steps and process controls; and

III - scale of manufacture and yield ranges for each manufacturing step.

Art. 20. A flow chart of the manufacturing process, containing the sequence of unit operations and indication of input and output of materials and process controls, should be provided.

Art. 21. If routine reprocessing is performed, the procedure and circumstances in which it is employed should be described.

Art. 22. If solvents or other recovered materials are used, the maximum ratio and steps from which the solvent/material is recovered and reintroduced should be informed.

Art. 23. Alternative processes with substantially differente synthetic routes should constitute separate DIFAs, even if the specifications and impurity profile of downstream intermediates and the API are the same.

Art. 24. If recycled mother liquors are employed, the information should be described in the sequential procedural narrative.

Art. 25. Reworking procedures shoud not be included in the DIFA.

Art. 26. For sterile APIs, the description of the sterilization process should be provided.

Art. 27. For APIs obtained through fermentation or in which the substance isolated from the fermentation process or a downstream intermediate does not meet the criteria for selection of starting materials for synthetic APIs, the following additional information should be provided:

I - description of the manufacturing process;

II - source and type of microorganism;

III - procedures and controls for preparation of master and working cell banks;

IV - composition of media;

V - control of microbial bioburden in the fermentation process;

VI - precursors or metabolic substrates if applicable;

VII - process parameters (time, temperature, rate of aeration, etc.);

VIII - name and composition of preservatives;

IX - potential presence of adventitious agents based on the type of microorganism used (e.g. mycotoxins, enzymes).

Art. 28. For APIs derived from botanical materials in which the substance isolated from the botanical material or a subsequent intermediate does not meet the criteria for selection of starting materials for synthetic APIs, the following additional information should be provided:

I - description of the botanical species and the part of plant used for extraction;

II - geographical origin;;

III - time of harvest, if relevant;

IV - information on the use of chemical fertilizers, pestices, fungicides, etc.;

V - potential sources of contamination; and

VI - process controls and operating conditions.

Subsection III

Control of Materials (3.2.S.2.3)

Art. 29. A list of raw materials used in the manufacturing process should be provided.

Single clause. All materials used in the manufacturing process are classified as raw materials, including starting materials, reagents, solvents, catalysts, substrates, auxiliary materials and recovered materials.

Art. 30. The specification and analytical methods for all raw materials should be provided, as well as batch analysis, when relevant.

§ 1º The quality of raw materials should be appropriate for their intended use.

§ 2º The specification of recovered solvents and recovered materials should be justified.

§ 3º If the specification of a recovered material contains wider acceptance criteria than those of the fresh grade, the DIFA holder should demonstrate that the quality of the API manufactured with the recovered material is equivalent to that of the API manufactured with the fresh grade.

Art. 31. For starting materials, the following information should be provided:

I - name and chemical structure;

II - specification;

III - analytical methods;

IV - name and address of manufacturers;

V - synthetic route for each manufacturer, including reagents, solvents and catalysts;

VI - batch analysis; and

VII - justification for selection of the starting material.

§ 1º The specification of the starting materials should be justified and should include, as applicable, tests for specified and unspecified impurities, total impurities, solvents, catalysts, elemental impurities and mutagenic impurities.

§ 2º For semisynthetic APIs whose starting material is obtained by fermentation or derived from a substance obtained by fermentation, the justification for selection of the starting material should include a discussion on the carry-over of impurities arising from the fermentation process (ex. DNA, proteins) into the API.

§ 3º For semi-synthetic APIs whose starting material is isolated from a botanical material or derived from a substance isolated from a botanical material, the justification for selection of the starting material should include a discussion on the carry-over of impurities arising from cultivation (ex. pesticides, heavy metals, aflatoxins) and the extraction process into the API.

§ 4° When there is more than one manufacturer of a starting material, a discussion regarding the specification of the starting material with respect to the differences in the manufacturing processs of different sources should be provided.

§ 5º A technically inadequate justification of the starting material will lead to a redefinition request.

Subsection IV

Controls of Critical Steps and Intermediates (3.2.S.2.4)

Art. 32. Tests and acceptance criteria, with justification including experimental data, performed at critical steps identified in the sequential procedural narrative should be provided.

Art. 33. The specification and analytical methods of isolated intermediates should be provided.

Single clause. The specification of intermediates should be justified and should include, as applicable, tests for specified and unspecified impurities, total impurities, solvents, catalysts, elemental impurities and mutagenic impurities.

Art. 34. For non-isolated intermediates, tests and parameters used to determine reaction end-points should be provided or their absence justified.

Subsection V

Process Validation (3.2.S.2.5)

Art. 35. The manufacturing process of the API, from the starting material, should be validated prior to marketing.

Art. 36. For sterile APIs, the following information should be provided:

I - justification for the sterilization method; and

II - validation studies, protocols and reports for sterilization and aseptic processing steps.

Subsection VI

Manufacturing Process Development (3.2.S.2.6)

Art. 37. For new chemical entities, a description and discussion regarding significant changes made to the manufacturing process or manufacturing site of the API should be provided, including:

I - non-clinical batches;;

II - clinical batches;

III - scale-up batches;

IV - pilot batches; and

V - commercial scale batches, if available.

Single clause. For APIs not classified as new chemical entities, the DIFA holder may include data from the manufacturing process development to support the control strategy.

Art. 38. For APIs developed by quality by design, the studies that support the design space should be provided.

Single clause. For APIs developed by quality by design, the DIFA holder should comply with ICH Q8(R2) (Pharmaceutical Development), Q9 (Quality Risk Management) e Q10 (Pharmaceutical Quality System).

Section III

Characterization (3.2.S.3)

Subsection I

Elucidation of Structure and Other Characteristics (3.2.S.3.1)

Art. 39. Elucidation of the chemical structure should be provided, based on the synthetic route and appropriate instrumental methods.

Single clause. For APIs for which a pharmacopoeial reference standard is available, comparative identification tests may be provided.

Art. 40. A discussion and characterization of solid phase properties of the API should be provided, as applicable.

Subsection II

Impurities (3.2.S.3.2)

Art. 41. A detailed discussion regarding all potential impurities should be provided, incluing reagents, catalysts, by-products, solvents and degradation products. The discussion should comprise:

I - formation, fate and purge; and

II - control strategy and proposed acceptance criteria.

§ 1º The discussion should comprise specified and unspecified impurities, total impurities, elemental impurities, mutagenic impurities and justification for the absence of tests for potential impurities that are not controlled.

§ 2º Based on risk assessment, the validation of critical parameters of analytical procedures used in carry-over studies should be provided.

Section IV

Control of the API (3.2.S.4)

Subsection I

Specification (3.2.S.4.1)

Art. 42. The specification of the API should be provided, including tests, references to analytical procedures and acceptance criteria to which the API should comply to be considered acceptable for its intended use.

Subsection II

Analytical Procedures (3.2.S.4.2)

Art. 43. Analytical procedures used for release and stability studies should be provided.

Subsection III

Validation of Analytical Procedures (3.2.S.4.3)

Art. 44. Validation of analytical procedures used for release and stability studies should be provided, according to RDC 166/2017 or ICH Q2 (Validation of Analytical Procedures).

Subsection IV

Batch Analyses (3.2.S.4.4)

Art. 45. Batch results for at least three batches manufactured according to the proposed manufacturing process and specification should be provided.

Single clause. Batch analysis to support significant variables of the manufacturing process should be provided, according to Annex II of this Resolution.

Art. 46. For new chemical entities, batch analysis of batches referenced in art. 37 should be provided.

Art. 47. Batch analysis should contain, at least, the following information:

I - date of manufacture;

II - size and batch number;

III - site of manufacture; and

IV - results for all tests listed in the specification.

Single clause. The absence of tests that are listed in the specification or unexpected results should be justified.

Subsection V

Justification of Specification (3.2.S.4.5)

Art. 48. A justification for the API specification should be provided.

Art. 49. The justification of the API specification should be based, as applicable, on:

I - non-clinical and clinical studies;

II - impurity qualification studies;

III - batch results;

IV - monographs of officially recognized compendia by ANVISA, according to RDC 37/2009;

V - in-process controls, control of intermediates and critical steps;

VI - carry-over studies for impurities; and

VII - ICH guidelines listed on art. 11 of this Resolution.

Section V

Reference Standards or Materials (3.2.S.5)

Art. 50. Information on reference and working standards should be provided.

Section VI

Container Closure System (3.2.S.6)

Art. 51. The description and specification of packaging materials should be provided.

§ 1º For functional secondary packaging materials, information relevant to the function should be provided.

§ 2º For non-functional secondary packaging materials, a brief description should be provided.

§ 3º The specification of primary packaging materials should contain identification and description tests.

Art. 52. A discussion regarding the following attributes should be provided, as applicable:

I - protection from light;

II - protection from moisture;

III - compatibility between the primary packaging material and the API, including the possibility of sorption to container or leaching of impurities that might compromise the API quality; and

IV - compliance with requirements for food grade materials.

Section VII

Stability (3.2.S.7)

Subsection I

Stability Summary (3.2.S.7.1)

Art. 53. A summary of the stability protocol, stability studies and results should be provided, according to RDC 318/2019.

Single clause. The proposed storage conditions and retest period or shelf life should be stated.

Subsection II

Post-approval Stability Protocol and Stability Commitment (3.2.S.7.2)

Art. 54. A post-approval stability protocol and stability commitment should be provided, according to RDC 318/2019.

Art. 55. If the proposed retest period or shelf life is based on extrapolation, a commitment to continue the stability studies until the appropriate time-point should be provided.

Subsection III

Stability Data and Reports (3.2.S.7.3)

Art. 56. The stability results should be provided, according to RDC 318/2019.

CHAPTER V

LIFE CYCLE OF THE API

Art. 57. The DIFA holder should submit the changes to the DIFA to ANVISA, according to the conditions and supporting documentation of ANNEX II of this Resolution.

§ 1º The changes to the DIFA are classified as:

I - annual notification;

II - immediate notification;

III - minor; or

IV - major.

§ 2º Changes not described in ANNEX II should be classified as minor..

§ 3º For changes for which the column “documents” is blank or changes referenced in § 2º, the supporting documentation should be compatible with the nature and complexity of the change, considering:

I - DIFA sections directly affected by the change; and

II - DIFA sections in which additional studies should be included to support the change.

Art. 58. If a change is approved, ANVISA will issue a revised CADIFA in the following cases:

I - Notification or minor change that alter the content of the CADIFA; or

II - Major change, regardless of whether it alters the content of the CADIFA.

Art. 59. The DIFA holder should inform the marketing authorization applicant/holder of changes that are subject or not to regulatory approval, when required by good manufacturing practices or quality agreements.

Section I

Submission of Changes

Art. 60. For each change, the DIFA holder should submit to ANVISA the:

I - application form; and

II - supporting documentation.

Art. 61. Changes that are associated with or arise from other changes should be submitted in a single application and classified according to stricter reporting category among the changes.

Section II

Classification of Changes

Art. 62. Annual and immediate notification changes do not require prior communication to ANVISA for implementation.

Art. 63. Annual notification changes should be submitted within 12 months of implementation.

Art. 64. Immediate notification changes should be submitted immediately after implementation.

Art. 65. Minor and major changes require approval from ANVISA for implementation.

Single clause. If ANVISA does not issue a communication within 60 (sixty) days of receipt of the documentation, for minor changes, or 180 (one hundred and eighty) days, for major changes, the change can be implemented.

Art. 66. The implementation of the change does prevent its assessment, at any time, at which point ANVISA can request additional information, approve or reject the change.

Single clause. If a change is rejected, the approved condition prior to the change should be immediately reestablished after the communication by ANVISA.

CHAPTER VI

LETTER OF SUITABILITY OF THE ACTIVE PHARMACEUTICAL INGREDIENT (CADIFA)

Art. 67. If the DIFA is approved, ANVISA will issue a Letter of Suitability of the Active Pharmaceutical Ingredient (CADIFA) to the DIFA holder.

Single clause. When issued according to single clause of art. 4º, the name and address of the DIFA holder, DIFA version number e CADIFA number will be published on ANVISA's website.

Art. 68. The following information will be included in the CADIFA:

I - number and issue date of the CADIFA;

II - Brazilian nonproprietary name (DCB), DCB number and CAS registry number;

III - name and address of DIFA holder;

IV - name and address of manufacturing sites;

V - API specification and, if applicable, compendial reference;

VI - container closure system;

VII - storage conditions of the API;

VIII - retest period or shelf life; and

IX - field for declaration of access.

§ 1º Additional information considered relevant may be included in the CADIFA.

§ 2º Item IV comprises:

I - manufacturing sites of the API and intermediates; and

II - sterilization sites and sites that perform physical steps (e.g., micronization, milling, sieving, lyophilization), when these steps are conducted under the oversight of the DIFA holder.

Art. 69. Manufacturing sites must comply with good manufacturing practices for APIs.

Single clause. The CADIFA will not be issued if non-compliance with good manufacturing practices is evidenced.

CHAPTER VII

SUSPENSION AND WITHDRAWAL OF THE LETTER OF SUITABILITY OF THE ACTIVE PHARMACEUTICAL INGREDIENT (CADIFA)

Art. 70. The suspension and withdrawal of the CADIFA will be communicated to the DIFA holder and marketing authorizations holders to which the CADIFA is associated.

Single clause. When the CADIFA is issued according to single clause of art. 4º, the suspension and withdrawal of the CADIFA will be published on ANVISA's website.

Section I

Suspension of the CADIFA

Art. 71. The following circumstances may lead to the suspension of the CADIFA:

I - inspection conducted by the National System of Health Surveillance (SNVS) or by organizations with which ANVISA has cooperation agreements that shows critical and/or major deficiencies that lead to the conclusion that the manufacturing process of the API does not comply with GMP, posing a public health risk;

II - evidence that the API is not manufactured according to the DIFA;

III - failure to reestablish the previously approved conditions, in the case of rejection of changes implemented with no prior approval from ANVISA;

IV - failure to conduct technical changes to which the DIFA holder committed prior to the CADIFA issuance or due to mandatory updates; or

V - refusal to be inspected.

§ 1º The CADIFA will be restored if compliance with current regulations, deficiency letters or other requests issued by ANVISA or, when applicable, by organizations with which ANVISA has cooperations agreements is demonstrated.

§ 2º ANVISA may suspend the CADIFA for reasons not mentioned in this Resolution, as an adequately justified preventive measure, with the objective of avoiding exposure of the population to health risks.

Art. 72. The CADIFA holder may request its suspension if unable to comply with regulatory requirements.

§ 1º The suspension is limited to a period of 2 (two) years, except if a justification is provided and accepted by ANVISA.

§ 2º The restoration of a CADIFA must requested by its holder.

Art. 73. The suspension of a CADIFA may lead to suspension of importation for imported APIs or suspension of manufacture or marketing for APIs manufactured in Brazil.

Art. 74. The suspension of a CADIFA may lead to the suspension of importation, manufacture or marketing of drug products whose marketing authorization are associated with the CADIFA.

Section II

Withdrawal of the CADIFA

Art. 75. A CADIFA poderá ser cancelada em decorrência de:

I - inspection conducted by the National System of Health Surveillance (SNVS) or by organizations with which ANVISA has cooperation agreements that shows critical and/or major deficiencies that lead to the conclusion that the manufacturing process of the API does not comply with GMP, posing a severe public health risk.;

II - conclusion that the API is not manufactured according to the DIFA, posing severe public health risks;

III - submission of falsified information in the initial submission of API lifecycle;

IV - recurrence in issues that lead to the suspensaion of a CADIFA;

V - failure to comply with ANVISA’s requests after the suspension of a CADIFA;

VI - cessation of production or closure of the site; or

VII - two-year period elapsed for a suspended CADIFA, except in the case of § 1º of art. 72.

Single clause. ANVISA may withdraw the CADIFA for reasons not mentioned in this Resolution, as an adequately justified preventive measure, with the objective of avoiding exposure of the population to severe public health risks.

Art. 76. The CADIFA holder may request its withdrawal.

Art. 77. The CADIFA withdrawal, when due to public health risks, will lead to the suspension of importation for imported APIs or suspension of manufacture or marketing for APIs manufactured in Brazil.

Art. 78. The CADIFA withdrawal may lead to the suspension of importation, manufacture or marketing of the drug product whose marketing authorization is associated with the CADIFA.

TITLE III

FINAL AND TRANSITORY PROVISIONS

Art. 79. The manufacturers of APIs listed below that have not been regularized according to Resolution RDC nº 57/2009 are excluded from the drug product marketing authorizations in which they are listed as approved.

§ 1° Art. 79 applies to:

I - aciclovir;

II - aciclovir sodium;

III - ampicillin;

IV - ampicillin benzathine;

V - ampicillin potassium;

VI - ampicillin sodium;

VII - ampicillin trihydrate;

VIII - azithromycin;

IX - azithromycin dihydrate

X - azithromycin monohydrate;

XI - benzylpenicillin;

XII - benzylpenicillin benzathine;

XIII - benzylpenicillin potassium;

XIV - benzylpenicillin procaine;

XV - benzylpenicillin sodium;

XVI - cabergoline;

XVII - carbamazepine;

XVIII - lithium carbonate

XIX - carboplatin;

XX - cefalexin

XXI - cefalexin monohydrate;

XXII - cefalexin sodium;

XXIII - cefalotin;

XXIV - cefalotin sodium;

XXV - ceftazidime;

XXVI - ceftazidime pentahydrate;

XXVII - ceftazidime sodium;

XXVIII - ceftriaxone;

XXIX - ceftriaxone disodium hemipentahydrate;

XXX - ceftriaxone sodium;

XXXI - cyclophosphamide;

XXXII - cyclophosphamide monohydrate;

XXXIII - ciclosporin;

XXXIV - ciprofloxacin;

XXXV - cisplatin;

XXXVI - clarithromycin;

XXXVII - clindamycin;

XXXVIII - cephalexin hydrochloride;

XXXIX - ciprofloxacin hydrochloride;

XL - ciprofloxacin hydrochloride monohydrate;

XLI - clindamycin hydrochloride;

XLII - clindamycin hydrochloride monohydrate;

XLIII - penicillamine hydrochloride;

XLIV - tiabendazole hydrochloride;;

XLV - valacyclovir hydrochloride;

XLVI - clindamycin palmitate hydrochloride

XLVII - clozapine;

XLVIII - efavirenz;

XLIX - phenytoin;

L - phenytoin sodium;

LI - clindamycin phosphate;

LII - thiabendazole hypophosphite;

LIII - ciprofloxacin lactate;

LIV - clarithromycin lactobionate;

LV - lamivudine;

LVI - cefalexin lysinate;

LVII - methotrexate;

LVIII - methotrexate sodium;

LIX - nevirapine;

LX - nevirapine hemihydrate;

LXI - penicillamine;

LXII - rifampicin;

LXIII - ritonavir;

LXIV - sultamicillin;

LXV - thiabendazole;

LXVI - sultamicillin tosylate;

LXVII - valaciclovir; and

LXVIII - zidovudine

§ 2º The manufacture of drug products whose marketing authorization does not have any remaining approved API manufacturers is suspended until a new API manufacturer is included.

Art. 80. Non-compliance with the requirements of this Resolution constitutes an infraction under Law nº 6.437/1977, not excluding penal, civil and administrative liability.

Art. 81. On March 1st, 2021, the following normatives are revoked:

I - Resolução de Diretoria Colegiada - RDC nº 57/2009, from November 17, 2009;

II - Instrução Normativa nº 15, from November 17, 2009;

III - Instrução Normativa nº 3, from June 28, 2013;

IV - Nota Técnica Conjunta 01/2016 - COIFA/GGMED - COINS/GIMED, from April 22, 2016; and

V - Nota Técnica nº 06-001/2015- COISC/GGINP/SUINP/ANVISA - COIFA/GGMED/SUMED/ANVISA.

Art. 82 This Resolution will take effect on August 3, 2020.

ANNEX I

IMPLEMENTATION OF ICH Q3D BY DIFA HOLDER

Regardless of this annex, specific tests for elemental impurities that are listed in the monograph should be part of the API specification, except if their absence is adequately justified.

For DIFAs submitted according to single clause of art. 4º, there will not be a final conclusion regarding the acceptability of the proposed acceptance criteria. This assessment will be conducted in the context of the marketing authorization application/variation.

When the risk assessment for elemental impurities of the API is integrated with that of the drug product, the DIFA holder does not have to provide additional information regarding elemental impurities. In the remaining cases, the DIFA holder should follow one of the following strategies (1 or 2):

1 Risk Management Summary provided (RMS):

DIFA holders should state this option in their application.

The RMS report should be preferably included in "Subsection II - Impurities (3.2.S.3.2)"" and it should detail the rationale used to conduct the study, as well as a justification of the control strategy implemented following the risk assessment. When there are confidentility restrictions, the RMS table should be included in the applicant's part.

If insufficient data is provided, the application will be considered as if no RMS is provided.

1.1 Requirements

In addition to ICH Q3D principles, the DIFA holder should consider the following instructions when opting for a RMS strategy:

a) How to conduct the RMS:

The RMS should consider all potential sources of contamination, including elemental impurities intentionally introduced into the process after the introduction of the starting material, contributions from materials (such as contaminants in starting materials, reagents, water), equipment, and packaging..

The intended route of administration/use of the substance should be indicated, which forms the basis of the risk management discussion.

The RMS should consider all 24 elemental impurities mentioned in ICH Q3D Table 5.1, as follows:

- Class 1 and 2A elements, as well as all elements intentionally added in the manufacture whatever their classification should be systematically discussed.

- If relevant, and depending of the use of the substance, Class 3 elements should be discussed.

- Justification as to why specific elemental impurities were included in the scope of the RMS is considered useful information and should be included.

b) How to define the control strategy:

The control strategy should focus on the absence or presence of elemental impurities in the API relying on the process capabilities and on the control of elemental impurities, using preferably option 1, or alternatively, an acceptance criterion derived from the permitted daily exposure and maximum daily dose.

Absence of an elemental impurity can be concluded when it is shown with convincing evidence that it is purged to a level which is consistently below 30% of the acceptable acceptanche criterion, in a minimum of 3 consecutive commercial batches or a minimum of 6 consecutive pilot batches of the API.

When applicable, a justified specification for elemental impurities in the API should be introduced. For any elemental impurity intentionally introduced into the last synthetic step of the process, a specification in the API is expected (as this is associated with an elevated risk for impurities being carried forward), unless it is consistently and convincingly demonstrated that the process is capable to purge the impurity from the API to a level which is below 30% of the acceptable acceptance criterion.

Screening results of several batches for elemental impurities may support but do not replace a RMS. This might be done in a similar manner as is illustrated in appendix 4 of the ICH Q3D guideline.

With respect to analytical procedures:

For screening purposes, the analytical methodology used should be mentioned along with minimum validation information such as indication of the specificity and sensitivity of the method (LOD/LOQ).

For test included in the API specification, a detailed description of the analytical method used should be provided. The analytical method should be validated in accordance with the requirements of “Subsection III - Validation of Analytical Procedures” of this Resolution.

c) RMS Table

The following table, containing the RMS conclusion, should be included in the RMS.

This table is intended to provide necessary information about the level of contamination of the API source, in order to implement the ICH Q3D component approach in the drug product.

It is recommended not to include individual batch results in the table. The DIFA holder should ensure that the substance complies with the maximum level indicated.

2 No Risk Management Summary provided

2.1 Requirements

If no risk assessment has been performed, the following instructions should be followed:

- Any elemental impurities (whatever the Class) intentionally introduced in the manufacture of the API after the introduction of the starting material(s) should be declared and data showing their level in the API should be provided.

- For any elemental impurity intentionally introduced into the last synthetic step of the process, a specification in the API is expected (as this is associated with an elevated risk for impurities being carried forward), unless it is consistently and convincingly demonstrated that the process is capable to purge the impurity from the API to a level which is below 30% of the appropriate acceptance criterion (preferably option 1, or alternatively, an acceptance criterion derived from the permitted daily exposure and maximum daily dose).

- The acceptance criteria applied for the control of elemental impurities in the API should reflect the process capabilities, and the PDE of ICH Q3D may be used as reference.

- The analytical procedure used to control elemental impurities in the API should be described in detail and validation data according to the requirements of “Subsection III - Validation of Analytical Procedures (3.2.S.4.3)” should be provided.

ANNEX II

CHANGES, CONDITIONS AND SUPPORTING DOCUMENTATION OF THE DIFA