RESOLUTION-RDC Nr- 48, OF OCTOBER 6, 2009

Transcription

1 RESOLUTION-RDC Nr- 48, OF OCTOBER 6, 2009 This resolution provides for the alteration, inclusion, suspension, reactivation and cancellation after registration of medications and sets forth other provisions. The Board of Directors of the Agência Nacional de Vigilância Sanitária [National Sanitary Surveillance Agency], under the attribution granted unto it by item IV of art. 11 of the Regulation approved by Decree Nr , of April 16, 1999, and according to the provisions of item II and of paragraphs 1 and 3 of art. 54 of the Internal Regiment approved in accordance with Attachment I of Administrative Ruling Nr- 354 of Anvisa, of August 11, 2006, republished in the DOU [Official Newspaper of the Union] of August 21, 2006, in a meeting held on October 5, 2009, whereas the directives, the priorities and responsibilities set forth in the National Medications Policy, instituted by Administrative Ruling nr /MS/GM, of October 30, 1998, which seeks to guarantee conditions for the safety and quality of medications consumed in the country and to promote the rational use and population access to those considered essential; whereas Anvisa s competence to regulate products and services that involve risk to public health, established by Law Nr , of January 26, 1999, and especially item 1 of paragraph 1 of its art. 8, which includes medications for human use, their active substances and other inputs, processes and technologies among the goods and products submitted to the sanitary control and supervision of the Agency; whereas the registration of products dealt with under Law nr , of September 23, 1976, may be the object of regulation by Anvisa, with the intent of eliminating bureaucracy and to gain speed in such procedures, as set forth in art. 41 of Law nr , of 1999, provided such does not imply in risks to the population s health or to the supervision condition of production and circulation activities; whereas Anvisa s activity shall be legally conditioned by principles of law, swiftness, purpose, reasonability, impersonality, impartiality, publicity, morality and process efficiency, as set forth by art. 29 of the Anvisa Regulation approved by Decree nr , of 1999; whereas the provisions contained in Law nr , of 1976, and in Decree nr , of January 5, 1977, regarding the sanitary surveillance system which medications are subject to; adopts the following Resolution of the Board of Directors and I, President Director, hereby determine its publication: Art. 1 The Technical Regulation that sets forth the minimum requirements for the procedures to alter, include, suspend, reactivate and cancel the post-registration of medications is hereby approved, in accordance with the provisions of this Resolution. Section I - Objective Chapter I

2 Art. 2 The purpose of this Regulation is to classify the post-registration modifications of medications and to establish the documentation and tests required by Anvisa. Section II - Scope Art. 3 This Regulation is applicable to specific, generic, new and similar medications already registered. Section III - Definitions Art. 4 For the purpose of this Technical Regulation, the following definitions shall be adopted: I. Product Change History (HMP): A form in which the post-registration changes/alterations or inclusions of medications shall be registered. Some changes considered as having a smaller impact, as defined in this standard, shall only be registered in this history and shall be exempt from an individual protocol process. II. Stability study protocol: A document by which the stability study plan is defined, including the acceptance criteria and proof, schedule, characteristics of the batch to be submitted to the study, number of samples, study conditions, analytical methods and conditioning material. III. Multiple concomitant changes: These are changes arising from a main request in accordance with the scope of this regulation. Whenever allowed according to this standard, they can be done together with the main change without the need of creating additional protocol processes. IV. Multiple parallel changes: Joint protocol processes of two or more change requests directly related and occurring simultaneously. Chapter II INITIAL PROVISIONS Art. 5 Anvisa grants, for the following topics of this Resolution, prior authorization for the immediate implementation, by means of a petition protocol or registry in the Product Change History, as set forth in the provisions of the specific chapters of this Regulation. I. Change or inclusion of secondary packaging location; II. Change or inclusion of primary packaging location; III. Minor change to the production process; IV. Change or inclusion of primary packaging equipment; V. Change or inclusion of equipment having the same design and operational principle; VI. Inclusion of batches up to ten times in size; VII. Minor change of excipient; VIII. Adjustment of analytical methods and specifications according to official compendium or stricter specification range; IX. Exclusion of drug fabrication location or primary packaging location or secondary packaging location or product manufacturing location; X. Reduction in shelf-life period with maintenance of the conservation precautions. Paragraph 1 The immediate implementation of the adjustments, changes, exclusions, inclusions or reductions listed in this article does not prevent the analysis, at any time, of the required documentation, when the requested changes may be deferred or undeferred.

3 Paragraph 2 The changes not listed in this article can only be implemented after a favorable analysis and conclusion by Anvisa, by observing other specific rules pertinent to each petition. Art. 6 All documentation shall be in agreement with the specific legislation and, in case there is a specific guideline, such shall be fully complied with. Art. 7 All change, inclusion, suspension, reactivation, and post-registration cancellation petitions that require protocol processes shall be accompanied by the following documents: I. Original copy the of fee payment slip of the sanitary surveillance supervision or exemption thereof, as the case may be; II. Petition Forms FP1 and FP2, duly filled out; III. Request justification containing the detailed description and reason for the proposal, in accordance with Attachment I. Art. 8 The Product Change History Attachment III shall be registered at Anvisa, where the presentation of Petition Forms - FP1 and FP2 thereof is waivered and it may be subject to an audit. Art. 9 In case of multiple parallel changes, the company shall register each individual change and present unique documentation that contemplates all the evidence relative to each one of the petitioned subjects, thereby suppressing repeated documentation. Art. 10 For cases in which stability study reports are requested, an accelerated stability study may be presented, necessarily accompanied by a long-term stability study in progress or a concluded long-term stability study. Art. 11 For cases in which a stability study report or protocol is required, the stability study data generated after the petitioning process shall be included in the Product Change History. Art. 12 Results outside the specification of the stability study in progress shall be immediately informed to Anvisa and, after conclusion of the investigation, a corrective action proposal shall be sent. Art. 13 The shelf-life period for the medication shall be defined in accordance with the presented stability results. Sole paragraph. For cases in which the sent study proves a temporary shelf life period less than the one already registered, such shall be reduced and it shall not be necessary to petition for a reduction in the shelf life period. Art. 14 For cases in which a stability study protocol is requested, the registered shelf-life period shall be maintained. Art. 15 Attachments I, II, IV, V and VI mentioned in this standard shall be presented in accordance with the proposed models, and shall be duly signed by the technician responsible from the company holding the registration. Art. 16 For the specific medication category, the submission of the following documents shall not be necessary: I. Technical reports of the relative bioavailability/bioequivalence study; and II. Profile report of the comparative dissolution.

4 Art. 17 It shall not be necessary to attach to the petition the new package insert text models and labeling for the post-registration changes that require updating thereof, except when required by this standard or at Anvisa s criterion. Paragraph 1 The company shall update the information on the package insert only after approval of the adjustments, changes, exclusions, inclusions or postregistration reductions. Paragraph 2 The company shall update the information on the package insert and labeling regarding items I, II, VII, IX and X of art. 5 immediately after the change, always observing other specific rules. Art. 18 For cases in which the post-registration request refers to more than one concentration of a same dosage form, it shall be registered with a stability report, production report and quality control report regarding the higher and lower concentration. Chapter III CHANGES RELATIVE TO MANUFACTURING LOCATION Section I - Change or inclusion of secondary packaging location Art. 19. It refers to the changes relative to the change or inclusion of the secondary packaging line location. Art. 20. The change petition described in this section shall be accompanied by the valid Fabrication Best Practices Certificated. Art. 21. The changes or inclusions to the secondary packaging location can be implemented immediately after the petition registration date. Section II - Change or inclusion of primary packaging location Art. 22. It refers to the changes relative to the change or inclusion of the primary packaging line location. Art. 23. The concomitant inclusion or change of primary packaging line equipment is permitted. Art. 24. The concomitant change or inclusion of secondary packaging location is permitted whenever it is the same location as the primary packaging one. Art. 25. The change petition described in this section shall be accompanied by the following documents: I. valid Fabrication Good Practices Certificated; II. Stability study protocol referring to the 1 st batch or report of the stability study referring to 1 (one) batch. Art. 26. The changes or inclusions to the primary packaging location can be implemented immediately after the petition registration date. Art. 27. The provisions of this section are not applicable to sterile medications. Section III Change or Inclusion of conventional release medication fabrication location

5 Art. 28. It refers to the change or inclusion of a location related to one or more steps or the full fabrication process of conventional release medications. Paragraph 1 For sterile products, a change or inclusion of a medication fabrication location is considered to be the substitution or addition of the fabrication location of the complete production line, where only the secondary packaging phase may be excepted. Paragraph 2 The changes or inclusions of a primary or secondary packaging location, when isolated, shall be done according to the sections specific thereto. Paragraph 2 For the purposes of this regulation, changes or inclusions of the phases involving the acquisition of materials, weighing, labeling, storage and expedition of the medication shall not be petitioned. Art. 29. A minor or moderate change to the production process or equipment change is concomitantly permitted. Art. 30. Petitions for Changing or Including the fabrication location of a conventional release medication shall be accompanied by the following documents: I. valid Good Fabrication Practices Certificate. II. Production report, including the comparative charts a and d of Attachment V; III. Analytical quality control report of the finished product referring to 1 (one) batch; IV. Comparative dissolution profile report between the previously registered condition and the new condition, when applicable; V. Stability study report regarding 1 (one) finished product batch; VI. Long-term stability study report referring to 3 (three) batches, to be included in the Product Change History; Sole paragraph. Whenever the change or inclusion of a fabrication location of conventional release medication does not result in changes to the productive process or to equipment, or results in a minor change to the productive process, or results in a change or inclusion of equipment having the same design and operational principle, item V may be substituted for Stability study protocol referring to the 3 (three) initial batches. Art. 31. For semi-solid and liquid products, except for perfect solutions, the following rules, besides those contained in art. 30, are applicable: I. Present comparative results between particle/droplet size distribution of the previously registered condition and the new one; II. Include a discussion relative to the impact of eventual changes in particle/droplet size distribution; III. Present comparative results between the cutaneous permeation rate of the previously registered condition and the new one. IV. Include a discussion relative to the impact of eventual changes to the cutaneous permeation rate; Art. 32. Changes or inclusions to the fabrication location of conventional release medication can only be implemented after a favorable analysis and conclusion by Anvisa, provided other rules specific to such petition have been observed. Section IV Change or Inclusion of modified release medication fabrication location Art. 33. It refers to the change or inclusion of a location related to one or more steps or the full fabrication process of modified release medications.

6 Paragraph 1 For sterile products, a change or inclusion of a medication fabrication location is considered to be the substitution or addition of the fabrication location of the complete production line, where only the secondary packaging phase may be excepted. Paragraph 2 The changes or inclusions of a primary or secondary packaging location, when isolated, shall be done according to the sections specific thereto. Paragraph 2 For the purposes of this regulation, changes or inclusions of the phases involving the acquisition of materials, weighing, labeling, storage and expedition of the medication shall not be petitioned. Art. 34. A change to the production process or equipment change is concomitantly permitted. Art. 35. Petitions for changing or including the fabrication location of modified release medications shall be accompanied by the following documents: I. valid Good Fabrication Practices Certificate. II. Production report, including the comparative charts a and d of Attachment V; III. Analytical quality control report of the finished product referring to 1 (one) batch; IV. Comparative dissolution profile report between the previously registered condition and the new condition, when applicable; V. Stability study report regarding 1 (one) finished product batch; VI. Long-term stability study report referring to 3 (three) batches, to be included in the Product Change History; VII. Technical report of the relative bioavailability/bioequivalence study; Paragraph 1 Whenever the change or inclusion of a fabrication location of modified release medication does not result in changes to the productive process or to equipment, or results in a minor change to the productive process, or results in a change or inclusion of equipment having the same design and operational principle, item V may be substituted for Stability study protocol referring to the 3 (three) initial batches; Paragraph 2 Whenever the change or inclusion of a fabrication location of modified release medication does not result in changes to the productive process or to equipment, or results in a minor change to the productive process, or results in a change or inclusion of equipment having the same design and operational principle, the presentation of item VII is waived. Art. 36. For semi-solid and liquid products, except for perfect solutions, the following rules, besides those contained in art. 35, are applicable: I. Present comparative results between particle/droplet size distribution of the previously registered condition and the new one; II. Include a discussion relative to the impact of eventual changes in particle/droplet size distribution; III. Present comparative results between the cutaneous permeation rate of the previously registered condition and the new one. IV. Include a discussion relative to the impact of eventual changes to the cutaneous permeation rate; Art. 37. Changes or inclusions to the fabrication location of modified release medication can only be implemented after a favorable analysis and conclusion by Anvisa, provided other rules specific to such petition have been observed. Chapter IV

7 CHANGES RELATIVE TO THE PRODUCTION PROCESS Art. 38. It refers to adjustments or changes to the finished product production process. Section I Minor change or inclusion to the production process Art. 39. A minor change or inclusion to the production process is considered as being an adjustment having a minor impact to the production process relative to the change of parameters of process phases, such as: speed, temperature, time and order of addition of formula components. Sole paragraph. The provision of this article is not applicable to changes to the sterilization process. Art. 40. Minor changes or inclusions to the production process shall be accompanied by the following documents: Anvisa may consult its database with the intent of proving the Technical II. Production report, including the comparative charts a and d of Attachment V; III. Analytical quality control report of the finished product referring to 1 (one) batch; IV. Comparative dissolution profile report between the previously registered condition and the new condition, when applicable; V. Stability study protocol referring to the 1st batch or report of the stability study referring to 1 (one) batch. Art. 41. Minor changes or inclusions to the production process can be immediately implemented, and do not require a protocol process and prior analysis by Anvisa. Sole paragraph. The required documentation shall be attached to the Product Change History. Section II Moderate change or inclusion to the production process Art. 42. Adjustments of moderate impact to the productive process that are not classified as minor or major changes to the production process are considered as a moderate change or inclusion to the production process. Sole paragraph. The provision of this article is applicable to changes to the sterilization process. Art. 43. Moderate change or inclusion petitions to the production process shall be accompanied by the following documents: Anvisa may consult its database with the intent of proving the Technical II. Production report, including the comparative charts a and d of Attachment V;

8 III. Analytical quality control report of the finished product referring to 1 (one) batch; IV. Comparative dissolution profile report between the previously registered condition and the new condition, when applicable; V. Stability study report regarding 1 (one) finished product batch; Art. 44. For semi-solid and liquid products, except for perfect solutions, the following rules, besides those contained in art. 43, are applicable: I. Present comparative results between particle/droplet size distribution of the previously registered condition and the new one; II. Include a discussion relative to the impact of eventual changes in particle/droplet size distribution; III. Present comparative results between the cutaneous permeation rate of the previously registered condition and the new one. IV. Include a discussion relative to the impact of eventual changes to the cutaneous permeation rate; Art. 45. Moderate changes or inclusions to the fabrication location can only be implemented after a favorable analysis and conclusion by Anvisa, provided other rules specific to such petition have been observed. Section III Major change or inclusion to the production process Art. 46. Changes that alter the type of production process, such as a change of a dry way for a wet one or vice-versa, or production changes that impact upon the drug release system are considered as major changes or inclusions to the production process. Art. 47. Major change or inclusion petitions to the production process shall be accompanied by the following documents: Anvisa may consult its database with the intent of proving the Technical II. Production report, including the comparative charts a and d of Attachment V; III. Analytical quality control report of the finished product referring to 1 (one) batch; IV. Comparative dissolution profile report between the previously registered condition and the new condition, when applicable; V. Stability study report regarding 1 (one) finished product batch; VI. Long-term stability study report referring to 3 (three) batches, to be included in the Product Change History; VII. Technical report of the relative bioavailability/bioequivalence study; Art. 48. For semi-solid and liquid products, except for perfect solutions, the following rules, besides those contained in art. 47, are applicable: I. Present comparative results between particle/droplet size distribution of the previously registered condition and the new one; II. Include a discussion relative to the impact of eventual changes in particle/droplet size distribution; III. Present comparative results between the cutaneous permeation rate of the previously registered condition and the new one. IV. Include a discussion relative to the impact of eventual changes to the cutaneous permeation rate;

9 Art. 49. Major changes or inclusions to the fabrication location can only be implemented after a favorable analysis and conclusion by Anvisa, provided other rules specific to such petition have been observed. Chapter V EQUIPMENT-RELATED CHANGES Art. 50. It refers to the change or inclusion of equipment having equal or different capacity, design or operational principle or equipment automation. Section I - Change or inclusion of primary packaging equipment Art. 51. It refers to the change or inclusion of primary packaging equipment. Art. 52. Changes or inclusions to primary packaging equipment can be immediately implemented, and do not require a protocol process and prior analysis by Anvisa. Sole paragraph. Said change shall be registered in the Product Change History. Section II - Change or inclusion of equipment having the same design and operational principle Art. 53. It refers to the change or inclusion of equipment having the same design and operational principle, except for packaging line equipment. Art. 54. Variation in capacity, equipment automation or a minor change to the production process together with the change object of this section is permitted. Art. 55. Changes or inclusions to equipment having the same design and operational principle shall be accompanied by the following documents: Anvisa may consult its database with the intent of proving the Technical II. Production report, including the comparative charts a and d of Attachment V; III. Analytical quality control report of the finished product referring to 1 (one) batch; IV. Comparative dissolution profile report between the previously registered condition and the new condition, when applicable; V. Stability study protocol referring to the 1st batch or report of the stability study referring to 1 (one) batch. Sole paragraph. Whenever dealing with the inclusion of equipment having the same capacity, automation system and productive process, the presentation of items IV and V is waived. Art. 56. Changes or inclusions to equipment having the same design and operational principle can be immediately implemented, and do not require a protocol process and prior analysis by Anvisa. Sole paragraph. The required documentation shall be attached to the Product Change History.

10 Section III - Change or inclusion of equipment having a different design or operational principle Art. 57. It refers to the change or inclusion of equipment having a different design and operational principle or of equipment having a different design and same operational principle, except for packaging line equipment. Art. 58. A minor and moderate change to the production process as a function of equipment change is concomitantly permitted. Art. 59. The change or inclusion petition for equipment having a different design and operational principle or equipment having a different design and same operational principle shall be accompanied by the following documents: Anvisa may consult its database with the intent of proving the Technical II. Production report, including the comparative charts a and d of Attachment V; III. Analytical quality control report of the finished product referring to 1 (one) batch; IV. Comparative dissolution profile report between the previously registered condition and the new condition, when applicable; V. Stability study report regarding 1 (one) finished product batch; VI. Long-term stability study report referring to 3 (three) batches, to be included in the Product Change History; Art. 60. For semi-solid and liquid products, except for perfect solutions, the following rules, besides those contained in art. 59, are applicable: I. Present comparative results between particle/droplet size distribution of the previously registered condition and the new one; II. Include a discussion relative to the impact of eventual changes in particle/droplet size distribution; III. Present comparative results between the cutaneous permeation rate of the previously registered condition and the new one. IV. Include a discussion relative to the impact of eventual changes to the cutaneous permeation rate; Art. 61. Changes or inclusions to equipment having a different design or operational principle can only be implemented after a favorable analysis and conclusion by Anvisa, provided other rules specific to such petition have been observed. Chapter VI BATCH SIZE RELATED CHANGES Section I - Inclusion of batches up to ten times in size Art. 62. It refers to the inclusion of a batch size up to 10 times the size of the pilot batch/biobatch. Sole paragraph. The provision of this article does not apply to medications having a concentration less than 0.99 mg per posologic unit, except for perfect solutions.

11 Art. 63. A concomitant minor change to the production process and change or inclusion of equipment having the same design and same operational principle, where the equipment capacity and/or automation may vary, is permitted. Art. 64. The inclusion of batches up to 10 times in size shall be accompanied by the following documents: Anvisa may consult its database with the intent of proving the Technical II. Production report, including the comparative charts a, c and d of Attachment V; III. Analytical quality control report of the finished product referring to 1 (one) batch; IV. Comparative dissolution profile report between the previously registered condition and the new condition, when applicable; V. Stability study protocol referring to the 1st batch or report of the stability study referring to 1 (one) batch. Art. 65. The inclusion of batches up to 10 times in size can be immediately implemented, and does not require a protocol process and prior analysis by Anvisa. Sole paragraph. The required documentation shall be attached to the Product Change History. Section II - Inclusion of batches up to ten times in size Art. 66. It refers to the inclusion of a batch size greater than 10 times the size of the pilot batch/biobatch. Art. 67. It applies to any batch size inclusion for medications having a concentration of less than 0.99 per posologic unit, except for perfect solutions. Art. 68. A concomitant minor change to the production process and change or inclusion of equipment having the same design and same operational principle, where the equipment capacity and/or automation may vary, is permitted. Art. 69. The batch size inclusion petition shall be accompanied by the following documents: Anvisa may consult its database with the intent of proving the Technical II. Production report, including the comparative charts a, c and d of Attachment V; III. Analytical quality control report of the finished product referring to 1 (one) batch; IV. Comparative dissolution profile report between the previously registered condition and the new condition, when applicable; V. Stability study report regarding 1 (one) finished product batch;

12 Art. 70. The inclusion of a batch size greater than 10 times the size of the biobatch/pilot batch can only be implemented after a favorable analysis and conclusion by Anvisa, provided other rules specific to such petition are observed. Chapter VII CHANGES RELATIVE TO EXCIPIENTS Art. 71. It refers to quantitative and qualitative changes to the formulation excipient(s) Section I Inclusion of a new presentation due to flavor change Art. 72. It refers to the inclusion of flavor by adding or excluding aromatizers, sugar substitutes, flavor or color additives in an already registered formulation. Art. 73. The present inclusion results in a new registration number and does not cancel the previous one. Paragraph 1 In case there is no interest in maintaining the previous presentation, presentation cancellation shall be requested. Paragraph 2 In case the company intends to change the flavor, in accordance with the provision of Art. 72, without generating a new registration number, a minor or moderate excipient change shall be petitioned. Art. 74. The flavor, odor or color inclusion petition shall be accompanied by the following documents: Anvisa may consult its database with the intent of proving the Technical II. GTIN code for the new presentation(s); III. Production report, including the comparative charts a and b of Attachment V; IV. Analytical methodology and specification, with the used bibliographic reference, or, whenever not pharmacopoeic, description of the methodology for the excipients which information has not yet been included in the registry. V. Information relative to transmissible spongiform encephalopathy, for excipients which information has not yet been registered; VI. Analytical quality control report of the finished product referring to 1 (one) batch; VII. Comparative dissolution profile report between the previously registered condition and the new condition, when applicable; VIII. Validation report of the new finished product analytical method; IX. Stability study report regarding 1 (one) finished product batch; Sole paragraph. For cases in which the request results in exclusion of a color additive, sugar substitute, flavor additive and/or aromatizer from an already registered formulation, it is permitted to present the stability protocol of the 1 st batch in substitution of the stability study report for 1 (one) batch Art. 75. The inclusion of a new presentation due to change of flavor can only be implemented after a favorable analysis and conclusion by Anvisa, provided other rules specific to such petition have been observed.

13 Section II - Minor change of excipient Art. 76. It refers to the reduction or exclusion of colorant, sugar substitute, flavor additive or aromatizer and to the quantitative changes that fall under the limits described in the Excipients Attachment Attachment II. Art. 77. The minor excipient change petition shall be accompanied by the following documents: Anvisa may consult its database with the intent of proving the Technical II. Production report, including the comparative charts a and b of Attachment V; III. Analytical quality control report of the finished product referring to 1 (one) batch; IV. Comparative dissolution profile report between the previously registered condition and the new condition, when applicable; V. Validation report of the new finished product analytical method; VI. Stability study protocol regarding 1 (one) finished product batch; VII. Report with the method and results of the preservative efficacy tests, for the cases in which the preservative system itself is changed; Sole paragraph. When dealing with the reduction or exclusion of excipients relative to color, flavor or odor, the presentation of item V shall be waived. Art. 78. For semi-solid and liquid products, except for perfect solutions, the following rules, besides those contained in art. 77, are applicable: I. Present comparative results between particle/droplet size distribution of the previously registered condition and the new one; II. Include a discussion relative to the impact of eventual changes in particle/droplet size distribution; III. Present comparative results between the cutaneous permeation rate of the previously registered condition and the new one. IV. Include a discussion relative to the impact of eventual changes to the cutaneous permeation rate; Art. 79. A minor excipient change can be implemented immediately after the petition has been formally presented. Section III Moderate excipient change Art. 80. It refers to quantitative and qualitative excipient changes that fall under the limits described in the Excipients Attachment Attachment II and to the changes regarding dosage forms not contemplated in said Attachment. Art. 81. The moderate excipient change petition shall be accompanied by the following documents:

14 Anvisa may consult its database with the intent of proving the Technical II. Production report, including the comparative charts a and b of Attachment V; III. Analytical methodology and specification, with the used bibliographic reference, or, whenever not pharmacopoeic, description of the methodology for the excipients which information has not yet been included in the registry. IV. Information relative to transmissible spongiform encephalopathy, for excipients which information has not yet been registered; V. Analytical quality control report of the finished product referring to 1 (one) batch; VI. Comparative dissolution profile report between the previously registered condition and the new condition, when applicable; VII. Validation report of the new finished product analytical method; VIII. Stability study report regarding 1 (one) finished product batch; IX. Report with the method and results of the preservative efficacy tests, for the cases in which the preservative system itself is changed; Art. 82. For semi-solid and liquid products, except for perfect solutions, the following rules, besides those contained in art. 81, are applicable: I. Present comparative results between particle/droplet size distribution of the previously registered condition and the new one; II. Include a discussion relative to the impact of eventual changes in particle/droplet size distribution; III. Present comparative results between the cutaneous permeation rate of the previously registered condition and the new one. IV. Include a discussion relative to the impact of eventual changes to the cutaneous permeation rate; Art. 83. The moderate excipient change can only be implemented after a favorable analysis and conclusion by Anvisa, provided other rules specific to such petition have been observed. Section IV - Major change of excipient Art. 84 It refers to quantitative and qualitative changes that are above the limits set forth by the Excipients Attachment Attachment II for moderate change. Art. 85. The major excipient change petition shall be accompanied by the following documents: Anvisa may consult its database with the intent of proving the Technical II. Production report, including the comparative charts a and b of Attachment V; III. Analytical methodology and specification, with the used bibliographic reference, or, whenever not pharmacopoeic, description of the methodology for the excipients which information has not yet been included in the registry. IV. Information relative to transmissible spongiform encephalopathy, for excipients which information has not yet been registered; V. Analytical quality control report of the finished product referring to 1 (one) batch; VI. Comparative dissolution profile report between the previously registered condition and the new condition, when applicable; VII. Validation report of the new finished product analytical method;

15 VIII. Stability study report regarding 1 (one) finished product batch; IX. Long-term stability study report referring to 3 (three) batches, to be included in the Product Change History; X. Report with the method and results of the preservative efficacy tests, for the cases in which the preservative system itself is changed; XI. Technical report of the relative bioavailability/bioequivalence study; Art. 86. For semi-solid and liquid products, except for perfect solutions, the following rules, besides those contained in art. 85, are applicable: I. Present comparative results between particle/droplet size distribution of the previously registered condition and the new one; II. Include a discussion relative to the impact of eventual changes in particle/droplet size distribution; III. Present comparative results between the cutaneous permeation rate of the previously registered condition and the new one. IV. Include a discussion relative to the impact of eventual changes to the cutaneous permeation rate; Art. 87. The major excipient change can only be implemented after a favorable analysis and conclusion by Anvisa, provided other rules specific to such petition have been observed. Chapter VIII CHANGES RELATIVE TO THE UPDATING OF FINISHED PRODUCT ANALYTICAL METHODS AND SPECIFICATIONS Art. 88. It refers to the change, inclusion or exclusion of a finished product method and/or specification that does not arise from a post-registration change. Sole paragraph. The change, inclusion or exclusion of a finished product method and/or specification that arises from a post-registration change shall be analyzed together with the proposed change. Section I - Adjustment of analytical methods and specifications according to official compendium or stricter specification range Art. 89. It refers to a change to the specification range and to the update, inclusion or substitution of the analytical method for the purpose of adjusting it according to the official compendium, or even to any stricter specification range. Sole paragraph. The provision of this article is not applicable to the update/inclusion/substitution of an analytical method referring to products of degradation and a biological method of content quantification. Art. 90. The adjustment of analytical methods and specifications according to the official compendium or to a stricter specification range shall be accompanied by the already approved analytical method or specification description and by the altered one, including the new reference. Art. 91. The adjustment of the analytical method and specifications according to the official compendium or to a stricter specification range can be immediately implemented, and does not require a protocol process and prior analysis by Anvisa. Sole paragraph. The required documentation shall be attached to the Product Change History. Section II Analytical methods and specifications updating

16 Art. 92. Refers to: a. The updating of the analytical method(s) and specifications for cases in which an analytical method(s) or specification(s) change(s) or inclusion(s) occur(s) that are not listed in the official compendiums accepted by Anvisa; b. Update or substitution or inclusion of analytical method(s) or specification(s) of products of degradation or of biological method(s) of content quantification; c. Exclusion of analytical method(s) or specification(s). Art. 93. The analytical method and specifications update petition shall be accompanied by the following documents: Anvisa may consult its database with the intent of proving the Technical II. Description of the already approved or altered analytical method or specification, including the new reference; III. Bibliographic references and/or compendium copy; IV. Analytical quality control report of the finished product referring to 1 (one) batch; V. Validation report of the new finished product analytical method; Art. 94. The exclusion of a mandatory test, analytical method or specifications for the dosage form is not allowed. Art. 95. The update of specifications and analytical methodology can only be implemented after a favorable analysis and conclusion by Anvisa, provided other specific rules for such petition are observed. Chapter IX CHANGES RELATIVE TO THE SHELF LIFE PERIOD OR TO CONSERVATION PRECAUTIONS Art. 96. It refers to the change of the shelf life period or change to the conservation precautions of the finished product, of the product after reconstitution or of the product after dilution. Section I - Reduction in shelf-life period with maintenance of the conservation precautions Art. 97. It refers to the reduction of the shelf life period of the finished product, of the product after reconstitution or of the product after dilution by maintaining the conservation precautions unaltered. Art. 98. The petition to reduce the shelf life period with maintenance of the conservation precautions shall be accompanied by the stability study report referring to 1 (one) long duration or accompaniment batch. Art. 99. The reduction of the shelf life period, by maintaining the conservation precautions unaltered, can be implemented immediately after the petition protocol process, and does not require a prior analysis by Anvisa. Section II - Reduction in shelf-life period with changes to the conservation precautions

17 Art It refers to the reduction of the shelf life period of the finished product, of the product after reconstitution or of the product after dilution while changing the conservation precautions. Art The petition to reduce the shelf life period with change to the conservation precautions shall be accompanied by the long duration stability study report referring to 3 (three) batches; Art The reduction of the shelf life period with change to the conservation precautions can only be implemented after a favorable analysis and conclusion by Anvisa, provided other rules specific to such petition have been observed. Section III - Increase in shelf-life period or changes to the conservation precautions Art It refers to the increase of the shelf life period or change to the preservation cares of the finished product, of the product after reconstitution or of the product after dilution. Art The increase of the shelf life period or change to the conservation precautions shall be accompanied by the long duration stability study report referring to 3 (three) batches; Art The increase of the shelf life period or change to the conservation precautions can only be implemented after a favorable analysis and conclusion by Anvisa, provided other rules specific to such petition have been observed. Chapter X INCLUSION OF A NEW COMMERCIAL PRESENTATION Art It refers to the inclusion of a new presentation in which change to volume or to the number of pharmacotechnical units previously registered, or inclusion, change or removal of accessories occurs. Paragraph 1 In case there is no interest in maintaining the previous presentations, presentation cancellation shall be requested. Paragraph 2 The new presentation shall be in agreement with the product posology. Paragraph 3 For the inclusion of a new dividable presentation, the provision of the specific norm, besides that set forth in this chapter, shall apply. Section I - Inclusion of a new commercial presentation Art It refers to the inclusion of the new commercial presentation of a nonsterile product and to all cases in which inclusion, change or removal of accessories occurs. Art The inclusion petition of a new commercial presentation for a non-sterile product shall be accompanied by the GTIN code for the new presentation(s); Sole paragraph. For liquid products for which the new presentation undergoes change of volume, the stability study protocol referring to the 1 st batch or report of the stability study referring to 1 (one) batch shall be presented. Art The inclusion of a new commercial presentation for a non-sterile product and all cases in which an inclusion, change or removal of accessories occurs can

18 only be implemented after a favorable analysis and conclusion by Anvisa, provided other rules specific to this petition have been observed. Section II - Inclusion of a new commercial presentation for a sterile product Art It refers to the inclusion of a new commercial presentation for a sterile product. Art The inclusion petition of a new commercial presentation for a sterile product shall be accompanied by the GTIN code for the new presentation(s); Sole paragraph. For sterile liquid products for which the new presentation undergoes change of volume, a stability study report shall be presented referring to 1 (one) batch. Art The inclusion of a new commercial presentation of a sterile product can only be implemented after a favorable analysis and conclusion by Anvisa, provided other rules specific to such petition have been observed. Chapter XI INCLUSION OF NEW CONDITIONING Art It refers to the inclusion of a new conditioning material or a dividable conditioning material for an already registered product. Sole paragraph. In case there is no interest in maintaining the previous conditioning, the bearer shall request cancellation of the presentation registration in the technical justification. Art The presentations resulting from the inclusion of a new dividable conditioning material shall meet, besides the provision of this chapter, that set forth in the specific norm. Art The concomitant change of the equipment exclusively used for the packaging process is allowed. Art The inclusion petition of the new conditioning material shall be accompanied by the following documents: Anvisa may consult its database with the intent of proving the Technical II. Stability study report regarding 3 (three) batches; III. Report containing the method and results of the packaging quality control for small and large volume parenteral solutions and parenteral nutrition; IV. Conditioning material specification; V. GTIN code for the new presentation(s). Art For cases of inclusion of a new conditioning material that meets the conditions described in Attachment VII - Conditioning materials, item II of Art. 116 can be substituted for the stability study protocol referring to the 3 (three) initial batches. Sole paragraph. The provision of this article does not apply to injectable medications.

19 Art For cases of inclusion of a new conditioning material that meets the conditions described in Attachment VII Conditioning materials, the shelf life period and the conservation precautions of the already registered conditioning shall be maintained for the new conditioning material. Art The inclusion of a new conditioning material can only be implemented after a favorable analysis and conclusion by Anvisa, provided other rules specific to such petition have been observed. Chapter XII CHANGES RELATIVE TO THE DRUG Art It refers to the change or inclusion in the drug synthesis route or in the drug fabrication location. Sole paragraph. The provision of this chapter does not apply to the category of specific medications. Art All documentation issued by the drug manufacturer shall be sent on company letterhead. Sole paragraph. The Drug manufacturer(s) may opt to send the documentation relative to the drug directly to Anvisa, provided it is duly identified with the name of the company bearing the registration, the process number and the order number which it relates to. Section I Change or inclusion of the drug synthesis route Art It refers to the change or inclusion to the drug synthesis route, where the manufacturer already informed in the registration remains the same. Art The change or inclusion petition of the drug synthesis route shall be accompanied by the following documents: Anvisa may consult its database with the intent of proving the Technical II. Comparative impurity profile between 1 (one) drug batch obtained from the synthesis route approved in the registration and 1 (one) drug batch obtained from the new synthesis route; III. Stability study report of 1 (one) drug batch; IV. Complete synthesis route with intermediate products; V. Analytical drug quality control report referring to 1 (one) batch issued by the medication manufacturer; VI. Analytical drug quality control report referring to 1 (one) batch issued by the drug manufacturer; VII. Analytical quality control report of the finished product referring to 1 (one) batch; VIII. Comparative dissolution profile report between the previously registered condition and the new condition, when applicable; IX. Validation report of the new finished product analytical method; X. Stability study report regarding 1 (one) finished product batch;

20 Paragraph 1 The synthesis route shall contain the information regarding the solvents used, list of residual solvents, polymorphism, limits, quantification and specification of synthesis impurities and products of degradation, besides information regarding the chirality and proportion of isomers. Paragraph 2 A discussion regarding the impact of eventual changes to the impurity profile and validation, or revalidation, of the analysis methodology shall be presented. Art For semi-solid and liquid products, except for perfect solutions, the following rules, besides those contained in art. 123, are applicable: I. Present comparative results between particle/droplet size distribution of the previously registered condition and the new one; II. Include a discussion relative to the impact of eventual changes in particle/droplet size distribution; III. Present comparative results between the cutaneous permeation rate of the previously registered condition and the new one. IV. Include a discussion relative to the impact of eventual changes to the cutaneous permeation rate; Art The change or inclusion of the drug synthesis route can only be implemented after a favorable analysis and conclusion by Anvisa, provided other rules specific to such petition have been observed. Section II Change or inclusion of the drug fabrication location Art It refers to the substitution or addition of the drug fabrication location. Art Concomitant change or inclusion of the drug synthesis route as a function of change or inclusion of the drug fabrication location is permitted. Art The change or inclusion petition of the drug fabrication location shall be accompanied by the following documents: Anvisa may consult its database with the intent of proving the Technical II. Comparative impurity profile between 1 (one) drug batch obtained from the synthesis route and/or fabrication location approved in the registration and 1 (one) drug batch obtained from the new synthesis route and/or fabrication location; III. Stability study report of 1 (one) drug batch; IV. Complete synthesis route with intermediate products; V. Analytical drug quality control report referring to 1 (one) batch issued by the medication manufacturer; VI. Analytical drug quality control report referring to 1 (one) batch issued by the drug manufacturer; VII. Analytical quality control report of the finished product referring to 1 (one) batch; VIII. Comparative dissolution profile report between the previously registered condition and the new condition, when applicable; IX. Validation report of the new finished product analytical method; X. Stability study report regarding 1 (one) finished product batch;

21 Paragraph 1 The synthesis route shall contain the information regarding the solvents used, list of residual solvents, polymorphism, limits, quantification and specification of synthesis impurities and products of degradation, besides information regarding the chirality and proportion of isomers. Paragraph 2 A discussion regarding the impact of eventual changes to the impurity profile and validation, or revalidation, of the analysis methodology for the drug shall be presented. Art For semi-solid and liquid products, except for perfect solutions, the following rules, besides those contained in art. 128, are applicable: I. Present comparative results between particle/droplet size distribution of the previously registered condition and the new one; II. Include a discussion relative to the impact of eventual changes in particle/droplet size distribution; III. Present comparative results between the cutaneous permeation rate of the previously registered condition and the new one. IV. Include a discussion relative to the impact of eventual changes to the cutaneous permeation rate; Art The change or inclusion of the drug fabrication location can only be implemented after a favorable analysis and conclusion by Anvisa, provided other rules specific to such petition have been observed. Chapter XIII CHANGES RELATIVE TO POSOLOGY Art It refers to a posology change for an already registered product having the same concentration, dosage form and therapeutic indication. Section I Posology change Art It refers to posology change cases in the registration of new and reference medications. Art The posology change petition shall be accompanied by the following documents: I. Phase III clinical study report. II. Updated package insert text Art The posology change can only be implemented after a favorable analysis and conclusion by Anvisa, provided other rules specific to such petition have been observed. Section II Posology change for specific medications Art It refers to posology changes to the registration of specific medications. Art The posology change petition for specific medications shall be accompanied by the following documents: I. Clinical studies report or clinical studies published in indexed magazines, for posologies that are not within the limits already set forth by norms in effect; II. Updated package insert text. Art The posology change for specific medications can only be implemented after a favorable analysis and conclusion by Anvisa, provided other rules specific to such petition have been observed.

22 Chapter XIV USE EXPANSION Art It refers to the increase of the target population for an already registered product under the same therapeutic indication. Section I Use expansion Art It refers to use expansion in the registration of new and reference medications. Art The use expansion petition shall be accompanied by the following documents: I. Phase III or IV clinical study report II. Updated package insert text Art The use expansion can only be implemented after a favorable analysis and conclusion by Anvisa, provided other rules specific to such petition have been observed. Section II Use expansion for specific medications Art It refers to use expansion in the registration of the specific medications category. Art The use expansion petition shall be accompanied by the following documents: I. Clinical studies report or clinical studies published in indexed magazines II. Updated package insert text Art The use expansion for specific medications can only be implemented after a favorable analysis and conclusion by Anvisa, provided other rules specific to such petition have been observed. Chapter XV INCLUSION OF A NEW ROUTE OF ADMINISTRATION Art It refers to the inclusion of a new route of administration for an already registered product having the same concentration, therapeutic indication and dosage form. Section I Inclusion of a new route of administration in the country Art It refers to new and reference medications. Art The inclusion petition for a new route of administration in the country shall be accompanied by the following documents: I. Phase II and II clinical study report II. Updated package insert text Art The inclusion of a new route of administration in the country can only be implemented after a favorable analysis and conclusion by Anvisa, provided other rules specific to such petition have been observed. Section II Inclusion of a new route of administration already registered in the country

23 Art It refers to generic and similar medications that include a new route of administration already approved for the reference medication. Art The inclusion petition for a new route of administration already registered in the country shall be accompanied by the following documents: I. Pharmaceutical equivalency report; II. Comparative dissolution profile report, whenever applicable. III. Technical report of the relative bioavailability/bioequivalence study; Art The inclusion of a new route of administration already registered in the country can only be implemented after a favorable analysis and conclusion by Anvisa, provided other rules specific to such petition have been observed. Section III Inclusion of a new route of administration for specific medications Art It refers to the specific medications category. Art The inclusion petition for a new route of administration for specific medications shall be accompanied by the following documents: I. Clinical studies report or clinical studies published in indexed magazines, for a new route of administration in the country; II. Updated package insert text. Art The inclusion of a new route of administration for specific medications can only be implemented after a favorable analysis and conclusion by Anvisa, provided other rules specific to such petition have been observed. Chapter XVI INCLUSION OF THERAPEUTIC INDICATION Art It refers to the inclusion of a therapeutic indication for an already registered product having the same concentration and dosage form. Section I Inclusion of a new therapeutic indication in the country Art It refers to new and reference medications. Art The inclusion petition for a new therapeutic indication in the country shall be accompanied by the following documents: I. Phase II and II clinical study report; II. Updated package insert text. Art The inclusion of a new therapeutic indication in the country can only be implemented after a favorable analysis and conclusion by Anvisa, provided other rules specific to such petition have been observed. Section III Inclusion of a therapeutic indication for specific medications Art It refers to the specific medications category. Art The inclusion petition for a therapeutic indication for specific medications shall be accompanied by the following documents: I. Clinical studies report or clinical studies published in indexed magazines; II. Updated package insert text.

24 Art The inclusion of a therapeutic indication for specific medications can only be implemented after a favorable analysis and conclusion by Anvisa, provided other rules specific to such petition have been observed. Chapter XVII INCLUSION OF NEW CONCENTRATION Art It refers to the inclusion of a new concentration for an already registered product having the therapeutic indication and dosage form. Section I Inclusion of a new concentration in the country Art It refers to new and reference medications. Art The inclusion petition for a new concentration in the country shall be accompanied by the technical reports and all documentation in accordance with the norms in effect regarding the registration of new medications. Art The inclusion of a new concentration in the country can only be implemented after a favorable analysis and conclusion by Anvisa, provided other rules specific to such petition have been observed. Section II Inclusion of a new concentration already registered in the country Art It refers to generic, new and similar medications. Art For generic and similar medications, the inclusion petition of a new concentration already registered in the country shall be accompanied by the following documents: Anvisa may consult its database with the intent of proving the Technical II. GTIN code for the new presentation(s); III. Production report; IV. Analytical drug and finished product quality control report referring to 1 (one) batch including the bibliographic references and specifications (in case of an analytical methodology change, attach the corresponding validation); V. Pharmaceutical equivalency report; VI. Comparative dissolution profile report, whenever applicable. VII. Conditioning material specification; VIII. Report containing the method and results of the packaging quality control for small and large volume parenteral solutions and parenteral nutrition; IX. Stability study report regarding 3 (three) batches; XI. Report presenting the preservative efficiency test results and method, whenever applicable. XII. Technical report of the relative bioavailability/bioequivalence study; Art For new medications, the inclusion petition for a new concentration already registered in the country shall be accompanied by the following technical reports and all documentation in accordance with the norms in effect regarding the registration of new medications.

25 Art For semi-solid and liquid products, except for perfect solutions, the following rules, besides those contained in art. 167, are applicable: I. Determine, using an adequate methodology, the particle/droplet size distribution; II. Determine, using an adequate methodology, the cutaneous permeation rate. Art The inclusion of a new concentration already registered in the country can only be implemented after a favorable analysis and conclusion by Anvisa, provided other rules specific to such petition have been observed. Section III Inclusion of a new concentration for specific medications Art It refers to the specific medications category. Art The inclusion petition for a new concentration for specific medications shall be accompanied by the following documents: Anvisa may consult its database with the intent of proving the Technical II. GTIN code for the new presentation(s); III. Production report; IV. Analytical drug and finished product quality control report referring to 1 (one) batch including the bibliographic references and specifications (in case of an analytical methodology change, attach the corresponding validation); V. Conditioning material specification; VI. Report containing the method and results of the packaging quality control for small and large volume parenteral solutions and parenteral nutrition; VII. Stability study report regarding 3 (three) batches; VIII. Report presenting the preservative efficiency test results and method, whenever applicable IX. Clinical studies report or clinical studies published in indexed magazines, for new concentrations in the country or for concentrations that are not within the limits already set forth by norms in effect. X. Updated package insert text Art For semi-solid and liquid products, except for perfect solutions, the following rules, besides those contained in art. 172, are applicable: I. Determine, using an adequate methodology, the particle/droplet size distribution; II. Determine, using an adequate methodology, the cutaneous permeation rate. Art The inclusion of a new concentration for specific medications can only be implemented after a favorable analysis and conclusion by Anvisa, provided other rules specific to such petition have been observed. Chapter XVIII INCLUSION OF A NEW DOSAGE FORM Art It refers to the inclusion of a new dosage form for an already registered product having the same therapeutic incidation. Section I Inclusion of a new dosage form in the country Art It refers to new and reference medications.

26 Art The inclusion petition for a new dosage form in the country shall be accompanied by the technical reports and all documentation in accordance with the norms in effect regarding the registration of new medications. Art The inclusion of a new dosage form in the country can only be implemented after a favorable analysis and conclusion by Anvisa, provided other rules specific to such petition have been observed. Section II Inclusion of a new dosage form already registered in the country Art It refers to new and similar medications. Art For generic and similar medications, the inclusion petition of a new dosage form already registered in the country shall be accompanied by the following documents: Anvisa may consult its database with the intent of proving the Technical II. GTIN code for the new presentation(s); III. Production report; IV. Analytical drug and finished product quality control report referring to 1 (one) batch including the bibliographic references and specifications (in case of an analytical methodology change, attach the corresponding validation); V. Pharmaceutical equivalency report; VI. Comparative dissolution profile report, whenever applicable. VII. Conditioning material specification; VIII. Report containing the method and results of the packaging quality control for small and large volume parenteral solutions and parenteral nutrition; IX. Stability study report regarding 3 (three) batches; X. Report presenting the preservative efficiency test results and method, whenever applicable. XI. Technical report of the relative bioavailability/bioequivalence study; Art For new medications, the inclusion petition for a new dosage form already registered in the country shall be accompanied by the following technical reports and all documentation in accordance with the norms in effect regarding the registration of new medications. Art For semi-solid and liquid products, except for perfect solutions, the following rules, besides those contained in art. 180, are applicable: I. Determine, using an adequate methodology, the particle/droplet size distribution; II. Determine, using an adequate methodology, the cutaneous permeation rate. Art The inclusion of a new dosage form already registered in the country can only be implemented after a favorable analysis and conclusion by Anvisa, provided other rules specific to such petition have been observed. Section III Inclusion of a new dosage form for specific medications Art It refers to the inclusion of a new dosage form for the specific medications category.

27 Art The inclusion petition for a new dosage form for specific medications shall be accompanied by the following documents: Anvisa may consult its database with the intent of proving the Technical II. GTIN code for the new presentation(s); III. Production report; IV. Analytical drug and finished product quality control report referring to 1 (one) batch including the bibliographic references and specifications (in case of an analytical methodology change, attach the corresponding validation); V. Conditioning material specification; VI. Report containing the method and results of the packaging quality control for small and large volume parenteral solutions and parenteral nutrition; VII. Stability study report regarding 3 (three) batches; VIII. Report presenting the preservative efficiency test results and method, whenever applicable. IX. Clinical studies report or clinical studies published in indexed magazines, for a new dosage form in the country X. Updated package insert text Art For semi-solid and liquid products, except for perfect solutions, the following rules, besides those contained in art. 185, are applicable: I. Determine, using an adequate methodology, the particle/droplet size distribution; II. Determine, using an adequate methodology, the cutaneous permeation rate. Art The inclusion of a new dosage form for specific medications can only be implemented after a favorable analysis and conclusion by Anvisa, provided other rules specific to such petition have been observed. Chapter XX CHANGES RELATIVE TO THE LABELING Art It refers to the change in labeling of already registered medications that have not been contemplated with a specific norm or that does not arise from a post-registration change. Art The labeling change petition shall be accompanied by the new label layout and packaging. Art The labeling change of already registered medications that have not yet been contemplated in a specific norm or that do not arise from post-registration changes can only be implemented after a favorable analysis and conclusion by Anvisa, provided other rules specific to such petition have been observed. Chapter XXI CHANGES RELATIVE TO THE COMMERCIAL NAME Art It refers to the change to the commercial name of already registered medications. Art The commercial name change petition shall be accompanied by a product non-commercialization statement.

28 Art The commercial name change can only be implemented after a favorable analysis and conclusion by Anvisa, provided other rules specific to such petition have been observed. Chapter XXII TEMPORARY FABRICATION SUSPENSION Art It refers to the temporary fabrication suspension of a registered product and does not imply in cancellation of its registration. Art The request shall be made with a notice 180 days prior to halting fabrication, except in emergency situations. Art The temporary fabrication suspension of a registered product can only be implemented after a favorable analysis and conclusion by Anvisa, provided other rules specific to such petition have been observed. Sole paragraph. The company may implement the suspension in case there is no manifestation from Anvisa within a 180 day period. Chapter XXIII REACTIVATION OF MEDICATION FABRICATION Art It refers to the request to resume the fabrication of an already registered product. Art For cases in which the fabrication suspension was motivated by noncompliance of technical requirements, the fabrication reactivation shall be conditioned to the fulfillment of the requirements that gave rise to the suspension. Art The fabrication reactivation petition shall be accompanied by a valid Good Fabrication Practices Certificate or a protocol requesting the inspection by Anvisa, provided the company presents a satisfactory situation in accordance with the last inspection performed; or a protocol requesting the inspection by Anvisa together with a valid Good Fabrication Practices Certificate issued by the competent sanitary authority, for international manufacturers; or Anvisa may consult its database with the intent of proving the Technical Operational Conditions of the requesting company. Art The medication manufacturing reactivation can only be implemented after a favorable analysis and conclusion by Anvisa, provided other rules specific to such petition have been observed. Chapter XXIV REGISTRATION CANCELLATION Section I Cancellation of the medication presentation registration Art It refers to the registration cancellation of certain medication presentations. Art The medication presentation cancellation can only be implemented after a favorable analysis and conclusion by Anvisa, provided other rules specific to such petition have been observed. The cancellation can only be requested after approval

29 of the Temporary Fabrication Suspension as provided for in Chapter XXII, except under the following situations: Paragraph 1 Cancellations in which the company shall maintain the product registration under the same dosage form and concentration; Paragraph 2 Cancellations in which the presentations were not commercialized. Section II Cancellation of the medication registration Art It refers to the registration cancellation of all medication presentations. Art The medication registration cancellation can only be implemented after a favorable analysis and conclusion by Anvisa, provided other rules specific to such petition have been observed. The cancellation can only be requested after approval of the Temporary Fabrication Suspension as provided for in Chapter XXII, except for medications that have not been commercialized. Chapter XXV EXCLUSION OF DRUG MANUFACTURING LOCATION OR OF THE PRIMARY PACKAGING LOCATION OR OF THE SECONDARY PACKAGING LOCATION OF PRODUCT MANUFACTURING LOCATION Art The exclusion petitions referred to in this chapter shall be accompanied by the list of locations that remain valid, signed by the responsible technician of the registration bearer. Art The exclusions referred to in this chapter can be implemented immediately after the petition protocol process. Chapter XXVI FINAL AND TRANSITORY CONSIDERATIONS Art The imperative need to present the documents relative to the particle/droplet size distribution shall start within a period of 180 (one hundred and eighty) days as of the publication date of this norm. Art The imperative need to present documents relative to the determination of the cutaneous permeation rate according to the provisions of this regulation shall start within the period to be determined in a specific norm. Art The Anvisa decisions as to the evaluation of post-registration request shall be the object of a publication in the Official Daily Newspaper of the Union, or in another means of institutional disclosure, whenever applicable. Art For cases not foreseen in this Resolution, or that do not meet some of the specified requirements, Anvisa shall establish, at its criterion, the tests and documentation to be presented. Art For similar medications that have not yet met the necessary criteria according to the specific legislation, the bioequivalency technical report, when required by this standard, shall be waived until the moment such criteria are met.

30 Art Anvisa may request additional documents whenever it deems necessary. Art Anvisa recommendations for medication post-registration shall be made available for consultation on the website of said Agency. Art Default of the provisions contained in this Resolution and in the regulation approved by it constitute a sanitary infraction, as set forth by Law nr , of August 20, 1977, without prejudice of the applicable civil, administrative and penal responsibilities. Art Resolution RE nr. 893 of May 29, 2003, Resolution RE nr. 321 of September 13, 2004, Resolution RE nr. 215 of June 24, 2004, Resolution RE nr of May 31, 2005, Resolution RE nr of September 20, 2005, Normative Instruction IN nr. 1 of March 21, 2007, Normative Instruction IN nr. 10 of August 21, 2007, and Normative Instruction IN nr. 3 of June 4, 2008, and Normative Instruction IN nr. 6 of May 25, 2009 are revoked. Art This Resolution enters into effect within a period of 5 (five) days as of the date of its publication DIRCEU RAPOSO DE MELLO ATTACHMENT I REQUEST JUSTIFICATION Request description 1 Reason for request 2 I hereby declare that no change, besides the above proposed, shall be made and that the information in the package insert text and labeling shall be changed in accordance with the aforementioned request and shall only be made upon approval by this ANVISA Responsible technician 1. Report containing the change proposal requested by the company 2. Reason for the change proposed by the company including the technical argumentation to make the change. Whenever pertinent, the company shall attach the documentary evidence of the reason ATTACHMENT II EXCIPIENT ATTACHMENT 1. It determines the criteria to qualify excipient changes in a minor, moderate and major excipient change. 2. For solid dosage forms for immediate release a) Any excipient change shall be based upon the initially registered formulation or on the last formulation that already has safety and efficacy proven by means of clinical studies or bioequivalency, when applicable; b) The change of one of the excipients and the total additive effect of the changes shall be calculated considering the excipient changes expressed as a weight/weight (w/w) percentage of the formulation total. The percentages of table 1 are based on the premise that the product was formulated taking into account the active ingredient with 100% of its potency stated on the labeling. The total weight of the dosage form shall remain within the originally specified range;

31 Table I - Solid dosage forms for immediate release Minor Change Limit (%) Moderate Change Limit (%) 1. Diluent ± 5,0 ± 10,0 2. Desintegrant 2.1. Starch ± 3,0 ± 6, Others 3. Agglutinants ± 1,0 ± 0,5 ± 2,0 ± 1,0 4. Lubricant 4.1. Magnesium or Calcium stearate ± 0,25 ± 0, Others 5. Glidant ± 1,0 ± 2, Talcum 5.2. Others ± 1,0 ± 0,1 ± 2,0 ± 0,2 6. Lining film ± 1,0 ± 2,0 The additive effect of excipient changes not related to the modified release system of the drug cannot surpass 5%, for a minor change, and 10% for a moderate change. 3. For solid dosage forms for modified release a) Any excipient change shall be based upon the initially registered formulation or on the last formulation that already has safety and efficacy proven by means of clinical studies or bioequivalency, when applicable; b) The change of one of the excipients and the total additive effect of the changes shall be calculated considering the excipient changes expressed as a weight/weight (w/w) percentage of the formulation total. The percentages of table 1 are based on the premise that the product was formulated taking into account the active ingredient with 100% of its potency stated on the labeling. The total weight of the dosage form shall remain within the originally specified range; c) The change of each one of the excipients and the total additive effect of the changes on excipients related to the modified release system shall meet that presented in table II, considering the excipient changes expressed as a weight/weight (w/w) percentage of the total sum of excipients that control the drug release; Table I Solid dosage forms of modified release Excipients not related to the drug modified release system. Minor Change Limit (%) Moderate Change Limit (%) 1. Diluent ± 5,0 ± 10,0 2. Desintegrant 2.1. Starch ± 3,0 ± 6, Others 3. Agglutinants ± 1,0 ± 0,5 ± 2,0 ± 1,0 4. Lubricant 4.1. Magnesium or Calcium stearate ± 0,25 ± 0, Others 5. Glidant ± 1,0 ± 2, Talcum ± 1,0 ± 2, Others ± 0,1 ± 0,2 6. Lining film ± 1,0 ± 2,0

32 The additive effect of excipient changes not related to the modified release system of the drug cannot surpass 5%, for a minor change, and 10% for a moderate change. Table II Solid dosage forms of modified release Excipients related to the drug modified release system. Minor Change Moderate Change Limit (%) Limit (%) I. Medications with a narrow therapeutic ± 5,0 n/a* window II. Others ± 5,0 ± 10,0 The additive effect of excipient changes related to the modified release system of the drug cannot surpass 5%, for a minor change, and 10% for a moderate change. * For medications having a narrow therapeutic window, any change above 5% in excipients related to the modified release system of the drug shall constitute a major excipient change. Header Process Number Commercial Name Active Ingredient Dosage Form Concentrations Presentations 1 Period 2 Was there any change? ( ) Yes ( ) No Post- Registration 2 Order number and protocol date 3 Presentations involved in the change Justification/description/ reason for change 4 Date of approval and execution of the change 5 Attachment referring to the change 6 1. Inform all registered presentations; 2. Period which the Product Change History refers to in the format: "mm/yyyy to mm/yyyy"; 3. Subject name, according to the valid norm, filled out according to the chronological order of the change execution; 4. For cases in which a protocol process occurred for the change, inform, in this field, the corresponding order number and date; 5. The company shall place in this field the justification of the request by placing a detailed description and the reason for such, including the technical argumentation to make the post-registration change; 6. Inform the date of approval and execution of the proposed change. For postregistrations requests to be immediately put into effect, only inform the date of execution; 7. Place the number of the attachment referring to the documents containing the generated data as a function of the change, in accordance with the valid norm. The attachment shall contain the following documents: a. For cases in which the post-registration is only reported in the Product Change History, all documents required by the matter shall be attached; b. For cases in which a stability protocol is requested or an accelerated stability study is presented with the post-registration request, the long duration stability study shall be attached once concluded; ATTACHMENT IV

33 PRODUCTION REPORT Active Ingredient Commercial Name Dosage Form Concentration Header Substance DCB, DCI or CAS Number Master Formula Quantity % w/w of the dosage form Function in the Formula Biobatch / Pilot batch size Maximum approved size Minimum approved size Produced batch size Batch Information Production Order 1 Productive Process Complete Address (including city, country and legal entity tax registration number (CNPJ)) Equipment list (including automation, capacity, design, and operational principle) Description of pharmacotechnical process 2 Process control methodology (including bibliographic reference - Validation) Production Flow Diagram Phase 3 Substance 4 Unit Unit Operation operation parameters Equipment Process control 6 1. Send a copy of the production order relative to the batch to be evaluated; 2. Describe the process in topics by numbering each of the phases 3. According to the numbering of the pharmacotechnical process description 4. Indicate the substance addition order during the phase in which it occurs 5. Information regarding speed, temperature, time, etc. 6. Inform which tests shall be conducted and in which phase they will occur COMPARATIVE CHARTS ATTACHMENT V Chart A - Header Active Ingredient Commercial Name Dosage Form Concentration Chart B Formula Comparison Substanc e DCB, DCI or CAS Numbe Function Previous formula Proposed formula Difference Concentratio % in formula Concentratio % in s between n in mg n in mg formul % a

34 Active Ing Excipient 01 Excipient 02 Excipient 03 Excipient 04 r Approved production flow diagram Phase (2) Substanc e (3) Average weight = Average weight = of changes in % = Unit Operation Unit operation parameters(4 ) Equipment Process control (5) Proposed production flow diagram Phase (2) Substanc e (3) Unit Operation Unit operation parameters(4 ) Equipment Process control (5) 7. Describe the process in topics by numbering each of the phases 8. According to the numbering of the pharmacotechnical process description 9. Indicate the substance addition order during the phase in which it occurs 10. Information regarding speed, temperature, time, etc. 11. Inform which tests shall be conducted and in which phase they will occur ATTACHMENT VI STABILITY REPORT 1. Information to be listed in the stability report Type of Study/Conditions: Study start date: Total # of samples: Drug manufacturer: Drug batch: Product: Presentation: Primary packaging specification: Manufacturing Location/Fabrication Date: Batch number/batch size: SOLIDS Specificatio n Method referenc e Star t 1) Aspect 1.2 & 3 2) Contents 1.2 & 3 3) 1.2 Degradation & 3 product 3 month s 6 month s 9 month s 12 month s 18 month s 24 month s & 3 1 & 2 1 & & & 3 1 & 2 1 & & & 3

35 quantificatio n 4) 1.2 Dissolution & 3 5) Microbial 1.2 limits & 3 6) Hardness 1.2 & 3 LIQUIDS & SEMI- SOLIDS Specificatio n Method referenc e Star t 1) Aspect 1.2 & 3 2) Contents 1.2 & 3 3) 1.2 Degradation & 3 product quantification 4) ph 1.2 & 3 5) Sedimentatio n after agitation in suspensions 6) Clearness in solutions 7) Phase separation in emulsions and lotions 8) Weight loss in waterbased product 9) Microbial limits 1.2 & & & & & 3 1 & 2 1 & & & 3 3 month s & & 3 6 month s 9 month s 12 month s 18 month s 24 month s & 3 1 & 2 1 & & & 3 1 & 2 1 & & & 3 1 & 2 1 & & & & & & & & Accelerated 2 - Long 3 - Accompaniment a. The company shall include the additional tests necessary for product assessment; b. Additional studies such as photo-stability, product shelf life after reconstitution/dilution and stability after opening the packaging, shall be included in the stability report in accordance with the GUIA PARA REALIZAÇÃO DE ESTUDOS DE ESTABILIDADE [GUIDE FOR CONDUCTING STABILITY STUDIES]; c. Whenever any of the foregoing tests is not applicable to the product, the company shall send a technical justification regarding the lack thereof; CONDITIONING MATERIALS ATTACHMENT VII Criteria applicable to the substitution of the stability study report for the stability study protocol for changes of a new conditioning material - Change of conditioning material to flasks of solid, semi-solid and liquid non-sterile products.

36 Registered Condition Polystyrene PVC Polyethylene Proposed Condition PVC Polyethylene Polypropylene Glass Polyethylene Polypropylene Glass Higher density polyethylene Polypropylene with density greater than 0.89 Glass Any change between glass, metal, polypropylene having a density higher than 0.89 and polyethylene having a density higher than Specific conditions: The use of this attachment for semi-solid and liquid products shall only be accepted in case such are of an aqueous base and do not contain organic solvents; The proposed conditioning material shall have a light barrier property equivalent to that which it is being compared with or a photo-stability study or technical justification shall be presented with scientific evidence that the active agents do not undergo degradation in the presence of light or that the new primary packaging does not allow the passage of light. - Change of conditioning material for solid, semi-solid non-sterile product blisters. Registered Condition PVC PVC/PVDC PP PVC Any plastic Proposed Condition PVC/PVDC PVC/PCTFE PVC/PVDC/PE PVC/PCTFE PVC/PVDC/PE PVC/PVDC PVC/PVDC/PE PP Blister AL/AL Strip AL/AL The proposed conditioning material shall have a light barrier property equivalent to that which it is being compared with or a photo-stability study or technical justification shall be presented with scientific evidence that the active agents do not undergo degradation in the presence of light or that the new primary packaging does not allow the passage of light.