Keynote Speaker

Brazilian Regulations Update

Jair Calixto

Manager of Good Practices & Audits,

Sindusfarma

New Brazilian regulations

Jair Calixto

April 11 & 12th.

AGENDA GMP for Excipients Degradation Products Brazilian economic situation

INTRODUCTION OVERVIEW OF SINDUSFARMA

Sindusfarma is the first pharmaceutical association Industry in the São Paulo State,

founded in April 26, 1933.

Sindusfarma

205 members,

90% of the Brazilian pharma market.

“Official” entity to dialogue to

Workers Unions regarding to several

labor issues (i.e., salaries, labor

agreements, etc).

OVERVIEW

OTHER PHARMA ORGANIZATIONS

OTHERS STATES

UNIONS

ABIMIP

ABRASP

SINDUSFARMA PRÓ-

GENÉRICOS

GRUPO FARMABRASIL

ALANAC

INTERFARMA Sindusfarq Sinfar

Sindifargo Sindifar

10.695.532

6.249.682

10.439.601

3.480.937

732.793

451.227

668.689

6.569.683

7.588.078

14.021.432

19.595.309

3.033.991

1.560.501

2.449.341

8.448.055

3.168.133

3.766.834

8.796.032

3.120.922

2.068.031

3.512.672

15.993.583 41.252.160

3.119.015

6.004.045

1.383.453

2.562.963

Population in

2016

205.000.000

BRASIL – POPULAÇÃO POR ESTADO

Sindusfarma

Sinfar

Sindifar

Sinqfesc

Sinfacope

Sindusfarq

Sinquifar-JF

Quifarmo

Sindifargo

Sindquímica

Sinquifar-

NP

Sinqfar

Sinquifarma

GMP FOR EXCIPIENTS RESOLUTION NR. 34/2015

Apply to manufacturers of Pharmaceutical Excipients;

GMP Certification is not required;

Define GMP criteria for excipients manufactured in Brazil.

Companies concerns: currently does not have specific license/authorization for manufacturing certain Pharmaceutical Excipients (e.g., colourants, sugar manufacturers, glucose, starch, etc)

ANVISA COMMENTS

The Resolution has the objective to equalize companies regarding to the QA aspects. After an adaptation period by regulated industries, it will be necessary specific discussions regarding criteria to certain pharmaceutical excipients.

ANVISA COMMENTS

Art. 66. Tests shall be carried out to verify the identity of each batch of material received. Question: Considering the definition of materials from the RDC 34 (raw materials, reagents, solvents, auxiliary materials, intermediates, excipients , pharmaceutical packaging and labelling materials), it will be need to test the identity of all these items? What is the test for verifying the identity? A. Each material has its specific identity test that identifies without misunderstandings, avoiding the inadvertent use of some material. The pharmacopoeia has instructions for each existing substance in the compendium. If there is no guidance in any Pharmacopoeia, the manufacturer of the material can be consulted on this.

QUESTIONS & ANSWERS

Art. 78. There should not be a mixture of lots of Pharmaceutical Excipients with purpose to adapt it to a non-compliant product. Question: reworked are allowed through mixture of lots when the objective is not mask or dilute any contamination? A. This should be evaluated on a case by case basis during the inspections. If it is verified that the company perform batch mixture in order to mask problems and that it incurs risk to the patient, this will be considered a non-conformity.

QUESTIONS & ANSWERS

Art. 109. All raw materials must be checked before use. The verification and identification test includes additional tests to confirm the specifications. Question: can be verified via the supplier's certificate of analysis, independent of the dangerousness of the material? What would be the test of identity? A. the verification consists in carrying out analysis on the material received in order to verify their conformity to predefined specifications. What would be the test of identity? A. each material has identity test (s) (s) listed in the official textbooks, when available, or are defined by the manufacturer in specific cases.

QUESTIONS & ANSWERS

Art. 120. The stability program must include: II-storage conditions for samples retained; IV-recommended conditions and storage containers that simulate its use on the market. Question: is there a guide detailing how the stability study should be performed? What should be the condition of storage? How to evaluate the stability of materials sold in drums since there are available packages similar in size suitable for testing (< 1 kg)? A. we are evaluating the possibility to publish a stability guidance. The stability study should be conducted in the zone IV b. Smaller packs can be purchased for testing. There are currently available types of packaging in different sizes. The medicines manufacturer is responsible to solve this issue.

QUESTIONS & ANSWERS

Art. 85 – When manufacturing lots of the same product in continuous system or campaign, should be established the frequency of equipment cleaning, so that the waste materials, which can be carried out to successive batches, do not modify the product quality. Q: How the manufacturer shall prove it? Cleaning validation is required? A: The resolution does not establish cleaning validation. Must be carried out studies that prove the frequency of equipment cleaning, which do not alter the quality of the product.

QUESTIONS & ANSWERS

Art. 3 The procedures and practices outlined in this resolution shall be applied by the manufacturer to assure that facilities, methods, processes, systems and controls used are appropriate to afford the quality of the pharmaceutical excipient. Paragraph. Due to the diversity of the excipients, some guidelines of this standard may not be applicable, should be technically justified on the basis of risk assessment for the quality of the excipient.

GENERAL TOPICS

Art. 4. The manufacturer must define from which stage in the process will be implemented the GMP rules, i.e. from which step of the raw material/intermediate process that has critical influence on the quality of the excipient. § 1. The definition must be documented and based on technical and scientific justification.

GENERAL TOPICS

Art. 7 The manufacturer of Pharmaceutical Excipients must be able to identify the critical points where sampling and control are necessary to monitor the performance of the process. Art. 8. All activities undertaken by the company, that have impact on the quality of pharmaceutical excipient, should be described in standard operating procedures. Art. 9. There must be a quality unit, independent of production department, which is responsible for ensuring that pharmaceutical excipients comply with required quality standards. § 1 the quality unit may delegate some of its functions, but not their responsibility.

GENERAL TOPICS

Art. 11. Should be made audits reaching all QS, at least once a year. Art. 12. The team should be composed by professionals qualified in GMP. Members of the team could belong to the own company or external specialists, totally independents. Art. 13. Audits must be registered by documents. Art. 14. Corrective actions for the nonconformities realized in the Audit Report should be implemented and conclude within the proposed period.

INTERNAL AUDITS

Art. 40. The equipment used for the production of Pharmaceutical Excipients must be designed, have suitable dimensions and location to facilitate the use, cleaning, sanitization and maintenance. Art. 41. In the production of excipients, must be used “closed equipment and containers”. When using “open equipment”, must be adopted procedures to avoid the risk of contamination. Art. 42. The manufacturer shall provide proof of the effectiveness of cleaning and sanitization procedures, where applicable, residues of cleaning agents, microbiological contamination and degradation products. Art. 43. The procedures for cleaning and sanitization of equipment must be documented, containing enough details to enable operators to clean every type of equipment so reproducible and effective.

EQUIPMENT

Art. 49. All manufacturing docs should be prepared, revised, approved, updated, controlled and distributed according to the procedures. Art. 50. Datas, electronic or manual, should be registered as reliable. Art. 51. Electronics signatures used in docs should be safety. Art. 52. Manufacturing registers should be filled immediatelly after be implemented. Art. 53. Critical documents should be retained; retention period must be stablished by preocedures.

DOCUMENTATION AND REGISTERS

Art. 54. Registers of the cleaning : §1º Registers must be tracking. Art. 55. Specifications, analitical methods and acceptance criterias should be established & documented for raw materials, excipients, packaging materials, labelling used in the manufacturing. Art. 57. Each batch of excipient should have manufacturing register. Art. 59. Procedures must be implemented in order to investigate critical deviation. Art. 60. QC registers should include all complete datas obtained from the tests.

DOCUMENTATION & REGISTERS

Art. 61. The materials must be received, identified, stored, quarantined, sampled, analyzed according to established specifications and identified as its situation, in accordance with standard operating procedures. Art. 62. The critical materials should only be purchased according to the qualification procedure. Art. 63. All materials received shall be checked, in order to assure that the delivery is in accordance with the request. Art. 66. the test shall be carried out to verify the identity of each batch of material received. Art. 68. The sampling must be conducted in locations defined, under appropriate environmental conditions, in such a way as to prevent contamination, and according to standard operating procedures.

MATERIALS CONTROL

Art. 69. Only materials approved by QC can be used for the excipient manufacturing. Art. 70. All tools/recipients used in the sampling procedures must be clean, and, when appropriate, sanitized and/or sterilized. Art. 71. The materials must be stored and handled under conditions in order to prevent the degradation and contamination.

REJECTION AND RE-USE OF MATERIALS Art. 73. RM, Intermediates and Excipients that do not meet the specifications must be identified and controlled so that there is no utilization or releasing for sales.

MATERIALS CONTROL

Art. 74. The rework of the pharmaceutical excipient shall be executed according to pre-established procedures, should be preceded by investigation to identify the reason of failure, after an assessment of the risks to the quality of pharmaceutical excipient. Art. 77. The reworked batch should be evaluated to ensure that it has met established specifications. Art. 78. There should not be be no mixing of batches of pharmaceutical excipients in order to tailor a nonconforming product. Art. 79. There must be procedures for the recovery of RM, intermediates and Pharmaceutical Excipients from waters and others. Art. 80. The new raw materials and solvents recovered can be mixed if they are within the specifications defined.

MATERIALS CONTROL

CHAPTER VIII - PRODUCTION Art. 81. Production operations must follow by clearly defined SOP. Art. 82. Production shall be carried out by qualified/trained personnel. Art. 84. Each step of the manufacturing process must be controlled so that the pharmaceutical excipient is produced according to the established specifications. Art. 86. Production operations must be conducted in a manner to prevent contamination and cross-contamination of intermediates or excipients. Art. 87. Methods such as heating, radiation and other methods to reduce the microbiological load of excipients is acceptable, since the manufacturer demonstrates that product meets the microbiological specifications and the manufacturing process is under control.

Art. 104. Minimum requirements for quality control: I-run tests in accordance with procedures and analytical methods; II-the instruments and equipment are calibrated at set intervals; III-there are instruments and equipment necessary for the carrying out of the trials; and IV-that there are qualified and trained. Art. 106. Reference standards must be appropriate to carry out the analyses of the Intermediates and Pharmaceutical Excipients; Art. 107. The work standards must be properly prepared, identified, analyzed, and stored, approved according to SOP. Art. 108. OOS should be investigated and documented. Art. 109. All raw materials must be checked before use. Art. 110. The process steps that cause quality variability of the pharmaceutical excipient should be monitored.

CHAPTER X – QUALITY CONTROL

Art. 111. in-process controls must be performed by qualified personnel. Art. 113. Must be performed tests on each batch to ensure that the excipient complies with its specifications. Art. 114. Certificate of analysis for each batch of excipient. Art. 116. There should be a written procedure that defines all activities related to the retention samples. Art. 118. When possible, the manufacturer must identify and set appropriate limits for impurities. Art. 119. Should run a program or an evaluation test documented to determine the stability characteristics of the excipient. Art. 121. additional Samples can be stored in conditions of forced degradation (e.g. high temperature, light, humidity etc.) to simulate conditions found during distribution and storage. Art. 122. The results of the tests/assessments of the excipient stability shall be used to determine the appropriate storage conditions and retest dates/validity.

CHAPTER X – QUALITY CONTROL

Art. 123. The manufacturer shall establish a change control system, including the evaluation and approval of changes that may have an impact on the excipient quality. Art. 124. All procedures affected by the changes should be reviewed. Art. 125. Significant changes that may impact on product quality should be notified to customers.

COMPLAINTS AND RECALLS 126. All complaints related to the quality of Pharmaceutical Excipients should be recorded and investigated. Art. 127. The competent health authorities shall be informed immediately. Art. 129. Establishing the person responsible for the measures to be adopted as well the coordination of the recall. Art. 130. Excipients recalled can only be sold or reused after they have been evaluated and released by quality unit.

CHANGE CONTROL

RDC NR. 53/2015 DEGRADATION PRODUCTS

Applies to: Medicines (sinthetics or semi-sinthetics): New Prod; Generics; Similars Do not apply to: Biologics; Biotecnologics; Excipients; Peptídes; Oligonucleotídes; Radiopharmaceuticals; Fermentation Products; Herbal medicines; Vitamins/minerals; Crude Products from animals; Poly aminoacids; Inorganics; Notificação simplificada (notified prods).

Establishes parameters to the verification of the degradation products to perform degradation profile and notify, identify and qualify degradation products formed during the medicines shelf life.

RESOLUTION NR. 53/2015 – DEGRADATION PRODUCTS

Conducted in 1 batch (laboratorial, pilot or industrial); To compare, the sudies should be made with the formulation, placebo and APIs, isolated and associated. DF Studies must be done in all dosage of the medicine. Associations: DF with the APIs isolated and in association and in the fomulation. Companies should present studies with the following conditions: Heating, Humidity; Acid solutions, Base Solutions; Oxidants, Fotolitic exposition; metals ions. If is not possible to apply any of the conditions above technical justification could be used. Tests should promote a degradation upper 10%.

Forced Degradation studies - Requirements

Notification, Identification and Qualification of the Degradation Products during the Stability study of the medicine evaluated with the following conditions:

NOTIFICATION, IDENTIFICATION & QUALIFICATION OF THE DP

Where: 1 – Maximum quantity of the APIs administered per day. 2 – Limites of the DP are expressed as % of the API or Total Diary Dose of the DP. The assessment of the need for notification, identification and qualification of the degradation product (s) should consider the greatest concentration of impurity of degradation found during the stability study. The product (s) with percentage above the degradation limits of the notification establishedmust be reported (s) in the study of stability and be included in the limit of total impurities. The product (s) of degradation with corresponding value or percentage above the identification limits established must have their chemical structure identified and held individual quantification.

NOTIFICATION, IDENTIFICATION & QUALIFICATION OF THE DP

The DP can be considered qualified when it meets, at least, one of the following conditions: (I) – the DP is a significant metabolite found during studies in

humans or animals;

(II) – the amount observed and the proposed acceptance limit of a DP are properly justified in the scientific literature or official textbooks; or

(III) – the amount observed and the acceptance limit proposed for a DP does not exceed the appropriate limit observed in toxicity studies.

QUALIFICATION OF THE DP

This resolution shall enter into force on 23 December 2015 for all marketing authorization, new dosage inclusions or inclusions of new dosage form. To medicines already registered, present in the classification list in annex I to this resolution shall enter into force on 31 December 2017. To medicines already registered, present in the classification list in annex I to this resolution shall enter into force on 31 December 2019. For other medicines already registered, this resolution shall enter into force on 31 December 2020.

ENTRY IN FORCE

ECONOMIC SITUATION X

PHARMA INDUSTRY IMPACTS Perspectives to 2016

BRASIL

Economic situation in 2015

&

Perspectives to 2016

Fonte: Jornal Valor econômico (2 de dezembro de 2015)

Elaboração: Sindusfarma / Gerência de Regulação de Mercados

Fonte: Jornal Valor econômico (2 de dezembro de 2015)

Elaboração: Sindusfarma / Gerência de Regulação de Mercados

BRASIL - GDP Gross Domestic Product – Real rowth rate

Period: 2006 to 2016 (*)

Fonte: Banco Central do Brasil

Elaboração: Sindusfarma / Gerência de Regulação de Mercados / Consultoria Econômica

(*) Estimativa de Mercado

Relatório Focus de 24-03-2016

Aspects of the

Pharmaceutical

Market

Fonte: Jornal Valor econômico (3 de março de 2016)

Elaboração: Sindusfarma / Gerência de Regulação de Mercados

PPP (Pharmacy Purchase Price ou Preço de compra da Farmácia) - é a base de pesquisa que

mede os eventuais descontos das farmácias

PMB – Preço Fábrica sem descontos com imposto inclusos

Pharmaceutical Market- Brasil (Pharmacy)

PeríodoVendas em

Reais PPPVariação %

Vendas em

UnidadesVariação %

Vendas em

Reais PMBVariação %

Percentual de

descontos

2009 24,93 - 1,77 - 30,17 - -17,37%

2010 28,66 14,96% 2,07 16,95% 36,19 19,95% -20,81%

2011 30,41 6,11% 2,36 14,01% 43 18,82% -29,28%

2012 33,89 11,44% 2,61 10,59% 49,92 16,09% -32,11%

2013 37,54 10,77% 2,92 11,88% 58,13 16,45% -35,42%

2014 41,96 11,77% 3,16 8,22% 65,98 13,50% -36,40%

2015 45,03 7,32% 3,39 7,28% 75,55 14,50% -40,40%

27,3%

23,6%

0

100,000,000

200,000,000

300,000,000

400,000,000

500,000,000

600,000,000

700,000,000

800,000,000

900,000,000

1,000,000,000

1,100,000,000

0

1,000,000,000

2,000,000,000

3,000,000,000

4,000,000,000

5,000,000,000

6,000,000,000

7,000,000,000

8,000,000,000

9,000,000,000

10,000,000,000

11,000,000,000

12,000,000,000

13,000,000,000

14,000,000,000

15,000,000,000

16,000,000,000

17,000,000,000

18,000,000,000

19,000,000,000

20,000,000,000

21,000,000,000

22,000,000,000

2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016(*)

Ven

das e

m U

nid

ad

es

Ven

das e

m R

$ e

US

$

PHARMACEUTICAL MARKET - BRASIL (Pharmacy) GENERICS SAILS in (R$), in (US$) and in Units

Period: 2003 to 2016 (*)

Vendas em R$ (**)

Vendas em US$ (**)

Vendas em Unidades

Fonte: IMS Health Elaboração: Sindusfarma / Gerência de Regulação de Mercados (*) 12 meses móveis até Março/2016

Fonte: IMS Market Prognosis, Setembro de 2015

World Market Ranking

1º EUA

2º Japão

3º China

4º Alemanha

5º França

6º Itália

7º Reino Unido

8º Espanha

9º Canadá

10º Brasil

11º Coréia do Sul

12º Austrália

13º Índia

14º México

2010 2015 1º EUA

2º China

3º Japão

4º Alemanha

5º França

6º Reino Unido

7º Brasil

8º Itália

9º Canadá

10º Espanha

11º Venezuela

12º Índia

13º Russia

14º Coréia do Sul

2020 1º EUA

2º China

3º Japão

4º Alemanha

5º Brasil ?

6º Reino Unido

7º Itália

8º França

9º Índia

10º Canadá

11º Espanha

12º Rússia

13º Coréia do Sul

14º México

Politics /Economic Situation Government Changes: Vice president will assume. Stock Exchange: is erasing with the perspective to the Governament remodelling. New govern promises a hard control of expenses and a strong stimulate to the economy. Investiments: International capital will comeback. Pharmaceutical Market: Not affected by the crisis. Until this moment there is not significantly impact.

Thank you / Obrigado!

www.sindusfarma.org.br

Jair Calixto Good Practices & Audit Manager

jaircalixto@sindusfarma.org.br