Título da Apresentação Subtítulo da Apresentação 00.00.0000

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
INTERFARMA
Sindusfarq Sinfar
Sindifargo Sindifar
PRÓGENÉRICOS
GRUPO
FARMABRASIL
SINDUSFARMA
ALANAC
ABRASP
BRASIL – POPULAÇÃO POR ESTADO
451.227
668.689
Sinquifarma
Sindquímica
6.569.683
8.448.055
3.480.937
7.588.078
3.168.133
3.766.834
3.119.015
Population in
2016
205.000.000
3.033.991
732.793
8.796.032
3.120.922
1.383.453
1.560.501
14.021.432
2.068.031
Sinfacope
2.562.963
Sindifargo
6.004.045
19.595.309
2.449.341
3.512.672
SinquifarNP
Sindusfarq
Sinquifar-JF
Quifarmo
10.439.601
41.252.160
15.993.583
Sinfar
6.249.682
Sinqfar
Sindusfarma
10.695.532
Sinqfesc
Sindifar
GMP FOR EXCIPIENTS
RESOLUTION NR. 34/2015
ANVISA COMMENTS
 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.
QUESTIONS & ANSWERS
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.
GENERAL TOPICS
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.
INTERNAL AUDITS
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.
EQUIPMENT
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.
DOCUMENTATION AND REGISTERS
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 & 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.
MATERIALS CONTROL
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.
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.
CHAPTER X – QUALITY 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.
CHANGE 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.
RDC NR. 53/2015
DEGRADATION PRODUCTS
RESOLUTION NR. 53/2015 – DEGRADATION PRODUCTS
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.
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).
Forced Degradation studies - Requirements
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%.
NOTIFICATION, IDENTIFICATION &
QUALIFICATION OF THE DP
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.
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.
ENTRY IN FORCE
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.
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 (*)
(*) Estimativa de Mercado
Relatório Focus de 24-03-2016
Fonte: Banco Central do Brasil
Elaboração: Sindusfarma / Gerência de Regulação de Mercados / Consultoria Econômica
Aspects of the
Pharmaceutical
Market
Fonte: Jornal Valor econômico (3 de março de 2016)
Elaboração: Sindusfarma / Gerência de Regulação de Mercados
Pharmaceutical Market- Brasil
(Pharmacy)
Período
2009
2010
2011
2012
2013
2014
2015
Vendas em
Reais PPP
24,93
28,66
30,41
33,89
37,54
41,96
45,03
Variação %
14,96%
6,11%
11,44%
10,77%
11,77%
7,32%
Vendas em
Unidades
1,77
2,07
2,36
2,61
2,92
3,16
3,39
Variação %
16,95%
14,01%
10,59%
11,88%
8,22%
7,28%
Vendas em
Reais PMB
30,17
36,19
43
49,92
58,13
65,98
75,55
Variação %
19,95%
18,82%
16,09%
16,45%
13,50%
14,50%
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
Percentual de
descontos
-17,37%
-20,81%
-29,28%
-32,11%
-35,42%
-36,40%
-40,40%
22,000,000,000
21,000,000,000
20,000,000,000
19,000,000,000
18,000,000,000
17,000,000,000
16,000,000,000
15,000,000,000
14,000,000,000
13,000,000,000
12,000,000,000
11,000,000,000
10,000,000,000
9,000,000,000
8,000,000,000
7,000,000,000
6,000,000,000
5,000,000,000
4,000,000,000
3,000,000,000
2,000,000,000
1,000,000,000
0
1,100,000,000
1,000,000,000
Vendas em R$ (**)
900,000,000
Vendas em US$ (**)
800,000,000
Vendas em Unidades
700,000,000
600,000,000
500,000,000
400,000,000
300,000,000
200,000,000
100,000,000
0
2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016
(*)
Fonte: IMS Health
Elaboração: Sindusfarma / Gerência de Regulação de Mercados
(*) 12 meses móveis até Março/2016
Vendas em Unidades
Vendas em R$ e US$
PHARMACEUTICAL MARKET - BRASIL (Pharmacy)
GENERICS SAILS in (R$), in (US$) and in Units
Period: 2003 to 2016 (*)
World Market Ranking
2010
2015
2020
1º EUA
1º EUA
1º EUA
2º Japão
2º China
2º China
3º China
3º Japão
3º Japão
4º Alemanha
4º Alemanha
4º Alemanha
5º França
5º França
5º Brasil ?
6º Itália
7º Reino Unido
6º Reino Unido
8º Espanha
7º Brasil
9º Canadá
8º Itália
10º Brasil
9º Canadá
11º Coréia do Sul
12º Austrália
13º Índia
14º México
Fonte: IMS Market Prognosis, Setembro de 2015
10º Espanha
11º Venezuela
12º Índia
13º Russia
14º Coréia do Sul
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
[email protected]