IJRPC 2020, 10(2), 173-190 Nutan Rao et al ISSN: 22312781

INTERNATIONAL JOURNAL OF RESEARCH IN PHARMACY AND CHEMISTRY

Available online at www.ijrpc.com Review Article

DOI: https://dx.doi.org/ 10.33289/IJRPC.10.2.2020.10(31)

COMPARITIVE STUDY BETWEEN ICH

GUIDELINE AND ANVISA GUIDELINE
Kritika Rai, Poornima Potphode, Chandan Gupta and Nutan Rao*
Oriental College of Pharmacy, Sanpada, Navi Mumbai,
Mumbai University, Maharashtra, India.

..
ABSTRACT
In November 2016, The Brazilian National Agency for Health Surveillance (AgênciaNacional de
VigilânciaSanitária - ANVISA) became a member of the International Council for Harmonisation
of Technical Requirements for Pharmaceuticals for Human Use (ICH). Brazil was the first
country in Latin America to join the ICH as a member, and together with South Korea, were the
first two countries to be accepted into ICH as regulatory members. Joining the ICH, the agency
has to fulfil with some obligations such as implementation of guidelines. As a commitment,
within five years, ANVISA should adopt a set of five ICH guidelines that mainly concerns the
Quality, Pharmacovigilance, Clinical Research, implementation of the Common Technical
Document (CTD) and Medical Dictionary for Regulatory Activities (MedDRA). In which we have
focused on Quality. The paper provides a critical assessment to implement the ICH guidelines in
Brazil, with focus on the ICH guidelines for stability studies, analytical validation and
pharmaceutical development. Both guidelines have been selected due to major differences
between the current Brazilian regulations and ICH guidelines, leading to a huge challenge for
the Brazilian Health Authority and the locally established Pharmaceutical Companies to
implement these guidelines. Although many differences still in existing and efforts will be
needed to implement the ICH guidelines in Brazil, ANVISA is putting a lot of efforts to
implement the guidelines within the next years, in an open communication with the Industries,
in order to reduce as much as possible, the impact. The implementation of the ICH guidelines
will bring many benefits for the Industry and Regulator. By implementing the ICH guidelines in
Brazil, the country will contribute to the global regulatory harmonisation, which will bring a
great benefit to the public health and important medicines will be faster available to the
patients.

Keywords: ICH guidelines, ANIVISA guidelines, WHO, Stability Studies.

HISTORY designed in April 1990 at a meeting

ICH in Brussels. The initial goal of ICH is
In the 1980s the European Union began coordinating the regulatory activities of the
harmonizing regulatory requirements. In 1989, European, Japanese and United States
Europe, Japan, and the United States started regulatory bodies in consultation with the
creating plans for harmonisation. The pharmaceutical trade associations from these
International Conference on Harmonisation of regions, to discuss and agree the scientific
Technical Requirements for Registration of aspects arising from product
1
Pharmaceuticals for Human Use (ICH) was registration. Since the new millennium, ICH's

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observation has been directed towards maintaining safeguards on quality, safety,

extending the benefits of harmonisation efficacy, and regulatory obligations to protect
beyond the founding ICH regions. In 2015, public health.
ICH was named as International Council for As per the public health ICH must include the
Harmonisation of Technical Requirements for professional qualifications in their
Pharmaceuticals for Human Use while requirements on the expect of pharmacists
becoming anofficial association in Switzerland must be qualified and organizations
2,3
as a non-profit organisation. The objective of should be enclosed solely pharmacist connect
these reforms was to transform ICH into a truly ed of all health organization.
8
global initiative supported by a powerful and The ICH comprises the following bodies:
4
transparent governance structure. The ICH 1. ICH Assembly
Association established an Assembly as the 2. ICH Management Committee
broadscalegoverning body with an objective of 3. MedDRA Management Committee
focusing global pharmaceutical regulatory 4. ICH Secretariat
harmonisation work in one venue that permits
pharmaceutical regulatory authorities and The ICH Assembly brings alongall Members
concerned industry organisations to be more and Observers of the ICH Association as the
passionately involved in ICH’s harmonisation overarching governing body of ICH. It adopts
work. The new Assembly met for the first time decisions in particular on matters such as on
5
on 23 October 2015. the adoption of ICH Guidelines, admission of
recent Members and Observers, and the ICH
ANVISA Association’s work plans and budget. Member
Brazilian Health Regulatory Agency (in representatives appointed to the Assembly are
Portuguese, AgênciaNacional de supported by ICH Coordinators who
VigilânciaSanitária) is a regulatory body of the represents Member to the ICH Secretariat on
Brazilian government, build in 1999 during a usual.
President Fernando Henrique Cardoso's term The ICH Management Committee (MC) is the
of office. It is authoritative for the regulation body that oversees operational aspects of ICH
and approval of pharmaceutical drugs, on behalf of all Members, as well as
sanitary standards and regulation of the food administrative and financial matters and
industry. oversight of the Working Groups (WGs).
The agency bills itself as "an independently The MedDRA Management Committee (MC)
administered, financially autonomous" is responsible for direction of MedDRA, ICH’s
regulatory body. It is administered by a five- standardized medical terminology. The
member collegiate board of directors, who MedDRA MC has the role of managing,
oversee five thematic directorates, assisted by supporting, and facilitating the maintenance,
5 9
a five-tier oversight structure. Since development, and dissemination of MedDRA.
September 2018 the agency is headed The ICH Secretariat is responsible for day-to-
6
by William Dib. day management of ICH, coordinating ICH
activities as well as providing support to the
INTRODUCTION Assembly, the MC and Working Groups and
International Council for Harmonization of also provides support for the MedDRA MC.
Technical Requirements for Pharmaceuticals The ICH Secretariat is located in Geneva,
for Human Use (ICH) Switzerland.
The International Council for Harmonization of When a new technical topic is accepted for
Technical Requirements for Pharmaceuticals harmonization the ICH WGs are established
for Human Use (ICH) is an initiative that brings by the Assembly, and are charged with
together regulatory authorities and developing a harmonized guideline that meets
pharmaceutical industry to discuss scientific the objectives outlined in the Concept Paper
and technical aspects of pharmaceutical and Business Plan. Face-to-face conference
product development and registration. of the WG will normally only take place during
The ICH mission is to promote public health by the biannual ICH meetings. Interim reports are
achieving greater harmonization through the created at every meeting of the Assembly and
growth of technical Guidelines and made publicly available on the ICH website.
requirements for pharmaceutical product Guidelines
7
registration. The ICH topics are divided into four categories
Harmonization ends up in a lot of rational use and ICH topic codes are assigned according to
10
of human, animal and different resources, the these categories
elimination ofunnecessary delay within Q : Quality Guidelines
the international development S : Safety Guidelines
and handiness of latest medicines whereas E : Efficacy Guidelines

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M : Multidisciplinary Guidelines process lies in the commitment for

ICH Guidelines don't seem to be necessaryfor implementation by ICH Regulatory Members
11
anybody per se but the strength of the ICH using appropriate national/regional tools .

Brazilian agency: ANVISA surveillance. This mission should be carried

Brazil is the largest country in South America out in coordination with states, municipalities
with a population of over 200 million people . and the Federal District, according to the
As a growing market, Brazil has become the Brazilian Unified Health System principles, to
second largest pharmaceutical market in the improve the quality of life of the population.”
emerging world, with an expectation of ANVISA was accepted as a new regulatory
economic growth between 7 to 10% annually member of the International Council on
until 2020. Global pharmaceutical companies Harmonization of Technical Requirements for
are also highly interested in investing in this Registration of Pharmaceuticals for Human
vast and growing market. However, this Use (ICH). As part of the aim to extend its
opportunity may present a significant global outreach, ICH, in November 2016,
challenge when navigating through the welcomed ANVISA from Brazil and the
complex Brazilian regulatory method. Ministry of Food and Drug Safety (MFDS) from
The Brazilian Health Surveillance Agency, South Korea. There are now 13 members and
usually called ANVISA, abbreviated from 22 observers.
Portuguese “Agencia Nacional de Vigilancia
Sanitaria,” is the food and drug regulatory STABILITY GUIDELINE
agency in Brazil. ANVISA was invented in Stability – ICH Guidelines
1999 which is linked to the Ministry of Health. The goal of a stability study is to control the
It is characterized by its administrative quality of drug product or drug substance,
independence, financial autonomy, and by the which may vary with time. There are several
stability of its directors. ANVISA’s vision is to environmental factors such as temperature,
attain legitimation in society as an integral part humidity and light which has to be considered
of the Brazilian Unified Health System, via a during stability study. By means of a stability
nimble, modern, transparent, and domestic study appropriate storage conditions for the
and international benchmark in health drug substance or the shelf-life for the drug
surveillance and regulation. ANVISA’s mission product are established. The ICH has
is “to guard and promote public health and to published several guidelines in order to give
intervene in the risks caused by the production guidance to the applicant on stability testing.
and use of products regulated by health

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Module Topic Last update Information Contained

This Document provides guidance on stability testing
Stability Testing of new drug for new drug substances and drug products considering
Q1A 2003
substances and products relevant temperature and humidity values of different
climatic zones.
Stability Testing : As annex to the main stability guideline (ICH Q1A),this
Q1B Photostability Testing of new drug 1996 document gives guidance on how to evaluate the light
substances and products. sensitivity of new drug substances and products.
This Document provides stability guidance for new
Stability Testing for new Dosage formulation of already approved medicines and
Q1C 1996
forms definition of circumstances under which reduced
stability data can be accepted.
Bracketing and Matrixing Designs
General principles for reduced for stability testing (e.g.
Q1D for Stability Testing of new drug 2002
bracketing matrixing designs)
substances and products
This guidance provides possible situations where
extrapolated of retest period/shelf –lives beyond the
Q1E Evaluation of stability data 2003
real time data may be appropriate (e.g. Statistical
appropriate to stability data analysis)
The ICH Steering Committee endorsed the Withdrawal
Stability Data Packaging for
2006 of the Q1F guideline decided to leave definition of
Q1F Registration Application in Climatic
(Withdrawn) storage condition in Climatic Zones III and IV to the
Zones III and IV
respective Region s and WHO

1.Stability Studies – Active Pharmaceutical

Ingredient the climatic zone classification. However, due
The stability study requirements for the Active to the lack of support from Zone IV countries
Pharmaceutical Ingredient (API) differ claiming higher humidity than the
depending on the country of API manufacture. recommended 65%, Brazil implemented the
In accordance with ANVISA guidance no. 02 WHO (World Health Organization) climatic
from 2013, if the API is manufactured in Brazil zone IVB category (hot/very humid; 30ºC/75%
or manufactured in other climate zones and RH) (refer to Annex 2 for an overview of the
18, 19
used for the manufacture of drug products climatic zones)
within Brazil for dedicated for the Brazilian These are the general requirements for long-
market. API does not need to be tested term and accelerated stability studies in
12 13
according to ANVISA requirements . Brazil
1. Climatic Zone IVB (WHO) hot and
2. Stability Studies – Drug Product humid (30°C ± 2°C/75% RH or 40°C ±
Brazil established different regulations with 2°C/75% RH)
regard to the conduction of drug product 2. Minimum data for submission 3
related stability studies. These cover different batches covering a minimum storage
study aspects: period of 12 months for long-term
13
 RE 01/2005 on medicinal products stability studies or 6 months for
 RDC 45/2012 on active pharmaceutical accelerated and ongoing / long-term
14
ingredients stability studies
 RDC 08/2001 on some specific 3. Shelf-life For a New Drug Application
15
medicines (NDA), the maximum provisional shelf-
 Legislative Ruling IN 04/2007 on life is 24 months. Accelerated stability
16
homeopathic medicines data or 12-months long-term stability
data, which confirm the stability-
There are more mandatory tests then required indicating quality parameters of a drug
by the ICH guidelines. The necessity of these product to change equal to or less
tests is justified by ANVISA due to Brazil’s than 5.0% in comparison to the batch
13, 17
location in climatic zone IVB release analysis results are accepted
In addition, the current valid Brazilian for granting the initial, provisory shelf-
regulations require follow-up stability tests of life.
drug product every 12 months; those studies
must be performed in Brazilian territory, even Frequency of the tests 0, 3, 6, 9, 12, 18, 24
for imported products (in bulk or primary months in case of long-term stability studies
packaging). and 0, 3, 6 months for accelerated stability
studies
It is important to mention that Brazil initially Mandatory tests, unless a technical
adopted the ICH guideline Q1F with regard to justification is presented

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 appearance 2. Clarity of solutions

 quantification of active ingredient 3. Phase separation (for emulsions and
 microbiological limits creams)
 quantification of degradation products 4. Loss of weight (for water-based products)
 In addition for solids
 Storage conditions for accelerated and
Dissolution (solids) long-term stability studies
Hardness (solids)  The following table 3 and table 4 gives an
13
 In addition for semi-solids or liquids overview of the storage conditions
1. Sedimentation rate after agitation (for
suspensions)

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3. Follow up Stability Studies  Quantification of degradation products and

A follow-up stability study is mandatory for the corresponding analytical method
drug product and requested every 12 months,  Microbiological limits
including all tests of a long-term stability study.  Dissolution (solid form)
The number of selected batches depends on  Hardness (solid form)
how many batches are produced per year  pH (liquid and semisolid forms)
(e.g.: one batch of follow-up stability for  Sedimentation rate after agitation in
13
production above 15 batches/year) . suspensions (liquid and semisolid forms)
 Clarity of solutions (liquid and semisolid
4. Photostability Studies forms)
Assessment of Brazilian Requirements  Phase separation in emulsions and
In 2005, ANVISA published a guideline for creams (liquid and semisolid forms)
photostability studies together with the  Loss of weight in water-based products
resolution RE 01/2005, which Compare with (liquid and semisolid forms)
the ICH Q1B.A photostability study intended
for the initial marketing authorisation 5. Stress Testing (DS) / Photostability
application of a drug product in Brazil is testing (DP)
mandatory to be performed with three batches ICH Requirements
.20
for the drug product In addition to the The identification of degradation products
guideline on photostability studies, the under the stress conditions supports the
Brazilian resolution RDC 53/2015 established development and validation of analytical
requirements for the control of degradation procedures. The aim of these studies is to
products and the performance ofspecific ensure that the external factors (e.g.: light
studies with regard to degradation products, exposure) does not result in unacceptable
20, 21
which are not in line with the ICH guidelines . change in the product .

Assessment of implementation regarding Assessment of Brazilian Requirements

ICH Q1 – Stability Studies ANVISA issued a guideline on how to perform
The ICH Q1 guideline provides guidance on photostability studies as attachment to the
the core stability data, which are required for current Brazilian resolution for stability studies
new drug substances and products. The (RE 01/2005). The guidance is aligned with
20
currently valid Brazilian requirements for the ICH Q1B .However, while the ICH
stability studies contain rigid requirements, guidelines require the photostability study to
which are not in accordance with the ICH be performed with at least one drug product
guidelines. batch, three drug product batches are required
13
It is important to know that the Brazilian to be photostability tested by ANVISA .
regulatory system is based on Resolutions, Besides of the requirements regarding
which are mandatory to be followed. Even photostability studies, the Brazilian Resolution
though there are additional guidelines in place, RDC 53/2015 establishes requirements for the
they are only in place for explanatory / control of degradation products. The scope of
recommendatory purposes, but they have to this regulation was expanded beyond the ICH
be aligned with the relevant Resolutions in guideline, as The company must perform the
force (stability and photostability). degradation studies for all strengths of the
medicinal product.
According to the current Brazilian resolution ANVISA accepts technical rationale when any
for stability studies of new medicinal products, of these conditions do not apply. For the
all stability protocols and reports, regardless of implementation of the degradation studies,
the pharmaceutical form, must contain the ANVISA published prioritisation list (Resolution
13
following information RDC 53 Annex I and II) based on the
22
 Description of the drug product and therapeutic classes of the products .
specification of the primary package
 Batch number of each batch involved in 6. Specification and required tests
the study ICH Requirements
 Manufacturer’s description of the drug These tests are needed to monitor and confirm
product, active ingredients that the drug substance / drug product does
 Appearance not experience any change in quality during
 Study plan: material, methods (design) storage under the defined conditions, which
and schedule. can potentially impact safety and/or efficacy of
 Start date of the study the drug product.
 Amount of active ingredient and According to the guideline ICH Q6A on
corresponding analytical method specifications for test procedures and

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acceptance criteria for new drug substances MINIMUM

TIME PERIOD
and new drug products (chemical substances), STORAGE STUDY
STORAGE
COVERED BY
CONDITION
the following tests are mandatory: description, DATE AT
SUBMISSION
identification, assay and impurities including ◦
25 C±2 C / 60%
◦

organic impurities, inorganic impurities Long -

RH ± 5% RH
(degradation products) and residual solvents. Room Or 12 MONTHS
term ◦ ◦
30 C±2 C/ 65%
Tests other than those listed above may be RH ± 5% RH
21, 23
needed in special situations . Long –
Refrigerator 5◦C ±3◦C 12 MONTHS
term
Assessment of Brazilian Requirements Long - ◦ ◦
Freezer -20 C ±5 C 12 MONTHS
The Brazilian regulation has more mandatory term
◦ ◦
tests than established by the ICH Interme 30 C ±2 C/ 65%
Room 6 MONTHS
diate* RH ± 5% RH
guidelines..For all drug products the following Acceler
◦ ◦
40 C ±2 C/ 75%
Room 6 MONTHS
test are mandatory: appearance, quantification ated RH ± 5% RH
◦ ◦
Acceler 25 C ±2 C/ 60%
of active ingredient, microbiological limits. In Refrigerator
ated RH ± 5% RH
6 MONTHS
addition, for solids: dissolution and hardness
tests and for semi-solids or liquids: pH, ◦ ◦
* If 30 C ±2 C / 65% RH ± 5% RH is the long
sedimentation rate after agitation in term condition, there is no intermediate
suspensions, clarity of solutions solutions, condition.
phase separation in emulsions and creams Assessment of Brazilian Requirements
and loss of weight in water-based products. All In 2005, Brazil implemented the stability study
tests must be performed at each stability test requirements for WHO climatic Zone IVb
point, except for the tests for hardness and category (hot/very humid; 30ºC/75% RH); this
microbiological purity, which are solely condition is not considered in the ICH
obligatory at the beginning and at the end guidelines. For the registration of the product,
13
point (= shelf-life) of the stability study . according to the specific resolution for stability
studies (RE 01/2015), long-term stability study
7. Testing Frequency of 12 months or the report of the 6 months
ICH Requirements accelerated stability study are mandatory.
The testing frequency for the long term However, RDC 200/2017 which regulates
stability studies should be every 3 months over general requirements for the registration of
the first year, every 6 months over the second new products, requests long-term and
year, and annually thereafter through the accelerated stability studies. Both regulations
proposed re-test period/shelf-life. For the are in force with contradictory information. The
stability test under accelerated storage main issue is that, after the official approval of
conditions, a 6 months study is recommended a drug product, the Brazilian regulation
employing a testing frequency of three months requires follow-up stability studies every year.
(0, 3 and 6) (ICH, Q1A(R2) guideline- Stability In addition, stability studies for imported
Testing of New Drug Substances and products (as bulk or in primary packaging),
Products, 2003). have to be carried out on Brazilian territory
21,
Assessment of Brazilian Requirements 13, 24
.
The testing frequency for stability studies in
Brazil is the same as defined in the ICH 9. Stability Evaluation
guidelines. The reduced designs (matrixing ICH Requirements
and/or bracketing), where the testing The results of the stability studies need to be
frequency is reduced or certain factor evaluated in order to guarantee that the
combinations are not tested at all, can be also physical, chemical, biological and
applied (ANVISA, Brazilian Resolution – RE Nº microbiological aspects do not show relevant
1 – Stability Studies on medicinal products, changes over the storage period, which might
2005). impact the quality of the drug substance / drug
product. Certain variability can be accepted;
8. Storage Conditions however, the results must be within the pre-
ICH Requirements specified parameter ranges. Extrapolation of
In general, the stability studies for drug the real time data applying long term storage
products applying long-term and accelerated conditions is accepted and the applicant can
storage conditions are sufficient. However, if request to extend the re-test period/shelf-life
there is any significant change in the quality of for the drug substance / drug product based
the drug product (e.g.: failure to meet the on this data. However, in order to be accepted,
acceptance criteria), studies employing this request needs to be technically justified
intermediate storage conditions must be (allowing extrapolation to 36 months based on
21
conducted . 25
24 months stability data) .

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Assessment of Brazilian Requirements  Identification tests;

The Brazilian regulations offer limited options  Quantitative tests for impurities' content;
for alternative risk-based approaches and  Limit tests for the management of
scientific justifications with regard to impurities;
extrapolating stability data. Brazil regulations  Quantitative tests of the active moiety in
RE Nr. 1 and RDC Nr. 45 do not allow samples of drug substance or drug
extrapolation of shelf-life beyond 24 months product or alternative selected
for Drug Product and API. This approach component(s) in the drug product.
presents challenges to globally operating
companies as they cannot harmonize product Although there are several other analytical
shelf life during product launch. while such procedures, like dissolution testing for drug
shelf-life is limited to 24 months in Brazil until products or particle size determination for drug
13
actual 36 months data are available. substance, these have not been addressed in
the initial text on validation of analytical
ANALYTICAL VALIDATION procedures. Validation of these additional
Validation of analytical methods analytical procedures are equally important to
Resolution number 166, dated July 24th, 2017 those listed herein and may be addressed in
establishes the factor for the validation of subsequent documents.
analytical methods and alternative provisions.
Similarly to other resolutions from ANVISA, the Identification tests are meant to make the
non-fulfillment of any criteria shall be identity of an analyte in a sample. Thiscan
technically justified and after the justification it commonly be achieved by comparison of a
will be subjected to analysis by ANVISA. property of the sample to that of a reference
Resolution 166 brings clarity on validation standard;
parameters for methods used for  Impurities for can be either a quantitative
pharmaceutical ingredients, drug products, test or a limit test for the impurity in a
and biological products in all productionstages sample. Test intends to accurately reflect
filling an important gap in guidance for the the purity characteristics of the sample.
sponsors. The scope of this resolution does  Assay procedures to measure the analyte
not embrace microbiological methods that are present in a given sample. For the drug
compendial or have been technically justified. product, similar validation characteristics
The major point in this resolution is that an also apply when assaying for the active or
analytical method that is not described in the for the other selected component(s).
official compendium recognized by ANVISA
requires an analytical validation. A full The aim of the analytical procedure should be
validation should embrace accuracy, clearly understood since this will govern the
repeatability precision, intermediate precision, validation characteristics which are needed to
selectivity, and limit of detection, limit of be evaluated. The Validation characteristics
quantification, linearity, and interval. A partial which need to be considered are listed below:
validation mustinclude at least the parameters  Accuracy
of precision, accuracy, and selectivity. A copy  Precision
of the approved validation report or the petition  Repeatability
number under which the final version of such  Intermediate
report was filed must be provided In case of  Precision
transfer of methods that have already been  Specificity
approved by ANVISA. A revalidation of an  Detection
analytical method will only be considered  Limit Quantitation
when there are  Limit Linearity
- Changes in the synthesis or acquiring of  Range
Active Pharmaceutical Ingredient (API);  Robustness
-Changes in product composition;
-Changes in the analytical method; In the following circumstances furthermore
-Other changes that may considerably impact revalidation may be necessary are:
26
the validated method.  Changes within the synthesis of the drug
substance;
1. GENERAL PROVISIONS  Changes within the composition of the
ICH Requirements finished product;
Types of Analytical Procedures to be validated  Changes within the analytical procedure.
The discussion of the validation of analytical The degree of revalidation required usually
procedures is directed to the four most typical depends on the nature of the changes. Certain
varieties of analytical procedures: other changes may require validation as well.

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- signifies that this characteristic is not normally evaluated

+ signifies that this characteristic is normally evaluated
(1) In cases where reproducibility (see glossary) has been performed, intermediate precision is not
needed
(2) Lack of specificity of one analytical procedure could be compensated by other supporting
analytical procedure(s)
10
(3) May be needed in some cases

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Assessment of Brazilian Requirements  Linearity

In the case of analytical methodology not  Interval
described in pharmacopoeias or official forms,  Precision
duly recognized by ANVISA, the methodology  Detection Limit (Sensitivity)
will be validated, provided that the following  Limit of Quantification
parameters are evaluated, as specified in  Accuracy
Tables  Robustness
 Specificity and Selectivity

In the case of transfer of methodologies from headquarters to its subsidiaries in the Brazil and / or
national companies to the equivalence study centers the methodology will be considered validated,
provided parameters of precision, specificity and linearity. To guarantee the analytical quality of the
results, all equipment used in the validation should be properly calibrated and analysts should be
qualified and properly trained.

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Validation shall demonstrate that the analytical results from samples which do not contain the
method produces reliable results and is analyte. Additionally, the identification test may
suitable for the purpose it is designed in a be applied to materials structurally similar to or
documented way and by objective criteria. closely related to the analyte to confirm that a
The use of analytical method described in positive response is not obtained.
official compendia not recognized by Anvisa Assay and Impurity Test(s) - For
requires conducting an analytical validation, as chromatographic procedures, representative
parameters established, taking into chromatograms ought to be used to
consideration the technical operating demonstrate specificity and individual
conditions. components should be appropriately labelled.
The compendial analytical methods should In cases where a non-specific assay is used,
have demonstrated their suitability for the alternate supporting analytical procedures
intended use, the operating conditions in the should be used to demonstrate overall
laboratory, by presenting a partial validation specificity. The approach is same for both
study. assay and impurity tests. Impurities are
The partial validation should evaluate at least available for the assay, this should include
the parameters of precision, accuracy and demonstration of the discrimination of the
selectivity. analyte in the presence of impurities and/or
1. In the case of analytical methods for the excipients; practically, this can be done by
quantification of impurities, partial spiking pure substances (drug substance or
validation shall include the quantification drug product) with appropriate levels of
limit. impurities and/or excipients and demonstrating
2. In the case of limit test, replacing the that the assay result is not affected by the
heading of parameters should be presence of these materials. For the impurity
evaluated the parameters of selectivity test, the discrimination could also be
and detection limit. established by spiking drug substance or drug
product with appropriate levels of impurities
In the case of transfer method between and demonstrating the separation of these
laboratories, this will be deemed valid, impurities individually and from other
provided that it is a study of partial validation components in the sample matrix.
premise receiver laboratory. The transfer Impurities are unavailable - If impurity or
method between laboratories with the same degradation product standards are not
quality management system can be available, specificity may be demonstrated by
accomplished through a study of partial comparing the test results of samples
validation, in accordance with the assessment containing impuritiesor degradation products
27, 28
of reproducibility. to a second well-characterized procedure.
Peak purity tests could also be useful to show
2. Analytical Parameters of Validation that the analyte chromatographic peak is not
1. Specificity attributable to more than one component (e.g.,
10
ICH Requirements diode array, mass spectrometry).
An investigation of specificity ought to be
conducted throughout the validation of Assessment of Brazilian Requirements
identification tests, the determination of Analytical method selectivity shall be shown by
impurities and also the assay. The procedures means of its ability of identifying or quantifying
which are used to demonstrate specificity will the analyte of interest undoubtedly in the
depend on the intended objective of the presence of components that may be found in
analytical procedure. Demonstration that an the sample, such as impurities, diluents and
analytical procedure is specific for a particular matrix components. For chromatographic
analyte (complete discrimination) is not always methods, the chromatographic purity of the
possible. In this case a combination of two or analyte signal shall be proven, except for
more analytical procedures is usually biologic products. Identification methods, its
recommended to achieve the mandatory level ability of obtaining a positive result for the
of discrimination. sample containing the analyte and a negative
Identification appropriate identification result for other substances present in the
testsought be able to discriminate between sample shall be demonstrated.
compounds of closely related structures which To demonstrate the selectivity of identification
are likely to be present. The discrimination of a methods, the test shall be carried out with
procedure is also confirmed by obtaining substances that are structurally similar to the
positive results (perhaps by comparison with a analyte, and the acceptance criterion is a
known reference material) from samples negative test result.
containing the analyte, including with negative

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For active pharmaceutical ingredients of analytical response should be detailed by an

vegetal origin and drug products containing appropriate function of the concentration of an
such APIs, the method’s ability to distinguish analyte in a sample. For the establishment of
the material of interest from other similar linearity, a minimum of 5 concentrations is
vegetal materials, especially those found as recommended. Other approaches should be
10
adulterants and substituents, shall be justified .
demonstrated.
To reach the required level of selectivity, a Assessment of Brazilian Requirements
combination of two or more analytical methods The calibration curve represents the
of identification may be needed. relationship between the instrument response
For quantitative methods and limits test, and the known concentration of the analyte. A
selectivity shall be demonstrated by calibration curve should be generated for each
evidencing that the analytical response is due drug and analytical run, which will be used to
to the analyte only, without interference of the calculate the drug concentration in the
diluent, matrix, impurities or other degradation samples using the same biological matrix
products. To show the lack of interference of proposed for the study.
degradation products, the sample has to be The calibration curve shall include analysis of
exposed to degradation conditions with a wide the white sample (drug-free and internal
range of pH, oxidation, heat and light. The standard-free biological matrix), the zero
following are exempted from the sample (biological matrix plus the internal
demonstration described above: standard) and at least 6 (six) samples
I – products whose adequacy to the resolution containing drug and internal standard,
establishing parameters for notification, contemplating the expected range of variation,
identification and qualification of degradation from LOQ up to 120% of the highest
products in drug products has already been concentration to be analyzed.
shown. To determine the calibration curve, samples
II - performance methods; extracted from the appropriate matrix should
27, 28
III - non-chromatographic methods. be analyzed for at least 6 (six) different
concentrations.
2. Linearity Alternative procedures should be justified,
ICH Requirements such as in obtaining a nonlinear correlation,
A linear relationship ought to be evaluated where a greater number of standard
across the range of the analytical procedure. It concentrations will be required.
may be demonstrated directly on the drug Results should be analyzed by appropriate
substance and separate weighing of synthetic statistical methods, such as the least-squares
mixtures of the drug product components, linear regression calculation. The curves
using the proposed procedure. The latter obtained (experimental and the resulting from
aspect can also be studied during investigation the mathematical treatment), the linear
of the range. Evaluation of the linearity can be correlation coefficient, the angular coefficient
done by visual inspection of a plot of signals and the line intercept must be presented.
as a function of analyte concentration or Calibration curve acceptance criteria
content.  less than or equal to 20% (twenty
Test results should be evaluated by percent) deviation from the nominal
appropriate statistical methods if there is a concentration for the LOQ;
linear relationship, for example, by calculation  deviation less than or equal to fifteen
of a regression line by the method of least percent (15%) from the nominal
squares. In some cases, to obtain linearity concentration for the other
between sample concentrations and assays, concentrations of the calibration curve;
the test data may need to be subjected to a  At least four out of six calibration
mathematical transformation prior to the curve concentrations must meet the
regression analysis. The y-intercept, above criteria, including the LOQ and
correlation coefficient, slope of the regression the highest calibration curve
line and residual sum of squares should be concentration;

submitted. Plots of the data need to be The linear correlation coefficient must
27, 28
included. Additionally, an analysis of the be equal to or greater than 0.98
deviation of the actual data points from the
regression line may also be helpful for
evaluating linearity.
Some analytical procedures, example
immunoassays, do not demonstrate linearity
after any transformation. In this case, the

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1. For the assay of a drug substance

normally from 80 to 120 % of the test
concentration;
2. For content uniformity, which covers a
minimum of 70 to 130 % of the test
concentration, unless a wider more
appropriate range, based on the
nature of the dosage form (e.g.,
metered dose inhalers), is justified;
3. For dissolution testing the range is +/-
20 % over the specified range
4. For the determination of an impurity:
from the reporting level of an impurity
from 1 to 120% of the specification;
5. For impurities known to be unusually
potent or which produce toxic or an
unexpected pharmacological effect,
the detection/quantitation limit should
be commensurate with the level at
which the impurities must be
controlled;
6. For validation of impurity test
procedures carried out during
development, it may be necessary to
consider the range around a
suggested limit.
7. If purity and assay are performed
together as one test and only a 100%
standard is used, linearity should
cover the range from the reporting
level of the impurities from 1 to 120%
10
3. Range of the assay specification .
ICH Requirements
The specified range is normally derived from Assessment of Brazilian Requirements
linearity studies which depends on the Interval
intended application of the procedure. It is The range specified is the range between the
established by confirming that the analytical upper quantitation limits and the bottom of an
procedure provides an acceptable degree of analytical method. It is usually derived from
accuracy, linearity and precision when applied the study of linearity and depends on the
to samples containing amounts of analyte intended application of the method. It is
within or at the limit of the specified range of established by confirmation that the method
the analytical procedure. The following has adequate accuracy, precision and linearity
minimum specified ranges will be considered: when applied samples containing quantities of
substances within the specified range.

Table: Percentage limits of analyte content that must be contained

27, 28
in the linearity range for some analytical methods
Test Scope
Quantitative determination of analyte in
80% to 120% of theoretical test concentration
raw materials or pharmaceutical forms
From the expected impurity level up to 120% of the
specified upper limit. Where they are of toxicological
significance or unexpected pharmacological effects,
Determination of impurities
the limits of quantitation and detection should be
appropriate to the amount of impurities to be
controlled.
Content uniformity 70% to 130% of theoretical test concentration
± 20% over the specified value for the range. If the
specification for dissolution involves more than one
Dissolution test
time, the Method range should include -20% over the
smallest value and + 20% over the largest value.

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4. Accuracy a) Drug
ICH Requirements 1. Applying the proposed analytical
Accuracy should be accepted across the methodology in the analysis of a
specified range of the analytical substance of known purity (reference
procedurevarious methods for determining standard)
accuracy are available: 2. Comparison of the results obtained with
a) Implementation of the analytical those resulting from a well characterized
procedure to synthetic mixtures of the second methodology, the accuracy of
drug product components to which which has been established.
known quantities of the drug
substance to be analyzed have been b) Pharmaceutical form
added; 1. Analyzing a sample in which known
b) In cases where it is impossible to get amount of drug was added to a mixture
samples of all drug product of drug components (contaminated
components, it may be acceptable placebo);
either to add known quantities of the 2. Where samples of all drug components
analyte to the drug product or to are unavailable, analysis by the
differentiate the results obtained from standard addition method is accepted, in
a second, well characterized which known amounts of analyte
procedure, the accuracy of which is (reference standard) are added to the
stated and/or defined; drug.
c) Accuracy should be concluded once
precision, linearity and specificity have c) Impurities
been established. 1. Analysis by the standard addition
d) Impurities Accuracy should be method, in which known amounts of
assessed on drug substance/drug impurities and / or degradation
product spiked with known amounts of products are added to the medicament
impurities. In cases where it is or drug
impossible to get samples of certain 2. In the case of unavailability of samples
impurities and/or degradation of certain impurities and / or
products, it is considered acceptable degradation products, comparison of
to differentiate results obtained by an the results obtained with a second
independent procedure. The response well-characterized method
factor of the drug substance can also (pharmacopoeial methodology or
27,
be used. other validated analytical procedure)
28
Recommended Data Accuracy should be
evaluated using a minimum of 9
determinations over a minimum of 3 Accuracy is calculated as a percentage
concentration levels covering the specified recovery of the known amount of analyte
range (e.g., 3 concentrations/3 replicates each added to the sample, or as the percentage
of the total analytical procedure). Accuracy difference between the means and the
should be described as percent recovery by accepted true value plus confidence intervals.
the assay of known added amount of analyte The accuracy of the method must be
in thesample or as the difference between the determined after establishing the linearity, the
mean and the accepted true value together linear range and the specificity of the method,
10
with the confidence intervals. being verified from at least 9 (nine)
determinations considering the linear range of
Assessment of brazilian requirements the procedure, ie 3 (three). Concentrations,
The accuracy of an analytical method is the low, medium and high, with 3 (three) replicates
proximity of the results obtained by the method each. Accuracy is expressed by the
under study to the true value. relationship between the experimentally
Several methodologies for determining determined mean concentration and the
accuracy are available: corresponding theoretical concentration

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29
Table: Analyte recovery at different concerntration

1. Precision 1. Repeatability (intra-run precision)

ICH Requirements Agreement between results within a short time
Validation of tests for quantitative with the same analyst and same
determination of impurities and for assay instrumentation.
includes an investigation of precision. The repeatability of the method is verified by at
least 9 (nine) determinations, considering the
1. Repeatability linear range of the method, that is, 3 (three)
Repeatability should be assessed using: concentrations, low, medium and high, with 3
a) a minimal of 9 determinations covering the (three) replicates each or minimum of 6. 100%
specified range for the procedure (e.g., 3 determinations of the test concentration.
concentrations/3 replicates each);
b) a minimal of 6 determinations at 100% of 2. Intermediate precision (inter-race
the test concentration. precision)
Agreement between results from the same
2. Intermediate Precision laboratory, but obtained on different days, with
The range to which intermediate precision different analysts and / or different equipment.
should be proved depends on the For the determination of intermediate accuracy
circumstances under which the procedure is a minimum of 2 different days with different
intended to be used. The applicant should analysts is recommended.
prove the effects of random events on the
precision of the analytical procedure. Typically, 3. Reproducibility (inter-laboratory
the variations which need to be studied include precision)
days, analysts, equipment, etc. Agreement between results obtained in
different laboratories as in collaborative
3. Reproducibility studies, generally applied to standardization of
Reproducibility is evaluated by means of an analytical methodology, for example, to
inter-laboratory trial. Reproducibility should be include methodology in pharmacopoeias. This
considered in the case of the standardization data need not be submitted for registration
of an analytical procedure, for inclusion, for grant.
instance of procedures in pharmacopoeias. The Precision of an analytical method can be
expressed as the standard deviation or relative
4. Recommended Data standard deviation (coefficient of variation) of a
The standard deviation, relative standard series of measurements.
deviation that is coefficient of variation and Precision can be expressed as relative
confidence interval should be reported for standard deviation (DPR) or coefficient of
10
each type of precision investigated. variation (CV%) according to the formula,

Assessment of Brazilian Requirements

Precision is the evaluation of the proximity of
the results obtained in a series of
measurements of a multiple sampling of the where SD is the standard deviation and CMD
same sample. This is considered on three the mean concentration determined.
levels. The maximum acceptable value should be
defined according to the methodology

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employed, the concentration of the analyte in Table: Factors that must be considered in
the sample, the type of matrix and the purpose determining the robustness of the
of the method, with values not exceeding analytical method
27, 28
5%. Stability of Analytical Solutions
Sample Preparation
Extraction Time
Solution pH variation
4. Robustness Spectrophotometry Temperature
ICH Requirements Different solvent manufacturers
The evaluation of robustness depends on the Mobile phase pH variation
type of procedure under study and should be Mobile phase composition
variation
considered during the development phase. It Liquid
Different column batches or
should show the accuracy of an analysis with Chromatography
manufacturers
respect to deliberate variations in method Temperature
parameters. If measurements are similar to Mobile phase flow
Different batches or column
variations in analytical conditions, the manufacturers
analytical conditions should be suitably Gas Chromatography
Temperature
controlled or a precautionary statement should Carrier gas velocity
be included in the procedure. One outcome of
the evaluation of robustness should be that a PHARMACEUTICAL DEVELOPMENT
sequence of system suitability parameters For the pharmaceutical development ANVISA
(e.g., resolution test) is established to ensure follows the ICH Guidelines but the only
that the validity of the analytical procedure is difference is that, they require dissolution
maintained whenever used. Examples of development report.
typical variations are: The harmonization of pharmaceutical
 stability of analytical solutions; development requirements and mutual
 extraction time. recognition of pharmaceutical development
For liquid chromatography, examples of typical inspections, is necessary to avoid duplication
variations are: of work (less inspections) and also decrease
 impact of variations of pH in a mobile of costs - for the manufacturer as well as for
phase; the authority. Also, it would speed up the
 influence of variations in mobile phase process of bringing new medicines to the
composition; Brazilian market. As Brazil is an ICH member
 different columns (different lots and/or adhering to ICH principles, ANVISA could rely
suppliers); on ICH development of pharmaceutical
 temperature; product and Agencies from US/EU/JP could
 flow rate. rely on Brazilian inspections in future. This
In the case of gas-chromatography, examples would be a benefit for the evolving ICH
of typical variations are: community and would save time and money.
 different columns (different lots and/or
suppliers); CONCLUSION
 temperature ANVISA was the first regulatory authority in
10
 flow rate. Latin America to become a member of the
ICH. Joining the ICH, the agency has to fulfill
Assessment of Brazilian Requirements some obligations such as the implementation
The robustness of an analytical method is a of ICH guidelines. The aim of this work was
measure of its ability to withstand small and the critical assessment of the implementation
deliberate variations of analytical parameters. of the ICH guidelines in Brazil with specific
Indicates your confidence during normal use. focus on the requirements for both guidelines
During the development of the methodology, have been selected due to the major
the robustness assessment should be differences between the current Brazilian
considered. Given the susceptibility of the resolutions and ICH guideline.
method to variations in analytical conditions, Based on the present assessment, many
these should be controlled and precautions differences still exist between the current
27, 28
should be included in the procedure. Brazilian resolutions and the ICH guidelines.
Substantial efforts from both sides, ANVISA as
well as the pharmaceutical industry, will be
required in the beginning in order to implement
the ICH guidelines in Brazil. But although
many efforts and investments will be needed,
it is clear that the adaption of the Brazilian
dossier to the CTD format and the
implementation of further ICH requirements

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will result in a tremendous benefit for both, the 9. Mullin Theresa . International
pharmaceutical industry, avoiding the need to Regulation of Drugs and Biological
reformat the dossier for each new drug Products. In Gallin, John I, Ognibene,
application in Brazil, as well as for ANVISA, Frederick P, Lee Johnson and Laura
facilitating the regulatory reviews and (eds.). Principles and Practice of
communication with other health authorities. Clinical Research. Academic Press.
ANVISA is putting a lot of effort in 2017;92.
implementing the ICH guidelines. This 10. http://www.ich.org.
includes open conversation with the 11. Van Boxtel, Chris J, Santoso Budiono,
pharmaceutical industry, in order to reduce the Edwards annd Ralph. Drug Benefits
impact for both sides as much as possible and and Risks: International Textbook of
ultimately achieve the goal. ANVISA is gaining Clinical Pharmacology. IOS Press.
experiences on the ICH principles and soon 2008;70.
they will feel more confident to completely 12. ANVISA Guidance n02, on climatic
fulfill all ICH requirements, and reduce the zone for Active Pharmaceutical
number of additional requirements for Brazil. Ingredient, February
The harmonization of the documents will 2013http://portal.anvisa.gov.br/docum
reduce duplication of studies such as different ents/33836/352852/Orienta%C3%A7
stability studies, analytical validation and %C3%A3o+de+Servi%C3%A7o+n%C
pharmaceutical development which are 2%BA+02+de+2013+-+GGMED%2C+
currently performed in order to comply with de+01+de+ fevereiro+de
different regulations of individual countries. +2013/92b4e625-d090-400e-bbc2-
This will speed up the access to medicinal f90ec3a93b57
products for the patients in Brazil. 13. ANVISA- Brazilian Resolution – RE Nº
1 – Stability Studies on medicinal
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