Correia (GSK), Vozone (Hovione), Sigari (Merck), Evans (Catalent), Castro (AstraZeneca), Gonzalo (Novartis), Nagao (IPAC-RS) †Corresponding Author (lee.nagao@dbr.com)

A Comparison of Brazil ANVISA and ICH Stability Requirements for Inhalation Products

Paula Correia, Carla Vozone, Nastaran Sigari, Carole Evans, Eva Castro, Lilian Gonzalo, Lee Nagao†

Brazil is in the Zone IV climate condition (hot/humid). ICH Q1F adopted in 2002 and withdrew in 2006 the idea of a single long-term stability condition (30°C/65% RH) for Zone IV countries which would also serve as an intermediate condition/alternative long-term condition for Zone II countries. Brazil had initially adopted ICH Q1F, but due to lack of support from Zone IV countries claiming higher relative humidity than the recommended 65%, Brazil implemented the World Health Organization (WHO) Zone IVb category (hot/very humid; 30ºC/75% RH). [3] The tables below summarize the long-term and accelerated testing conditions for Drug Product applicable to products locally manufactured or imported. The stability of the Active Pharmaceutical Ingredient (API) has different storage requirements depending on the country of manufacture. If the API is manufactured in Brazil or manufactured in other climate zones and exported to Brazil for use in manufacturing of drug products for the Brazil market, it must comply with the requirements of Zone IVb. [1] If the drug product is manufactured overseas, the API doesn’t need to be tested according to Brazilian requirements.[4]

Stability Testing Conditions

The IPAC-RS Global Regulatory Review and Outreach (GRRO) Brazil Group

Mission: formed in 2012 to lead outreach to Brazil regulatory, standards, and industry bodies; and to provide information and education about Brazil regulatory issues for inhalation and nasal products, to IPAC-RS members.

Deliverables: Provided comments to the Brazil National Agency of Health Surveillance (ANVISA) on its inhalation products equivalence draft technical notices, worked with the IPAC-RS Population Bioequivalence (PBE) Working Group to provide perspectives on current “state of the science” of PBE to ANVISA, and is providing, via its local members, information on current OIP related activities in Brazil.

Analysis of ANVISA and ICH Stability Requirements

The Brazilian pharmaceutical market includes products from multinational companies that must meet local requirements in addition to International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) requirements. This poster identifies major points of dissimilarity between ICH and Brazilian stability approaches focusing on storage conditions, shelf-life determination, reduced testing approaches and data analysis, and identifies areas for potential harmonization. Pharmaceutical product stability for registration, renewals and post-approval changes in Brazil is regulated by the National Agency of Health Surveillance (ANVISA) and are included in two key regulations for stability studies, RE Nr. 1 and RDC Nr. 45. [1,2]

Introduction

* minimum data at submission

* 12 months minimum data at submission (12 months long term data is the minimum data at submission when 6 months accelerated data are not provided)

ANVISA accepts at registration of a new product or API, data from 3 different batches, which can come from pilot scale production in most circumstances. A fully representative process is typically established by a minimum quantity equivalent to 10% to a third of the commercial batch size, also considering the minimum capacity of the industrial equipment used. For post-approval changes, the variation can be submitted with stability data of one to three batches, depending on the nature of the changes implemented. However, unlike FDA and EMA, ANVISA doesn’t accept pilot batches if the dosage is below 0.99 milligrams.

At drug product or API registration, ANVISA requires 12 months long term or 6 months accelerated data (together with preliminary on-going, long term study results). A maximum provisional shelf-life of 24 months is allowed, if the data supports it. This period must be confirmed with actual long term studies of 24 months. Contrary to ICH [5], Brazil regulations RE Nr. 1 and RDC Nr. 45 do not allow extrapolation of shelf-life beyond 24 months for Drug Product and API. This approach presents challenges to globally operating companies as they cannot harmonize product shelf life during product launch. For instance, ICH might allow extrapolation to 36 months based on 24 months data, while such shelf-life is limited to 24 months in Brazil until actual 36 months data are available.

RE Nr. 1 introduces the concept of “follow-up stability studies” (annual stability studies), which are studies done post-approval and required for renewals. These studies are necessary for administrative reasons related to registration maintenance and are done in all circumstances. Follow-up studies of imported products (both bulk or in primary package) must be carried out in Brazilian territory. Thus, Brazil requests studies on imported bulk materials as well as final product.

The frequency of tests in follow-up studies, including imported batches, is every 12 months. Selection of batches are (i) one batch per year, for production above 15 batches/year; (ii) one batch every 2 years, for production equal to or lower than 15 batches/year; (iii) for products with different concentrations and presentation, follow-up stability can be done in the one with more batches manufactured in the year.

Shelf-life at Approval and Follow-up Stability Studies

ICH guidelines require evidence that the analytical method is stability indicating to its formulation. ANVISA lists in RE 01 a number of tests that are mandatory unless a technical justification is presented (see table). These stability tests are mandatory for approval and follow-up stability testing. In some cases, such technical justification is not always accepted.

Stability Indicating Tests

ANVISA has provided a technical recommendation (Annex I of RE Nr. 1) regarding the use of reduced models of the stability study plan. The concepts of Agrupamento (Bracketing) and Matrizacao (Matrixing) are similar to those of ICH Q1D.[6]

The ANVISA perspective on data analysis for extrapolation to the provisional shelf-life of maximum 24 months, is described in RE Nr. 1 part 2.10. ANVISA allows for extrapolation when the 12 months long-term or 6 months accelerated stability report shows test variation equal to or smaller than 5.0% of the batch release analysis. Moreover, if dosage (assay) variations are from 5.1% to 10.0% in the accelerated stability study, the provisional shelf life is limited to 12 months, thus dis-allowing extrapolation of the data beyond 12 months. This contrasts with the ICH approach to extrapolation, which considers it appropriate to extend the shelf life following a stepwise approach described in the ICH Q1E Decision Tree – this allows an extension of shelf life up to a maximum of 12 months beyond the period covered by long-term data. [7] In some circumstances, a statistical analysis is required. An appropriate approach to shelf life estimation is to determine, for a certain test, the earliest time at which the 95% confidence limit for the mean intersects the specification limit.

Data Analysis

Conclusions The stability requirements for registration of pharmaceutical products in Brazil follow, for the most part, international guidances, in particular ICH. Nonetheless, there are specific differences particular to Brazil which have the potential for being harmonized. IPAC-RS identifies the following potential areas for harmonization that would benefit global drug development:

• Shelf life estimation based on extrapolation of accelerated and long term stability studies could follow ICH, EU and FDA guidelines, allowing extrapolation beyond the maximum provisional shelf-life of 24 months permitted by ANVISA

• The follow-up stability requirements on imported intermediate products could be waived as it is redundant to the requirement in the finished drug product

• Stability studies required at submission on OINDPs with dosage below 0.99 milligrams could be allowed in pilot scale batches

• Stability tests should be those attributes that are susceptible to change during storage and are likely to influence quality, safety and/or efficacy . Tests should be selected based on the type of pharmaceutical dosage form and knowledge of the formulation and process and in consideration of a risk assessment of the potential quality impacts resulting from changes in scale or manufacturing, rather than using a prescribed list of mandatory tests. These tests should cover, as appropriate, the physical, chemical, biological, and microbiological attributes, preservative content, and functionality test and the analytical procedures should be stability indicating

References

1. ANVISA Resolution RE Nr 1, of July 29, 2005. Guide for the Undertaking of Stability Studies

2. ANVISA Resolution RDC Nr 45, of August 9, 2012 . Regulates the Conductance of Studies on Active Pharmaceutical Ingredients Stability

3. World Health Organization (WHO). Annex 2. Stability testing of active pharmaceutical ingredients and finished pharmaceutical products. WHO Technical Report Series, No. 953, 2009.

4. GMED/ANVISA service order Nr 02/2013, of February 1st, 2013 . API Stability Studies

5. ICH Q1A(R2) Stability Testing of New Drug Substance and Products, 2003

6. ICH Q1D Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products, 2002

7. ICH Q1E Evaluation of Stability Data, 2003

Acknowledgements

The authors thank the GRRO Brazil Group for input and support of this poster, the IPAC-RS Board of Directors for support, and ANVISA for providing general information.

*No stability indicating tests specific for OINDPs are listed in RE Nr. 1

Long

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Conditions Package Stability

Temperature Stability Humidity

Storage Condition

Frequency of Tests

Room Condition

Semi-

permeable 30ºC ± 2 ºC 75% RH ± 5 % 15-30ºC

0, 3, 6, 9, 12*,

18 and 24

months

Impermeable 30ºC ± 2 ºC None 15-30ºC Same

Frozen All -20ºC ± 5 ºC None -20ºC Same

Refrigerated All 5ºC ± 3 ºC None 2-8ºC Same

Acce

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Stab

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Prod

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Conditions Package Stability

Temperature Stability Humidity

Storage Condition

Frequency of Tests

Room Condition

Semi-

permeable 40ºC ± 2 ºC 75% RH ± 5 % 15-30ºC

0, 3, 6* months

Impermeable 40ºC ± 2 ºC None 15-30ºC

Refrigerated Semi-

permeable 25ºC ± 2 ºC 60% RH ± 5 % 2-8ºC

Refrigerated Impermeable 25ºC ± 2 ºC None 2-8ºC

Frozen All -20ºC ± 5 ºC None -20ºC

Long

Ter

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Stud

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Activ

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Conditions Stability

Temperature Stability Humidity

Storage Condition

Minimum Data at Submission

Room Condition

30ºC ± 2 ºC 75% RH ± 5 % 15-30ºC

12 months

5ºC ± 3 ºC None 2-8ºC

Refrigerated -20ºC ± 5 ºC None -15ºC to -25ºC

Frozen 30ºC ± 2 ºC 75% RH ± 5 % 15-30ºC

Acce

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Sta

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Conditions Stability

Temperature Stability Humidity

Storage Condition

Data at Submission

Room Condition 40ºC ± 2 ºC 75% RH ± 5 % Up to 30ºC

6 months

Refrigerated

25ºC ± 2 ºC 60% RH ± 5 % 2-8ºC

Man

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in R

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Pharmaceutical Forms Mandatory stability tests

All pharmaceutical forms

Appearance Contents of Active Ingredient Quantification of degradation products Microbial limits

All solid pharmaceutical form Dissolution Hardness

Liquid and semi-solid forms

pH Sedimentation after shaking Clarity in solutions Phase separation in emulsions and creams Weight loss in aqueous base products