Regulatory Strategy for Long-Term Stability Conditions to Support Submission in Zone IV Countries

This paper provides a recommendation for selection of long-term stability conditions for submission of room temperature storage drug products in Zone IV countries in the face of a confusing mixture of expectations from international regulatory bodies. This confusion has resulted from multiple messages from groups such as the International Conference on Harmonization (ICH), the World Health Organization (WHO), regional associations of nations, and several individual countries themselves. The scope of this paper covers drug products currently in development as well as approved drug products which may be required to provide Zone IV stability data as a condition for registration renewal or to support post-approval changes.

Drug substances (active pharmaceutical ingredients) are not explicitly covered in this paper. However, it is worth noting that stability study conditions for API are based on the mean kinetic temperature and anticipated humidity exposure of the actual storage conditions for the API. Drug substances manufactured or used by many firms typically are not exposed to Zone IV storage temperatures for any significant period of time. Short-term exposure to local ambient conditions during the transportation period to drug product manufacturing sites can be supported by accelerated stability data packages (40ºC/75%RH).

It has long been recognized that the difference in climatic conditions in varying regions of the world need to be taken into consideration when planning stability studies to determine the shelf-lives of drugs. Grimm examined world climatic data and demonstrated the importance of taking this into account by proposing different stability conditions for different climatic zones [1,2]. Zone I was defined to Temperate, Zone II Subtropical or Mediterranean, Zone III hot and dry, and Zone IV hot and humid. This work provided a basis for the ICH to propose a unified approach among the United States, the European Union, and Japan, all in climatic Zone II, for stability studies to be performed at 25ºC/60% RH for long-term testing in 1993 [3].

Further work by the ICH Stability Working Group led to the idea of a single long-term stability condition for Zone IV countries which would also serve as an intermediate condition/alternative long-term condition for Zone II countries. Their proposal to use 30°C/65% RH as this condition was embodied in ICH Q1F, which was adopted by the ICH Steering Committee in February 2002 [4]. However, the proposal did not receive sufficient support from Zone IV countries, many of which noted that they experienced higher relative humidity than the recommended 65%.

In 2005 the ASEAN group of nations (Indonesia, Malaysia, the Philippines, Singapore, Thailand, Brunei, Burma (Myanmar), Cambodia, Laos, and Vietnam) published a draft regional stability guidance that called for long-term stability studies to be performed at 30ºC/75% RH [5]. Soon after, Brazil, which had changed its long-term stability requirement from 30ºC/70% RH to 30ºC/65% RH after the publication of ICH Q1F, changed again, this time to 30ºC/75% RH [6]. As a result, ICH withdrew the Q1F guidance in 2006 [4].

In October of 2005, the WHO took the position of creating a Zone IVa and IVb which would have long-term stability data requirements of 30ºC/65% RH and 30ºC/75% RH, respectively, and allowing each country to designate which sub-zone it was in [7]. The current WHO stability guidance has an appendix listing countries and the sub-zone they have selected [8].

In addition to requiring Zone IV stability data for registration of new drugs, a number of countries, such as Brazil, also require that firms provide Zone IV stability data for registration renewals or to support post-approval changes, even where such data was not in the original submission [6].

RECOMMENDED APPROACH FOR PROVIDING STABILITY DATA FOR ZONE IV COUNTRIES

Since some Zone IV countries require 30ºC/75%RH stability studies while others will accept 30ºC/65%RH data, firms wishing to register their drugs globally are faced with a dilemma. It is not economically practical to perform two sets of Zone IV stability studies, one at 30ºC/65%RH and another at 30ºC/75%RH.

Therefore, we recommend that room temperature drug products to be registered in Zone IV countries be supported by:

1. 30ºC/75%RH long-term stability data on at least one package configuration for dry solid oral products.
2. 30ºC long-term stability data on at least one package configuration for parenteral products.
3. Other package configurations for solid oral products and parenterals may be tested under Zone IV conditions as above or dealt with by bracketing.

One clarification regarding point (b) above is useful to note. The exclusion of humidity in the recommended conditions for stability studies of parenterals is specific to drug products packaged in impermeable containers. The exclusion is not based on the product itself but on whether it is packaged in an impermeable container and intended for room temperature storage. The classification of packaging as moisture impermeable should be evaluated based on Moisture Vapor Transmission Rate (MVTR) data. It should be noted that glass vials with a rubber stopper are not automatically defined as impermeable by any regulatory authority. Where 30°C/75%RH data do not exist, but either 30ºC/65%RH data or 30ºC/ambient humidity data are available, it may be possible TESTINGto demonstrate that a particular vial/stopper/crimp combination is impermeable by providing actual MVTR data to the regulators.

Development teams must look carefully at early stability data and at marketing plans and decide on packaging that will provide adequate protection at 30ºC/75%RH. Packaging more protective than that used for Zone II countries may be needed. Teams will also have to determine when to begin the primary stability studies at Zone IV conditions. This timing will be a business decision based on submission plans in the Zone IV countries which require this data, therefore communication between marketing and development and Regulatory Affairs is essential.

For products marketed in Zone IV countries which require 30ºC/75% RH or 30ºC/65%RH stability data for registration renewal or to support post-approval changes, the development team should assess the available stability data. Data may have been generated at 30ºC/65%RH (per the withdrawn ICH Q1F recommendations). Many Zone IV countries will accept this data, in some cases even where 30ºC/75% RH is expected for new products. If neither 30ºC/75% RH or 30ºC/65%RH data is available, new stability studies may need to be initiated. This may mean that the product packaging has to be reevaluated, as some products that are stable at 25ºC or 30ºC at low humidity, may not be so at 30ºC/75% RH.

Table 1 - Countries Recommended for Zone II Long-Term Stability Conditions
A: From regional harmonization groups (e.g., ASEAN, ICH and GCC) or country regulators to WHO
B: From country regulators to WHO at 13th International Conference of Drug Regulatory Authorities (ICDRA),16–18 September 2008
C: Information provided by the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) based on literature references

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The remainder of this paper includes three tables derived from the 2009 WHO stability guidance [8] covering approximately 200 countries and listing both the long-term stability conditions provided for in the WHO document and our recommended long-term stability conditions. Table 1 lists those countries for which 25ºC/60%RH is recommended in the WHO guide. Our recommendation for the countries listed in Table 1 is to use either 25ºC/60%RH or 30ºC/75%RH. If a drug product is sufficiently stable, then 30ºC/75%RH represents a single long-term stability condition TESTINGfor all global submissions. If the drug product is not sufficiently stable, then 25ºC/60%RH would be used for registration in the US, EU, and other Table 1 countries. For registration in other countries, more protective packaging or other measures to ensure stability at 30ºC/75%RH would be necessary.

Table 2 - Countries Known to Expect Zone IV Long-Term Stability Conditions
A: From regional harmonization groups (e.g., ASEAN, ICH and GCC) or country regulators to WHO
B: From country regulators to WHO at 13th International Conference of Drug Regulatory Authorities (ICDRA),16–18 September 2008

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Table 3 - Countries Estimated to Have Zone IV Climatic Conditions That Did Not Provide Specific Requirements to WHO
C: Information provided by the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) based on literature references

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Table 2 lists those countries for which 30ºC/75%RH is recommended in the WHO document based on information taken from a regional guidance such as the ASEAN stability guidance [5] or from direct communication from a specific country’s health authorities to WHO [8]. Table 3 lists countries for which 30ºC/75%RH is recommended based on climatic information obtained by WHO from the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA). For countries listed in Table 3, because WHO could not obtain a clear indication of their long-term stability requirement, it is essential to verify current expectations on a country-by-country basis for every planned regulatory document which requires stability data whether for registration, re-registration, or post-approval changes. If the current stability requirements for a country cannot be verified, then 30ºC/75% RH data requirements for countries in Table 3 must be assumed as accurate and such data provided in regulatory submissions.

In summary, this paper represents a snapshot in time with our current best understanding of expectations in approximately 200 countries; verification of a country’s regulatory expectations in respect to Zone IV stability should be considered as country expectations continue to evolve and change.

SOME COUNTRY-SPECIFIC NOTES

1. The entry for Canada in the WHO guidance lists the long-term stability condition as 30ºC/65%RH only [8]. This is at odds with Canada’s adoption of its own version of the ICH Q1A guidance which clearly states, “It is up to the applicant to decide whether long-term stability studies are performed at 25 ± 2°C/60% RH ± 5% RH or 30°C ± 2°C/65% RH ± 5% RH [9]." Therefore we have placed Canada in Table 1.
2. The entry for Iraq in the WHO guidance provides for a long-term stability condition of 30°C/35% RH [8]. This is presumably because Iraq is actually a climatic Zone III country, that is, hot and dry. Long-term stability testing at low humidity is particularly important for drugs in aqueous solution in semi-permeable containers to ensure that moisture loss from the drug product over time does not lead to excessive concentration, erroneous dosing or drug substance precipitation. Such testing is provided for in ICH Q1A [3]. If it cannot be established that the container is of sufficiently low permeability, then long-term testing at 30°C/35% RH should be considered.
3. The entry for Israel in the WHO guidance provides for a long-term stability condition of 30°C/70% or 30°C/75% RH, but it is our understanding that Israeli regulators consider it to be a Zone II country and are working with WHO to change its entry in the guidance. As noted above, regulatory expectations must be verified.
4. Questions frequently arise regarding the classification of Australia. As stated in the Australian Regulatory Guidelines for Prescription Medicines, Appendix 14, Australia has climatic conditions encompassing ICH Zones II-IV, and accepts data generated at stability conditions as laid out in ICH Guidelines [10]. Australia, therefore, does not require Zone IV stability data.
5. Questions also frequently arise regarding Puerto Rico. As a territory of the US with commonwealth status, Puerto Rico is subject to U.S. Federal Laws, e.g., 21CFR 276 (b)(13). “United States means the Customs territory of the United States (i.e., the 50 states, the District of Columbia, and the Commonwealth of Puerto Rico), but not the Territories." The U.S. FDA expectation of Zone II stability conditions therefore includes Puerto Rico.

CONCLUSION

There has been a great deal of confusion about the proper choice of long-term stability conditions for various countries. This has resulted from conflicting advice from sources such as ICH and WHO that would otherwise have been expected to provide clear, scientifically based recommendations in this area. The decision of WHO to accept a mixture of 30°C ± 2°C/65% RH ± 5% RH and 30°C ± 2°C/75% RH ± 5% RH on a country-by-country basis for climatic Zone IV lead to our recommendation to select 30°C ± 2°C/75% RH ± 5% RH as a single condition to be used for all Zone IV countries since running parallel stability studies at both conditions would be prohibitively expensive. There have also been questions of how, exactly, it can be determined whether a country is a Zone IV country or not. Since the WHO has decided to let each country determine its own status without providing a clear cut set of temperature/humidity criteria to differentiate one climatic zone from another, a list of countries with assignments is needed. This paper provides such a list in Tables 1-3, basing it on the 2009 WHO stability guidance. It is important to remember, however, that the information in this paper represents the situation at the time of writing and with 200 countries to deal with, some change must be expected over time. Therefore, the recommendations provided in this paper should be verified prior to initiating stability studies.

REFERENCES

1. Grimm, W. Drugs Made in Germany, 28, 196-202 1985.
2. Grimm, W. Drugs Made in Germany, 29, 39-47 1986.
3. ICH Q1A (R2), Stability Testing of New Drug Substances and Products (current version 2003). http://www.ich.org/LOB/media/MEDIA419.pdf.
4. ICH Q1F, Stability Data Package for Registration Applications in Climatic Zones III and IV, (published 2002, withdrawn 2006) http://www.ich.org/LOB/media/MEDIA3124.pdf.
5. ASEAN Guideline On Stability Study Of Drug Product 2005.http://pharmalytik.com/images/stories/PDF/asean%20stability%20guidelines%20-%2022%20feb%202005.pdf.
6. Resolution No. 1 of July 29, 2005, Guide For The Undertaking Of Stability Studies, Brazil 2005.
7. Consultation of Stability studies in a global environment, WHO 2005. (http://www.who.int/medicines/areas/quality_safety/quality_assurance/ConsultStabstudies/en/).
8. WHO Expert Committee on Specifications for Pharmaceutical Preparations, 43rd Report, Annex 2, Stability testing of active pharmaceutical ingredients and finished pharmaceutical products, WHO Technical Report Series, No. 953, 2009, pages 87-127.http://www.who.int/medicines/publications/pharmprep/pdf_trs953.pdf#page=101.
9. Canada: Adoption of ICH Guidance: Stability Testing of New Drug Substances and Products - ICH Topic Q1A(R2), file number 03-118437-914 2003. http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/ich/qual/q1a(r2)-eng.php.
10. Australian Regulatory Guidelines for Prescription Medicines, Appendix 14, Stability Testing, 2004. http://www.tga.gov.au/pmeds/argpmap14.pdf.