USP Controlled Room Temperature Range Expansion

1 STIMULI TO THE REVISION PROCESS Stimuli articles do not necessarily reflect the policies of the USPC or the USP Council of Experts USP Controlled room Temperature Range Expansion Desmond G Hunt,a Chris Chandler,b David A. Ulrich,c Richard Poska,c and Arminda Monteroc ABSTRACT This article provides a brief overview of drug product stability studies and practices with a focus on Temperature control during storage and distribution. Recent stability studies support redefining Controlled room Temperature (CRT) by broadening the permitted Range when appropriate for specific products. The objectives of this Stimuli article are to initiate discussion and solicit public comments regarding a potential revision as yet unproposed in PF of USP's definition for Controlled room Temperature from 20 25 to 2 30 . BACKGROUND The design of stability studies during pharmaceutical product development and registration takes into account expected supply-chain storage and distribution conditions in anticipated markets.

2 These studies include open-dish research on newly discovered drug substances, studies on various clinical formulations, and evaluation of varied packaging configurations. Relatively early in the development process, research teams gain awareness of the general stability of a compound as well as the effects of formulation on product stability. By the time formal registration studies are initiated, Temperature and humidity conditions are built into the studies to represent environments outside the typical International Congress on Harmonization (ICH) Zone II conditions and to include ICH Zone IVb conditions, if within product capability (See Table 1, Table 2, and Table 3.). Thus, stability studies support the most stringent markets and storage and distribution environments. Table 1. ICH Stability Zones Zone Type of Climate Zone I Temperate zone Zone II Mediterranean/subtropical zone Zone III Hot dry zone Zone IV Hot humid/tropical zone Zone IVb ASEANa testing conditions: hot/higher humidity a ASEAN, Association of Southeast Asian Nations.

3 Table 2. Long-Term Testing Conditions Climatic Zone Temperature Humidity Minimum Duration Zone I 21 2 45% 5% rH 12 months Zone II 25 2 60% 5% rH 12 months Zone III 30 2 35% 5% rH 12 months Zone IV 30 2 65% 5% rH 12 months Zone IVb 30 2 75% 5% rH 12 months Refrigerated 5 3 No humidity 12 months Frozen (ICH) 20 5 No humidity 12 months Frozen (USP) 10 to 25 No humidity Table 3. Accelerated and Intermediate Testing Conditions Climatic Zone Temperature Humidity Minimum Duration Accelerated ambient 40 2 75% 5% rH 6 months Accelerated refrigerated 25 2 60% 5% rH 6 months Accelerated frozen 5 3 No humidity 6 months Intermediate 30 2 65% 5% rH 6 months Temperature ranges permitted during pharmaceutical product distribution, as well as the labeled storage conditions, are inseparably linked to stability data for each product. In 2004, regulations for cold chain shipping practices established the requirement that distributed products had to be shipped within their labeled storage Temperature Range (typically 2 8 as per USP general chapter Packaging and Storage Requirements 659), regardless of unlabeled stability data supporting otherwise.

4 As for the impact of ambient humidity excursions during distribution, if a drug product's primary packaging system has been qualified and offers moisture protection matching the product's stability testing and sensitivity over its shelf life, there is no need to monitor for the humidity Thus, the pharmaceutical industry has focused solely on ensuring Temperature control during distribution. Changes in the regulatory landscape since 2004 have expanded the definition of Temperature - Controlled distribution to include all storage conditions for pharmaceuticals, including Controlled room Temperature (CRT) products. Expansion of the regulations to encompass CRT makes it difficult to ship products at their labeled storage Range . A significant reason for this is that currently marketed CRT products are not labeled to conform to a standard storage Temperature Range , as with cold chain products. The Temperature Range for USP CRT is defined as 20 25 however distribution is allowed in a cool 8 15 place or refrigerated 2 8 CRT ranges on product labels can vary, even within an organization, and can differ from the USP definition (see Figure 1).

5 Figure 1. CRT ranges on product labels. The current USP Temperature Range for CRT is very narrow and does not take into account expanded drug product stability data. Tight storage ranges can result in perceived shipping excursions and rejected lots for products that would certainly meet USP product specifications. Thus, the lack of an industry-accepted CRT label Range creates difficulties in distribution controls. In addition, the current technology ( , Temperature monitoring, packaging) in place for Temperature - Controlled products has been developed specifically for products distributed at 2 8 , and when utilized for CRT distribution, tends to be costly and extremely inefficient. REDEFINING Controlled room Temperature : LABELING FOR STORAGE AND DISTRIBUTION CONDITIONS The pharmaceutical industry aims to generate stability data that can support labeling products with a wide Temperature Range . A wide Range can encompass typical excursions encountered when shipping products, including pharmacy mail order distribution and the patient in-use period.

6 As industry accomplishes this objective, the current CRT Range of 20 25 is becoming outdated, creating the need to redefine the Temperature ranges around which industry can continue to design stability studies. For example, if a drug product (chemical molecule/solid dosage form) is stable at room Temperature (25 or 30 ) for 24 months and is also stable at 2 for 24 months, there is no benefit, and potentially a disadvantage, to label as opposed to 20 25 vs. 2 30 . Furthermore, if freeze-thaw studies for solid dosage forms demonstrate that there are no physical stability issues at 15 , then labeling the product 15 to 30 would be appropriate; however, labeling that says store below 30 or do not freeze could create confusion without including the lower limit. Such stability data, which are generated at all stages of a product's life cycle, can be and are being used to expand the distribution Temperature ranges on the labels of drug products. Utilizing mean kinetic Temperature (MKT) is acceptable if a program is developed to use MKT with upper and lower Temperature boundaries and the destination country allows the use of CONCLUSION Historically, stability studies supported product storage in a relatively narrow Temperature Range such as 20 25 or 15 25.

7 In light of recent research and requirements from governments, pharmacists, and patients, this Stimuli article advances a view that the definition of CRT in USP general chapter Packaging and Storage Requirements 659 be revised to take into account and permit ranges supported by stability data, for example store between 2 and 30 . The proposed expansions of the CRT Range in USP would facilitate the distribution of drug products, remove uncertainty, and promote long-term value to industry by building a strong foundation of stability data. The aforementioned will ultimately promote the efficient distribution of products among global partners in the ever-expanding CRT and cold chain environment (see PDA Technical Report 53).4 This will also help standardize the definition of CRT and develop a CRT Range that is more consistent with other countries' Ministries of Health and current distribution It is recommended that both the primary packaging and the case labels list both the storage conditions (and distribution conditions if different) and typical excursion Temperature data, , store below 30 , excursion to 40 for 1 month.

8 A USP Scientific Liaison. Correspondence should be addressed to: Desmond G. Hunt, , Senior Scientific Liaison, USP, 12601 Twinbrook Parkway, Rockville, MD 20852-1790; ; e-mail b USP Packaging, Storage, and Distribution Expert Committee. c AbbVie Inc. 1 Seevers , Yoon S., and Schineller. An Assessment of the Impact on Pharmaceutical Product Quality Resulting from Humidity Exposure during Distribution by Modeling Moisture Ingress, PF 38(6), 2012. 2 Packaging and Storage Requirements 659, USP 36 NF 31, 2013. 3 Seevers , Hofer J., Harber P., Ulrich , and R. Bishara. The Use of Mean Kinetic Temperature (MKT) in the Handling, Storage, and Distribution of Temperature Sensitive Pharmaceuticals. 4 PDA Technical Report No. 53: Guidance for Industry: Stability Testing to Support Distribution of New Drug Products, 2011. 5 Annex 5 Good Distribution Practices (GDP) for Pharmaceutical Products, World Health Organization, 2010.