Humidity Effect On Pharmaceuticals

38(6) Stimuli to the Revision Process: An Assessment of the Impact on Pharmaceutica...
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STIMULI TO THE REVISION PROCESS

Stimuli articles do not necessarily reflect the policies of the USPC or the USP Council of Experts
An Assessment of the Impact on Pharmaceutical Product Quality Resulting from Humidity Exposure during Distribution by Modeling Moisture Ingress Robert H Seevers, PhD,a b Seung-yil Yoon, PhD,b Matthew K Schineller, MSb c ABSTRACT Temperature excursions during pharmaceutical product storage and distribution may present a risk to product quality. What if any risk to product quality is associated with relative humidity excursions encountered during storage and distribution? This question was the subject of a 2009 Romanian regulation (since withdrawn) that would have required monitoring of humidity conditions during transport of medicines. This Stimuli article re-addresses this question by examining the protective properties provided by various types of primary packaging using a validated moisture-vapor transfer model. The information presented here is relevant to topics discussed in Good Storage and Shipping Practices 1079 , Monitoring DevicesTime, Temperature, and Humidity 1118 , and other general chapters that address pharmaceutical product storage. Future revisions to these chapters may benefit from the information presented in this Stimuli article. DEFINITIONS At the beginning of any discussion of the effects of humidity on the quality of drugs, it is essential to start with the following definitions: Absolute humidity is the actual amount of water vapor in a volume of air. Normally this is expressed as the mass of water vapor per cubic meter of air. Relative humidity is the ratio of the partial pressure of water vapor in air to the vapor pressure of saturated air at a given temperature. A brief calculation illustrates this point: For an air temperature of 25 C, the amount of water vapor in saturated air is 23.0 g/m . If 3 the actual measured value instead is 13.8g/m , then the relative humidity is 60%. The values for absolute humidity and corresponding relative humidity at various temperatures have been tabulated (1). Water activity (Aw) is a measure of the vapor pressure of water in a substance divided by the vapor pressure of pure water at the same temperature and is essentially a measure of the free water in a material. SCOPE The inquiry presented in this paper applies to all pharmaceutical materials, including drug products, active pharmaceutical ingredients, bulk drug products held for packaging, or other intermediates that may be exposed to varying levels of humidity during distribution. For the purposes of this paper, distribution includes everything that happens to a
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pharmaceutical material from the date of manufacture through end use and comprises both storage and transportation by various means. Refrigerated and frozen materials are excluded from this discussion because the humidity risks to these products are taken to be minimal because absolute humidity is low under these long-term conditionseven though the relative humidity may be high. THEORY OF MOISTURE PERMEATION THROUGH A BARRIER Pharmaceutical packaging, including bottles, blisters, and vials, serves as a barrier to protect the product from its external environment and to ensure that a product's safety and efficacy are not compromised during storage. Although the containers provide a means to limit entry of moisture into the product, the barrier they provide is permeable and may be penetrated by moisture. After bottles or blisters containing a pharmaceutical product are closed, the contents of the package reach equilibrium vapor pressure with the headspace inside the package. Zografi et al. developed a mathematical model to predict the final relative water vapor pressure in a closed system for a multicomponent mixture of solids, such as a pharmaceutical product within a package, using the water content for each component (2). Because packaging is permeable to moisture, if the vapor pressure outside the package is greater than that inside the package, moisture may permeate into the system. In this case, the components of the package (product, desiccant, headspace, air, etc.) reach equilibrium dynamically while moisture permeates through the packaging materials into the package. Once inside the package, moisture equilibrates among the headspace and the material contained, including a desiccant if present. Normally, equilibrium among the components is achieved faster than moisture permeation from outside the package through the packaging material, so within several days the vapor pressure inside the package achieves equilibrium. At the initial equilibrium point, the headspace, product, and any desiccant all have the same vapor pressure. However, they have different moisture contents: the moisture in the product and the moisture in the desiccant both have the same thermodynamic state. If the package is exposed to a greater external vapor pressure, e.g., an environment with 75% relative humidity (RH), moisture permeates through the package into the interior. The basic equation for moisture transfer through a permeable package is derived from Fick's law in combination with Henry's law (3):
where M = moisture content (dry weight), g H2O/g dry weight of solid t = storage time P = permeability of the package A = surface area
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= thickness of the material Wd = dry weight of the solid pout = vapor pressure of water outside the package at a given temperature pin = vapor pressure of water inside the package at a given temperature Any moisture that permeates into the package is distributed among components of the package, including product, desiccant, and the package headspace based on each component's moisture-sorption isotherms. Kontny et al. developed a mathematical model to estimate the moisture content of the components in a permeable package using a sorptiondesorption moisture transfer (SDMT) model (4). Kontny then used this model to develop a method to determine the amount of moisture permeation into a container over storage time. This approach predicts the moisture distribution among the product, desiccant, and headspace. The amount of moisture in the package at time t = 0 (mT, at time=0) can be determined by Equation [2]: mT, at time=0 = WdAMA + WdBMB + mh [2]
mT = total mass of moisture inside the package WdB = dry weight of solid B WdA = dry weight of solid A MA = moisture content of solid A, g H2O/g dry weight of solid A MB = moisture content of solid B, g H2O/g dry weight of solid B mh = mass of moisture in the package headspace. Once the amount of moisture permeating into the package is calculated for a time interval j, this mass of water can be added to mT, at time=0 to obtain mT, at time=j, the amount of water inside the container at the end of this time increment. After time interval j, the total moisture in the system (mT, at time=j) can be expressed by Equation [3]: mT, at time=j = mT, at time=0 + w [3]
where w = mass of moisture that has permeated into the package. The SDMT model can be applied to obtain the relative vapor pressure (p/ps)in inside the package at a time equal to time interval j. This method then can be iterated to obtain (p/ps) in at each time interval through the total storage time, where the time associated with a calculated (p/ps)in is obtained by summing the time interval j. In order to calculate the vapor pressure (p/ps)in inside the package, analysts must know the mathematical relationship of each component's moisture content with respect to RH via the sorption isotherm. The sigmoidal moisture-sorption isotherms of tablets fit well with the Guggenheim/Anderson/De Boer (GAB) equation (5), and the hyperbolic moisturesorption isotherms of desiccants such as silica gel fit well with the Langmuir equation over
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the range of RH between 10% and 90% (6). From Equation [2] the mass of moisture (mA) in component A can be calculated with either the GAB or the Langmuir equation: mA = WdA MA(GAB) mA = WdA MA(Langmuir) [4a] [4b]
where, MA(GAB) or MA(Langmuir) = moisture content associated with component A as given by the GAB or Langmuir equation for component A at any relative humidity. Although water vapor does not behave as a perfectly ideal gas, it is still possible to apply the ideal gas law to closely approximate the mass of moisture in the headspace volume (mh):
where ps = saturation vapor pressure of water at a given temperature p/ps = relative water vapor pressure. R = gas constant, 0.08205 Latm/molK T = absolute temperature ( K) In order to determine ps, analysts can consult a psychrometric chart or a table of moisture vapor pressure in saturated air at a given temperature. Alternatively, ps can be calculated by using saturation vapor pressure equations. These equations also are necessary to compute the equilibrium vapor pressure values by the iterative method described above. This iterative process is the basis of a computer model that can calculate the equilibrium vapor pressure for the components of a system as a function of time when the initial state is known. When the temperature changes, the saturation vapor pressure at the new temperature is easily calculated mathematically. For an example, the GAB equation for a product and the Langmuir equation for a desiccant can be used, so Equation [2] written in its entirety takes the form:
where WmA, CgA, and KA = GAB constants of component A WmB and CLB = Langmuir constants of component B. The mass of moisture (w) that permeates into a package during a time interval j can be calculated by Equation [7]: w = P j [(p/ps)out (p/ps)in] [7]
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Equation [3] written in its entirety takes the form: mT, at time=j = mT, at time=0 + {P j [(p/ps)out time interval j. Verification of the Model Modeling results using this approach have been compared to experimentally determined moisture content or water activity and have been found to be consistent. The following examples verify the application of modeling: Several different package configurations were prepared: a. Four-count 75-cm induction heat sealed bottles of product A tablets containing 0.6 g of silica gel desiccant. b. Thirty-count 75-cm induction heat sealed bottles of product A tablets containing 1.5 g of molecular sieve desiccant. c. One product B tablet in 2-mil PCTFE blister. We used 2 different tablets and desiccants to verify the modeling results as shown in Table 1. Samples were stored 6 months under accelerated stability conditions (40 C/75% RH). In addition, samples stored at ambient conditions were periodically evaluated for water activity. Sorption isotherms between 25 C and 40 C are similar, so the experimentally measured water activity at ambient temperature can be used to estimate water activity by modeling at 40 C. Water vapor transmission rates were determined experimentally at 40 C/75% RH and then were converted to permeability constants at 40 C. Table 1. Inputs for the Modeling Packages P at 40 C 75-mL bottles: Products Desiccants Tablet A Silica gel Wd: 180 mg/tablet Mi: 3% Molecular sieve Mi: 2.6% Mi: 3% Tablet B Wd: 100 mg/table Mi: 2.2%
3 3
(p/ps)in]}
[8]
where (p/ps)in is the final relative water vapor pressure in the equilibrated system at each
2-mil Aclar:
Figure 1 shows estimated water activity (Aw) from the modeling and experimentally determined Aw for the various packaging configurations considered. The molecular sieve has a higher sorption capacity than the silica gel has at low RH, so the water activity change over time is different between tablets that contain silica gel and molecular sieve
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Figure 1. Comparison of water activity between estimated and experimentally determined values for various packaging configurations. Figure 1 shows good agreement between estimated and experimentally determined Aw over time. Therefore, this model can be used to accurately estimate the product's Aw change for RH and temperature excursion during storage and distribution. Moisture prediction modeling has been verified and is well known throughout industry. This modeling can be applied to estimate the moisture content (or Aw) of products that may experience an RH excursion. METHODS USED TO APPLY MODELING TO ASSESS THE RISK OF HUMIDITY EXCURSIONS We considered several scenarios to evaluate the risk resulting from exposure to RH outside of approved long-term storage conditions. We considered a packaged pharmaceutical product and, based on the known moisture vapor transmission rate of its containerclosure system, determined the amount of water that would enter or leave the package as a result of various humidity excursions that might be encountered during the distribution process. We designed worst-case scenarios of time, temperature, and RH exposure. The first scenario represents drug product stored in a warehouse and portrays the environmental conditions that would result from a heating, ventilation, or air conditioning (HVAC) failure for extended periods, chosen to be 7 days and 45 days. This failure would increase the temperature and RH exposure of the drug product in storage. Critically, the temperature increase, assumed to rise from 25 C to 30 C, permits a much higher absolute value of water content in the storage environment. Thus, the RH is assumed to rise from 60% to 75% at the higher temperature. A 45-day loss of HVAC is unlikely but was chosen as a worst-case scenario. The second case is shipment by truck with no environmental controls assuming that the environment in the trailer begins at 25 C/60% RH, but the temperature increases to 60 C (7). The absolute humidity in a trailer at 25 C/60% RH would lead to an RH of 10% at 60 C at equilibrium. To evaluate a worst case, we assumed that the RH instead would be 20% at 60 C and that the duration of the excursion would be 7 days. This time frame exceeds the expected time for a coast-to-coast truck shipment in the United States. Humidity external to the truck is assumed not to readily permeate into the interior of the truckotherwise such circulation would inevitably lead to a decrease in temperature.
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The final scenario models shipment by ocean vessel. Available data suggest that ambient conditions would be 25 C and 80% RH (J.P. Emond, personal communication). This represents a humidity excursion from the assumed ICH long-term storage condition of 25 C/60% RH. Because such a temperature excursion might occur during ocean shipment, conditions of 40 C/35% RH also were modeled. An RH of 35% was selected as representative of expected RH during an ocean voyage. The excursion was assumed to last for the duration of the voyage, which was set at 45 days. Table 2. Scenarios of Excursions Scenario Warehouse Storage Real-time Stability Conditions 25 C and 60% RH Excursions 30 C and 75% RH for 7 days or 30 C and 75% RH for 45 days 60 C and 20% RH for 7 days 25 C and 80% RH for 45 days or 40 C and 35% RH for 45 days
Truck Shipment 25 C and 60% RH Ocean Shipment 25 C and 60% RH
INPUTS For modeling, we selected a typical tablet formulation containing a sugar or starch matrix. The individual tablet weight, 300 mg, was arbitrarily chosen to produce a tablet that would fit in size 0 blister cavities. Moisture sorption isotherms were determined experimentally at 25 C and 40 C. The moisture sorption isotherm at 60 C was not determined because we assumed that isotherms between 40 C and 60 C would not be significantly different. Certain dosage form and package combinations (e.g., vials, cartridges, and foil/foil blisters) were not selected because they offer little or no moisture vapor permeability, and thus products packaged in these formats are subject to negligible risk because of humidity excursions. Bottle and blister formats were chosen as inputs because they represent the most common packaging for solid oral drug products and because they are subject to moisture vapor permeation. We selected polyvinyl chloride (PVC) blisters, polychlorotrifluoroethylene (PCTFE) blisters, and high density polyethylene (HDPE) bottles for modeling. We experimentally determined water vapor transmission rates of packages at 60 C. When package permeability was not available (e.g., at 30 C), we used the Arrhenius relationship to estimate the permeability. We found that the permeability of blisters at 60 C is approximately 30 times higher than that for blisters at 25 C, and the permeability of bottles at 60 C is approximately 18 times higher than that of bottles at 25 C. MODELING RESULTS We performed moisture prediction modeling using the inputs described above. The model exposed the packaged product for an initial 6-month period to standard ICH controlled room temperature conditions (25 C and 60% RH). Packages then were exposed to the
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excursion conditions defined in Table 2. Following the excursion, the model returned the packages to ICH controlled room temperature conditions. For this exercise, the same moisture isotherm was used for all temperatures to simplify the modeling. In addition, we assumed that the Aw of the packaged tablets does not change during temperature transitions (e.g., from 25 C to 60 C) corresponding to the environment temperature. In reality, tablets hold less moisture at higher temperatures and release moisture to the container headspace as temperature increases. Because of this thermodynamic phenomenon the absolute amount of moisture in the package headspace increases, but the RH may not increase at all because more moisture is required to produce the same RH at higher temperatures. Figure 2 shows the estimated Aw of tablets during the 45-day excursion during warehouse storage. PVC is a poor moisture barrier that allows water vapor to permeate in or out of the blister. When tablets in PVC blisters are exposed to 25 C/60% RH in the model, the tablets achieve equilibrium with the storage environment over several weeks. When these same blisters then are exposed to 30 C/75% RH, the Aw of the tablets quickly increases, and if environmental conditions return to normal the Aw of the tablets also quickly returns to the previous equilibrium value. Modeling predicts that products in the other package configurations considered initially experience an increased Aw that then returns and converges with the normal Aw profile. The effect of the additional moisture exposure depends on the sensitivity and degradation patterns of individual drug products. However, a negative effect of this extended additional moisture exposure cannot be ruled out. In contrast, as shown in Figure 3, a 7-day exposure in the warehouse scenario produces only a nominal change in Aw for all package configurations other than PVC, which, as expected, shows the results of essentially free passage of water vapor in and out of the blister. Thus, for all non-PVC packages the quality effects of the shorter duration excursion are expected to be nondetectable. Figure 4 shows the modeling results for the humidity excursion during truck shipment. The key observation here is that at 60 C the moisture capacity of the air is so high that the direction of moisture vapor transmission is out of the packages rather than into them. Again, PVC is a poor moisture barrier, so Aw rapidly decreases. Then when PVC blisters are exposed to 60 C/20% RH, this actually is a drier condition because of the high moisture-carrying ability of air at that temperature. Therefore the tablets actually lose moisture, and water vapor permeates out of the blister. The other package configurations considered also lose moisture because the internal vapor pressure is still higher than the external vapor pressure. As explained, the permeability at 60 C is approximately 30 times higher than that for blisters at 25 C and 18 times higher than that for bottles at 25 C. This means that increased temperature creates a pull for moisture to leave the packages even though the RH of the truck was set twice as high as it would be expected to become. Because Aw does not go below the initial value, there is no anticipated risk to solid oral drug products from a temperature and humidity excursion of this type. Although
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a large-volume parenteral in a semipermeable bag might be at risk of significant water loss, that scenario was not explored in this study. Note that a temperature excursion to 60 C would, by itself, be a significant risk to product quality because of temperature-related degradation. This scenario, however, is outside the scope of the present inquiry. Figure 5 shows the modeling results for the ocean shipping scenario during which the product is exposed to higher humidity but a uniform temperature over the course of the voyage, i.e., 25 C/80% RH. The PVC package shows a notable increase in Aw following this exposure but rapidly returns to the previous equilibrium when the package is stored at 25 C/60% RH. The other types of package show only minimal increases in Aw when exposed to the modeled conditions for an ocean voyage. As shown in Figure 6 changing the ocean shipping conditions to 40 C/35% RH does not lead to additional moisture exposure of practical importance for any of the packaging other than PVC.
Figure 2. Modeling results for a warehouse excursion (45 days at 30 C/75% RH).
Figure 3. Modeling results for a warehouse excursion (7 days at 30 C/75% RH).
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Figure 4. Modeling results for the truck excursion of 7 days at 60 C/20%RH.
Figure 5. Modeling results for ocean shipment at 25 C/80% RH.
Figure 6. Modeling results for ocean shipment at 40 C/35% RH. CONCLUSIONS Exposure of drug products to elevated temperatures raises concerns about product quality, and this Stimuli article has examined similar concerns following humidity exposure during the distribution process. In 2009 Romanian regulators promulgated a rule that would have required monitoring of humidity conditions during transport of medicines, but this rule was subsequently withdrawn (8). The risk to drug product quality from humidity excursions is not the same as that from temperature excursions. This is because a change in environmental temperature leads rapidly to a change in the temperature experienced by the packaged drug product, but a change in environmental humidity results in a much slower change in the moisture exposure of the drug product because of the protection afforded by packaging material. The exception to this observed in the modeling results presented in this paper is PVC blister packaging, which is infrequently used because it does not provide good moisture
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protection. The packaging for a particular drug product is selected so that its moisture-protective properties are matched to the observed moisture sensitivity of the drug product over its entire shelf life. In general this means that short-term humidity excursions do not cause any observable quality degradation for a properly packaged drug product. Based on the modeling in this paper, extensive moisture exposure is observed only when a humidity excursion is accompanied by a temperature excursion for an extended period. The role of pharmaceutical packaging is to serve as a functional barrier to protect the product and thus help maintain its quality. Selection of proper packaging components for a particular product depends on the product's physical and chemical attributes. This selection is based on stability studies as part of the development program to provide the appropriate level of protection. Because of the moisture protection afforded by proper packaging, humidity excursions of 7 days or less are unlikely to result in loss of product quality. Therefore, humidity monitoring during transportation is of no practical value. However, appropriate humidity control in long-term storage facilities is as necessary as proper temperature control. These findings are germane to USP general chapters that address packaging, storage, and distribution of drug substances, drug ingredients, and drug products and should be considered when these chapters are updated. REFERENCES 1. Transport Information Service. Climate/humidity table. 2012. http://www.tis2. gdv.de/tis_e/misc/klima.htm. Accessed 01 May 2012. Zografi G, Grandolfi GP, Kontny MJ, Mendenhall DW. Prediction of moisture transfer in mixtures of solids: transfer via the vapor phase. Int J Pharm. 1988;42 (1):7788. Yoon S. Design a Package for Pharmaceutical Tablets in Relation to Moisture and Dissolution [dissertation]. East Lansing: Michigan State University; 2003. Kontny MJ, Koppenol S, Graham ET. Use of the sorptiondesorption moisture transfer model to assess the utility of a desiccant in a solid product. Int J Pharm. 1992;84(3):261271. Bizot H. Using the GAB model to construct sorption isotherms. In: Jowitt R, ed. Physical Properties of Foods. New York, NY: Applied Science; 1983:4353. Bell LN, Labuza TP. Moisture Sorption: Practical Aspects of Isotherm Measurement and Use. 2nd ed. St. Paul, MN: American Association of Cereal Chemists; 2000. Okeke CC, Bailey LC, Medwick T, Grady LT. Temperature fluctuations during mail order shipment of pharmaceutical articles using mean kinetic temperature approach. Pharmacopeial Forum. 1997;23(3):41554182. Romanian Minister of Public Health and Order. Guideline 30/24.09.2009 for the explanation of the meaning of some obligations that wholesale distributors of
3. 4.
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8.
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medicines must undertake in order to comply with the provisions of Law no. 95/2006, Order no. 1963/2008 of the Minister of Public Health and Order no. 1964/2008. Bucharest, Romania: 2009.
a b c
Member, <1118> Monitoring DevicesTime, Temperature, and Humidity Expert Panel Eli Lilly and Company
Address correspondence to: Desmond G Hunt, PhD, Senior Scientific Liaison, US Pharmacopeial Convention, 12601 Twinbrook Parkway, Rockville, MD 20852-1790; e-mail dgh@usp.org.
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38(6) Stimuli to the Revision Process: An Assessment of the Impact on Pharmaceutica...

STIMULI TO THE REVISION PROCESS

Truck Shipment 25 C and 60% RH Ocean Shipment 25 C and 60% RH

Figure 3. Modeling results for a warehouse excursion (7 days at 30 C/75% RH).

Figure 4. Modeling results for the truck excursion of 7 days at 60 C/20%RH.

Figure 5. Modeling results for ocean shipment at 25 C/80% RH.

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