Determining Drug Stability and Selecting Packaging

08_P070_PM_070901_Bilcare.qxd HTJ Pg: 70 Blisters Determining Drug Stability and Selecting Packaging Using rapid forced degradation studies may allow you to predict the conditions under which products will fail and to select blister materials accordingly.

By Remco van Weeren, PhD, Senior Vice President, Marketing and Technology, Bilcare Inc., and Ajith Sashidharan PhD, Vice President, Global Research Services, Bilcare Ltd.

edicinal products need does not lead to Peak absorption Rate at various conditions

protection from moisture, a quantitative 2.0000 oxygen, light, and chemi- understanding 1.8000 cals. In 1999, the Interna- of why and 1.6000 tional Conference on when a tablet 1.4000 M 1.2000 A Harmonization (ICH) implemented fails. In addition, 1.0000 B guidelines that are now well established there is little 0.8000 C for the stability testing of new drug sub- account for inter- 0.6000

stances. The actual conditions used for actions between Peak absorption rate 0.4000 the ICH guidelines were based on many parameters. 0.2000 years of development work using forced- Bilcare has 0.0000 25/75 25/90 40/75 40/90 degradation studies or stress testing. worked for more Exposure condition These guidelines have standardized sta- than 10 years to bility testing and package determina- develop a 30- to Figure 1. Peak absorption rate of case-study products at various tion. However, there are some 45-day protocol conditions, with temperatures shown in Celsius at left and relative limitations to current ICH testing. These that aids in humidities at right. guidelines were primarily developed for quantifying the stability nature of drugs. defines accelerated testing as the following: climatic zones I and II, and therefore they do not cover the requirements of FORCED DEGRADATION Studies designed to increase the other climatic zones. There are no detailed regulatory rate of chemical degradation or Pharmaceutical customers often rely guidelines that describe how to carry out physical change of an active sub- on ICH stability studies of the packed stress testing, as was recently mentioned stance or drug product using exag- product as their only method to select in a book serving as a practical and sci- gerated storage conditions as part packaging. Some, though, fail to select entific guide for the pharmaceutical sci- of the formal, definitive storage the optimum package, as the stability entist. As one of the authors highlights, program. These data, in addition becomes only a confirmatory test for the stress testing is often used synonymously to long-term stability studies, may selected packaging material. with accelerated testing. However, the also be used to assess long-term Moreover, the stability study often two are distinctly different. The ICH chemical effects at nonaccelerated conditions and to evaluate the Exposureconditions Observedresult Notation impact of short-term excursions 1 25ºCand75%RH Nominalchange NA outside label-storage conditions such as might occur during shipping. 2 25ºCand90%RH Severechange Tabletbreaksand becomes wet and sticky Stress testing is defined as the following: 3 40ºCand75%RH Severechange Tabletbreaksand becomes wet and sticky Studies undertaken to elucidate 4 40ºCand90%RH Severechange Tabletbreaksand the intrinsic stability of the drug becomes wet and sticky substance. Such testing is part of the Table I. Testing matrix from a case study describing visual observations after exposure.

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Maximum moisture gain at different conditions

70.0

60.0

development strategy and is normally carried out under 50.0 more severe conditions than those used for accelerated 40.0 A testing. B 30.0 C From a regulatory perspective, stress testing or forced- 20.0 % Moisture absorption degradation studies are a scientific tool to understand stabili- 10.0 ty issues and are inherently predictive in nature. Accelerated 0.0 testing, on the other hand, is purely focused on whether or 25/75 25/90 40/75 40/90 not stability is maintained at a preset condition. Exposure conditions

Bilcare has developed a testing protocol called Bilcare- Figure 2. Maximum moisture gains of case-study products at various Optima that helps users gain a detailed and precise under- conditions, with temperatures shown in Celsius at left and relative humidities at right. standing of the nature of their applications and failure modes. It is intended to identify the conditions under which Average grading, the failure happens and to identify the moisture-, gas-, and Exposure conditions light-barrier properties in the protective packaging. 3 batches Rather than evaluating the solid oral dose as part of a set 1 25ºCand75%RH 5.5 of packaging materials, this protocol evaluates the actual 2 25ºCand90%RH 9.8 dosage form in an open-dish environment. The dosage form is tested under a range of different conditions, aimed at 3 40ºCand75%RH 7.3 determining the critical characteristics that determine the 4 40ºCand90%RH 10.0 shelf life of the product. An evaluation of the test data, in conjunction with a blister cavity model, results in a recom- Table II. Hygroscopicity grading (0 is lowest, 10 is highest).

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September 2007 Pharmaceutical & Medical Packaging News • pmpnews.com 71 Moistsure absorption Capacity at different Conditions 08_P070_PM_070901_Bilcare.qxd HTJ Pg: 72 1.40 Blisters

1.20

1.00

0.80 A B mendation for the best material specific to that dosage form. 0.60 C Three batches of dosage forms are studied under various 0.40 environmental conditions for a more precise understanding of the following: Absorption capacity0.20 value 0.0 • Hygroscopic tendency. 25/75 25/90 40/75 40/90 • Dehydration tendency (if needed). Exposure conditions • Degradation tendency (physical and chemical). Figure 3. Moisture absorption capacity of case-study products at • Effect on drug release properties. various conditions, with temperatures shown in Celsius at left and • Effect on hardness. relative humidities at right. • Photosensitivity as a function of RH and temperature. Moisture • Gas liberation tendency. Conditions Threshold • Dimensional aspects. Value (%) After evaluating these properties, an exact determination is 1 Realtimemildclimaticcondition 3.30 made as to which oral-dose characteristic is the most sensitive 2 Realtimetropicalcondition 4.36 to the environment. Based on that determination, the blister configuration for the solid oral dose is modeled, and the maxi- 3 ICHacceleratedcondition 3.78 mum amount of moisture transmission is determined, result- 4 Tropicalacceleratedcondition 3.44 ing in the appropriate material selection. Because all polymers thin upon thermoforming, a critical understanding of the thin- Table III. The moisture threshold value that is used to determine the O packaging material. ning characteristics of the various polymers in relation to the

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cavity design through a software pack- the EMC. The absorption rate thus many cases show different behavior than age using cavity-forming parameters is becomes an important parameter that the EMC given the presence of a sec- critical to optimize the barrier properties defines the moisture absorption in the ondary phenomena, such as desorption. of the blister structure for the specific packaged condition. Peak absorption Figures 1, 2, and 3 show the results for application. rate (PAR) as well as the maximum the EMC, MAC, and PAR, clearly indi- Based upon the test data and the blis- absorption capacity (MAC) are depen- cating in the results of the PAR and ter cavity design work, a recommenda- dent on the exposure condition, and in EMC that the maxima are happening at tion is made regarding the appropriate moisture-vapor transmission rate (MVTR) and packaging material.

CASE STUDY A customer approached us with a specific packaging problem. One of its current applications was on the market in a foil strip pack. There was a desire to move to a transparent blister pack, but all earlier stability trials had failed. The product was studied under the BilcareOptima process to identify the critical parameters and to be able to convert the product to a blister pack with certain additional requirements. Certain important findings from the study are correlated to find the barrier requirements for the product. When the testing was initially per- formed under four conditions, the resul- tant visual observations give enough clues for the product’s sensitivity towards moisture. The results are in Table I. One of the most important observations detailed in Table I is that the product’s physical degradation is as severe under the low-temperature, high- humidity condition as it is under the accelerated conditions. This low-temperature, high-humidity condition is a realistic condition for most tropical areas and was heretofore not evaluated. Nor- mally, moisture sensitivity of the product is defined based on moisture and absorption isotherms and equilibrium moisture content (EMC). However, it has been our experience that measuring the hygroscopic tenden- cies of the product cannot be complete using only the EMC. Absorption rate as well as absorption capacity play important roles, especially when a product is packaged in semipermeable packaging like a blister pack. In real-world packaged conditions, most products within their shelf-life period do not approach

September 2007 Pharmaceutical & Medical Packaging News • pmpnews.com 73 08_P070_PM_070901_Bilcare.qxd HTJ Pg: 74 Blisters

the lower-temperature conditions. the standard accelerated conditions this case is the hardness variation as a A striking observation is that under (40°C and 75% RH), the product does function of the exposure conditions. not exhibit the full severity The hardness requirement of the tablet Change Hardness Reduction vs exposure time of the product’s moisture for a strip pack (or even a bottle) is very

1234sensitivity. Hence, even if different for a blister pack. The push- 0.00 the product exhibits sta- through force can break the tablet if the bility at standard acceler- tablet has become too weak. We have -20.00 ated conditions, it could developed a testing apparatus to under- degrade beyond accept- stand the hardness requirement for -40.00 able limits under realistic push-through of a solid oral dose and conditions prevailing in use the required force as a key charac- -60.00 tropical areas. teristic during testing. Figure 4 shows Based on the overall the drastic drop in hardness during

% DT Reduction -80.00 hygroscopic nature of the exposure at all conditions. product, we have devel- A similar approach is used to study -100.00 oped a grading scale that and quantify the sensitivity of the prod- allows us to rank different uct with respect to other parameters like -120.00 products as a function of chemical stability, drug release pattern, Exposure time (Hr.) their hygroscopicity on an dehydration effect, photosensitivity, gas Figure 4. The drastic drop in hardness 25/75 absolute scale. It is shown liberation tendency, and various other during exposure at all conditions, clearly in Table II. environmental parameters. The study 25/90 showing that the hygroscopic nature of 40/75 the tablet has a tremendous effect on a One of the key physical shows that the moisture had very little 40/90 key characteristic of the tablet. characteristics to study in effect on the chemical assay, drug release

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74 pmpnews.com • Pharmaceutical & Medical Packaging News September 2007 08_P070_PM_070901_Bilcare.qxd HTJ Pg: 75 Blisters

Max. Moisture Flat Film Time WVTR of Conditions Threshold WVTR period package Value (%) 2 pattern, or gas liberation, nor were there (g/day) (g/m /day) any photosensitivity effects for this prod- 1 Real-time mild climatic condition 3.30 24 months 0.00007 0.11 uct. Based on these results, it was con- cluded that physical degradation is the 2 Real-time tropical condition 4.36 12 months 0.000025 0.04 critical parameter for this product and 3 ICH accelerated condition 3.78 6 months 0.00016 0.26 that the influencing environmental para- 4 Tropical accelerated condition 3.44 3 months 0.0008 0.11 meter was humidity. Table IV. The case-study recommendations as a function of the exposure condition. A further detailed study was con- ducted to estimate the moisture threshold values at various storage conditions and the package barrier properties needed to ensure the moisture level stays below a critical moisture threshold value to ensure that parameter does not fail. Table III shows the moisture threshold value (MTV) that is used to determine the packaging material. Recommenda- tions for the optimum packaging material were made based on these MTVs and a design model of the blister cavity evaluating the expected thinning of the packaging material as a function of the blister size, shape, and design, using a simulation mathematical model. Table IV shows the recommendations as a function of the exposure condition. These data give a clear picture why earlier stability studies failed. The packaging material selected earlier was not able to give the required barrier, especially in the real-time conditions. From this study, it became clear that even if the product passes accelerated stability studies, it may not pass real- time studies. It was evident that the product needed to be packaged in PVC/Aclar or alu/alu to give the required stability for the stipulated period. However, there was a strong desire to minimize the packaging costs. A suit- able alternative was selected to satisfy cost and stability requirements: Bilcare’s aluminum-coated, PVC-based material, Ultra, with a flat film WVTR of 0.18, was selected as the primary packaging material. Because the actual barrier requirements are higher than 0.18 for long-term stability, a secondary pack of an aluminum composite, which provides a complete barrier to moisture, was selected to give the required protection for the period of shipping, transit, and storage, exposing the primary pack for a limited period only. I

September 2007 Pharmaceutical & Medical Packaging News • pmpnews.com 75 ADVERTORIAL Cutting Edge Solutions 21st Century Solutions

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