Medical Device Link.

Originally Published IVD Technology June 2002

Processing Technologies

Dealing with humidity

Stefan Dick and Jean Thomas Woynicki

Exposure to moisture can reduce the shelf life and performance of IVD products, but manufacturers can minimize such risks by selecting an appropriate desiccant.

Tubes and desiccant stoppers provide ideal moisture and product protection for diagnostic test strips. During the early phases of development, IVD manufacturers should consider the variety of protective packaging options available in order to ensure product integrity and maintain product quality.

For IVD manufacturers, maintaining quality and reliability in their products is of utmost importance. To ensure that they are producing high-quality products, companies implement stringent quality assurance systems that comply with international quality systems standards for key steps such as raw-material sourcing, production, and software validation. Another equally important task is to ensure that the end-user has the full benefit of this high quality long after the product has been manufactured. Companies maintain this quality during shipping, storage, and use of the product by choosing the proper packaging materials and methods.

Packaging provides solutions for IVD manufacturers in four functional areas: protection (e.g., from moisture, light, and for mechanical stability), dispensing, safety (e.g., child resistance, tamper evidence), and information. Although this article focuses primarily on desiccants as components of a protective packaging system, references to the other functions of packaging are made when different packaging methods are compared.

Moisture Damage

Moisture can harm IVD products in a number of ways, mostly by reducing their shelf life and quality. For example, experiments have shown the negative influence of moisture on the reliability of gold-based rapid tests.¹ In addition to damaging conjugates and rendering capture antibodies inactive by hydrolyzing antibodies, excess moisture during storage may lead to the crystallization of sugar and subsequent poor conjugate release.

Humidity may also influence the aging and migration of adhesives that are used in the construction of lateral-flow assays. It has been demonstrated that the aging of such adhesive components has a significant impact on shelf life.²

Membrane components can suffer from moisture-related aging, membrane immobilization effects, and the interference of water through hydrogen bond protein–membrane binding.³

Finally, without moisture control, nonsterile IVD systems can be ruined by microbial activity.

Desiccant Types

Three types of desiccants are currently used for moisture protection in IVDs: silica gel, molecular sieves, and desiccant clay. Each of these desiccants exhibits different properties under various temperature and humidity conditions (see Table I).

Figure 1. Absorption capacity of desiccants as a function of relative humidity (temperature = 25°C; constant humidity conditions; maximum airflow). (Click to enlarge)

Silica Gel. Among these desiccants, silica gel is the most widely used for IVD applications. This desiccant is a synthetic amorphous modification of silicon dioxide (SiO₂) and is characterized by a large number of mesopores that allow for effective binding of water molecules. When tested at a constant temperature, silica gel's absorption capacity for water is relatively small at low humidity levels, but rises with increasing humidity (see Figure 1). Since silica gel reacts slowly in low humidity and quickly in high humidity, it slowly reduces low levels of humidity in a closed environment (e.g., bottle, pouch, tube), but rapidly loses this capacity if exposed to high levels of humidity (e.g., during dispensing).

Molecular Sieves. Generally 25–50% more expensive than the equivalent amount of silica gel, molecular sieves are synthetic crystalline zeolites with a general formula of M^y_x/y[Al_xSi_1–xO₂]. The 4A-zeolite in which the metal ion in this formula is sodium is the most widely used molecular sieve for IVDs. These 4A molecular sieves contain a network of interconnecting micropores with a uniform diameter of 4 Å (0.4 nm) and can capture and effectively bind water molecules even at very low humidity levels. In fact, the absorption capacity of molecular sieves is almost independent of relative humidity at constant temperature. Since molecular sieves react rapidly at both high and low humidity levels, they quickly reduce the humidity in closed environments to a very low level, but can be difficult to handle in uncontrolled manufacturing environments (see Figure 2).

Figure 2. Development of relative humidity in a closed container after the addition of desiccant (200-ml vial; 1 g of desiccant; and starting conditions of 25°C, 20% relative humidity). The time axis is on a square-root scale. (Click to enlarge)

Desiccant Clay. In contrast, desiccant clay is a cheaper option and generally 5–15% less expensive than the same amount of silica gel. This desiccant is derived from naturally occurring bentonite clay, and its main component is the layered mineral Ca-montmorillonite, Ca_0.16 [Al_1.68Mg_0.32(OH)₂(Si₄O₁₀)]. With water molecules binding predominantly to the cation interlayers of the fine clay crystals, the absorption capacity of clay increases with rising humidity and is higher than the absorption capacity of silica gel when conditions are below 30% relative humidity. Since clay reacts relatively slowly at low as well as high humidity levels, it slowly reduces the humidity in closed containers, but it is easy to handle. In addition, desiccant clay granules have up to 30% greater density than either silica gel or molecular sieve beads, thereby occupying less space.

Desiccant Products

To meet the requirements of different industries, desiccants are prepared using particular materials in a variety of sizes and shapes. Manufacturers should be careful to select the proper desiccant type and product, according to their required performance, insertion process, packaging preferences, and cost considerations. In the IVD industry, desiccant products are available as packets, canisters, tablets, cap inserts, desiccant stoppers, and desiccant polymer blends (see Figure 3). A description of each of these desiccant products follows.

Canisters. Desiccant canisters are considered the gold standard among the desiccants used in the pharmaceutical industry. In the United States, the most popular canister sizes are 13.9 x 17.8 mm, 13.9 x 25.7 mm, and 19.4 x 15.8 mm. Also available are canisters as thin as 3.6 mm, and as large as 62.8 mm in diameter. In addition to being able to contain between 0.25 g and 27 g of desiccant, canisters are specifically designed for high-speed product insertion and have less potential for contamination and machine jamming than desiccant packets.

Figure 3. Desiccant products for IVD packaging (clockwise: tube and desiccant stoppers, desiccant canisters, desiccant packets, and desiccant tablets).

Packets. Desiccant packets are available as either individual packets or long strips that are cut into separate packets upon being inserted into a package. While these packets have fill weights that contain between 0.25 g and 10 g of desiccant, various facestock materials are used to form the actual packets, with GDTII (polyester and polyolefin nonwoven) and Tyvek (spunbonded polyolefin) being the most commonly used in the United States. Each facestock material has different effects on the appearance, seal strength, absorption rate, and dusting properties of the desiccant packet. IVD manufacturers should especially consider dusting properties since it has been reported that desiccant dust contamination can affect the reliability of test strips.

Tablets. Desiccant tablets can be made into virtually any size and shape in order to fit the packaging needs of IVD devices. Inserting these preformed desiccants is relatively easy and can be automated to accommodate high-speed production. Some IVD manufacturers have found that using desiccant tablets instead of packets allows them to speed up their packaging processes tremendously.^4,5

Cap Inserts. Desiccant cap inserts are used in conjunction with screw-on caps for rigid containers. Since desiccant-filled inserts fit directly into the cap, the desiccant does not take up any extra space in the container itself, and no additional equipment is needed to insert the desiccant during the packaging process. A desiccant cap insert is always designed to fit exactly into a special packaging configuration, so it cannot be considered an off-the-shelf item.

Tube and Stopper Systems. The tube and desiccant stopper system is the most advanced moisture-protection packaging solution for IVD test strips. Similar to the cap insert, the desiccant is contained in the stopper, does not consume any extra space in the tube, and requires no additional desiccant feeding system. The desiccation and protection functions of the stopper can also be combined with such safety features as child resistance and tamper evidence.

Desiccant-Filled Polymers. Another moisture-protection option is to incorporate a desiccant into the polymer material that is used in tubes for strip storage and housings for test kits. These tubes and devices consist of an outer layer of moisture-impermeable material and an inner layer of desiccant-filled polymer material. Absorption capacity and rate can be adjusted by choosing certain plastic materials, desiccant types, desiccant amounts, and additives. Extreme care has to be exercised when choosing such a system to ensure that the additives used by some suppliers in their desiccant-entrained plastics do not react with the test strips. Contamination can occur because of direct contact between strips and tubes, and through the air that is contained in the tube if an additive exhibits considerable vapor pressure under shelf life conditions. Other possible side effects include interaction with adhesives and membranes, and protein attachment.³

Quality Parameters

Desiccant manufacturers usually specify the absorption capacity and residual moisture of their products. Absorption capacity is measured by exposing the desiccant to specified, static conditions and observing its weight increase, which is given as a percentage of the desiccant weight. Residual moisture is measured by heating the desiccant to its reactivation temperature and observing the weight loss, which is also given as a percentage of the desiccant weight.

In most cases, these two parameters are redundant. They measure the same quality parameter of the desiccant, because absorption capacity decreases the same amount as residual moisture increases. When desiccant users set up incoming-quality procedures or want to compare quality data from different suppliers, they should not depend solely on the data provided by the supplier. They should also confirm the suppliers' quality procedures. For example, residual moisture data, especially for molecular sieve products, is extremely sensitive to changes in testing temperatures and procedures.

Choosing the Right Solution

A manufacturer's choice of desiccant must ultimately be based on the performance characteristics required to protect the IVD product. Key measures of desiccant performance include absorption capacity, absorption rate, and the relative humidity level it is capable of maintaining within the packaging. Other important factors to consider are weight, size, and shape restrictions of the package; dust requirements; process restrictions; and cost.

Absorption Capacity. The required absorption capacity for moisture (M_total) is calculated by taking the sum of the initial moisture in the package (M_initial) and the amount of water flowing into the package during shelf life (M_inflow). M_initial is the sum of headspace air humidity (M_headspace) and available residual moisture in the packaged good (M_rm). M_total = M_initial + M_inflow = (M_headspace + M_rm) + M_inflow

M_headspace is the product of headspace volume and absolute air humidity in the environment during the packaging operation. This contribution to total moisture is usually negligible, because headspace is minimized during packaging design or when packaging is done under controlled low-humidity conditions.

M_rm is the amount of water that can be desorbed from the packaged good by the desiccant during shelf life. This amount depends on the overall moisture content of the good after manufacturing, the desorption energy for water from the packaged good, and the desorption kinetics. The product's residual moisture is usually determined at 110°C and gives an upper limit for this amount.

M_inflow can be calculated from the water ingress data of the package (in mg/day) under shelf life conditions for the desired number of days. This factor very much depends on the type of packaging (e.g., flexible, rigid) and the packaging materials that are used. For example, various flexible packaging materials exhibit different water-vapor transmission rates (WVTRs; see Table II).

Water ingress into flexible packaging can only be roughly estimated from such data. The reason is that even though the seal area is the most likely spot for moisture ingress, its contribution is not included in the pure-material data. Another source of uncertainty is that WVTRs are sometimes reported for conditions that are unlike shelf life conditions and therefore have to be recalculated for specific requirements.

On the other hand, rigid packaging solutions, such as tube and stopper systems, have an advantage in that moisture ingress, rather than WVTR, is specified by the supplier and does not require extra testing.

Relative Humidity. In order to calculate the minimum amount of desiccant that is needed based on the total amount of moisture to be absorbed (M_total), the maximum allowable relative humidity in the packaging during shelf life must also be known. The amount of desiccant needed is then the quotient of M_total and the absorption capacity of the desiccant at the maximum allowable relative humidity.

For example, if M_total is 0.1 g and the maximum allowable relative humidity is 20%, the absorption capacity of desiccant clay is 13%, so the minimum amount of clay needed is 0.78 g (0.1 / 0.13). Under these same conditions, 0.87 g of silica gel or 0.55 g of molecular sieve would be needed. It must be kept in mind that the data used for these calculations are valid only for pure desiccants.

The effect of residual moisture, which is usually specified by the desiccant supplier, also needs to be taken into account. In most cases, it is sufficient to round up to the nearest standard desiccant product size. For the above example, 1 g of clay, 1 g of silica gel, or 0.75 g of molecular sieve would suffice.

In addition, stability tests usually establish the maximum moisture level that should not be exceeded during shelf life. It is also useful to check whether there is a minimum moisture level to be maintained during shelf life in order to avoid problems as a result of moisture loss in the product (e.g., altered membrane and adhesive aging). For example, molecular sieves are able to reduce the humidity level in a closed environment to virtually zero, while silica gel and clay leave a small amount of residual moisture in the air and consequently in the product (see Figure 2). Thus, knowledge of minimum and maximum humidity levels that should be maintained can further enhance the correct choice of desiccant.

Absorption Rate. Another parameter to consider is absorption rate. Molecular sieves reduce the relative humidity in a closed container from 20% to virtually 0% within 5 minutes; desiccant clay absorbs the moisture within 20 minutes; and silica gel needs about 60 minutes (see Figure 2). In most cases, however, these time differences are irrelevant because the products packaged are not so moisture sensitive that they would suffer from the 15-minute difference between molecular sieve and clay.

Under real-life conditions, the products being packaged contain some water, or residual moisture, which has to be picked up by the desiccant and therefore increases the reaction time. In most cases, the kinetics for desorption of water from the product are slower than the absorption kinetics of the desiccant, such that the desorption reaction is the rate-limiting step for overall dehumidification. This factor eliminates the differences between the desiccant reaction rates and leads to reaction times of hours and days instead of minutes.

Process Restrictions

As discussed above, at elevated humidity levels, different desiccants exhibit different reaction rates, a factor that influences the moisture uptake of the desiccant product during exposure on the packaging line. Moisture uptake during this exposure time reduces the desiccant's absorption capacity. Consequently, this loss of capacity has to be considered when the required amount of desiccant is calculated, or the desiccant must be dispensed under moisture-controlled conditions. For example, small molecular sieve packets are extremely difficult to handle and require humidity control during dispensing.

In addition, the choice of desiccant product determines the loss of capacity during exposure. Generally, desiccant canisters, inserts, and stoppers react more slowly than packets or tablets.

Humidity Indicators

As a value-added feature, a humidity indicator can be added to packaged IVD test strips. This indicator allows the consumer to read the humidity level inside the packaging and gives an indication of whether the test strips can still be used or should be discarded. Custom indicators can be designed to change color at specific critical humidity levels of a product or packaging combination. The indicator may also contain additional consumer information and instructions, and thus add informational value to the packaging solution.

Conclusion

Many options exist for protective packaging of moisture-sensitive IVD products. It is important to consider the desiccant as part of the whole packaging solution. The choice of desiccant should be taken into account in the early stages of packaging development. Such early planning enables the IVD manufacturer and the desiccant supplier to find an optimum packaging solution in terms of performance, appearance, market acceptance, and overall cost. A complete cost comparison includes cost of packaging materials as well as investments and process costs that are associated with packaging speed, potential downtime, and overall efficiency.

References

1. J Chandler, N Robinson, and K Whiting, "Handling False Signals in Gold-Based Rapid Tests," IVD Technology 7, no. 2 (2001): 34–45.

2. K Jones, and A Hopkins, "Effects of Adhesive Migration in Lateral-Flow Assays," IVD Technology 6, no. 5 (2000): 57–63.

3. K Jones, "Troubleshooting Protein Binding in Nitrocellulose Membranes, Part 1: Principles," IVD Technology 5, no. 2 (1999): 32–41.

4. "Desiccant Tablet Boosts Throughput 3000%," Pharmaceutical & Medical Packaging News 7, no. 5 (1999): 38–41.

5. "Desiccant Tablet Helps Streamline Production," Pharmaceutical & Medical Packaging News 9, no. 3 (2001): 94.

Stefan Dick, PhD, is product group manager, and Jean Thomas Woynicki is the key account manager for the U.S. pharmaceutical and diagnostics industries at Süd-Chemie Performance Packaging (Albuquerque, NM). The authors can be reached at sdick@sud-chemieinc.com and jwoynicki@sud-chemieinc.com, respectively.

Copyright ©2002 IVD Technology