Wednesday, July 21, 2010

QUALITY CONTROL - Moisture Content | High and Dry: Incorporate moisture testing in risk-based quality programs

Testing—extensive, complete, complex testing—has long been synonymous with safety in the pharmaceutical industry. The assumption is that the more you test your product, the safer you prove it is. This approach only works, however, when you know what you’re testing and that your test measures what you need to know.

As the U.S Food and Drug Administration’s quality by design (QbD) initiative recognizes, a thorough understanding of the product and the manufacturing process is more important than a big pile of testing data. Both International Conference on Harmonisation (ICH) guidelines and the QbD initiative encourage a thoughtfully designed risk management program backed by scientifically sound testing metrics.

Water is critical to the microbiological stability of most pharmaceuticals. By reducing the water in a product, manufacturers ensure that microbes can’t grow. But how do you measure whether or not a product is “dry” enough to prevent the growth of microorganisms?

Guidelines recently published in ICH Q6A decision trees six and eight simply ask, “Is the drug substance/excipient capable of supporting microbial growth or viability?” and “Is the drug product a dry dosage form?” Decisions on those questions must be supported by scientific evidence.

The assumption in the pharmaceutical industry is that measuring the moisture content, or amount of water, in a product can establish dryness. Since the work of Scott in the 1950s, however, it has been well established that the water activity, or energy of water, is actually what determines whether or not microorganisms can access the water in a system.

In fact, pharmaceutical manufacturers have always manipulated and controlled water activity. They’ve typically done so, however, without explicitly understanding what they were doing. And instead of measuring the effects of these manipulations in terms of water activity, they’ve measured them in terms of water content.

Figure 1. Moisture sorption isotherm of a freeze-dried active  ingredient
Figure 1. Moisture sorption isotherm of a freeze-dried active ingredient

Controlling Water Activity

There are many ways to manipulate and control water activity in a product. Adding substances that bind water—humectants, excipients, solutes, and polyols, for example, can lower it. It can also be controlled using processes like freeze-drying. But without understanding and measuring how the water activity of the product has changed, it’s hard to maintain control of the process.

Take, for example, the process of freeze-drying. The widespread perception of this process is that the product’s safety and stability come from lowered water content. Actually, the product’s microbial stability comes from lowered water activity. Figure 1 (see below) shows the relationship of water content to water activity in a freeze-dried pharmaceutical ingredient. This graph, called a moisture sorption isotherm, demonstrates how confusing it can be to manipulate water activity while measuring water content.

Many intermediate moisture products and ingredients have an S-shaped isotherm like this one. In the middle of the isotherm, a small increase in water content causes a big increase in water activity. At both ends of this range, the product looks “dry.” Without measuring water activity, it’s impossible to know whether or not the product is capable of supporting microbial growth.

As the isotherm graph shows, water content and water activity are related—but they shouldn’t be confused. QbD encourages manufacturers to go from simply collecting mountains of data to developing deep product knowledge. When working through ICH Q6A, manufacturers need to dig down and explicitly understand how they are using water activity to make their products safer. By directly measuring the variables they are manipulating, manufacturers can show the kind of rich product knowledge and process understanding that are at the heart of QbD.

Is the Test Relevant?

Water in pharmaceuticals has traditionally been measured using Karl Fischer titration to determine percent water content. There’s no question that this is a high quality test. But is it relevant?

Karl Fischer titrations are very precise and are effective at quantifying even “tightly bound” water. In fact, part of the method’s reputation is built on its ability to measure the bound water that other methods, like loss-on-drying, miss. Yet, while it may provide a more complete determination of total water content, it still measures only the amount of water and not the water’s energy status.

Water activity is a different measurement, one more closely related to processes within the product. It may help to picture water activity as a measure of how “available” water is in a system or product. That availability is measured not in quantity but in degree. Water activity describes how closely the water in the product resembles and behaves like pure water. Pure water has a water activity of 1.0. As water activity numbers decrease, they indicate a decrease in the water’s energy, showing that the water is less available to migrate, to act as a solvent, to participate in chemical reactions, or to be used by microbes.

In other words, water activity describes the thermodynamic energy status of the water in a system. It measures the quality of the water in a product—how much is free from physical and chemical bonds—as opposed to the quantity, as Karl Fischer and other water content methods do.

A product may contain a relatively large percentage of moisture, but if the water is chemically bound to humectants or solutes such as salts, sugars, or polyols, the water is biologically unavailable for microbial growth. Similarly, a relatively dry product can contain enough “free” water to make it capable of supporting microbial activity.

A Surprise for Manufacturers

This can come as a surprise to manufacturers. For example, a lip balm product contained so little moisture—only one to two percent—that the manufacturer didn’t think there was any question of spoilage. The water activity, however, was 0.8, showing that the product was clearly capable of supporting microbial proliferation.

Before measuring water activity, the manufacturer didn’t know enough about the water in the product to even suspect that there might be a problem. Water activity tests provided the deep product knowledge needed to understand and correct the formulation. The manufacturer added ingredients to the aqueous phase, making the product naturally preserving by reducing water activity dramatically.

This is the kind of risk-based, science-backed approach advocated by QbD. Water activity measurements helped the manufacturer to both diagnose and fix the problem and provided tools for specifying relevant performance requirements so that the manufacturer could manage variation and maintain quality in future batches of the product.

Every microorganism has a limiting water activity below which it cannot grow (see Table 1, above). These limits are well established in the literature and in USP <1112>. No direct relationship exists for moisture content and microbial growth.

Therefore, water activity is the scientifically correct way of determining whether or not a substance or excipient is “capable of supporting microbial growth or viability,” as required in ICH Q6A. Water activity is also involved in other ICH guidelines, though it may be called by other names. ICH Q1A, which outlines stability testing programs for newly released drug products, requires products to be held at various humidity levels. Water activity and equilibrium relative humidity are actually the same measurement (aw = %ERH/100). Humidity is a critical part of these stability programs because water activity (or %RH) is a critical parameter of product stability.

Table 1. Water Activity Limits for Growth of Microorganisms
Table 1. Water Activity Limits for Growth of Microorganisms

Water Activity Critical

In developing a product using the QbD approach, water activity should clearly be considered a critical process parameter to establish microbial safety, and it also has merit as a measure of other critical quality attributes such as product integrity, active pharmaceutical ingredient stability, and dissolution.

Water activity predicts moisture migration and shelf stability, especially of moisture-sensitive substances. It may seem that water only migrates from a wetter ingredient to a drier one. But if one component has a higher water activity than another (meaning that the water it contains is not chemically or physically bound), the free water will migrate until the water activities of the two components come to equilibrium.

This happens even when the two components have the same percentage moisture content. In a gel capsule, for example, water can migrate out to make the capsules swollen and sticky, or in to make them dried and cracked. In the process, the properties of the drug formulation may be changed. Water activity, not water content, predicts this migration process.

Water activity can also be used to determine the effectiveness of various preservative methods, ensure quality of raw materials, monitor and prevent changes and spoilage during storage, and test and improve packaging. Water activity tests may also be helpful in validating product expiration dates, monitoring physical, chemical, and microbial stability of drugs under use conditions, and screening to decide whether or not more extensive microbiological tests for contamination and impurities are needed.

Pharmaceutical quality programs have been slow to adopt water activity as an effective tool. Some may not understand the critical role water activity plays in quality and safety. Others may not understand what the measurement is. Many assume that Karl Fischer moisture analysis gives them all the water-related information they need.

ICH and QbD refocus attention on using relevant, risk-based, science-backed tests and understanding exactly what is going on during formulation and manufacturing. Water activity provides a critical piece of the water picture. Read more about the benefits and possibilities of using water activity as a critical process parameter in Water Activity Applications in the Pharmaceutical Industry, an excellent new reference text by Anthony Cundell and Anthony Fontana.

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