Technology Helps Take Drama Out of Pharma
New tools improve post-approval quality
Q uality control is at the heart of pharmaceuticals, one of the most tightly regulated industries across the globe. Estimates of the cost of taking a drug to market sit at the $1 billion mark, and much of this expense is pumped into lengthy trials and rigorous analytical tests. 1 Proving the efficacy, quality, and safety of a pharmaceutical product in order to gain 100% confidence and approval for market is clearly a significant investment.
But what happens to the product when it is approved for market? Does investment in quality evaluation stop? With Americans spending approximately $20 billion on over-the-counter medicines each year and an estimated $250 billion annually on prescription drugs, manufacturers who want a share of this expenditure need to stay ahead. 2-3 While the development of a new product in itself requires extensive analysis and control, the process of distributing it to the wider market raises a whole new set of challenges.
Texture Analysis Instruments
One of the most challenging aspects of pharmaceutical manufacturing and distribution involves handling and storage stability. Producing a single unit of a product to the required quality specification is one thing, but packaging and transporting it, with hundreds of thousands of others, is a different matter. Weaknesses in structure or formulation can present product failure risks at various stages of the distribution process. Pharmaceutical manufacturers need to ensure that products are robust enough to withstand packing procedures, storage and transit conditions, and consumer handling. The implications of product failure are as disastrous for over-the-counter medicines as they are for prescription drugs-dissatisfied consumers, lost contracts, damaged reputations, and, ultimately, reduced profits.
The industry has long worked to develop and enhance quality control measures designed to predict and refine product stability. Texture analysis instruments have played a key role. These tools offer repeatable, scientific quantification of material robustness, the results of which can first identify product weaknesses and then predict-and subsequently avoid-product failure. Traditional tests have analyzed parameters such as tablet hardness, gel strength, and mucoadhesion. While these tests continue to provide valuable data, materials analysis experts must now respond to rapid innovation within the pharmaceutical industry, as new delivery and encapsulation formats are introduced. In response to this growth, the scope and capabilities of testing instruments have broadened significantly.
Capturing Capsule Weakness
One of the latest developments in testing is the Capsule Tensile Rig (see Figure 1, above left). This instrument measures the force required to split one half of a hard gel capsule. It allows manufacturers to investigate the effects of fillings on the mechanical strength of the capsule shell and identify changes that may impact their stability and long-term performance.
The simplified manufacture process of hard gelatine capsules and their ability to withstand higher filling temperatures is attractive to many manufacturers. Yet the introduction of certain types of liquid to hard capsules-hydrophilic solvents, for instance-can affect the mechanical properties of the shells, causing them to become brittle or to soften. If the texture of a capsule is compromised, it may not be able to withstand handling and storage, resulting in the filling leaking from the capsule.
Because effects are likely to be progressive, with only very small changes showing up initially, compressive tests may not be adequate for distinguishing anomalies. The capsule tensile rig is designed to help identify subtle degradation, providing valuable information that can be used to avoid subsequent capsule failure. For example, manufacturers can identify the effect of a liquid filling on the strength and stability of capsules and reformulate liquid type or capsule accordingly.
Before testing, the filling of the capsule is removed; the empty shell is mounted to a separating rod fixture on the TA.XTPlus Texture Analyzer. Vertical movement of the upper rod is then applied until the capsule splits; Exponent software records the force required to reach this point. This test highlights three important parameters: elastic stiffness (if a linear region on the graph is present), tensile force, and elongation at break point. A reduction in elastic stiffness and tensile strength occurs when capsules become softer and develop a tendency to fail.
Cracks Under Control
The pharmaceutical industry is one of the world's biggest users of powder. Many products, including paracetamol, are first produced in powder form and then compressed into tablets. Powder compaction is an essential step in the manufacturing process, and it is critical to avoid cracking products during processing. A product's potential to fail is influenced by the powder's processing properties, such as density variations introduced during die filling or compaction.
The characterization of powder in its bulk format can enable manufacturers to predict its behavior when compressed. The need for more targeted analysis of powder compaction has been identified, however, and, as a result, the Powder Compaction Rig was developed (seeFigure 2, above).
While the development of a new product in itself requires extensive analysis and control, the process of distributing it to the wider market throws up a whole new set of challenges.
Available in high- or low-tolerance variants, this rig accurately measures the force and/or punch displacement required to compress powders into tablets. Using Exponent software, the rig produces precise measurements that enable pharmaceutical product manufacturers to produce powder compacts with consistent porosity. It can accurately assess the force needed for the punch to travel a specified distance, or it can be used in target force mode to assess the effect of fill level on tablet thickness.
The high tolerance powder compaction rig is suited to high-force applications in which the punch/die clearance is critical. This fixture is auto-aligned using a universal adapter, which saves time and avoids human error. The low tolerance version is suited to other powder compaction applications like assessing granule friability, in which punch/die clearance is less important.
Sophisticated methods for powder characterization, along with analysis techniques for hardness and coating adhesion, have enabled manufacturers to obtain valuable data on the stability of standard tablet formats. The development of bi-layer tablet formats, which contain isolated immediate and controlled release component layers, has given rise to new analytical requirements, however.
Such formulations are increasingly popular because they provide both efficacy for consumers and ease of production for manufacturers. Ensuring that one tablet layer does not impact on the other is instrumental in guaranteeing the remedial benefits of bi-layer medication and the safety of the consumer. But isolating two release components in separate layer formations can prove complex for manufacturers. The characteristics of each active pharmaceutical ingredient in a bi-layer tablet often differ, leading to problems in tablet composition that may in turn result in cross-contamination. Common issues include layer separation, insufficient hardness, and inaccurate individual layer weight control.
In order to ensure that the product reaches its user in its intended format, manufacturers must be able to gauge the stability of the layers.
One potential answer to this challenge is the bi-layer Tablet Shear Rig. This new attachment analyzes the strength of bi-layer tablets, allowing pharmaceutical manufacturers to identify weaknesses and improve the quality and stability of their products.
The simplified manufacture process of hard gelatine capsules and their ability to withstand higher filling temperatures is attractive to many manufacturers. Yet the introduction of certain types of liquid to hard capsules-hydrophilic solvents, for instance-can affect the mechanical properties of the shells, causing them to become brittle or to soften.
The rig is attached to the TA.XTPlus Texture Analyzer, which uses Exponent software to analyze layer separation. The tablet sample is placed in the central cavity of a guillotine-type blade, which is then compressed until the two components of the tablet are sheared apart. The force taken to shear the tablet, as well as the distance to failure, is calculated. The lower the force required to shear the tablet, the more likely it is that the layers will fail during manufacture, packing, or consumption. Visual characterization of the fracture surface enables quantification of the percentage of each fracture failure, a factor that enables manufacturers to optimize adhesion between the two tablet components.
Stability Equals Profitability
The stability of a pharmaceutical product is paramount to the consumer's acceptance of it, as well as to its subsequent efficacy and safety. It is vital, therefore, that manufacturers scientifically assess any potential changes in the structure or character of their products throughout processing and distribution. Texture analysis instrumentation enables manufacturers to do just this, offering targeted, repeatable testing that produces actionable data. As the pharmaceutical industry innovates, so does materials analysis, developing and adapting to provide new instruments for emerging test requirements.�
1. Houlton S. The demise of a blockbuster. Chem World. 2007;4(12):56-59.