Taking the drama out of pharma

As one of the most tightly regulated industries across the globe, quality control sits at the heart of all things pharmaceutical. Jo Smewing, takes a look at some of the issues and reviews the latest innovations designed to help manufacturers overcome distribution challenges

ESTIMATIONS of the cost of taking a drug to market sit comfortably at the $1 billion mark , with much of this vast spend being pumped into lengthy trials and rigorous analytical tests. Proving the efficacy, quality and safety of a pharmaceutical product to gain 100% confidence and approval for market is, clearly, a significant investment.

But what of the product when it is approved for market? Does investment in quality evaluation stop here? With the over-the-counter (OTC) market in UK expected to grow 2.8% by 2011 , and the NHS doubling it’s spend on prescription drugs in the last decade to £8.2bn a year , manufacturers who want a share of this expenditure need to stay ahead. 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.

One of the most challenging aspects of pharmaceutical manufacturing and distribution is achieving 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 products are robust enough to withstand packing procedures, storage and transit conditions, as well as consumer handling. The implications of product failure are as disastrous for over-the-counter medicines as they are for prescription drugs – dissatisfied customers, disgruntled consumers, lost contracts, damaged reputation and, ultimately, reduced profits.

For a long time, the industry has worked hard to develop and enhance quality control measures that will help to predict and refine product stability. Texture analysis instruments have played a big role. These offer repeatable, scientific quantification of material robustness, the results of which can identify product weaknesses and predict, and subsequently avoid, product failure. Traditional tests have enabled the analysis of parameters such as tablet hardness, gel strength and mucoadhesion. While these tests continue to provide valuable data, texture analysis experts now have to respond to rapid innovation within the pharmaceutical industry, as new delivery and encapsulation formats are introduced. As a result, the scope and capabilities of testing instruments have widened significantly.

One of the latest developments in testing is the capsule tensile rig. This

Stable Micro Systems’ Capsule Tensile Rig measures the force required to split one half of a hard gel capsule, enabling manufacturers to investigate the effects of fillings on the mechanical strength of the capsule shell

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, such as hydrophilic solvents, to hard capsules can often affect the mechanical properties of the shell, causing them to become brittle or soften. If the texture of a capsule is compromised, it may not be able to withstand handling and storage, resulting in fillings leaking from the capsule.
 
As effects are likely to be progressive, only displaying very small changes initially, compressive tests may not be able to distinguish the anomalies adequately. The capsule tensile rig is designed to help identify subtle degradation, providing valuable information which can be used to avoid subsequent capsule failure. For example, manufacturers can identify the effect of liquid filling on the strength and stability of capsules and therefore reformulate liquid type or capsule accordingly.

Before testing, the filling of the capsule is removed and the empty shell is mounted to a separating rod fixture on the TA.XTPlus texture analyser. Vertical movement of the upper rod is then applied until the capsule is split apart, while Exponent software records the force required to do so. 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 therefore show a tendency to fail.

The pharmaceutical industry is one of the world’s biggest users of powder. Many products, such as paracetamol, are produced in powder format and then compressed into tablets. Powder compaction is an essential step in the manufacturing process and it is essential to avoid products cracking during processing. Their liability to failure is influenced by the powder’s processing properties, such as density variations introduced during die filling and/or compaction.

The characterisation of powder in its bulk format can enable manufacturers to predict the behaviour of the powder when compressed. However, the need for more targeted analysis of powder compaction has been identified and, as a result, the powder compaction rig was developed.

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 powder compaction rig produces precise measurements that enable pharmaceutical product manufacturers to produce powder compacts with consistent porosity. It accurately assesses the force needed for the punch to travel a specified distance, or 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 where 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, such as assessing granule friability, where punch/die clearance is less important.

Sophisticated methods for powder characterisation, along with analysis techniques for hardness and coating adhesion, have enabled manufacturers to obtain valuable data on the stability of standard tablet formats. However, the development of bi-layer tablet formats, which contain isolated immediate and controlled release component layers, has given rise to new analytical requirements.

Such formulations are increasingly popular as they provide efficacy for consumers as well as ease of production for manufacturers. Ensuring that one tablet layer does not impact on the other is instrumental to the remedial benefits of bi-layer medication, and to 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 which may in turn result in cross-contamination. Common issues include layer separation, insufficient hardness and inaccurate individual layer weight control.

Manufacturers need to be able to gauge the stability of the layers, to ensure the product reaches the user in its intended format. In response, the bi-layer tablet shear rig has been launched. A new attachment, it analyses the strength of bi-layer tablets, allowing pharmaceutical manufacturers to identify weaknesses and improve the quality and stability of their products.

The rig is attached to the TA.XTPlus texture analyser. 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 characterisation of the fracture surface enables quantification of the percentage of each fracture failure, which is important in enabling manufacturers to optimise adhesion between the two tablet components.

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 has enabled manufacturers to do just this, offering targeted, repeatable testing that produces actionable data. As the pharmaceutical industry innovates, so materials analysis evolves, developing and adapting to provide new instruments for emerging test requirements.