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Characterizing powders for better solids processing: optimizing both the product and the process can help pharma producers to eliminate long-term manufacturing problems.

The pharmaceutical industry is moving towards greater emphasis on efficient manufacture. In simple terms, the regulators aim to reduce risk by encouraging developers to design product quality into the manufacturing process from the outset (ICH Q8, Q9 and Q10-Quality by Design). For producers, this approach also addresses tough industry challenges, such as waste, time-to-market and capital utilization. It is clear, however, that the foundations for successful manufacture must be laid during the early stages of product development.

Many pharmaceutical products are powders or solid dosages: tablets or capsules; premetered doses for dry powder inhalers; or materials reconstituted in situ for intravenous use. During formulation, the emphasis is desirable clinical performance. The properties of both active and excipient are fundamental to therapeutic success and can affect key factors such as bioavailability and solubility. During the longer term though, these or closely related properties may influence process design and manufacturing efficiency. This necessitates a more holistic view from the outset: the simultaneous optimization of product and process.

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Analysing Powders

Working towards better process design and long-term operability during early product development requires tools that help predict in-process behaviour. For powders this means

* reproducible properties measurement

* understanding how measured properties relate to performance under specific conditions

* analysis of the conditions to which a process subjects the powder.

Recent advances in powder characterization help with the first issue. Modern instruments, such as the FT4 powder tester, employ sample conditioning and automation, achieving reproducible measurement of shear, bulk and dynamic properties. These measurements generate a reliable database that characterizes a powder comprehensively.

Using this database to improve processing requires that the other two issues are addressed. Consider a pharmaceutical manufacturer sourcing alternative supplies of an excipient. The excipient specification covers composition and properties such as particle size and bulk density. Feeding a new material matching this specification into the plant, however, causes efficiency to plummet: blockages become commonplace and final product quality is inconsistent. The excipient specification is clearly inadequate, incorrect or insufficiently detailed.

A successful specification should reference all variables that impact in-process behaviour. Choices made during formulation should be similarly well informed. Analysing the conditions imposed by the process and identifying the properties correlating with behaviour within these conditions, delivers the required knowledge.

Analysing the Process

During a 'single' process, a powder is often subjected to many different conditions, complicating the identification of optimal formulation properties. Tabletting illustrates this point.

A starting point for direct compression tabletting is flow from a hopper through the feed frame onto the table. Flow should be smooth, controlled and consistent. Flowability is clearly important, with shear properties an established means of assessing hopper performance. Other factors, such as the powder's response to compression, are also relevant because material in the hopper is subject to the compressing force of the powder above it.

During die filling (the next step), flowability remains important; both flow into the empty die and confined flow as the die fills. Dynamic parameters reflect both behaviours, and the powder's response to air; permeability data provide additional insight. For complete filling, the powder must release air easily as it settles in the die: air retention compromises fill weight and tends to cause tablet breakage--capping and lamination.

Finally, at the compression stage, compressibility, cohesion and adhesion are key parameters. For a stable tablet, the powder must compress uniformly. Some cohesion is crucial, but excessive 'stickiness' leaves material on the punch, compromising production rates and product quality.

Matching Powder and Process

Long-term manufacturing success relies on processing steps, equipment and operating practices being compatible with powder properties. Modern powder testing techniques deliver raw property data. Analysing the process and rationalizing experience of measured properties, provides the information needed to exploit these data for commercial advantage.

A final example illustrates this. Comparative studies of the die filling performance of two different powders, A and B, show A performs robustly and consistently; B's performance deteriorates as a result of consolidation by vibration or compression. Compaction index (CI--ratio of compacted to conditioned flow energy) correlates with this behaviour. Sample A has a CI (tapped) of 1.11, sample B of 2.32. Knowing this, a formulator may choose to modify a new product to achieve a CI similar to sample A. A process designer with a fixed formulation may counter a high CI by: specifying a more accommodating hopper; reducing equipment vibration; and/or ensuring rapid release of a blocked hopper. A manufacturing team with little room for manoeuvre can at least adopt better operational practice. Refilling the feed hopper more frequently with smaller quantities will probably reduce process upsets for material sensitive to consolidation.

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This analysis illustrates how considering processing from the start can eliminate the root cause of long-term manufacturing problems. It also serves to highlight the way precise powder characterization leads to understanding that informs every stage of the product life cycle.

For more information

Tim Freeman

Director of Operations Freeman Technology Ltd.

Tel. +44 1684 310 860

info@freemantech.co.uk

www.freemantech.co.uk
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Title Annotation:EXCIPIENTS & SOLID DOSAGE
Author:Freeman, Tim
Publication:Pharma
Geographic Code:4EUUK
Date:May 1, 2010
Words:841
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