Manufacturing processes have not kept pace with inventions in the pharmaceutical industry. However, the Quality by design approach which integrates quality into every aspect of the design and the manufacturing process of drugs, promises more powerful and yet cost effective production of drugs. The use of factorial design principles in the QbD approach enables researchers to alter the various critical parameters to establish the quality target product profile. However, in order to create the optimal tablet formulation, a thorough study of the mechanical properties of the active ingredient as well as the excipients is a prerequisite. Variation of excipient properties are known to impact the tablet performance. Studies have indicated that excipients are very sensitive to environmental conditions and they affect dissolution rate of the active pharmaceutical ingredient. Also, environmental variables such as moisture, temperature affect the bonding properties of powders. For instance, ‘air entrapment’ is a big problem during the compaction process as it leads to development of cracks and disintegration of the tablet. Furthermore, decompression effects and the capping mechanisms of tablets also pose problems for the compaction process. The usefulness of the QbD principles in the powder compaction process offers immense scope for pharmaceutical researchers to achieve optimal formulations while at the same time adheres to the strict drug safety standards.
QbD provides a paradigm shift in drug manufacture and enables the research processes to be streamlined and helps to drastically cut the time to market. Computational fluid dynamics and particle based simulations are already significantly impacting the process analysis in powder compaction. Furthermore, technologies such as small angle X-ray scattering (SAXS) and Finite element simulations have provided new tools for pharmaceutical researchers to more thoroughly investigate the compaction process. These tools enable the study of swelling and disintegration behavior of compacted tablets. This present research studies ‘powder compaction’ and aims to focus on how variations in excipient properties affect the flow and compaction properties of pharmaceutical powders and how an optimal formulation could be achieved using QbD approach that links formulation and development. For the purpose of this research an extensive review of current pharmaceutical literature pertaining to powder compaction and QbD would be complemented by comprehensive laboratory experiments.
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Since the 2004 report by the FDA insisting on the development of a pharmaceutical manufacturing process that is centered on a risk based approach, regulatory processes have insisted on the need for a quality based approach that is integrated both in the design and the development of the drugs. (Kushner, 2011) The quality by design approach serves to eliminate the lengthy trial and error based manufacturing process by building quality at every stage of the drug product development cycle. The use of factorial design in QbD allows pharmaceutical researchers and manufacturers to coalesce design and development thereby optimizing the entire process.
One of the important issues in pharmaceutical industry currently is how powder compaction is affected by the variation in excipients and how this variation affects the functional properties of the final products. Pharmaceutical powders vary in their functionality and this presents a huge quality issue. Though excipients are therapeutically non- functional they are not totally inert. One of the very early reports pertaining to the changes in excipients and their impact on the dosage was the 1960 incidence of phenytoin toxicity that was found to be the result of changes in excipient used in the tablet formation. (Chamarthy, 2009) Today, it is understood that the functional performance of the drug is influenced by both the physical as well as chemical properties of all its ingredients. Since the active pharmaceutical ingredient is used in small quantities while the excipient constitutes roughly around 90% of the final pharmaceutical compound, understanding the potential role of the excipient, its variability and how it could impact the overall drug functionality has now acquired significance. (Chamarthy, 2009).
Market demands force pharmaceutical companies to look for alternative excipient suppliers for large scale production of the drug. This implies the need to ensure that excipients from the different sources are interchangeable. However, as the numerous reports from pharmaceutical industries suggest, excipient variation is not a rare occurrence but quite a common occurrence.
All pharmaceutical ingredients including excipients are routinely tested for their adherence to safety standards and performance specifications. Excipients, though not functional components, are necessary ingredients in a pharmaceutical product to improve its stability, bioavailability and for taste and product acceptability. Excipients are thoroughly tested for their purity, chemical stability etc. However, not much testing goes into assessing their powder physical properties. Previous studies have demonstrated cases where excipients deviate in their functional characteristics as described in their Pharmacopoeial monograph. This is due to the change in functionality of the excipients with relation to the changes in their solid state characteristics. (Gamble at.al, 2010)
There are considerable problems in establishing equivalency of product performance between different vendor products as well as between the various batch products form the same company. Moreton C. (2009). Furthermore, the functional quality certification for excipients derived from the pharmacopoeial monographs cannot be generalized and approved as studies have demonstrated that their functional properties are not strictly defined by their intrinsic properties but they vary in relation to specific formulations and applications.
Particle engineering studies have shown that changes in the solid state characteristics of a substance would result in molecular level alterations such as polymorphic and polytypic structural changes. These molecular changes in turn affect the bulk level properties such as flow, compressibility, moisture sensitivity, etc. (Panda, 2011)Since these bulk level properties are very crucial factors that affect the performance of the excipient, care must be exercised in choosing the appropriate excipient for the particular application to achieve the desired and consistent product functionality.
In explaining the variability in performance characteristics of an excipient, the case of Lactose which is a commonly used excipient for its diluent and binding properties, presents a simple example of how variations in solid state characteristics of the excipients can impact it functional properties. The use of Lactose as an excipient increases the hardiness of tablets as well as improves its disintegration.Lactose is available in four different solid forms namely – ‘?-
lactose monohydrate’, ‘amorphous lactose ‘, ‘anhydrous ?-lactose’ and ‘anhydrous ?-lactose’. The noticeable aspect about these different forms is their different compaction properties. (Gamble et.al, 2010) For instance anhydrous ? Lactose exhibits better compaction compared to the other forms due to its highly spherical structure. Furthermore, in the market commercial ? Lactose invariably includes a mix of at least 15% of the other forms of Lactose which also affects the compaction properties. (Gamble et.al, 2010)
Many studies have reported the changes in the functional properties of the excipients due to the variability in the raw materials used for the process. One study by Chamarthyet.al (2009) analyzed the variations in excipient functionality using starch as the excipient for the study. As was usual for pharmaceutical preparations, the researchers purified the starch excipient by washing it. They further divided the starch into two parts with one part receiving an additional wash. Both the parts then underwent a series of standard tests designed to analyze their physical characteristics. Both the parts were approved with similar test results pertaining to their physical characteristics. However, the researchers found that the part with the additional washing step exhibited better compaction compared to the other part. This variation in compaction ability, though both the parts were reported to have identical physical characteristics, clearly indicates that the surface properties of starch powder were significantly altered by the additional washing. The researchers concluded that the extra washing step created higher surface energy in the excipient which was reflected in its higher compaction activity. Chamarthyet.al (2009) The following figure illustrates how the surface energy levels between the two Starch lots vary due to the extra washing. For effective powder compaction it is necessary to assess the surface properties of excipients.
There are several analytical tests available to compare excipients from different batches or different suppliers. Several factors such as measuring the ‘True density’ of the products, (for example the use of helium pycnometer), Specific surface area using a typical adsorption analyzer, ’particle size image analysis’, infrared spectra analysis using Fourier transform infra red, and X-ray powder diffraction etc.
Variations in excipient properties from batch to batch and among different suppliers must be anticipated and control measures should be in place to ensure that the performance of the final drug product or the active ingredient is not compromised. This necessitates thorough knowledge of the excipient function along with the drug manufacturing process and the functional expectations of the final drug product. (USP, 2011) In other words, achieving consistent drug performance involves an integration of multiple factors including excipient properties, manufacturing design and process and specific applicational requirements. The QbD approach to drug development provides this integration by including the knowledge of product performance over a wide range of component characteristics. Having this knowledge of drug performance over varied material attributes is critical to achieving drug application specific consistency in performance. The following diagram illustrates how the QbD process for drug manufacture involves understanding product variability as a crucial aspect in the developmental process.
The intersection region in the above Venn diagram indicates that the product variability is influenced not only by the variations in the Active pharmaceutical ingredient but also due to the variations in the manufacturing process as well as the variations in the excipient. The central point behind the QbD approach to drug manufacture is that it takes into consideration the variations in the aspects including the process parameters and product components in order to make appropriate adjustments and optimize the design and development to achieve consistent drug performance as the end result. Without the QbD approach, it would simply be a case of variable raw material in a fixed manufacturing process which would inevitably result in variable product. (Schoneker, 2011)
It is important to understand that the excipients are in most cases not manufactured by the pharmaceutical company but obtained from large chemical manufacturing plants. Also these chemical plants cater to a wide variety of industries whose quality specifications may not match the requirements of the pharmaceutical industry. This would result in variations between suppliers and also batch to batch variations. The QbD process involves consideration of these variations and then designing formulations that adapt to the anticipated variations in the excipient properties. Understanding the excipient variation as one of the important input variables enables pharmaceutical companies to specifically choose excipients from a manufacturer who mainly produces the excipient for pharmaceutical use. Also by communicating the specific needs or the functionally related characteristics (FRCs) of the excipient to the manufacturing company, it would be possible to obtain pharmaceutical quality excipient with good batch uniformity and consistency. This would also enable the manufacturer to determine if they have the process capability to cater to the required quality specifications. (Schoneker, 2011) Surface characterization studies of the excipients should be carefully done as they help us understand and control the functional variability. Furthermore, such studies help us better understand important powder properties such as flow, blending, segregation, compaction, etc. This research will explore powder compaction in relation to variation of excipient and application of QbD to link formulation to development. A comprehensive literature review along with a study with sucrose as the excipient will be discussed in this paper.
- Moreton C. (2009), Functionality and performance of excipients in a quality-by-design world: obtaining information on excipient variability for formulation design space. Am Pharm Rev.; 12(5):28
- Amidon, G.E. Physical and Mechanical Property Characterization of Powders, in: Physical Characterization of Pharmaceutical Solids (Drugs and the Pharmaceutical Sciences, Volume 70) Eds: Brittain, H.G. 1995.
- Biswajit Panda, Abhinav Raoot, Vaishali Kilor (2011), Co-processed excipients : An overview of formulation aspects, physical characteristics and role as a pharmaceutical aid, viewed Apr 21st 2012, < http://www.pharmatutor.org/articles/overview-of-co-processed-pharmaceutical-excipients-formulation-aspects?page=0,0>
- David Schoneker, (2011), The impact of excipient variability of QbD, IPEC. Viewed Apr 20th 2012, <http://www.ich.org/fileadmin/Public_Web_Site/Training/GCG_Endorsed_Training_Events/APEC_LSIF_JCCT_workshop_Beijing__China_Dec_08/Day_3/Impact_of_Excipient.pdf>
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- USP, (2011), IPC-USP 10th Science and Standards symposium: Global Quality standards for Biologicals and Chemical Drugs, viewed Apr 20th 2012, < http://www.usp.org/sites/default/files/usp_pdf/EN/meetings/04TrackI-ChemicalsConcurrentSessions.pdf>
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