Understanding Excipient Interfaces
Regulatory drivers for testing to better predict attributes
By Andrew Parker, Ph.D.
Testing of excipients as described by pharmacopoeia monographs has advanced over recent years to include highly sophisticated techniques such as X-ray Diffraction (XRD) and Near Infrared (NIR). However, these monographs have mainly focused on standards for chemical product characteristics. A further important driver that has yet to be encompassed in compendial testing is the manner in which excipients are employed for different functional purposes and how this impacts on product quality and process performance. We will discuss the key drivers for understanding excipients, outline functionality-related testing criteria and critically discuss the merits of whether it is appropriate to list functionality-related testing in a monograph-type listing.
Key Drivers for Understanding Excipients
Quality by Design (QbD ) / PAT / ICH Guidelines
There are many diverse drivers for understanding excipients and, in particular, excipient interfaces in formulated drug products. These span from the financial incentives of reducing production cycle times and lowering reject rates, to IP and the need to gain better lifecycle management of a marketed product, through to scientific factors and the continuing quest to better understand the relationships between drug product structure and drug product function.
Key drivers such as regulatory initiatives, guidance and criteria are constantly updated by the FDA and expert working groups. One initiative in particular is the concept of Quality by Design (QbD), which moves away from the realm of reactive “testing to document quality assurance” to the proactive approach of “continuous quality assurance.” In order to achieve these goals, critical product attributes and critical process parameters for the product need to be identified and, to this end, a detailed understanding of the physical, chemical and material properties of the excipients and drug substance needs to be gained. Moreover, and no less importantly, regulatory guidance is designed to be implemented with a quality risk management system.
These regulatory initiatives are not compulsory at present, representing the desired state of a harmonized pharmaceutical quality system applicable across the lifecycle of the product. The net gain is an integrated approach to quality risk management and science, without extensive regulatory oversight. It is interesting to note that this desired state has already been realized in many other sectors, such as the automotive and aviation industries. So why not in the pharmaceutical industry already?
Until the start of this decade, there was not an integrated quality system in the pharmaceutical industry applicable from discovery to marketed product. Furthermore, regulatory authority requirements for post-approval changes presented a barrier to the improvement of manufacturing processes and controls, especially as different regulatory authorities frequently posed different demands based on common data. Continual improvement was not incentivized for the increasingly global nature of pharmaceutical manufacturing. This was a sector where changes to processes or controls may have necessitated dozens of application variations with approval times from two months to as long as three years. With respect to the latter, industry could thus only cope, for example, by building three years of stock, waiting three years to implement changes, or running old and new process controls simultaneously; none of these were optimal situations. Hence, breaking down these barriers and bringing pharmaceutical quality management out of the 1970s was one of the core challenges for regulators.
Let’s take a brief look at the evolution of regulatory guidance over this past decade and the implementation of QbD. Back in 2001 the FDA put forward PAT (Process Analytical Technology), which emphasized process understanding and process control rather than end-product testing. This really represented a paradigm shift, from having variable inputs such as starting materials and fixed processing parameters leading to potentially variable processing intermediates or products, to accommodating variable inputs by having compensating variable processing parameters to ensure consistent output and assurance of product quality.
Two key tenets for achieving PAT are that product quality and performance is assured by design of an effective and efficient manufacturing process(es), and that product specifications are based on mechanistic understanding of how formulation and process factors impact product performance. In practice this means that all critical sources of variability are identified and explained (starting materials, equipment, process, personnel etc.), on-line/at-line technologies are used to monitor processes, and variability is managed by the process. Comprehensive process understanding can then be demonstrated when product quality attributes can be reliably, repeatedly and accurately predicted.
PAT was ratified in 2004, but more recent regulatory guidance was put forward by the expert working groups1 of which the FDA is a part, clarifying the way in which PAT concepts can be integrated with the regulatory process. The ICH Q8 pharmaceutical development guideline outlines the main principles that should govern pharmaceutical development studies. It does not detail a ‘how to’ approach, but highlights the potential regulatory benefits through the concepts of regulatory flexibility based on a demonstrated ‘design space.’
Design space (see Figure 1) is the multidimension combination and interaction of input variables and process parameters that are demonstrated to provide assurance of end-product quality. Design space exists within the knowledge space that is formed during the development of a pharmaceutical product, the latter generated from sources extending from statistical experimental designs and first principles approaches to manufacturing experience and scale-up correlations. Manufacturing control space for production exists within the design space. When a working element within a demonstrated design space and control space needs to be altered, this alteration is not considered a “change” (regulatorily speaking). This provides opportunities for reduction of post-approval submissions and the concomitant benefits in reduction in resource expenditure required to introduce the change and the lead times with which it can be implemented. Crucially, design space is proposed by the applicant but is subject to regulatory assessment and approval based on the evaluation of risk and risk management (ICH Q9).
The ethos of this framework is that development and manufacturing are product-centric and that the concepts of design space and PAT are fundamentally linked. The cornerstone is an understanding of the influence of excipients and drug substance attributes on the critical process parameters and the critical quality attributes of the product.
The guideline mandates that excipients are chosen based on their compatibility and requirements for product performance. Further considerations are that the concentration and characteristics that can influence product performance or manufacturability should be considered relative to the respective function(s) of each excipient. This should include all substances used in the manufacture of the drug product, whether they appear in the finished product or not. The ability of excipients to provide their intended functionality and to perform throughout the intended drug product shelf life should also be demonstrated. For establishing a selection strategy of choosing excipients in line with QbD, this means: What is critical for functioning of a drug product? The next logical question is: What methods can be used to test for it? This inherently requires consideration of the concept of excipient functionality.
In understanding excipient functionality, it is important to remember that not only do excipients have a number of diverse roles in a formulation, they also originate from a diverse range of sources. Sources include minerals, vegetation and animal by-products. Only a small percentage of excipients find use in pharmaceuticals and the inherent level of quality and level of control can vary from lot-to-lot and from supplier to supplier. Source variability must be recognized and accepted. While this is accommodated within QbD/ICH principles, a key consideration is that most excipients impart different types of functionality depending on their use in a particular product. Thus functionality is specific to a product and to the process used to generate that product. For example, HPMC is commonly used as a binder in tablets but is also commonly used as a rate-controlling polymer in controlled release coatings to impart a desired product function. Micro-crystalline cellulose is used as a direct compression tablet diluent but also finds use an extrusion aid in the spheronization process.
That said, necessary functionality cannot be defined solely by the type or use of an excipient because, with respect to QbD, the specific API (and potential interactions), source of the excipient, intended dosage form and exact manufacturing process have to be considered as well.
Defining and Testing for Functionality?
The ICH guidelines require manufacturers to specify each method used for routine excipient testing, unless the method is exactly that of the pharmacopeia and full monograph testing is performed. Hence, while tests for functionality-related characteristics are detailed in pharmacopeia listings — e.g., particle size distribution, specific surface area, acid value and crystallinity — functionality testing is not currently detailed in monographs. This is due to the specificity with which the test would have to be adhered to, as it can only be assessed in the context of a particular formulation and manufacturing process. Indeed, one formulation’s functionality can be another formulation’s disfunctionality. While moves are afoot in the European pharmacopeia to list such tests in a nonmandatory section of monograph listings, there are numerous drawbacks to this approach. These include the fact that a comprehensive listing would create an almost infinite number of permutations for excipients and processes. This kind of testing information is far better suited to disclosure as part of design space in a regulatory submission, rather than facilitating potentially redundant testing because it is listed in a pharmacopoeia monograph. In addition, many excipients impart their functionality in a manner that is still not completely understood from a scientific standpoint. Since it is not possible to define what we do not understand, we cannot specify the anticipated results of any testing.
At present there is a strong school of thought that functionality is neither a pharmacopeial nor a public-standard issue2. Compendial testing focuses primarily on purity and safety; a certificate of analysis was never designed to assess functionality per se. Since functionality can mean different things to different people, it is hard for a monograph to go beyond fairly straightforward testing for standards of identity and grade.
Ideally, interactions between material attributes and critical process parameters should be understood so that critical process parameters can be varied to compensate for changes in, say, raw material sources while maintaining product quality. In achieveing this, functionality can be connected with material properties and process parameters, justify the choice and quality attributes of the excipient and support the justification of the drug product specification.
Testing Methodologies and Application Examples
Testing of excipients within a formulation for functionality cannot be performed in isolation from a process. So, what type of testing should now be considered important for better establishing a design space and demonstrating an enhanced knowledge of product performance over a wider range of material attributes? The two case examples that follow focus on surface/interfacial properties of commonly used excipients and their influence on the functionality of drug products.
Lactose, also referred to as ‘milk sugar,’ is contained in many millions of tablets for different functions, ranging from a filler to a coating. Traditionally used as a diluent in solid dosage forms, lactose is also frequently found in inhaled therapies where its surface properties and its action as a carrier become dictating attributes of functionality. Hence determination of its surface properties becomes critical to better understanding its functionality and how this is affected by various process parameters.
Lactose can exist in two diastereomer forms, alpha and beta (see Figure 2), which are related by an equatorial flip of a hydroxyl group, with the alpha stereoisomer being the more stable form. Recent reports have detailed how these two stereoisomers have differing material properties such as different recrystallization energies3. In addition, other researchers4 have showed that mutarotation between the two stereoisomers is initiated on heating the amorphous state, and reaches chemical equilibrium close above the glass transition temperature, existing as a ~1:1 alpha:beta ratio. Combining these two facts means that in the process of, for example, spray-drying lactose, significantly different surface material properties may be generated by subtle variation in either the input raw materials (in terms of alpha/beta content) or spray-drying parameters. This can lead to non-optimized products in terms of cohesion/adhesion balance when considering dry powder inhalers (DPI), potential loss of fine particle fraction, or out-of-specification results for drug recovery upon accelerated stability testing.
Mapping specific regions of various batches produced under controlled conditions using spatially resolved chemical spectroscopies such as confocal Raman microscopy enables the distribution of lactose in terms of its stereoisomers across a single crystal to be determined at the micron scale. This information can be correlated to product performance for DPIs such that a range of raw material parameters — e.g., starting alpha:beta ratios — and process parameters can be elucidated that give assurance of drug product quality.
Hydroxypropyl Methyl Cellulose
Hydroxypropyl methyl cellulose (HPMC) has many pharmaceutical uses, such as a binder, a coating agent, a tabletting agent and an emulsifier in ointments. Many excipients are measured in terms of viscosity to impart desired product function. Where HPMC is used as a rate-controlling polymer in controlled release coatings, it is very important to characterize not just viscosity and the number of hydroxypropyl groups but also the interfacial properties with other excipients — for example, ethylcellulose — which are often employed to tailor the coating release properties. These interactions influence the resultant microstructural attributes, which become critical in determining product functionality and maintaining batch-to-batch uniformity.
The final microstructural properties of the controlled release coatings can be affected by the methods used to create the coatings, such as solvent mixtures employed if a spray coating route is employed, solvent removal rate and temperature. Using spatially resolved techniques such as atomic force microscopy and scanning thermal microscopy, the microstructure can be determined on the nanometer-micron scale in terms of domain size, what material constitutes the continuous phase or whether a biphasic structure is present. Again, correlating microstructure to product performance and process parameters can give insight into the functionality of the coating, mechanism(s) of drug release and conditions (starting materials and process parameters) that assure quality of the drug product.
In conclusion, functionality of excipients exists only in the context of a specific formulation and process. Variability should be both anticipated and handled by the process for excipients, in alignment with QbD. The concept of developing design space should be considered throughout the development of a product and process to achieve long-term financial and regulatory benefits. Although the ICH initiatives are only guidelines at present, they are set to transform the chemistry, manufacturing and controls regulatory review into a modern, science based, pharmaceutical quality assessment.
- International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).
- R.C. Moreton, ‘Excipient functionality’, Pharmaceutical Technology, May 2004.
- S. E. Dilworth, G. Buckton, S. Gaisford, R. Ramos, International Journal Pharmaceutics, vol. 284, pp83-94, (2004).
- R. Lefort, V. Caron, J-F Willart, M. Deschamps, Solid State Communications, vol. 329, pp329-334, (2006).