Functionality and Performance of Excipients

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Functionality and Performance of Excipients
Oct 1, 2006
By: R. Christian Moreton
Pharmaceutical Technology

The objective of a medicinal formulation development project is to deliver drug to the patient in the required amount, at the required rate, consistently within a batch, from batch to batch, and over the product's shelf life.
The US Food and Drug Administration's Quality in the 21st Century initiative, which includes the quality by design (QbD) and process analytical technologies (PAT) initiatives, requires that the pharmaceutical industry better understand its product formulations and manufacturing unit processes. In addition, ICH Q8?Pharmaceutical Development (also issued by FDA as a Guidance for Industry), links in to the common technical document (CTD) and suggests the need for greater understanding in the design and development of pharmaceutical formulations and processes.
Consequently, industry is expected to demonstrate that it understands its formulations and processes and can define the appropriate design space that will allow the routine manufacture of pharmaceutical products that deliver the correct amount of drug to the patient, at the required rate, consistently from dose to dose and from lot to lot, over the shelf-life of the product (i.e., a "robust formulation").
A robust formulation may be defined as:
A formulation that is able to accommodate the typical variability seen in the API, excipients, and process without the manufacture, stability, or performance of the product being compromised.
The larger the design space, the more likely we will produce a robust formulation.

Product variability. Most formulations have three components: the active pharmaceutical ingredient drug (API), the excipient(s), and the manufacturing process(es) (see Figure 1). In some instances, there is a fourth component: the primary packaging.
To understand product variability, we must understand input variability. The variability of the API, excipients, and process parameters are obvious components of the overall variability. Nonetheless, other factors could affect the manufacture, stability, or performance of the product. For example, how materials are fed into the unit process, how materials interact together during processing, and how an operator carries out the operations can all affect the final product attributes.
Thus, for a given formulation and process, we must understand variability in the raw materials and their interactions to define the process and then demonstrate sufficient understanding of the process to define the design space for the product. We can represent this process schematically using variance as a measure of variability (see Figure 2).

Achieving consistency. Two main approaches can be used to achieve consistent products. The traditional approach is to specify the input parameters more tightly, particularly the excipients and process (but also the API), and to limit the product variability by limiting the input variability. This approach does not address the variability in interactions. This interaction factor, the sum of all the interactions, also can cause problems (see equation in Figure 2).
A second, more modern approach is to accept that there will be input variability and work to gain a sufficient understanding of the process to define an appropriate process end-point. A particular unit process is thus continued until the end-point is achieved. This second approach seems better matched to the intent of the QbD initiative, and also is likely to give a larger design space, and, thus, a more flexible formulation and process.
Functionality, functionality-related characteristics, and excipients performance
Functionality applies equally to APIs and excipients. Functionality has been defined as:
A desirable property of a [material] that aids manufacturing and improves the manufacture, quality or performance of the drug product (1).
In the context of pharmaceutical formulations and products, each formulation will have its own peculiar requirements for functionality. Thus, functionality can only be properly tested by the manufacture and subsequent testing of a batch of product. This process is less than desirable.
An approach currently in vogue is to identify a surrogate test, usually a physical test, that bears some relation to the required functionality. The European Pharmacopoeia defines such properties as "functionality-related characteristics"; the USP?NF uses the term "performance tests." The European Pharmacopoeia proposes to define functionality-related characteristics as they relate to pharmacopeia materials as follows:
Physical and/or physicochemical characteristics that are critical to the typical uses of an excipient (2).
In the context of a pharmacopoeia monograph, the term "typical" raises the question: what can be done for atypical uses? Will there eventually be further regulatory "creep" in Europe requiring formulators to stick to "typical" uses in the design and development of new medicines? To many pharmaceutical scientists, this would be an anathema because it suggests that we should stifle innovation in the use of excipients, without which the drug delivery sector of our industry would never have emerged.
This leads to a further point: most excipients are included in many different products and may impart several different types of functionality depending on a particular type of application. Is it better, in the context of the pharmacopeias, to try to define the functionality-related characteristics for a particular material? Or, to define the types of functionality for a particular application and then to suggest tests that may be appropriate as a performance test?
One final point is that excipients are a very diverse group of materials with a diverse range of properties and functionalities. We still do not know in detail why many excipients work as they do. Can we define what we do not understand? Can we specify what we cannot define?
In some instances, product manufacturers have established a correlation between a product and/or manufacturing performance and some physicochemical property of a key ingredient. In such circumstances, the product manufacturer may request an additional test to be included in its specification for that ingredient.
The perils of excipient lot selection
As a short-term fix for existing formulations or, in some cases, as a longer-term strategy, excipient companies are frequently approached by customers to supply material to a tighter specification than the regular material. How valid is such an approach?
It is important to remember that many excipients are not produced using simple batch processing. Most of the large-use excipients are produced using some form of continuous processing (24?7 operation). For such manufacture, the lot number refers to a defined time in the plant, and the lot size is governed by the risk to the manufacturer of a recall. The capacity of such manufacturing plants is rated in thousands of tons per annum. The plants are operated to produce material that passes specification, but there is an inherent variability in the output that cannot be avoided. In addition, the pharmaceutical usage of many excipients is small in comparison with the overall output.
The three batches are represented in Figure 3a. The key issue is to understand how the inherent variability affects the "functionality."
In Figure 3b, the effect of the variability is small in relation to the required specification. In this situation, there a negligible effect for either the excipient manufacturer or the user beyond the cost of the extra testing (of which more later). Nonetheless, this is frequently not the case.
The alternative scenario whereby only a proportion of batches meet the criteria is shown in Figure 3c. In this example, approximately 50% of batches meet the criteria. The schematics are idealized and show a very regular cyclical variation. Reality is not as regular, and the issue of how many lots must be tested to identify one lot that meets the criteria is economically important. In this example, three or four lots may need to be tested for each order.
Figures 3d and 3e are examples in which the required specification is at one or other extreme of the observed variability. In these examples, about 10% of excipient lots would meet specification, and 10 or more lots may need to be tested for each order.
In addition, the continuity of supply is an issue when lot selection is used. The excipient manufacturer may be forced to set aside particular lots for the particular customer to maintain supply continuity, which adds to the costs associated with the order. It is questionable in the circumstances depicted in Figures 3d and 3e whether lot selection is a viable strategy for supply and, thus, product manufacturing continuity.
Who pays for the extra testing?
Excipients, for the most part, are commodity items and are priced accordingly. Though some of the smaller-volume excipients are priced above $100/kg, most of the larger-volume excipients (e.g., microcrystalline cellulose and lactose) are less than $10/kg.

Table I: Economics of extra testing.

It is also important to understand how much of that amount is profit. Net profit for many excipients is about 5%. The market is competitive, with little room for slack. When the excipient user requests extra testing from its supplier, the economic effect can be considerable. It can mean the difference between profit and loss at these margins (see Table I).
The examples shown in Table I assume the following: the manufacturer does not routinely use the tests for the product and the equipment is not currently available (i.e., either the equipment must be purchased or the work contracted out by the supplier). Given the profit structures in Table I, any account taking less than about 50 tons per annum will scarcely break ev