Functionality and Performance of Excipients in a Quality-by-Design World. Part 3:
Excipient Quality in a QbD Context
Chris Moreton, Ph.D.
As I wrote in my earlier columns, excipients are going to be a major part of pharmaceutical formulation Quality by Design (QbD). It thus follows that excipient quality will also be an important part of QbD and Design Space. We therefore need to consider excipient quality in all its aspect very carefully to get the most out of pharmaceutical formulation QbD and Design Space. But first we should define what we mean by quality, and then examine what it means in the context of excipients in a QbD world.
There are many definitions of 'quality', and if we look at several commonly accepted definitions we can get a broad perspective. For example, Joseph M. Duran (perhaps the 'father' of quality assurance and quality by design) defined quality in two ways:
"Quality means those features of products which meet customer needs and thereby provide customer satisfaction,"[1]
and:
"Quality means freedom from deficiencies - freedom from errors that require doing work over again (rework) or that result in field failures, customer dissatisfaction, customer claims,
and so on."[2]
In addition, the American Society for Quality Control (ASQC), in its glossary, defines quality as follows:
"The totality of features and characteristics of a product or service that bear on its ability to satisfy given needs."[3]
These are not the only definitions of quality, there are other definitions; for example Wikipedia lists another nine definitions of quality from various sources.
Having defined quality, we can move on to the question of how to assess quality. The definitions listed above, and those listed in the Wikipedia entry, relate to customer needs or expectations and satisfaction. All the definitions thus suggest quality may be assessed in terms of product features, product performance and customer satisfaction. By these definitions, we should thus be assessing attributes and performance, and monitoring customer satisfaction. This applies to any product or service, and the pharmaceutical sector is no exception. For medicinal finished products, this would translate to conformance to specification, manufacture to cGMP, in vivo performance (therapeutic or clinical end-point, or bioequivalence) and customer complaints/pharmacovigilance (post-marketing surveillance).
How do these concepts translate to pharmaceutical excipients? For pharmaceutical excipients, the needs are conformance to specification, manufacture to appropriate standards of GMP (a USP-NF General Notices requirement, and also required by the FDA), satisfactory performance (functionality), and we also need to monitor customer satisfaction.
There is a distinction between these different aspects of quality in that conformance to specification and manufacture to appropriate standards of GMP are tested or implemented before the excipient leaves the manufacturing site. In fact, manufacture to appropriate standards of GMP must be decided before manufacture commences, and the appropriate systems implemented. By contrast, performance and customer satisfaction are criteria that can only be properly assessed after the excipient has been used in the manufacture of a finished medicinal product. They are therefore outside the scope of the monograph or specification. This is the gap that we need to bridge somehow for pharmaceutical excipients, in particular the performance aspect as this will be of considerable importance in the definition of the design space. Since performance or functionality can only be truly assessed in the application, i.e. in the manufacture of the medicinal finished product, we require some surrogate test(s) that is (are) predictive of ultimate performance required of the excipient.
However, before we discuss performance or any other test, we need to consider what the pharmaceutical customer requires in their excipients, and thereby what should be in the specification or monograph. It is not just about identity, assay, impurities and performance; there are other equally important customer needs. The tragic events of recent years in Haiti, Panama, Nigeria, China and the US have shown that pharmaceutical excipients and APIs, in common with many other materials, are vulnerable to adulteration and fraud. So not only do we require the excipient specification or monograph to address identity, assay, impurities andperformance, we also need to consider the chemical integrity and safety of excipients.
One of the major changes in the pharmaceutical field in recent years has been the globalization of so many aspects of the industry, particularly the supply of both APIs and excipients. Considerable quantities of both are sourced from outside the US, and this complicates the issues of integrity and safety. With globalization, supply lines are both extended and more complex. In some cases the supply is from countries or regions that have different rules and regulations and where the people have different attitudes to safety and integrity. These differences have led to misunderstandings as to what is required for a pharmaceutical excipient, whether compendial or non-compendial, for use in the US market. There is a prevailing belief in some countries and regions outside that US that all that is required is conformance to specification. As recent events have shown, there are unscrupulous individuals who have deliberately tainted (adulterated) pet food, milk and heparin so that lower strength materials will pass specification. Other incidents have occurred whereby industrial grade glycerin and propylene glycol containing significant quantities of diethylene glycol and/or ethylene glycol have been intentionally relabeled (misbranded) as USP or NF grade respectively. In all these cases, patients or customers or their pets have died.
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