Functionality and Performance of Excipients in a Quality-by-Design World: Part 1
Formulations
Chris Moreton, Ph.D. FinnBrit Consulting
This is the first of what will be a series of columns around the topics of excipients and Quality by Design (QbD). There are several reasons why I accepted the invitation to write this column. Partly it was timing, but it was mainly a sense of frustration from having listened to people expound on these issues, and yet, to be frank, having seemed to miss the point. I am a formulation scientist, although most people probably know of me from my association with IPEC-Americas. For a formulation scientist, excipients are an important part of the body of knowledge necessary to develop successful formulations. Yet there is considerable misunderstanding about excipients. QbD is part of the US FDA's Quality in the 21st Century Initiative. Parts of it, especially the Design Space concept are also included in ICH Q8 (R1). It is a recent initiative for the pharmaceutical industry and everyone is still coming to terms with it. For formulation scientists required to develop robust formulations, it is a good approach. Yet there also seems to be some misunderstanding about QbD. Over the next few issues, this column will deal with different aspects of these general topics. This first column will set the scene; and hopefully wet your appetite.
Excipients
One of the biggest misunderstandings is that there is somewhere an excipient industry. It is simply not true. Most excipient manufacturers are fine chemical companies who manufacture a small portion of their total output for the pharmaceutical industry. The reality is that very often the amount sold into pharmaceutical companies is less than 10% of the output of these materials. IPEC-Americas, and its sister organizations in China, Europe and Japan, is an association of excipient manufacturers, suppliers and users. The manufacturing members include some very large companies producing materials for the oil industry, food industry, engineering industry, and so on. The fact that they are members of IPEC shows that they recognize the importance of pharmaceutical excipients, but for some of them, if they were to cease selling into the pharmaceutical industry tomorrow, it would not make that much of a difference to their bottom line.
Pharmaceutical excipients are a very diverse group of materials. They cover all the states of matter; gas, liquid (semi-solid), and solid. They include materials of both synthetic and natural origin, including from plants, animals and minerals. Excipients comprise such materialsas saccharides (mono-, di-, oligo-, poly-, etc.), inorganic compounds, fats, waxes, and hydrocarbons, amongst others, and synthetic or semi-synthetic derivatives of some of these. Each excipient has its own process and associated know how. Excipients can also be used in a variety of dosage forms, and some may be used for more than one route of administration. Excipient manufacturing processes include harvesting, extraction, synthetic chemistry, agglomeration, size reduction and fermentation. They are very often manufactured on dedicated equipment, frequently using some form of continuous processing, but some are manufactured by batch processing. The scale of manufacture is very different to that typically encountered in pharmaceutical product manufacture.
To give some idea of the mismatch, consider the following. As a formulation scientist involved in technical transfer and production support, the largest batches I was involved with were about 2000 kg for solid dosage forms, about 3000 L for a liquid product, and about 400 kg for an ointment or cream. Working with excipients, the smallest plant I have been involved with was rated at 2000 metric tons per annum (tpa) and the largest at 30,000 tpa, and there are larger plants. Just for the 2000 tpa plant, that would translate to 20 batches of 2000 kg per week using my largest solid dosage form batch size, and thus three batches per day working 7 days per week, or four batches per day working 5 days per week. For one product, this represents 40 metric tons of material produced per week (and 40+ metric tons of raw materials). And this is for a small excipient manufacturing plant! In pharmaceutical product terms that would be a blockbuster drug with profits to match. But most excipients sell for less than $20 per kilogram, many for less than $10 per kilogram and the net profit may be 5% or less. Not only is there a scale mismatch, there is also an economic mismatch. This has important implications for how the excipient manufacturers respond to certain customer requests.
A key issue for pharmaceutical excipients is the standard of Good Manufacturing Practice (GMP) that must be applied. Under the US Federal Food Drug and Cosmetics Act the definition of a drug or drug product includes components of the drug product. As components of a drug product, excipients are thus required to be manufactured to GMPstandards. In addition, the General Notices section of the USP 31-NF 26 Second Supplement includes the following requirement:
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