Unlike with active pharmaceutical ingredients (APIs), there are no clear governmental good manufacturing practice (GMP) guidelines for excipients in the US, Europe or China. Now the International Pharmaceutical Excipients Council (IPEC) is launching a new guide for the GMP manufacturing of excipients and is warning the industry: agree on what the exact standards should be or the regulators will do it for you.
The European Commission (EC) is about to publish a questionnaire for the industry on GMP standards for excipients ahead of legislation, while regulatory bodies in the US and China are also set to move on the issue.
Currently the law in most cases holds pharmaceutical manufacturers responsible for the quality of excipients but does not define it neither does it tell them how to manage it, so the companies have to evaluate their excipient suppliers using testing, audits and questionnaires which are not the same across the industry, and suppliers often have to decide themselves what kind of methods and standards they use.
Although this is not primarily a safety problem - IPEC says most scares in excipients have come from failures in good distribution practices (GDP) - it has important economic implications for the sector.
This is of course because any regulation which eventually seeks to harmonise standards may place too high costs on producers of excipients who as a result become uninterested in servicing the needs of the pharmaceutical market, hampering the ability of finished drug manufacturers to develop better delivery systems.
Yet discrepancies in GMP are financially important also because pharmaceutical excipient manufacture is usually less than 10 per cent, and often less than 5 per cent, of the total production of that particular material, and so the manufacturer may have to adopt different standards for that portion of production.
For example, excipients such as solvents, preservatives and buffers also have applications in the bulk or speciality chemicals industries, and commonly used excipients in oral drug products include the colouring, flavouring, bulking and tastemasking agents, which are large-scale ingredients for the food industry.
Thus, in most cases excipients are produced in bulk and are low margin products, as opposed to APIs, which are high-value small-volume products made in dedicated plants.
"Companies are all over the place with regards to this, some make excipients as simple as salt or sugar," Kevin McGlue, Operations Director at Colorcon and chairman of the GMP committee at IPEC Europe, told In-PharmaTechnologist.com.
"This does not mean we need manufacturers who exclusively produce pharmaceutical excipients but that we must introduce specific GMP standards that do not compromise on safety and are also realistic for them to adopt."
Another challenge that needs to be overcome vis-à-vis GMP is the variability of excipients, both in composition and function.
Excipients may be used to facilitate processing during manufacturing of bulk product, to aid solubilisation for example, or during manufacture of the final dosage form, say to prevent adherence to machinery, and may be critical in the formulation to ensure the drug is acceptable to the patient, or be the actual mechanism for delivering or controlling the release of the API.
In fact, processing aids during packaging of the pharmaceutical product, such as stopper lubricants, or during the use of the final dosage form, such as syringe lubricants, can also be classed as excipients.
Moreover, there has also been a shift from the use of excipients as inactive ingredients to functionally active materials, while biotechnological developments and various emerging protein-based therapies are broadening the definition for excipients products, so as a result the definition for excipients is changing and includes a wider range of products such as anti-bodies and chimera product.
IPEC has responded to those issues by publishing, along with Pharmaceutical Quality Group (PQG), a new guide on the GMP manufacturing of excipients, not only to help excipient suppliers meet the increasingly stringent demands of the pharmaceutical industry, but also make it easier for pharma companies to ensure their suppliers are meeting acceptable quality levels.
"Adopting this GMP guide will make you more attractive to the pharma industry which has an obligation to secure good starting materials," McGlue said.
"The main benefit is that it will align you to their needs, so when regulation is introduced it will be workable and pragmatic."
The new guide draws together and improves upon all the existing voluntary guidances that have been applied to pharmaceutical excipients.
Particularly useful are recommendations for companies making excipients by continuous processing, which is commonly used in the chemical industry but less often in the pharmaceutical sector, which tends to manufacture using batch processes.
According to IPEC, up to 50 per cent of pharmaceutical excipient manufacturers are using continuous rather than batch processing.
The guide also sets out new recommendations on difficult issues such as validation, stability testing, change control and impurity profiling that have been lacking from earlier guidance, forcing companies to default to guidance on APIs that is inappropriate for excipients.
As pharmaceutical manufacturers feel the effects of patent expiries, growing generic competition and drug failures, they are compelled to cut expenditure on product development without compromising on quality, so excipients offer a welcome opportunity to add better functionality to products at lower costs.
At the same time the obligation to ensure the safety of excipients lies not with their producers but with pharma companies, thus it is hoped the new GMP guide will promote safety while encouraging investment.