Excipient manufacturers raise concerns over stability testing

By Phil Taylor

- Last updated on GMT

Stable excipients can be stored in uncontrolled warehouses
Stable excipients can be stored in uncontrolled warehouses

Related tags Active ingredient

Manufacturers of excipients are being sent inappropriate requests for stability data by some regulators and pharma companies, threatening to disrupt the supply chain, IPEC claims.

The requests started last year but numbers have accelerated in the first quarter of 2015, prompting trade organisation IPEC-Americas to publish a position paper in order to draw attention to the problem.

Jost Chemical – which manufactures salts such as potassium chloride that are used as pharmaceutical excipients – is among the companies that have received requests for 'accelerated stability' or 'stress' data, getting its first a couple of weeks ago from the health ministry of a South American country.

Guidelines: misunderstanding

Speaking to in-PharmaTechnologist.com, Phil Merrell, Jost's technical market manager who led the team that wrote the IPEC-Americas position paper, said the issue stems from a mis-interpretation of the ICH Q1A (R2) guideline on stability, which has been adopted since the early 1990s.

However, the paper also notes some excipient suppliers have received questions regarding differences between storage statements on Safety Data Sheets (SDSs) and product stability documents.

ICH Q1A applies to finished dosage forms and active pharmaceutical ingredients (APIs) – not bulk excipients – and in fact following the guide will not give out data under stressed conditions.

"The guideline requires that stability testing be carried out at room temperature and humidity,​' said Merrell, which is appropriate for finished goods that are stored on a pharmacy shelf or in the home under room temperature conditions.  

 However, nine out of ten products used as excipients are shipped and stored in uncontrolled conditions because they are known to be stable and have been used in medicines for decades.

Providing room temperature data on these products "does not really mean anything and is a wasted effort,​" according to Merrell, who was also on the team that prepared IPEC's widely-used 2010 stability guide, which recommends excipients are tested for stability in the warehouse where they are stored.


So what has prompted the recent spate of requests?

"I think some regulators are waking up to the realisation that room temperature data is not relevant to goods shipped across the world in uncontrolled conditions, and have started to ask for data under stressed conditions,​" said Merrell.

IPEC’s position is that manufacturers should provide data to show the excipient is stable in the marketed packaging under the conditions likely to be encountered in an uncontrolled warehouse.

In the case of unstable excipients, data should be generated based on accepted scientific principles and – if accelerated stability studies are run – they should be carried out under controlled storage conditions.

"It makes perfect sense to ask for data that shows the product is good when it arrives at its destination, but applying ICH Q1A is not appropriate and does not add any meaningful stability information for these products,​" said Merrell.

"Q1A should be rewritten to make it clear that it applies only to finished goods that are stored in these conditions.​"

Calls for ‘grandfather’ clause

Merrell noted that after the guideline was introduced Jost had to spend millions of dollars and employ around 20 people to provide stability data on products known for years to be completely stable, even with broad fluctuations in temperature and humidity.

"You can stick potassium chloride out on your desk for years and nothing will happen to it other than a gathering of dust,​" said Merrell.

He would like to see a grandfathering system for excipients known to be stable alongside clear stability testing requirements for new excipients, as are already laid out in IPEC's stability guide.

Meanwhile, the position paper also explains that storage conditions on an SDS "should not be confused with real-time stability.​"

Information in the SDS is meant to fulfil labelling requirements relating to worker occupational safety and health, and "is not connected with any pharmacopeia terminology, requirement or product stability testing programme,​" it points out.

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