EMEA view of atypical actives is a ‘pragmatic’ solution

By Phil Taylor

- Last updated on GMT

Related tags Active ingredient Pharmacology Pharmaceutical drug Emea

Manufacturers of ingredients used as excipients in pharmaceuticals have faced some regulatory problems with a series substances known as 'atypical actives'.

However, a new Question and Answer document from the European Medicines Agency seems to suggest that a pragmatic solution has now been found, according to industry organisation IPEC Europe​.

Atypical actives are substances which have been registered as the active ingredient in a medicine but whose primary industrial use is not as a pharmaceutical active substance. As actives, they are subject to EU regulations requiring manufacturing according to pharmaceutical GMP standards.

However, there is a serious snag, as well-recognised excipients such as glycerine, glucose, citric acid and even honey have ended up being registered as actives.

"Quite often the excipient manufacturer has no knowledge they are supplying an API​," according to Iain Moore, chair of IPEC Europe's GMP Committee.

Many of the substances in question are found in fairly old products, often over-the-counter or generic medicines that have a long history of safe use, he continued.

The legal status for atypical actives is very clear - defined and enshrined within the principles of ICH Q7. If the supplier is informed that their material has been registered as an API, they are legally bound to implement that level of GMP. This is often cost prohibitive for the business done with the atypical active and in all probability they will cease to provide it to that customer.

The EMEA acknowledges this, noting in the Q&A document that the producers of these substances "may not be aiming to meet the specific GMP requirements of their pharmaceutical customers, particularly where those customers represent an insignificant volume of business.​"

Previously, IPEC-Americas recommended that if the supplier had any suspicions that their excipient was being used as an Atypical Active that they should label it with "for excipient use only​". Until now, another alternative has been to agree with the customer that the ingredient is made to excipient GMP and not API GMP, and is aware of all concurrent liabilities from that position.

In 2006, the AESGP submitted a proposal to the European Commission suggesting that pharmaceutical manufacturers should perform a risk-assessment and determine whether the material in question is still fit-for-purpose as an API.

It seems the EMEA has largely accepted the principles of the AESGP proposal, and effectively placed the responsibility on the Qualified Person to determine whether the ingredient is fit for purpose after completion of such a risk assessment.

Where the ingredient is not made to API-standard GMP, alternative sources should be sought, says the document. "But in exceptional circumstances the manufacturing authorisation holder should assess and document to which extent GMP is complied with and provide a risk-based justification for the acceptance of any derogation​," it adds.

"The declaration provided by the Qualified Person should set out in detail the basis for declaring that the standards applied provide the same level of assurance as GMP​".

The Q&A document also notes that the EMEA "will collect experience with this approach which can be used as a basis for discussion on related amendments to guidelines in the future.​"

"This is a sensible and pragmatic approach, and to be successful the supplier and the user will have to join forces in a collaborative manner to complete a holistic risk assessment, which is always a good idea​," concluded Moore.

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