EMA adopts guidelines on phthalate excipients, cross-contamination in manufacturing

The guideline on phthalates​ as excipients, which comes into effect June 1, 2015, notes upfront that animal studies have found certain phthalates are associated with effects on reproduction and development, though human data on the plastic additives are limited.

The most commonly used phthalates in medicinal products licensed in the EU are: dibutyl phthalate (DBP), diethyl phthalate (DEP), polyvinyl acetate phthalate (PVAP), cellulose acetate phthalate (CAP), and hydroxypropyl methylcellulose acetate phthalate (HPMCP).

For DBP and DEP adverse reproductive and/or developmental effects have been observed in non-clinical studies and as a consequence, Permitted Daily Exposures (PDE) values of 0.01 and 4mg/kg/day, respectively are proposed.

However, the review of data concluded that there are at present “no data indicating that the presence of CAP and HPMCP in human medicinal products constitutes a potential risk for human safety​.” There is also no PDE for PVAP, the EMA says.

For already authorised drugs, the EMA has set a time limit of three years for the implementation of formulation changes.

“The recommendations of this guideline should be considered as precautionary measures in the absence of clinical evidence on phthalate-induced adverse effects in humans​,” EMA says, though it is expected that new drug applications for marketing authorisation will be in compliance with this guideline.

The new exposure levels follow the US FDA’s decision last year to call on manufacturers​ to avoid using DBP and di(2-ethylhexyl) phthalate.

Shared Facilities​

In addition to the excipient guidelines, the EMA adopted a final guideline for multiple medical products manufactured in the same, shared facility.

The objective of the finalized guideline​ is to recommend an approach to review and evaluate pharmacological and toxicological data of individual active substances and thus enable determination of threshold levels. These levels can be used as a risk identification tool and can also be used to justify carry-over limits used in cleaning validation, the agency says.

“The presence of such contaminants should be managed according to the risk posed which in turn are related to levels that can be considered safe for all populations…The derivation of such a threshold value (e.g. permitted daily exposure (PDE) or threshold of toxicological concern (TTC) should be the result of a structured scientific evaluation of all available pharmacological and toxicological data including both non-clinical and clinical data​,” the EMA says.

For medicinal products already produced in shared manufacturing facilities, the guidance will take effect, or existing arrangements should be scientifically justified, within:

• One year after publication of the guideline for manufacturers of products for human use including those who manufacture human and veterinary medicines using shared manufacturing facilities; or

• Two years after publication of the guideline for manufacturers solely producing products for veterinary use.