The European Medicines Agency (EMA) has issued guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities. These include antibiotics, hormones and cytotoxic drugs.

Now Indian pharma has largely supported the norms and have ensured that they have avoided manufacture of medicines in shared facilities.

The Schedule M of the Drugs & Cosmetics Act also mandates limits for production in shared units. Therefore the EMA guidelines would now further assert this need, said officials from Karnataka Drugs & Pharmaceutical Manufacturers Association (KDPMA).

The guideline applies to all human and veterinary medicinal products, including investigational medicinal products, and all active substances that are intended for manufacture in premises used for the manufacture of other products or active substances.

The scope of the present guideline is to ensure the safety of human patients and target animals exposed to residual active substances via medicinal products.

“When different medicinal products are produced in shared facilities, the potential for cross contamination becomes an issue for concern. Hence, residues of an active substance which remain after cleaning of production equipment and other product contact surfaces may contaminate other medicinal products produced in the same facility”, stated the regulatory authority.

The manufacturers should ensure there is no cross over contaminant of active substance contaminants. The derivation of a permitted daily exposure (PDE) 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.

Due to the perceived risk, certain classes of active substances have previously been required to be manufactured in dedicated or segregated self-contained facilities.  Pharmaceuticals not considered to be covered under these criteria were addressed by a cleaning validation process. It involved reduction of residual active substance to a level where the maximum carryover from the equipment would result in no greater than 1/1000th of the lowest clinical dose of the contaminating substance in the maximum daily dosage of the next product to be manufactured.

This criterion was applied concurrently with a maximum permitted contamination of 10 ppm of the previous active substance in the next product manufactured. Whichever of these criteria resulted in the lowest carryover, constituted the limit applied for cleaning validation. However, these limits do not take account of the available pharmacological and toxicological data and may be too restrictive. Hence, a more scientific case by case approach is warranted for all classes of pharmaceutical substances. Now in order to  accommodate a more scientific approach, Chapters 3 and 5 of the GMP guideline have been revised and refer to a toxicological evaluation’ for threshold values for risk identification, said the regulator.

In cases where scientific data does not support threshold values like for instance the allergenic potential from highly sensitizing materials or where the risk cannot be adequately controlled by operational and technical measures, dedicated facilities are required for manufacturing these high risk medicinal products, mentions the guideline.