Cleaning validation

Background: 

There is always a risk of cross-contamination during pharmaceutical manufacturing processes when the same facilities are used to produce different active pharmaceutical ingredients (API) or finished products. The Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities (EMA/CHMP/CVMP/SWP/169430/2012) therefore stipulates a systematic evaluation of the risk for every active ingredient and every product derived from it. To this end, a permitted daily exposure (PDE) limit is determined for each active substance, from which the required performance capability of cleaning procedures and the analytical procedures to be used to verify the success of the cleaning procedures are derived.

Strategic evaluation

The performance capability and verifiability of the cleaning procedures for the manufacturing equipment must be devised in such a way as to ensure that secondary products no longer contain any potentially harmful quantities of the precursor product or ingredient. As numerous combinations of active ingredients/secondary products are frequently manufactured in shared facilities, this topic is of great relevance when it comes to product safety, and ultimately for product liability as well.

Regulatory requirements

The maximum tolerable permitted daily exposure (PDE) limit is determined by comprehensively evaluating the available preclinical, clinical, pharmacological and toxicological data. It indicates the dose of a substance that a person (or animal) can ingest every day for a lifetime without experiencing adverse effects. This means that the daily dose of a secondary product may contain no more of an active ingredient than the applicable PDE limit. Specific characteristics of the secondary products must be taken into account in this respect, particularly including the vulnerability of specific groups of patients (e.g. children, pregnant/breastfeeding women, transplant recipients, patients with liver or kidney damage, etc.). The basic requirements for determining the PDE limits laid down in the Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities (EMA/CHMP/CVMP/SWP/169430/2012) supplement those specified in sections 3 and 5 of the GMP Guideline. A detailed description of the methodological approach for calculation of a PDE is given in ICH Guideline Q3C (R8) on impurities: guideline for residual solvents (EMA/CHMP/ICH/82260/2006).

Services offered by PhytoLab

Active ingredients of herbal origin pose a particular challenge when it comes to the determination of PDE limits, beginning as early as the initial database research stage. This not only applies to phytopharmaceuticals, but also herbal homeopathic/anthroposophic preparations, frequently contain plants with highly toxic ingredients (e.g. Atropa, Aconitum, Digitalis, Rauvolfia). Of course we help with your chemical API/products as well.

• Database research on toxicologically relevant information
• Analysis and evaluation of data availability and identification of toxicologically relevant ingredients
• Determination of a NOAEL or other reference point
• Calculation of the PDE

Rely on PhytoLab’s know-how and acknowledged expertise to determine the PDE limits for your products.

Your contacts at PhytoLab:

Medical Affairs:

DR. SYBILLE ULLRICH
Phone +49 9163 88-524
sybille.ullrich@phytolab.de

Sales:

ELKE LENZER
Phone +49 9163 88-597
sales@phytolab.de