Cleaning Validation Procedures in the Pharmaceutical Industry by TOC Analysis Application Note · multi N/C pharma

Introduction

To minimize or prevent cross contamination from product to product in pharmaceutical production equipment, manufacturers are obliged to establish defined cleaning processes in accordance with the pharmaceutical operating regulations. According to the ICH Q7 Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients, the effectiveness of these cleaning procedures is to be demonstrated regularly by the use of analytical measuring techniques. This means that after successful cleaning a check must be carried out for residues of active pharmaceutical ingredients (API), additives, detergents and their decomposition and reaction products, using a representative and validated sampling and analysis method.

Both, substance-specific techniques (HPLC, GC, etc.), as well as non-specific analysis techniques (sum parameters TOC or TN) are used, other indicators are conductivity, pH and surface tension. Since each of the possible contaminants listed above typically represents organic compounds and can be addressed by total organic carbon, TOC has been chosen and pushed by the FDA to become the number one non-substance specific screening parameter in cleaning validation.

Additionally TOC determination is a mandatory parameter in WFI (water for injection) and AP (aqua purificata – purified water for pharmaceutical use) quality control and a well described pharmacopoeia method with ultralow detection limits below 50 ppb according to Pharm. Eur. 2.2.44 and USP <643> monographs. Cleaning validation limits and acceptance criteria are calculated according to different approaches listed in the PDA technical report no. 29 and 49, e.g., based on drug active dose or toxicity to establish acceptable residue levels (ARL).

Two strategies – the post-final rinse and the swab test – are followed during cleaning validation to prove the cleanliness of production equipment. The particular advantage of the post final rinse or swab extracts procedure is that both sampling approaches can be established more easily, are less error-influenced and the resulting TOC samples can be processed by a standard TOC analyzer using typical method settings and quality assurance checks.