**TOC Analysis Compliant with USP <661.2>**

Plastic Packaging and Packaging Materials Testing

In the pharmaceutical industry, plastic packaging is used in various forms such as parenteral solution bags, bottles, cartridges or pre-filled syringes. The suitability of packaging for these applications is tested in accordance with USP 39-NF34, which has been in effect since May 2016. In the relevant guideline, the chapter is titled "Plastic Packaging and Packaging Materials" and two new sections have been prepared. This application note relates to one of these sections, 661.2

661.2 Plastic Packaging

This section addresses finished product testing applied to packaging consisting mostly of more than one plastic material. For characterization of finished products, biocompatibility, determination and identification of general physicochemical properties and additives are required. The TOC parameter is one of the physicochemical properties that must be determined as an indicator of extractable organic material. The packaging to be tested is filled with ultrapure water, sealed in an autoclave and heated. Temperature and waiting time depend on the plastic material used. To determine the blank value, ultrapure water is poured into a glass bottle and heated to the same temperature. The TOC values of both solutions are determined. The difference between the two measured TOC values must not exceed 8 ppm (mg/L).

TOC Analysis in Pharmaceutical Applications

TOC analysis is performed according to the relevant USP. This regulation addresses TOC determination for purified water, distilled water and injectable water. TOC systems must be able to distinguish between inorganic and organic carbon. This can be accomplished through removal of inorganic carbon (NPOC method) or by a special method (difference method). The TOC detection limit should be at least 0.05 mg/L. The applicability of the method should be determined by a system suitability test. However, due to dissolved organic substances, the TOC values of extracts from packaging materials may be higher than those of purified water. For this reason, the detection limits of the TOC analyses performed should be 0.2 mg/L and should show a linear dynamic range of 0.2–20 mg/L.

Shimadzu TOC System

In the Shimadzu TOC product portfolio, there are two models that work with different oxidation methods for TOC analysis in ultrapure water. The TOC-LCPH uses catalytic combustion method at 680°C, while the TOC-VWP/WS uses wet-chemical oxidation method. Both of these instruments with different oxidation methods can be used for TOC determination in accordance with the United States Pharmacopeia (USP <643>) and the European Pharmacopoeia (EP 2.2.44).

SHIMADZU TOC-L Series Total Organic Carbon Analyzer

Linear Dynamic Range between 0.2–20 mg/L

In order to obtain the required dynamic range, a calibration was performed with TOC-L CPH (high sensitivity catalyzed) in the range of 1.0 mg/L–20 mg/L.

Figure 1: Calibration Curve 20 mg/L, results

For dilutions, the automatic dilution function of the TOC-L system is applied.

The injection volume is determined based on the highest calibration standard. For 20 mg/L, the default injection volume is 50 μL.  

Figure 2: Calibration Curve 20 mg/L, graph

Calculation of detection limit according to DIN 32645:

Characteristics Slope a: 5.503 Intercept b: 0.091 Correlation coefficient r: 0.9999 Measurement uncertainty: 33.3% Error probability (a): 5.00% Number of injections: 2 © DINTEST Detection Limit: 0.2 mg/L These results demonstrate that the TOC-L CPH with high sensitivity catalyst covers the required linear dynamic range of 0.2–20 mg/L. This means that purified water and extraction solution can be measured with a single TOC-L CPH instrument. Zafer Bayram - Senior Chemical Engineer Pharmaceutical Group Director ANT Teknik Cihazlar Ltd. Şti.

Reference: Shimadzu Europa GmbH TOC Application Bulletin No. SCA-130-208