YY/T 1550.2-2019Guidance on the study of compatibility between infusion equipment and pharmaceutical products - Part 2: Leachables - Known substances (English PDF)

3.1 Leachable substance

The substance which can be released from a medical device or material during clinical use.

[GB/T 16886.12-2017, definition 3.10]

4.1.2 Methods for preparation of extract liquid

4.1.2.1 Preparation of extract liquid using drug

Take the equipment and drugs to be studied; according to the common infusion method given in the drug instruction manual or clinical investigation, prepare the extract liquid. Preparation parameters need to consider the dosage, infusion carrier (such as sodium chloride injection, glucose injection, etc.), dilution method, infusion method (such as gravity drip, infusion pump administration, administration from injection parts) , infusion rate, infusion temperature. If necessary, use clinically applicable infusion carrier to prepare 3 parts of drug infusion liquid in line with clinical practice. Among which, infuse 2 of the infusion liquids through the infusion equipment according to the common infusion methods given in the drug instruction manual or clinical investigation; collect the effluent as the test solution. Another prepared drug infusion liquid is stored under the same conditions for the same time as the drug control solution.

4.1.2.2 Preparation of extract liquid using alternative solvents

If simulated-use extraction is performed, it shall comprehensively consider the parameters and conditions of the medical device in actual clinical use, such as time, temperature, mode of action, etc. First, the preparation method of extract liquid shall be demonstrated, to prove that the extraction conditions selected by the device represent the greatest risk to the patient in the intended use of the product. The selection of simulated solvent shall comprehensively consider other characteristics such as the polarity and pH of the device to be studied in clinical contact with pharmaceutical product.

4.2 Study on known leachable substance

4.2.1 Methodological investigation items

4.2.1.1 Overview

Confirmed test methods should be used to determine known substances in leachables. Generally, methods recommended by national standards or industry standards or methods of determination that have been peer-reviewed are preferred. At present, the commonly-used analytical methods mainly include HPLC, LC-MS, GC-MS, GC, AAS, and ICP-MS. The first four methods are mainly used to evaluate organic leachable substance. The latter two methods are mainly used for the qualitative and quantitative determination of inorganic migratory substances, especially metal elements.

4.2.1.2 Specificity

Excipients in pharmaceutical preparations, related substances, infusion carriers in the preparation of extract liquid, and potential soluble substances in infusion equipment may interfere with the determination of the dissolution amount of the analyte. Appropriate methods should be used to verify specificity.

4.2.1.3 Linear range

Linearity refers to the degree to which the measured response value is proportional to the concentration of the analyte in the sample within the designed range. The range refers to the range of high-low concentrations or quantities when the analytical method can achieve certain precision, accuracy and linearity requirements. The selected method shall ensure that the concentration in the sample to be tested is within its linear range. At the same time, the setting of the range shall consider the toxicological evaluation value.

It is recommended to use at least 5 concentrations.

4.2.1.4 Detection limit

The detection limit refers to the minimum amount of the analyte in the sample that can be detected. The detection limit of the method shall meet the requirements of toxicological evaluation value of the analyte. Appropriate methods shall be used to examine the detection limit. It shall meet the requirements of its toxicological evaluation value. The evaluation method should be carried out in accordance with "Pharmacopeia of the People's Republic of China" (2015) Volume IV 9101.

4.2.1.5 Quantitation limit

The quantification limit refers to the minimum amount of the analyte in the sample that can be quantitatively determined. The determination results shall meet the requirements of accuracy and precision. Appropriate methods shall be used to examine the quantification limit. The evaluation method should be carried out in accordance with "Pharmacopeia of the People's Republic of China" (2015) Volume IV 9101.

4.2.1.6 Precision

Appropriate methods should be used to examine the precision of the proposed method for determination of the content. The evaluation method should be carried out in accordance with "Pharmacopeia of the People's Republic of China" (2015) Volume IV 9101.

4.2.1.7 Accuracy

Appropriate methods should be used to verify the accuracy of the results. Take the standard-addition recovery test as an example; add a quantitative standard substance to the blank sample matrix without the tested substance; according