TEST PREPARATION
Prepare the test specimens in the following sequence. Outside of the laminar enclosure, remove outer closures, sealing bands, and any loose or shedding paper labels. Rinse the exteriors of the containers with filtered distilled or deionized water as directed under Test Environment. Protect the containers from environmental contamination until analyzed. Withdraw the contents of the containers under test in a manner least likely to generate particles that could enter the sample. Contents of containers with removable stoppers may be withdrawn directly by removing the closures. Sampling devices having a needle to penetrate the unit closure may also be employed. Products packaged in flexible plastic containers may be sampled by cutting the medication or administration port tube or a corner from the unit with a suitably cleaned razor blade or scissors.
Dry or lyophilized products may be constituted either by removing the closure to add diluent or by injecting diluent with a hypodermic syringe having a 1.2-µm or finer syringe filter. If test specimens are to be pooled, remove the closure and empty the contents into a clean container.
The number of test specimens must be adequate to provide a statistically sound assessment of whether a batch or other large group of units represented by the test specimens meets or exceeds the limits. If the volume in the container is less than 25 mL, test a solution pool of 10 or more units. Single small-volume injection units may be tested if the individual unit volume is 25 mL or more. For large-volume injections, individual units are tested. For large-volume injections or for small-volume injections where the individual unit volume is 25 mL or more, fewer than 10 units may be tested, based on the definition of an appropriate sampling plan.
PRODUCT DETERMINATION
Depending upon the dosage form being tested, proceed as directed under the appropriate category below.
Liquid Preparations
Volume in Container Less than 25 mL
Prepare the containers as directed under Test Preparation. Mix and suspend the particulate matter in each unit by inverting the unit 20 times. [NOTEBecause of the small volume of some products, it may be necessary to agitate the solution more vigorously to suspend the particles properly.] In a cleaned container, open and combine the contents of 10 or more units to obtain a volume of not less than 20 mL. Degas the pooled solution by sonicating for about 30 seconds or by allowing the solution to stand undisturbed until it is free from air bubbles. Gently stir the contents of the container by hand-swirling or by mechanical means, taking care not to introduce air bubbles or contamination. Withdraw a minimum of three aliquots, each not less than 5-mL in volume, into the light obscuration counter sensor. Discard the data from the first portion. [NOTEFor some products, a pool of 15 or more units may be necessary to achieve a pool volume sufficient for three 5-mL sample aliquots. Smaller sample aliquots (i.e., less than 5 mL) can be used if the assay result obtained with the smaller aliquots is validated to give an assessment of batch suitability equivalent to that obtained with the 5-mL aliquots specified above.]
Volume in Container 25 mL or More
Prepare the containers as directed under Test Preparation. Mix and suspend the particulate matter in each unit by inverting the unit 20 times. Degas the solution by sonicating for about 30 seconds or by allowing the solution to stand undisturbed until it is free from air bubbles. Remove the closure of the unit or effect entry by other means so that the counter probe can be inserted into the middle of the solution. Gently stir the contents of the unit by hand-swirling or by mechanical means. Withdraw not fewer than three aliquots, each not less than 5 mL in volume, into the light obscuration counter sensor. Discard the data from the first portion.
Dry or Lyophilized Preparations
Prepare the containers as directed under Test Preparation. Open each container, taking care not to contaminate the opening or cover. Constitute as directed under Test Preparation, using the specified volume of filtered water or an appropriate filtered diluent if water is not suitable. Replace the closure, and manually agitate the container sufficiently to ensure dissolution of the drug. [NOTEFor some dry or lyophilized products, it may be necessary to let the units stand for a suitable interval, and then agitate again to effect complete dissolution.] After the drug in the constituted sample is completely dissolved, mix and suspend the particulate matter present in each unit by inverting it 20 times prior to analysis. Proceed as directed for the appropriate unit volume under Liquid Preparations, and analyze by withdrawing a minimum of three aliquots, each not less than 5 mL in volume, into the light obscuration counter sensor. Discard the data from the first portion.
Products Packaged with Dual Compartments Constructed to Hold the Drug Product and a Solvent in Separate Compartments
Prepare the units to be tested as directed under Test Preparation. Mix each unit as directed in the labeling, activating and agitating so as to ensure thorough mixing of the separate components and drug dissolution. Degas the units to be tested by sonicating or by allowing the solution to stand undisturbed until it is free from any air bubbles. Proceed as directed for the appropriate unit volume under Liquid Preparations, and analyze by withdrawing a minimum of three aliquots, each not less than 5 mL in volume, into the light obscuration counter sensor. Discard the data from the first portion.
Products Labeled Pharmacy Bulk Package Not for Direct Infusion
Proceed as directed for Liquid Preparations where the volume is 25 mL or more. Calculate the test result on a portion that is equivalent to the maximum dose given in the labeling. For example, if the total bulk package volume is 100 mL and the maximum dose volume is 10 mL, then the average light obscuration particle count per mL would be multiplied by 10 to obtain the test result based on the 10-mL maximum dose. [NOTEFor the calculations of test results, consider this maximum dose portion to be the equivalent of the contents of one full container.]