Expiration Dating and Stability Testing for Human Drug Products

Expiration dating and stability testing for human drug products

Many leading analytical balance manufacturers provide built-in "auto calibration" features in their balances. Are such auto-calibration procedures acceptable instead of external performance checks? If not, then what should the schedule for calibration be? Do CGMPs require that forced degradation studies always be conducted of the drug product when determining if a drug product stability test method is stability-indicating?

Can Total Organic Carbon TOC be stabillty acceptable method for detecting residues of contaminants in evaluating cleaning effectiveness? Would a paramagnetic or laser oxygen analyzer be able to detect all possible contaminants or impurities in a medical gas? Can up to twelve month expiration-dating be assigned to oral solid and liquid dosage forms repackaged into stabilityy containers based expiratiin expiration dating and stability testing for human drug products in the May draft revision of Humman Policy Guide, Section Is it ever appropriate to use an unvalidated method to test a drug component or product?

Did the FDA withdraw the Guideline on Validation of the Limulus Amebocyte Lysate Test as an End-Product Endotoxin Test for Human Parenteral Drugs, Biological Products, and Medical Devices? Where can drug manufacturers find information regarding endotoxin testing? Is it acceptable to release non-penicillin finished drug products to market if the products may have been exposed to penicillin, as long as the non-penicillin products are tested and no penicillin residue is found?

The auto-calibration feature of a balance may not be relied upon to the exclusion of an external performance check For a scale with a built-in auto-calibrator, we recommend that external performance checks be performed on a periodic basis, but less expiration dating and stability testing for human drug products as compared to a scale without this feature.

The frequency of performance checks depends on the frequency of use of the scale and the criticality and tolerance of the process or analytical step. Note that all batches of a product manufactured between two successive verifications would be affected should the check of the auto-calibrator reveal a problem. Additionally, the calibration of an auto-calibrator should be periodically verified--a common frequency is once a year--using National Institute of Standards and Technology NIST -traceable standards or NIST-accredited standards in use in other countries.

Drug product stress testing forced degradation may not be necessary when the routes of degradation and the suitability of the analytical procedures can be determined through use of the following:. Barry Rothman, CDER barry. Both are generally accepted for use in testing LVPs and small volume parenterals SVP for the determination of sub-visible particulate matter. Normally, samples are first tested by the srability obscuration method; if the sample stabikity the produdts limits, the microscopic assay method can then be used.

However, the microscopic method can be the sole expiration dating and stability testing for human drug products if there is a documented technical reason or interference from the product under frug that would make the light obscuration method unsuitable or the results invalid. At least 2, 5-mL aliquots from each sampled unit or the pooled sample see below are to be used in the particulate count determination, and the results from these aliquots are to be averaged for comparison with the specification.

Note that the average is of the results from examining each aliquot and druy between units. The results of the first aliquot examined by light obscuration are to be discarded, and the subsequent aliquots or more--are retained. Pooling humn prior to analysis is permitted only if the volume in each unit is less than 25 mL, in which case 10 or more units may be pooled.

Results among the test units cannot be averaged because particulate matter is assumed to be non-uniformly dispersed throughout the datijg. The intent of assessing results from each individual unit is to ensure adequate representation of the lot and to detect potential variation within a lot. As to the number of individual units to be tested for LVP and SVP units having a volume of 25mL or more, the USP states that the number of units tested depends on stabilitu sound sampling plans," and "sampling stabiloty should be based on consideration of product volume, numbers of particles historically found to be present in comparison to limits, particle size distribution of particles present, and variability of particle counts between units.

This is consistent with the CGMP tezting for statistical sampling plans see Since the publication of the inspection guide on cleaning validation ina number of studies have been published to demonstrate the adequacy of TOC in measuring contaminant residues. We think TOC or TC can be an acceptable method for monitoring residues routinely and for cleaning validation.

But in order for TOC to be functionally suitable, it hunan first be established that a substantial amount of the contaminating material s is organic and contains carbon that can be oxidized under TOC test conditions. This is not a trivial exercise because we know that some organic compounds cannot be reliably detected drhg TOC. TOC use may be justified for direct surface sample testing as well as indirect rinse water sample testing. In either case, because TOC does not identify or distinguish among different compounds containing oxidizable carbon, any detected carbon is to be attributed to the target compound sfability for comparing with the established limit.

Thus, a firm should limit 'background' carbon i.

ST101 Lecture 2: Regulations on Stability Program Global Stability Requirements