Development of a Content Uniformity Test Suitable for Sample Sizes between 30 and 100
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Myron Diener PhRMA CM&C Statistics Expert Team, sanofi-aventis, Kansas City, Missouri Greg Lorner PhRMA CMGC Statistics Expert Team, Pfizer, Kalamazoo, Michigan
Jim Pozdon PhRMA CMGC Statistics Expert Team, Novartis, East Hanover, New Jersey Lori Pfohler PhRMA CMGC Statistics Expert Team, Merck, West Point, Pennsylvania
Development of a Content Uniformity Test Suitable for Sample Sizes Between 30 and 100
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Spedmcopic methods such as nem infinred (ZVZR) for content uniformity (Cv)dow thc measurement of sign$cun@ more dosage units per batch than required by tmditiimal phmmae l l et al. copoeial testing of 10 to 30units. w proposed a nonparametric counting test for sample sizes greater than 100. There arc manufacturing situations such as small batch sizes or restrktions due to sampling equipment that will jidd medium sample sizes between 30and 100 units per batch. This work jnvvides alternative CU tests for medium sample sizes.
Helen Strickland PhRMA CM&C Statistics Expert Team, GlaroSmithKline. Zebulon. North Carolina Kim Erlond Vrkovinsky PhRMA CM&C Statistics Expert Team. Pfizer. Groton, Connecticut Soren Anderson Novo Nordisk. Bagsvaerd, Denmark
Key Words Uniformity ofdosage units (UDU); Content uniformity (CU);Specification; Coverage Correspondence Address Myron Diener, 10236 Marion Park Drive, Kansas City, MO 64134-0708 (email: myron.diener@ sanofi-aventisxom).
IN T R O D U C T l O N The measurement of larger sample sizes provides an opportunity for improved understanding and control of manufacturing processes. Spectroscopic methods such as near infrared (NIR) for content uniformity allow the measurement of significantly more dosage units per batch than required by traditional pharmacopoeial testing of 10 to 30 units. It has been noted in the literature that the compendial acceptance criteria (referred to as 'compendial test" hereafter), which is the standard for small sample sizes, should be adapted to reflect the increased sample size (1).In the new quality by design paradigm, companies are encouraged to take larger sample sizes to increase process understanding and control but may be reluctant when faced with increased risk of batch failure by applying the compendial test to these larger sample sizes (2). Sandell et al. (3) proposed a nonparametric counting test for samples greater than 100 dosage units that provides equal or better assurance of the batch quality relative to the compendial test. Alternative acceptance criteria for sample sizes of less than 30 and greater than 100 are available through the compendial test (1) and the counting test (3). There are manufacturing situations that create a need for acceptance criteria for sample sizes between 30 and 100 units
per batch. Automated equipment is capable of sampling and testing at a frequency beyond the compendial requirements. For small production runs only a moderate number of dosage units may be tested in a given time interval. Content uniformity testing of validation batches often yields sample sizes greater than routine release testing bu
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