The USP Performance Test Dissolution Systems Suitability Studies

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Subjects. Frameworks Suitability Studies for DissolutionCollaborative Study Design and AnalysisVariances: Correction to May 2005 DiscussionNext Steps. Framework Suitability. USP <1225> and ICH Q2b:

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The USP Performance Test Dissolution Systems Suitability Studies Walter W. Hauck, Ph.D. USP Consultant Presentation to Advisory Committee for Pharmaceutical Sciences October 25, 2005

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Topics Systems Suitability Studies for Dissolution Collaborative Study Design and Analysis Variances: Correction to May 2005 Discussion Next Steps

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System Suitability USP <1225> and ICH Q2b: … to guarantee that the legitimacy of the expository technique is kept up at whatever point utilized. Run of the mill varieties are the security of the scientific arrangements, gear, and investigators. … System appropriateness tests depend on the idea that the gear, gadgets, expository operations, and tests to be broke down constitute a necessary framework that can be assessed all things considered.

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Types of Dissolution Systems Suitability Studies Chemical Calibration The term is a misnomer—it is an occasional Systems Suitability or framework confirmation think about USP calibrator tablets bolster this sort of study The approach assesses the framework in general (device in addition to administrator in addition to methods) Acceptance ranges for disintegration estimations of the calibrator tablets dictated by communitarian examines for each new parcel (e.g., new Prednisone Lot P) Other Approaches Mechanical Calibration Engineering Approaches

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Terminology Apparatus One vessel One mixing component One position in the gathering Assembly One engine Same temperature controller Multiple contraptions (at least 6) Also called "shower" Experiment Single units tried in all devices in the get together (in the shared review, n= 6)

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Systems Suitability: Chemical Calibration strategy For get together under review, utilize standard disintegration technique; test all devices in the get together Assembly/device must be mechanically adjusted Acceptance connected to each position (device) If one position result is unsuitable then whole get together is additionally inadmissible Increased danger of bombing because of numerous testing Evaluates the incorporated capacity of the framework to set up a disintegration test

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Systems Suitability: Mechanical Calibration If a mechanical framework is legitimately adjusted and fits in with resistances built up for every single such framework, then the operation of the framework ought to be reasonable Dissolution test device and get together are mechanical frameworks If mechanical alignment is the main control, no further mind the framework is performed and framework is thought to be appropriate

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Systems Suitability: Mechanical Calibration Deficiency of absolutely mechanical adjustment Assumes that the coordinated framework is close to the aggregate of its parts Does not assess that standard stream of medium is accomplished Limited comprehension of the fitting extent and estimation mode for vibration Difficulty of verifying that vessel is appropriate (surface inconsistency, deviation from side of the equator and barrel) List of proposed enhanced mechanical resiliences in Dissolution Calibration: Recommendations for Reduced Chemical Testing and Enhanced Mechanical Calibration , PhRMA Dissolution Calibration Subcommittee, PF 26(4) [July-Aug. 2000]

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Topics Systems Suitability Studies for Dissolution Collaborative Study Design and Analysis Variances: Correction to May 2005 Discussion Next Steps

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Collaborative Study Design Standard item (tablet) Standard techniques utilized Determine scope of results from mechanically-aligned gatherings Determine limits for "adequate" results 25-35 teaming up labs, global

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Design Evolution Originally, every lab performed one investigation for every condition (e.g., bushel at 50 rpm) Beginning with 2003, every lab performs two examinations for each condition with isolated administrator and gear; Allows division of between lab and intra-lab (middle of the road) exactness

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Analysis Considerations Analysis is gone before by a control outline investigation to choose labs/tests for incorporation in assurance of acknowledgment reaches Follows what had been PhRMA strategy Statistical investigation decides three changes – device/tablet/test between-test, with-in lab between-lab

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Sample Xbar and S Control Charts for Apparatus 2, 30 Minutes

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Representative CV's (%)

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Comments Variability because of the blend of device, tablet, and test is low, especially for the wicker bin (Apparatus 1) Assay inconstancy around 2% CV, such a large amount of the commitment from contraption/tablet/test is because of the test

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Determination of Acceptance Ranges Acceptance extend in light of whole of the three fluctuations Intended to speak to scope of qualities not out of the ordinary from an arbitrary tablet tried at an irregular lab utilizing great practice

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Issue for Acceptance Ranges decided for a solitary tablet, however connected to sets of 6 and must pass every one of the 6 Possible arrangements Standard factual numerous testing conformity; i.e., augment the interims to 99% from 95% Allow retesting Set acknowledgment runs on test mean and standard deviation as done in community oriented review; i.e., would the information fit the bill for incorporation in the assurance of the acknowledgment go

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Topics Systems Suitability Studies for Dissolution Collaborative Study Design and Analysis Variances: Correction to May 2005 Discussion Next Steps

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Calibrator to Control Product Variability Total item changeability, σ 2 add up to = σ 2 item + σ 2 estimation σ 2 add up to for calibrator = σ 2 calibrator + σ 2 C*measurement Since σ 2 calibrator is not known utilize σ 2 add up to for calibrator σ 2 add up to for calibrator is given in the worthy extents σ 2 add up to = σ 2 item + calibrator run Argument against USP RS in disintegration framework reasonableness conveyed at different scenes

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Restating Concerns About Calibrator Variability This contention does not hold; perhaps σ 2 add up to < σ 2 item + calibrator go Calibrator changeability does not add to item inconstancy

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Topics Systems Suitability Studies for Dissolution Collaborative Study Design and Analysis Variances: Correction to May 2005 Discussion Next Steps

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Next Steps Continued work to enhance substance adjustment, e.g., way to deal with maintain a strategic distance from 'various testing' Acknowledge that disintegration is 'case by case'— settled with 'adaptable monograph'— contrasts satisfactory if bioequivalent Assess different ways to deal with Systems Suitability for the disintegration method; e.g., create procedure to gauge liquid stream that is material in QC condition (building approach) Setting acknowledgment criteria for promoted measurement shapes (not calibrators): resistance interim approach in light of clinical trial bunches (see Hauck et al ., Pharmaceutical Research 2005) USP willing to work with all partners on complex science/specialized issues for Performance test; 'Quality by Design' methodologies ought to be very profitable.

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