PDA Technical Report No. 25, (TR 25) Blend Uniformity Analysis: Validation and In-Process Testing (single user digital version)

Nov 1997
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Note: This Technical Report has been retired by PDA and is no longer considered to represent current industry best practices. It is available for historical/research purposes only.

This report was written to clarify the significant regulatory and technological issues impacting validation approaches and acceptance criteria.

One of the most challenging problems confronting oral solid dosage from manufacturers today is the difficulty in applying scientifically valid methods to blend uniformity validation. The Wolin decision in U.S. v. Barr Laboratories caused the FDA to reexamine and modify its policies on blend uniformity and sampling techniques. The resulting policies are predicated on the assumption that current technology provides a means to consistently collect minute representative samples from much larger static powder blends. A comprehensive review of the scientific literature indicates that current sampling technology is plagued by a propensity for sampling bias. This limitation is particularly troublesome to the pharmaceutical industry which must then hold these samples to very high standards. In response to these concerns the PDA Solid Dosage Process Validation Committee has reviewed approaches to blend uniformity analysis.

This Technical report provides:

  • a method to determine the appropriate sample size for each product,
  • a holistic approach for establishing meaningful acceptance criteria,
  • a discussion on the use of proper analytical techniques and
  • recommendations for conducting investigations for out-of-specification results.

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Table of Contents

Table of Contents;

1. Introduction
2. Compliance History
3. Sampling Technology
4. Determination of an Appropriate Sample Quantity
5. Evaluation of Blend Uniformity: A Step by Step Approach
6. Considerations for the Analysis of Blend and Dosage Form Samples
7. Evaluation of Out-of-Specification Blend Results
8. Conclusion
Appendix I. Acceptance Ranges Computed from Bergum's Method
Appendix II. Acceptance Criterion for SDPI - Data from a Nested Sample of the Blend
Appendix III. Operating Characteristic Curves
Appendix IV. FDA Comments, August 29, 1997
Appendix V. PDA Response to the FDA Letter, October 9, 1997