Blend Uniformity: Update

1. Blend Uniformity: Update Ajaz S. Hussain, Ph.D.

2. Background • Issue: Assuring and documenting “adequacy of mixing” operations • PQRI’s Proposal • Stratified sampling of dosage units (during routine production) • ACPS Meeting November 28, 2001 • ACPS Meeting May 8, 2002 • Proposal presented and discussed • General endorsement • FDA Peer Review (August 14, 2002) • PQRI Response (October 17, 2002)

3. FDA Peer Review • Chiu, Famulare, Holcomb, Hussain, Machado, Tsong, and Shen • Acceptability of the stratified sampling concept • Science/Engineering of powder blending and compaction/encapsulation • Examples of stratified sampling data made available to FDA by individuals • PQRI proposed decisions trees and scientific arguments/justification

5. FDA Peer Review • PQRI Datamining and Statistical Efforts • FDA perspective • Supporting data • Statistical simulation and assumption of normality • Different interpretation • Deviations from “normality” suggestive of potential content uniformity problems • Additional justification needed to support • Sample size during routine production (batch size, …) • Categorization - “readily” and “marginally” comply • Implications of of finding high RSD values during routine production

6. PQRI Response (10/17/02) • The following points made by PQRI were instrumental in the FDA’s decision to accept the proposal • “In general, non-normality = lack of homogeneity” • The type of segregation (start-up or run-out) will not be found by testing powder in the blender • Stratified sampling .. Specifically targets locations .. Which have a higher risk of producing failing content uniformity results • 20 locations represent every 5% of the batch. More sample locations would not change this substantially.. • Sampling theory is dependent upon sample being representative of the population

7. PQRI Response (10/17/02) • Implications of of finding high RSD values for routine production batches • “Standard” testing for “Readily” pass • S1, n=10, mean between 90-110% and RSD  5% • S2, n=30, mean between 90-110% and RSD  6% • “Tightened” testing for “Marginally” pass • n=30, mean between 90-110% and RSD  6% • When 5 each of consecutive batches (n=30) meet an RSD  5% then “Standard” testing

9. Next Steps • Internal FDA meeting • Define the outline for a new draft guidance based on the PQRI proposal (review and compliance roles) • Assess and plan for training needs • Assign the responsibility to a small group of individuals to write the guidance • Draft guidance to seek public comments • Formal training of FDA staff (if deemed necessary) • Final guidance

10. Other “Peer Review” Comments • A range of comments, most captured in the FDA review process • Except • Implications and perceptions resulting from continued recommendation of “blend testing” during validation • increased focus on end-product testing to document quality (moving away from “building quality in”) • New technological solutions ignored • PQRI WG was asked to focus on the existing problem within the confines of the draft ANDA guidance

11. PAT: Higher level of quality & efficiency not a requirement Traditional test methods Current PQRI proposal and draft Guidance Univariate Testing to Document Quality Approach Draft Guidance may include information on the use of NIR methods At-line test methods On- and/or At-line test methods for all critical components and processes Proposed PAT Guidance Incentive? Higher efficiency Lower “risk” leading to lower regulatory concern Multivariate Quality-by Design Approach

12. New Technological Solutions and PAT • Draft Guidance may include information on the use of NIR methods • PQRI BU/NT proposal on NIR (USP PF article) • Other excellent monographs on NIR validation • FDA’s own laboratory experience with NIR and NIR-imaging methods • The proposed PAT guidance will further elaborate how to introduce new technologies to improve process understanding and efficiency

13. Lyon, et al. Near-Infrared Spectral Imaging for Quality Assurance of Pharmaceutical Products: Analysis of Tablets to Assess Powder Blend Homogeneity AAPS PharmSciTech 2002; 3 (3) article 17

14. 19 July 2001, ACPS Meeting Non-homogeneous distribution of magnesium stearate: Dissolution

16. Just FYI - USP Weight Variation or the Content Uniformity • Compressed tablets • Content uniformity not required for products containing 50 mg or more of an active comprising 50% or more, by weight • S1, n=10, range 85-115% and RSD  6% • If 1 unit is outside 85-115% and no unit is outside 75-125% or if RSD is >6%, or both conditions prevail, test 20 additional units • S2, n=30, no unit is outside 75-125% and RSD  7.8%