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 Next Steps Internal FDA meeting –Define the outline for a new draft guidance based on the PQRI proposal (review and compliance roles) –Assess and plan for training needs –Assign the responsibility to a small group of individuals to write the guidance Draft guidance to seek public comments Formal training of FDA staff (if deemed necessary) Final guidance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 Univariate Testing to Document Quality Approach Multivariate Quality-by Design Approach Traditional test methods At-line test methods On- and/or At-line test methods for all critical components and processes Current PQRI proposal and draft Guidance Draft Guidance may include information on the use of NIR methods Proposed PAT Guidance Incentive? Higher efficiency Lower “risk” leading to lower regulatory concern

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

16. 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% Just FYI -