Introduction Background to the work of the BUWG Garth Boehm BUWG Draft Recommendations Tom Garcia Data Mining: Challenging the Theory

Why Test Blend Uniformity? 21CFR211.110 (a) To assure batch uniformity and integrity of drug products, written procedures shall be established and followed that describe the in-process controls, tests, or examinations to be conducted on appropriate samples of in-process materials of each batch. …….. (3) Adequacy of mixing to assure uniformity and homogeneity; …...

Why Test Blend Uniformity? OGD’s Draft Guidance All Solid Dosage forms <50% active or <50 mg require routine BUA Use 6 to 10 samples, 1 - 3 unit weights Must meet mean 90.0% to 110.0% label claim, RSD NMT 5.0%

Product Quality Research Institute PQRI (www.pqri.org) is a collaborative effort between FDA, Industry, and Academia. PQRI’s mission is to provide a scientific basis for developing Regulatory Policy. One of PQRI’s initiatives is to set up ‘expert’ Working Groups to analyze particular areas and make recommendations on future Regulatory Policy.

Blend Uniformity Working Group The Blend Uniformity Working Group was established in late 1999 The group is chaired by Tom Garcia and has members from academia, FDA (CDER and DMPQ), and industry (innovator and generic). The group is charged with making scientifically based recommendations on suitable procedures for assuring batch homogeneity.

BUWG Actions Conducted Industry Practices Survey Published Uniformity Troubleshooting Guide Held Public Workshop on BU testing issues Held several Working Group meetings Written Draft Proposal for use of Stratified Testing of Dosage Units Sought data to challenge proposed method

Industry Practices Survey Survey was blinded to assure confidentiality Sent to all solid dose sponsors with at least one approved NDA or ANDA that could be located Designed to elicit information on general practices regarding BU sampling and testing

Industry Practices Survey 28 of 134 replied (20%), mostly large manufacturers Survey asked questions on Demographics, Sampling, Routine Testing, Validation Testing, Cause of Failure, Cost, & New Technology Full Survey and Results can be found at www.pqri.org and a summary in August 2001 Pharmaceutical Technology

Industry Practices Survey The picture that emerged was of a conservative industry that: Samples with conventional sampling thieves taking 1 - 3 unit dose sample sizes Tests samples with conventional ‘wet’ analytical methods Uses established acceptance criteria

Industry Practices Survey About 2/3 for routine batches and 1/2 for validation batches are prepared to defeat failing BU results with enhanced testing Have trouble with 10% to 20% of products Think failures are due to sampling or analytical error Have not adopted any ‘new technology’

Troubleshooting Guide Early in the BUWG discussions it became apparent that no concise guide was available for diagnosing blend or dosage unit uniformity problems Jim Prescott and Tom Garcia took on the task of writing the guide and designing a companion chart Published in March 2001 Pharmaceutical Technology

Public Workshop Based around the theme “Is BU Testing a Value Added Test?” Held September 2000, about 200 people attended Several formal presentations on aspects of blending, blend sampling, acceptance criteria, new technology, BUWG progress Summary published in September 2001 Pharm Tech

Public Workshop Presentations based around the following: Blending of solids is a poorly understood process Very difficult to sample powder bed with conventional sampling thieves Sampling errors are common & occur both ways Post-blending segregation can be a serious problem

Public Workshop Major part involved break-out sessions to elicit feedback from attendees. Is Blend Uniformity Testing on every batch a value-added test? How do you validate a process when you have a sampling problem? What new technologies are available to assess blend uniformity?

Public Workshop Conclusions Blend Uniformity Testing on every batch is not a value-added test Appropriate and meaningful BU testing should be conducted during development and validation Higher costs are acceptable if they yield meaningful data

Desired Attributes of a BUWG Recommendation BUWG Draft Proposal “The Use of Stratified Testing of Blend and Dosage Units to demonstrate Adequacy of Mix for Powder Blends” 1. The test should be simple to perform, maximizing the use of data 2. Acceptance criteria should be easy to evaluate and interpret 3. Acceptance criteria should demonstrate when lack of homogeneity is suspected

PQRI BUWG Recommendation for the Use of Stratified Sampling to Demonstrate Blend & Dosage Unit Content Uniformity

PQRI BUWG Recommendation Utilizes stratified sampling Collectively considers the uniformity of the powder blends and dosage units. Acknowledges that the best way to assess blend uniformity may be indirectly by measuring the uniformity of the dosage units.

Scope of Recommendation Applies to: Process validation and marketed batches for solid oral drug products. Products where the active ingredients are introduced into the blend. Does not apply to: Drug products where the determination of dosage-form uniformity by weight variation is allowed.

Stratified Sampling “The process of selecting units deliberately from various locations within a lot or batch or from various phases or periods of a process to obtain a sample.” [Glossary and Tables for Statistical Quality Control , ASQC Quality Press, copyright 1983.] Stratified sampling of the blend and dosage units specifically targets locations either in the blender or throughout the compression/filling operation which have a higher risk of producing failing content uniformity results.

Stratified Sampling of Dosage Units Advantages More accurate & relevant Eliminates blend sampling errors Detects segregation following blending Eliminates issues related to blend sampling of toxic or potent drugs (operator safety) Disadvantages “Too late” Batch compressed/filled Not consistent with “quality by design” Parametric release Note: Control vs. Test BUA is utilized as a test

Process Development Stratified sampling plan is not a substitution for poor process development Sampling technique should be defined during process development Determine appropriate sampling device Identify an acceptable sampling plan (for both blend and dosage units) Recommendation allows blend sample sizes > 1-3X, if they can be scientifically justified

Validation Approach

Process Validation Blend: 10 locations 3 samples per location Assay 1 sample per location Acceptance Criteria: RSD  5.0% All individuals within +/- 10% of mean Fail Pass Assay 2nd and 3rd blend samples from each location Proceed to Stage 1 Dosage Unit Testing Mixing problem identified Yes No Investigation points to sampling bias or some other attributable cause Proceed to Stage 2 Dosage Unit Testing Blend is not uniform. Go back to development

Process Validation During compression/filling, sample from at least 20 locations, taking at least 7 dosage units per location Assay at least 3 dosage units per location Acceptance Criteria: RSD of all individuals  6.0% Each location mean within 90-110% target potency All individual within 75-125% target potency Pass Process Validated Fail Assay at least 4 additional dosage units per location Pass Acceptance Criteria: RSD of all individuals  6.0% Each location mean within 90-110% target potency All individual within 75-125% target potency Fail Blend is not uniform or post-blending practices cause segregation

Justification of Blend Sample Sizes and Acceptance Criteria Number of Sampling Locations At least 10 locations should be used for tumbling mixers to adequately map blender At least 20 locations should be used for convection mixers, which are more likely to have dead spots Replicates Per Location At least 3 samples/location required to perform component variance analysis to detect the presence of sampling error

Justification of Dosage Unit Sample Sizes and Acceptance Criteria Number of dosage unit samples and sample size through the use of OC curves, considering: Weight variability Assay variability Between location error Within location error USP Content Uniformity Test used as a reference for comparison

Justification of Dosage Unit Acceptance Criteria RSD  6.0% Consistent with Stage 1 USP Test All location means 90-110% target potency Detects drifting/segregation or non-uniform spots in the blend All individuals within 75-125% target potency Will pick up outliers, such as subpotent or superpotent (agglomeration) dosage units

Justification of Dosage Unit Acceptance Criteria Two stage test is consistent with USP Content Uniformity Test Stage 1 and Stage 2 criteria are the same Stage 2 test offers a second opportunity to comply with acceptance criteria, for those batches which barely fail Stage 1 testing

Routine Manufacture

Merging the cGMP Requirement with Compendial Release Testing Dosage units to be tested are in-process samples Perform two calculations on a single set of data cGMP Compliance - Normalize for weight Compendial Testing - No weight correction Acceptance criteria the same as that described in the USP Content Uniformity Test If the in-process sample is not the finished dosage form, you must demonstrate during validation that the in-process results provide the same or better control as the content uniformity data generated during compendial release testing of the corresponding finished dosage units.

Definition of “Readily Complies” and Impact on Degree of Testing Required “Readily Comply” is demonstrated if for each ANDA exhibit and/or validation batch: RSD  4.0%, all mean results within 90.0 – 110.0%, all individual results between 75.0 – 125.0% Stage 1 testing allowed (10 dosage units) Testing for products that do not “readily comply” Stage 2 testing (30 dosage units) for at least 5 batches If after testing 5 consecutive batches, the criteria for the mean is met and the RSD routinely is  5.0%, then Stage 1 testing is allowed

Routine Manufacture For ANDA exhibit and/or validation batches: RSD  4.0%, all mean results 90-110%, all values between 75-125% Yes [“Readily Complies”] No [Does not “Readily Comply”] Stage 1: Test 1 sample/location mean 90-110%, RSD  5.0% Stage 2: Test 3 samples/location mean 90-110%, RSD  6.0% No Yes Yes No Adequacy of mix demonstrated; perform 2nd calculation to satisfy compendial release requirements Adequacy of mix demonstrated; perform 2nd calculation to satisfy compendial release requirements Adequacy of mix not demonstrated Future lots After passing 5 Consecutive Batches

Justification of cGMP Compliance Sample Sizes and Acceptance Criteria Sample Size: At least 10 locations, 3 dosage units per location Consistent with the USP Content Uniformity Test cGMP Acceptance Criteria: RSD  5.0% and mean of all samples between 90-110% target potency Consistent with FDA Validation Acceptance Criteria for demonstrating adequacy of mix for powder blends

Alternative Approaches BUWG recommendation is one approach for evaluation of adequacy of mix The cGMP requirements are open to other approaches On-line monitoring techniques such as NIR PDA 25 approach Traditional methods (direct sampling/analysis of blend sample)

Results of PQRI Datamining Effort

Objectives of Datamining Effort Test the hypothesis “blend uniformity is not value added testing” Test the assumption that means are normally distributed Validate the use of computer simulated data Subject batches to PQRI, OGD, FDA Validation, PDA 25, USP, and modified USP (ICH) acceptance criteria

Summary of Data Analyzed Desired Categories of Data Active ingredient < 5% and between 15-25% Product made using direct compression and granulation processes (either wet or dry) Data for tablets and capsules Commercial batches both small (50-100 kg) and large (>400 kg) 8 companies submitted 149 batches

Characteristics of Submitted Data Dosage Form Tablets: 149 Capsules: 0 Manufacturing Process Direct Comp: 12 Wet Granulation: 67 Dry Granulation: 70

Test for Normality of Means Tested both location and within location means for normality using the Wilk-Shapiro test for normality Location: ~ 11% of batches had at least 1 value that was statistically different Most were at beginning/end of run Within Location: ~15% of batches had at least 1 value that was statistically different Conclusion: Computer simulations to estimate criteria rejection rates yield slightly smaller values (conservative) than reject rates based on actual data

Comparison of Blend and Dosage Unit Content Uniformity Data Primary means to test they hypothesis “blend uniformity testing is not value added” Plots prepared comparing dosage unit RSD as a function of blend RSD Break the curve down into 3 zones: Blend RSD <3% Blend RSD 3-5% Blend RSD > 5%

Comparison of Blend and Dosage Form RSDs

Blend RSD < 3%

Blend RSD 3-5%

Blend RSD >5%

Correlation Between Blend and Dosage Unit RSD Blend RSD < 3%: Blend data is predictive of final dosage form uniformity Dosage form RSD often higher (weight variability, segregation?) Blend RSD 3-5%: Diminished correlation between blend data & dosage form uniformity Blend RSD >5%: Blend data is not predictive of content uniformity of the final dosage form

Comparison of Acceptance Criteria

Datamining Results: “Readily” vs. “Marginally” Comply 83/88 (94%) passed PQRI Validation acceptance criteria Of the batches that met PQRI Validation acceptance criteria Readily Comply: 79/83 Marginally Comply: 4/83

Acknowledgements Jerry Planchard (Aventis) Garth Boehm (Purepac) Joep Timmermans (Merck) Jerry Mergen (McNeil) Fernando Muzzio (Rutgers) Jean-Marie Geoffroy (Abbott) Jim Prescott (Jenike & Johanson) Pedro Jimenez (Lilly) John Dietrick (FDA) Jon Clark (FDA) Neeru Takiar (FDA) Muralidhara Gavini (FDA) Laura Foust (Lilly)