# Presentation: 086712

## Introduction

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

## 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- 	 OGD’s Draft Guidance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**

**Assay 2nd and 3rd blend samples**
** ****from each location**

**Proceed to Stage 1**
**Dosage Unit Testing**

**Mixing problem**
**identified**

**Fail**

**Pass**

**Proceed to Stage 2**
**Dosage Unit Testing**

**Yes**

**No**

**Blend  is not uniform.**
**Go back to development**

**Investigation points to sampling **
**bias or some other attributable cause**

## 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 **

**Process**
**Validated**

**Assay at least 4 additional 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**

**Fail**

**Pass**

**Pass**

**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

## Slide 28

## Slide 29

## 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**

**Adequacy of mix demonstrated;**
**perform 2nd calculation to satisfy**
** ****compendial release requirements**

**No**

**Adequacy of mix**
**not demonstrated**

**After passing 5**
**Consecutive Batches**

**Adequacy of mix demonstrated;**
**perform 2nd calculation to satisfy**
** ****compendial release requirements**

**Future**
**lots**

## 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)