Process Validation: Solid Dosage Forms

Part I
by Pramote Cholayudth GPO, BIOLAB & VALITECH Tel 0-1932-2374 Email: cpramote2000@yahoo.com
August 22, 2006
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Learning Objectives
To review the Process Validation Rationale To learn about the Process Validation Practices in pharmaceutical industry To review the critical process parameters (CPP) for Solid Dosage Forms To learn about establishing Sampling Plan and Acceptance Criteria To learn about the Process Validation Protocol requirements

Scope of Presentation
Execute protocols Write protocols Develop procedure & specifications Define process & equipment Collect & interpret data Prepare summary reports Review & approve reports Change & Change Control

Validation Documentation Requirements

Process Validation Protocol Outline

European Medicines Evaluation Agency

Protocol Outline Objective Scope Rationale Personnel Responsibilities Process Description Process Flow Chart Equipment (Process/Lab) Sampling Plan Acceptance Criteria

PIC/S EMEA

EU

WHO

Process Validation Protocol Outline

Protocol Outline PIC/S EMEA Critical Steps to Validate Critical Process Parameters Critical Quality Attributes Product Specifications Analytical Methods IPC & Acceptance Criteria Description of Experiment Results Recording Methods Statistical Analysis of Results EU WHO

Process Validation Protocol Outline

Protocol Outline Times Schedules Batch Analytical Data Protocol Acceptance Criteria Supporting Data Definition Reference Appendix Attachment PIC/S EMEA EU WHO
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Process Validation Protocol Outline

Objective EMEA: Process Validation Scheme (Note Scope for Guidance on Process Validation); www.emea.eu.int/pdfs/human/qwp/084896en.pdf Rationale Process Description Bold with Process Flow Chart Detailed Responsibility List of Equipment Used Product Specifications and Analytical Methods Define Critical Steps to Validate

Process Validation Protocol Outline

Define CPPs to be Monitored Define Critical Quality Attributes (CQA) to be Tested Sampling Plan and Acceptance Criteria Supporting Data Definitions Pre-approved Protocol: References Original copy is kept One photocopy for one batch is Appendix executed with some notes taken Attachments

Validation Report Outline

Objective One Batch One Report Scope Validation Batch Information Deviation Report Critical Quality Attributes (CQAs) Test Data Statistical Evaluation of CQAs Conclusion Pre-approved Report:

Original is kept; One photocopy for one batch is used by hand-writing with final approval
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Validation Final Report Outline

Objective Three Batches One Report Scope Validation Batch Information Summary Summary on CQAs Test and Evaluated Data Overall Conclusion Recommendation
No Pre-approval / No Photocopy: Only single original copy is provided by typing (no hand-writing) for Final Approval (sign-off)

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Master Validation Package (Final Validation Package)

Validation Protocol Original Copy (Preapproved) 1 copy Validation Report Original Copy (Preapproved) 1 copy Validation Protocol Photocopies (Executed) 3 copies Validation Report Photocopies (Approved) 3 copies Validation Final Report (Approved) 1 copy

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Protocol Requirements

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Objective
To validate the manufacturing process of ProMed Tablets 2 mg, Enteric Film Coated, through demonstrating that
critical process parameters are controlled within the process limits critical product parameter data consistently & reproducibly meet the specifications using appropriate challenging conditions
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Scope
This protocol is applied to ProMed Tablets 2 mg, Enteric Film Coated, batch size 500,000 tablets, BPR # 001, manufactured in ProMed Pharma Plant, Suwannaphume. Execution of this protocol is planned in September 2006

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Process Validation Rationale: Scientific Reasons (Jerry Lanese, PhD)

Critical steps are validated Critical process parameters (CPP) and limits must be identified The process when operated within the process limits performs as intended i.e. meet the specs. The process (under routine condition) does perform consistently as intended i.e. consistently meet the specifications

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Rationale Transfer
PV Rationale
Critical steps are validated Critical process parameters and limits must be identified The process when operated within the process limits performs as intended The process does perform consistently as intended

PV Protocol Rationale
Define critical steps to validate Define critical process parameters and their limits Demonstrate that critical product data meet the specifications (an experiment) Demonstrate that critical product data consistently meet the specifications

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PV Protocol Rationale
Critical steps are defined and validated Critical process parameters are defined and demonstrated to be within the process limits Upon challenging the critical process parameters, the critical product parameter data always meet the specifications (separate trial) Using the CPPs in BPR, the critical product data consistently meet the specifications

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Process Description
Components of wet mass are dry-mixed in High Speed Mixer/Granulator. After addition of granulating liquid, the mixture is kneaded until a suitable granulation is obtained, then sieved through High Speed Granulator (4.0 mm). The granulation is dried in Drying Oven at 50 C until loss on drying (LOD) limit of 1.0-2.0 % is met, then sieved through High Speed Granulator (1.0 mm).
The API is moisture sensitive and will partially degrade upon moisture uptake.
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Process Description
Disintegrant and lubricant are sieved through 0.5 mm, add the first one and blend with the granules in V-Shape Blender to obtain a uniform blend and finally add the latter and blend further until the final blend is uniform. The final blend is compressed into tablets using rotary tablet compression machine. The core tablets are finally enteric film-coated using Film-Coating Machine.
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Quality Attributes Challenge IPC N/A API 3 lots API diff lots PV Challenge study RM Sieving IPC Appearance Sieve # (HS Gran) PV Follow IPC CPP should be specified e.g. temp = 50C, time = 30 min.
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Critical Process Parameter CPPs Mfg Steps

Process Flow Chart

Process Flow Chart

CPPs Time,speed mix method Time,speed torque Mesh #, type of m/c Mfg Steps Pre-Mixing (HS Mixer) Wet Gran (HS Mixer) Wet screening IPC Gran sizes PV Follow IPC
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Quality Attributes IPC Appearance PV Blend uniformity IPC Damp massing PV Follow IPC

Process Flow Chart

CPPs Temp, time batch size Screen size feed rate Time,speed (Dist, lub) Quality Attributes IPC LOD Drying (Tray Oven) PV LOD (3 samples) Milling (HS IPC Gran shape & size Granulator) PV Follow IPC Blending IPC Appearance (V-Blender) PV BU, flow., size dist
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Mfg Steps

Process Flow Chart

Quality Attributes Hold Time IPC N/A (Bulk Cont.) PV BU, flowability Speed Tableting IPC Perform IPC (Tab M/C) PV Assay, CU, DR com force IPC N/A Metal Sensitivity Detection PV N/A (verify SOP) check QC sampling included CPPs Max hold time Mfg Steps

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Process Flow Chart

CPPs Homo speed, time Mfg Steps Coating Susp Prep Coating par Batch size Coating (Coater) IPC Appearance Gastric resistance, PV DR, micro count
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Quality Attributes IPC Appearance Appearance, PV viscosity, microbial count

QC sampling included

Responsibility WHO
Several possible methods of organizing validation are available, one of which is the establishment of a validation group. The management appoints a person responsible for validation (validation officer), who then forms the group (team, committee). This is headed by a group leader, and represents all major departments: development, production, engineering, quality assurance and control. The composition of the group should be changed from time to time to give opportunities to other people to generate new ideas and to gain experience.

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Responsibility
Validation Coordinator is responsible for (1) providing this validation protocol, (2) ensuring the overall validation is in accordance with the protocol (3) collecting all the analytical results and all the validation batchs IPC data, (4) conclusion of the validation test results and (5) generating Validation Report for each validation batch and Validation Final Report for the three validation batches to be approved by the authorized Validation Team members.
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Responsibility
Quality Control (QC) is responsible for performing the chemical, physical, and microbiological analyses and supplying all the analytical results to the Validation Coordinator. Production, in coordination with QC and Validation Coordinator, is responsible for scheduling the validation batches and for taking, labeling, and submitting the validation samples to the Quality Control laboratory.
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Equipment Used
Mfg Steps Sieving Wet Granulation Drying Blending Compression Metal Detection Homogenization Film coating Equipment HS Granulator HS Mixer/Gran Drying Oven V-Shape Blender Tableting Machine Metal Detector Homogenizer Film Coater Brand/Model PMS PMS/100 kg SSS/100 kg PMS/100 kg NR/NRT 25 Lock Local PMS

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Equipment Used
IPC Testing LOD Tablet Weights Tablet Hardness Disint Time Friability Equipment Moisture Balance Top Load Balance Hardness Tester Disint Apparatus Friabilator Brand/Model MT/LP 16 MT/AX204 Erweka/TBH20 PT/PTZ3 PT/PTFR4

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Specifications & Analytical Methods

Quality Attributes Appearance Identification Diameter Thickness Hardness Friability Loss on Drying Disintegration Time Limits Specified Specified Specified Specified Specified Specified Specified Specified Analyt Method Spec # Spec # Spec # Spec # Spec # Spec # Spec # Spec #

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Specifications & Analytical Methods

Quality Attributes Assay Content Uniformity Dissolution Rate Gastric Resistance Test Degradation Product Limits Specified Specified Specified Specified Specified Analyt Method Spec # Spec # Spec # Spec # Spec #

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Critical Steps to Validate

Same Source

Mfg Steps Active Ingredient RMs Sieving Premixing (before Wet Granulation)

CPPs Particle Size Different lots Mesh # Type of machine Mixing time Mixing speed Mixing volume Mixing method

Impact on Quality Product dissolution Challenge study Breaking lump Foreign mat potential Blend uniformity
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Critical Steps to Validate

Mfg Steps CPPs Load size Mixing Speed Granulation Time Binder Amount Binder Conc. Water Added Feed Rate Ampere meter Impact on Quality Damp massing, API distribution, torque

Wet Granulation

Damp massing, torque End point indicator

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Critical Steps to Validate

CPPs Mesh # Wet Screening Type of machine Drying temp. Drying (Oven) Drying time Screen size Milling Milling speed (Fitzmill) Feed rate Mfg Steps Impact on Quality Granules size, ease of drying Loss on drying (LOD) Size distribution & shape Flowability
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Critical Steps to Validate

CPPs Blending time Final Blending Blending volume (without Mag Blending speed Stearate) Lub/Dist sieve # Blending time Final Blending Blending volume (with Mag Blending speed Stearate) Mag St sieve # Mfg Steps Impact on Quality Blend uniformity, size distribution, flowability Blend uniformity, size distribution, flowability, dissolution

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Critical Steps to Validate

Mfg Steps Hold Time of Final Blend CPPs Maximum hold time Tableting speed Dwell time Hopper level Comp. force Feeder speed IPC adjustment Impact on Quality Blend segregation, degradation product Assay, content uniformity, dissolution, physical & microbiological properties of tablets IPC data
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Tableting

Critical Steps to Validate

CPPs Repeatability Metal Detection ( by tested (PQ) Detector) Daily sensitivity Coating susp Homo speed homogenizatn Homo time Coating Film Coating parameters Load size Mfg Steps Impact on Quality Contamination of metal pieces Appearance (x100), viscosity, microbial Appearance (x10), gastric resistance, DR, microbial count
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Process Validation (WHO, FDA)

Each critical step of the manufacturing process must be (controlled and) validated Other steps in the process must be (also) under control to maximize the probability that the finished product meets all quality and design specifications
WHO: Search by Google Supplementary Guidelines on Good Manufacturing Practices (GMP) Validation FDA: http://www.fda.gov/CDER/GUIDANCE/pv.htm

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Define CPPs to be Monitored

Mfg Steps CPPs RMs Sieving Mesh # Mixing time Premixing (before Wet Mixing speed Granulation) Admixing method Process Limits # 20 20 minutes 200 rpm Geometric dilution

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Define CPPs to be Monitored

Mfg Steps CPPs Load size Mixing Speed Gran Time Binder Amount Binder Conc. Water Added Feed Rate Ampere meter Process Limits 90 kgs 200 rpm 15 minutes 15 kgs 4% PVP 2 kgs 5 kgs/min 25 amp

Wet Granulation

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Define CPPs to be Monitored

Mfg Steps Wet Screening Drying (Oven) Milling (Fitzmill) CPPs Mesh # Type of machine Drying temp. Drying time Screen size Milling speed Feed rate Process Limits 4 mm HS Gran 50-55C 15 hrs 1.2 mm Medium 5 kg/min
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Define CPPs to be Monitored

CPPs Blending time Final Blending volume Blending (without Mag Blending speed Stearate) Lub/Dist sieve # Blending time Final Blending volume Blending (with Mag Blending speed Stearate) Mag St sieve # Mfg Steps Process Limits 30 min 50-70% 24 rpm # 40 3 min 50-70% 24 rpm # 40

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Define CPPs to be Monitored

Mfg Steps CPPs Hold Time of Maximum hold time Final Blend Tableting speed Hopper level Tableting Comp. force Feeder speed Process Limits 5 days max 30K tab/hr 40-80% 4K newton 50 rpm

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Define CPPs to be Monitored

CPPs Repeatability tested Metal (PQ) Detection Daily sensitivity Coating susp Homo speed preparation Homo time Coating parameters Film Coating Load size Mfg Steps Process Limits Must be performed 2800 rpm 10 min See attached 100.- kgs
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Attachment: Coating Parameters

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Quality Attributes in Tablet Specifications

Quality Attributes Appearance Identification Diameter Thickness Hardness Friability Loss on Drying Disintegration Time IPC QC Testing

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Quality Attributes in Tablet Specifications

Quality Attributes Assay Content Uniformity Dissolution Rate Gastric Resistance Test Degradation Product (Microbial Count) IPC
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QC Testing

Identification of CQAs for Tablets

Quality Attributes (Final Blend, Tablets) Blend Uniformity CU Size Distribution % Compressibility Loss on Drying Max Hold Time Appearance Identification Guidance & Risk Analysis Impact on Patient Product Process
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Spec

Identification of CQAs for Tablets

Quality Attributes (Tablets) Diameter Thickness Hardness Friability Loss on Drying Disintegration Time Assay/Dissolution Content Uniformity Specification Spec & Guide Impact on Patient Product Process 50

Identification of CQAs for Tablets

Quality Attributes (Film Coated Tablets) Dissolution Rate Gastric Resistance Test LOD Stability Degradation Product Maximum Hold Time Microbial Count Guide Spec & Guide Impact on Patient Product Process
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Define CQAs to be Tested

Critical Quality Attributes (CQAs) Blend Uniformity Size Distribution % Compressibility Loss on Drying Max Hold Time Impact on Patient Product Process

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Define CQAs to be Tested

Critical Quality Attributes (CQAs) Assay/Dissolution (Cores) Content Uniformity (Cores) Dissolution Rate Loss on Drying (LOD) Gastric Resistance Test Degradation Product Microbial Count Impact on Patient Product Process
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Sampling Plan & Acceptance Criteria

Tablets (& Capsules/Powders)

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Sampling Plan and Acceptance Criteria

Sampling/testing plan and acceptance criteria will help demonstrate the Consistency of product data The consistency will be demonstrated in terms of high probability of meeting the specifications by using the protocol acceptance criteria which are based on statistical techniques
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Pre-Mixing
Blend Uniformity see Blend Uniformity Acceptance Criteria for Final Blending

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Drying
Loss on Drying (LOD): The Acceptance Criterion is based production specification for LOD Take at least 3 samples (10 g each) from three different locations throughout the oven chamber

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Final Blending
Critical Quality Attributes (CQAs) are as follows: Blend Uniformity Size Distribution (Sieve Analysis) % Compressibility Loss on Drying (LOD) Maximum Hold Time
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Blend Uniformity: Tablets/Capsules/Powders

Acceptance Sampling Plan * Criteria Mean 10% At least 10 samples Blend (absolute) @ 1-3x at 3 mixing Uniformity SD (n = 10) times (BU) 3.8% TP** * For product with active: < 25 mg/unit or < 25%; ** if exceeded, use RSD 5.0% (US FDA/PQRI)
Thai FDA: Use < 2 mg/unit or < 2%; But it will be harmonized
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Product Parameters

Target Potency (TP**)

Steps Pre-Mix Example Final Blend Example
Composition (%) Active(mg) Total(mg)

Target (Theory) 10

% Target Potency 100% TP 8.53/8.69 = 98.16% TP 100% TP 8.23/8.33 = 98.80% TP

115 291.57 120 292.51

8.69 8.53 8.33 8.23

24.87 10 24.07

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1-3 x Blend Sample Size

Eliminate handling and weighing bias (error) by taking blend sample size 1-3 times the dosage unit weight and analyze the whole mass of each sample

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Inherent Bias (Error)

Sampling bias segregation during sampling Handling bias segregation during handling Weighing bias segregation during weighing

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(www.ikev.org/haber/bozzone/may31.pdf)

V-Shape Blender

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(www.ikev.org/haber/bozzone/may31.pdf)

Bin Blender

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Establishing Blend Uniformity Acceptance Criteria: Tablets/Capsules

Dose \ Conc. < 25% 25 < 50% 50% 10 10 10 < 25 mg 10 6 6 25 150 mg 10 6 3 > 150 mg # of Samples Acceptance Criteria 10 SD* 3.8% TP Mean 10% 6 SD* 3.3% TP (absolute) 3 SD 2.0% TP * If exceeded, use RSD 5.0% (US FDA/PQRI)

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Why Use 25 mg and 25%?

Dosage Forms USP 28: Uniformity of Dosage Units < 25 mg or < 25% 25 mg & 25 mg & < 25 mg & < 25 mg & 25% < 25% 25% < 25%

Uncoated WV Content Uniformity (CU) Film Coat Content Uniformity (CU) Other Coat WV Hard Cap Content Uniformity (CU) In USP 27 or earlier, 50 is used in place of 25 mg and %
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Rationale for SD Limit

The SD limit will ensure with 90% confidence that the RSD result (for USP CU test sample size of 10) will not exceed 6.0% The SD limit, according to Standard Deviation Prediction Interval Method (SDPI Method) suggested by Hahn and Meeker, is widely accepted
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Calculating SD Limit: Tab/Cap

F0.9,n1 ,n2 =

2 S1 2 S2

S=

6 F0.9,9,n1

n = number of blend sample

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Calculating SD Limit: Tab/Cap

SDPI = Standard Deviation Prediction Interval

SD =

6 F0.1,9,n1

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Application of Bergum Method

Blend Uniformity data i.e. blend sample mean and RSD may be evaluated using Bergum method to predict a high probability of passing USP CU test for the upcoming validation CU data

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Establishing Blend Uniformity Acceptance Criteria: Powders

Acceptance Criteria (n = 10) Product Specifications AC Limit Max. SD * 4.2% 90 110% LA Mean 10% (abs) 4.2% 85 120% LA Mean 10% (abs) 3.0% 93 107% LA Mean 7% (abs) 2.1% 95 105% LA Mean 5% (abs) * Prediction interval method; if exceeded, use RSD 5.0% (US FDA/PQRI) Take 10 blend samples of smallest size at 3 mixing times 71

Prediction Interval Method

Prediction Interval (PI) comprises
Upper Prediction Limit (UPL) Lower Prediction Limit (LPL)

1 UPL = x + t 0.025,n1.s. 1 + n 1 x + 10 = x + 2.262.s. 1 + 10 10 = 2.37.s SD 4.2

There is 95% confidence that future test results will fall within mean 10% (absolute)
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Consistently Meet the Specification

LSL LPL UPL USL

Prediction Interval 95%

x x xx x x xx x x x LSL & USL = Lower & Upper Specification Limits LPL & UPL = Lower & Upper Prediction Limits = Sample mean k.SD

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SD Limits for Powders

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SD Limits for Powders

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Comparison of SD Limits

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Additive Contents
Additive contents e.g. preservative, wetting agent, antioxidant, or chelating agent, should be determined in process validation (if possible) A capsule product containing wetting agent has a problem of dissolution rate (DR) fluctuation poor distribution of the agent Verification of admixing method is required
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(www.ikev.org/haber/bozzone/may31.pdf)

Need for Pre-Blending

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(www.ikev.org/haber/bozzone/may31.pdf)

Scale-Up of Blending

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Acceptance Criteria: Final Blend (Other Parameters)

Acceptance Critical Quality Sampling Plan Attributes (CQAs) Criteria Sieve analysis Normal distribution 1x100 g LOD Meet specification 3x10 g %Compressibility * Refer guidelines 1x50 g * Carrs Compressibility Index = (bulk volume tapped volume)*100/bulk volume (Carr, RL, Evaluating Flow
Properties of Solids, Chemistry Engineering; 1965, 72: 163 168
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Establishing Bulk Uniformity Acceptance Criteria: Universal

SemiAcceptance Tabs Caps Pdrs Liqs Solids Criteria (n=10) BU Limits Mean 10% (abs) 4.2% SD 3.8% LA* LA* Prediction LPL > 90% LA, Interval UPL < 110% LA RSD 4.2% Specification Limits: 90 110% LA; LPL & UPL: Lower & Upper Prediction Limits; * if exceeded, use RSD 5%
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BPR Mixing Time: 30 minutes

Blend Sampled at Lot # 1 Lot # 2 Lot # 3 28 minutes Mixing 30 minutes Time 32 minutes A compromised combination of Optimization and Validation requirements (for non-optimized process) Optimization data will show how 30 minutes comes
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BPR Mixing Time: 30 minutes

Blend Sampled at Lot # 1 Lot # 2 Lot # 3 28 minutes Mixing 30 minutes Time 32 minutes A separate challenging data (e.g. 26, 28, 30, 32, 34 minutes) is required (in dossier) to show how 30 minutes comes
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BPR Mixing Time: 28-32 minutes

Blend Sampled at Lot # 1 Lot # 2 Lot # 3 28 minutes Mixing 30 minutes Time 32 minutes A separate challenging data (e.g. 26, 28, 30, 32, 34 minutes) is required to show how 28-32 minutes comes
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Example to Demonstrate Robustness & Optimization

80 70 Left shell 60 %Relative Standard Deviation Right shell Top 50 Middle Bottom 40

Lower Extreme
30 20

Normal Mixing Upper Extreme Time (Optimized)

10

0 0 5 10 15 20 25 Time (min) 30 35 40 45 50

Maximum Hold Time

Bulk of final blend is stored (in containers lined with PE bags) for not more than 5 days. Critical Quality Attributes (CQAs) are as follows: Blend Uniformity see Acceptance Criteria for Final Blending Loss on Drying see Acceptance Criteria for Drying
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Tableting
Critical Quality Attributes (CQAs) are as follows: Content Uniformity Assay Dissolution Rate

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Thai FDA: Content Uniformity Test 1st Stage (Not Recommended)

Product Parameters As-is Data WeightCorrected Data RSD 6.0% Means 90 110% TA (1)

Content Uniformity All units 85 (CU) 115% LA

= Fall within, = Fall outside (1) Location mean of 3s (TA = Target Amount) Sampling Plan: 10 x 7s, Testing Plan: 10 x 3s
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Thai FDA: Content Uniformity Test 2nd Stage (Not Recommended)

Product Parameters As-is Data WeightCorrected Data NMT 2 units 85 RSD 6.6% Content 115% LA, all units Means 90 Uniformity (CU) 75 125% LA 110% TA Testing Plan: 10 x 4s; Evaluating: 10 x 7s

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(Modified from US/Thai: 1st Stage; Recommended)

Product Parameters As-is Data (CU Data) Weight-Corrected Data (BU Data)

Establishing Content Uniformity Test

NMT c units 85 Means 90 Content 115% LA, all units 110% TA Uniformity (CU): 75 125% LA n = 30 RSD 4.8% RSD 4.8% c = 1 for tablets; c = 3 for capsules Sampling Plan: 10 x 7s, Testing Plan: 10 x 3s
90

(Modified from US/Thai: 2nd Stage; Recommended)

Product Parameters As-is Data (CU Data) Weight-Corrected Data (BU Data)

Establishing Content Uniformity Test

NMT c units 85 Means 90 Content 115% LA, all units 110% TA Uniformity (CU): 75 125% LA n = 70 RSD 5.4% RSD 5.4% c = 1 for tablets; c = 3 for capsules Testing Plan: 10 x 4s; Evaluating: 10 x 7s
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Establishing Content Uniformity Test

(Summary: Stage 1 & 2)
As-is Data (CU Data) Product Parameters Weight-Corrected Data (BU Data)

NMT c units 85 Means 90 115% LA, all units Content 110% TA Uniformity (CU) 75 125% LA RSD P% RSD P% c = 1 for tablets; c = 3 for capsules (for both stages) Stage 1: n = 30, P = 4.8; Stage 2: n = 70, P = 5.4 Sampling Plan: 10 x 7s, Testing Plan: 10 x 3s, 10 x 4s
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Weight Corrected (WC) Data

Steps Tablet CU As-is Data Composition % Target (%) Amount (TA) Active(mg) Total(mg) 10 120 8.33 100% LA Target (Theory)

10.1/10 = 101% LA 10.1 119 8.49 8.49/8.33 = CU WC Data 101.92% TA % Target Amount (% TA) = % Target Potency (% TP)
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(Obtained from cpramote2000@yahoo.com)

CU & WC CU Data in MS Excel

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Probability of Falling outside 85 115% LA

Products n
Prob of falling 85 115% LA (%)

0 unit 1 unit 2 units 3 units 30 54.5 33.4 1 Tablets 70 24.3 34.7 2 30 54.5 33.4 9.9 1.9 1 Capsule 70 24.3 34.7 24.5 11.3 2 This is in case of RSD = 4.8% (n = 30) or 5.4% (n = 70) For RSD < ABOVE, Probability for zero unit is increased
95

Stage #

PDA Technical Report # 25

While a batch failing the criterion for blend uniformity while passing the product (content) uniformity criterion will frequently be found to have significant thief sampling error,
Validation batches failing blend uniformity but pass content uniformity (satisfactory as-is & weightcorrected data) tests may be acceptable This is provided that IPC for tableting process is properly carried out
96

PDA Technical Report # 25: Blend Uniformity Analysis: Validation and InProcess Testing, October 1997
To be purchased from www.pda.org

97

Establishing CU RSD Acceptance Limit

Max RSD = 4.8%

98

Establishing CU RSD Acceptance Limit

Max RSD = 4.8%

99

Establishing CU RSD Acceptance Limit

Max RSD = 4.8%

100

Acceptance Region: RSD = 4.8%

Acceptance Region

101

Acceptance Region: RSD = 3.5%

Acceptance Region

102

Establishing CU RSD Acceptance Limit

Max RSD = 5.4%

103

Establishing CU RSD Acceptance Limit

Max RSD = 5.4%

104

Establishing CU RSD Acceptance Limit

Max RSD = 5.4%

105

Acceptance Region: RSD = 5.4%

Acceptance Region

106

Acceptance Region: RSD = 4.5%

Acceptance Region

107

USP 28: If Val. RSD 2%, no CU test but WV is required, cancelled in USP 29

108

Acceptance Limits for Tablet CU Test

109

Acceptance Limits for Tablet CU Means: n = 30

RSD LL UL RSD LL UL RSD LL UL 2.8 91.7 107.2 3.5 93.9 105.1 4.2 95.9 103.3 2.9 91.9 107.0 3.6 94.2 104.8 4.3 96.2 103.0 3.0 92.2 106.7 3.7 94.4 104.5 4.4 96.6 102.7 3.1 92.6 106.4 3.8 94.7 104.3 4.5 96.9 102.4 3.2 92.9 106.0 3.9 95.0 104.0 4.6 97.3 102.2 3.3 93.3 105.7 4.0 95.3 103.7 4.7 97.8 101.9 3.4 93.6 105.3 4.1 95.6 103.5 4.8 98.3 101.5 Meeting limits guarantees, with 95% assurance, that at least 50% of samples tested will pass the USP CU test 110

Acceptance Limits for Tablet CU Means: n = 30

111