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Transcript of PV_SDF_1_FDA
1August 22, 2006
Process Validation:Solid Dosage Forms
Part Iby
Pramote CholayudthGPO, BIOLAB & VALITECH
Tel 0-1932-2374Email: [email protected]
2
Learning Objectives
To review the Process Validation RationaleTo learn about the Process Validation Practicesin pharmaceutical industryTo review the critical process parameters (CPP) for Solid Dosage FormsTo learn about establishing Sampling Plan and Acceptance CriteriaTo learn about the Process Validation Protocol requirements
3
Scope of Presentation→
↓
Prepare summary reportsWrite protocols
↓↑Review & approve reports
Develop procedure & specifications
↓
Collect & interpret data
Change & Change Control←
Execute protocols
↑
↑Define process & equipment
4
Validation Documentation Requirements
5Acceptance Criteria
––––Rationale
––Equipment (Process/Lab)
––––Objective––––Scope
–Personnel ResponsibilitiesProcess DescriptionProcess Flow Chart
WHOEUEMEAPIC/SProtocol Outline
Sampling Plan
Process Validation Protocol OutlineEuropean Medicines Evaluation Agency
6––Statistical Analysis of Results
Critical Quality Attributes
––Description of Experiment
Critical Steps to ValidateCritical Process Parameters
––Product Specifications–Analytical Methods–IPC & Acceptance Criteria
WHOEUEMEAPIC/SProtocol Outline
Results Recording Methods
Process Validation Protocol Outline
7
––––Protocol Acceptance Criteria
––––Appendix
Times Schedules––Batch Analytical Data
––––Supporting Data––––Definition––––Reference
–
WHO
–
EU
–
EMEA
–
PIC/SProtocol Outline
Attachment
Process Validation Protocol Outline
8
ObjectiveScopeRationaleProcess DescriptionProcess Flow ChartResponsibilityList of Equipment UsedProduct Specifications and Analytical MethodsDefine Critical Steps to Validate
EMEA: Process Validation Scheme (Note for Guidance on Process Validation);www.emea.eu.int/pdfs/human/qwp/084896en.pdf
Process Validation Protocol Outline
Bold with Detailed
9
Define CPPs to be MonitoredDefine Critical Quality Attributes (CQA) to be TestedSampling Plan and Acceptance CriteriaSupporting DataDefinitionsReferencesAppendixAttachments
Process Validation Protocol Outline
Pre-approved Protocol:Original copy is keptOne photocopy for one batch is executed with some notes taken
10
ObjectiveScopeValidation Batch InformationDeviation ReportCritical Quality Attributes (CQAs) Test DataStatistical Evaluation of CQAsConclusion
Validation Report Outline
One Batch One Report
Pre-approved Report:Original is kept; One photocopy for one batch is used by hand-writing with final approval
11
ObjectiveScopeValidation Batch Information SummarySummary on CQAs Test and Evaluated DataOverall ConclusionRecommendation
Validation Final Report Outline
Three Batches One Report
No Pre-approval / No Photocopy:Only single original copy is provided by typing (no hand-writing) for Final Approval (sign-off)
12
Validation Protocol Original Copy (Pre-approved) – 1 copyValidation Report Original Copy (Pre-approved) – 1 copyValidation Protocol Photocopies (Executed) –3 copiesValidation Report Photocopies (Approved) – 3 copiesValidation Final Report (Approved) – 1 copy
Master Validation Package(Final Validation Package)
13
Protocol Requirements
14
To validate the manufacturing process of ProMed Tablets 2 mg, Enteric Film Coated, through demonstrating that
critical process parameters are controlled within the process limitscritical product parameter data consistently & reproducibly meet the specifications using appropriate challenging conditions
Objective
15
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
Scope
16
Critical steps are validatedCritical process parameters (CPP) and limits must be identifiedThe 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
Process Validation Rationale:Scientific Reasons (Jerry Lanese, PhD)
17
Define critical steps to validateCritical steps are validatedPV Protocol RationalePV Rationale
Define critical steps to validateCritical steps are validatedPV Protocol RationalePV Rationale
Define critical process parameters and their limits
Critical process parameters and limits must be identified
Define critical steps to validateCritical steps are validatedPV Protocol RationalePV Rationale
Demonstrate that critical product data meet the specifications (an experiment)
Define critical process parameters and their limits
The process when operated within the process limits performs as intended
Critical process parameters and limits must be identified
Define critical steps to validateCritical steps are validatedPV Protocol RationalePV Rationale
Demonstrate that critical product data consistently meetthe specifications
Demonstrate that critical product data meet the specifications (an experiment)
Define critical process parameters and their limits
The process when operated within the process limits performs as intended
The process does perform consistently as intended
Critical process parameters and limits must be identified
Rationale Transfer
18
Critical steps are defined and validatedCritical process parameters are defined and demonstrated to be within the process limitsUpon 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
PV Protocol Rationale
19
Components of wet mass are dry-mixed in HighSpeed 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).
Process Description
The API is moisture sensitive and will partially degrade upon moisture uptake.
20
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 usingrotary tablet compression machine. The core tablets are finally enteric film-coated using Film-Coating Machine.
Process Description
21
→ Challenge API diff lots
↓
Mfg Steps Quality AttributesCPPs
CPP should be specified e.g. temp = 50°C, time = 30 min.↓
AppearanceIPCRM Sieving (HS Gran)Sieve #
Follow IPCPV→
Challenge studyPVN/AIPC
API 3 lots
Process Flow ChartCritical Process Parameter
22
→ Pre-Mixing (HS Mixer)
↓
Wet screening
Mfg Steps Quality AttributesCPPs
↓Gran sizesIPC
→Mesh #, type of m/c Follow IPCPV
Damp massingIPCWet Gran (HS Mixer)
Time,speedFollow IPCPV
→torque
Blend uniformityPVAppearanceIPCTime,speed
mix method
Process Flow Chart
23
batch size→ Drying
(Tray Oven)↓
Blending (V-Blender)
Mfg Steps Quality AttributesCPPs
↓AppearanceIPC
→Time,speed
BU, flow., size distPV(Dist, lub)
Gran shape & sizeIPCMilling (HS Granulator)
Screen sizeFollow IPCPV
→feed rate
LOD (3 samples)PVLODIPCTemp, time
Process Flow Chart
24
→ Hold Time (Bulk Cont.)
↓
Metal Detection
Mfg Steps Quality AttributesCPPs
QC sampling included
↓N/AIPC
→Sensitivity check N/A (verify SOP)PV
Perform IPCIPCTableting(Tab M/C)
SpeedAssay, CU, DRPV
→com force
BU, flowabilityPVN/AIPCMax hold
time
Process Flow Chart
25
Batch size
→ Coating Susp Prep
↓
Mfg Steps Quality AttributesCPPs
QC sampling included
AppearanceIPCCoating(Coater)
Coating parGastric resistance, DR, micro countPV
→
Appearance, viscosity, microbial count
PV
AppearanceIPCHomo speed, time
Process Flow Chart
26
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.
Responsibility – WHO
27
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 validationbatch’s 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.
Responsibility
28
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.
Responsibility
29
Equipment Used
PMS/100 kgHS Mixer/GranWet GranulationSSS/100 kgDrying OvenDrying
PMSLocalLockNR/NRT 25PMS/100 kg
PMSBrand/Model
Film CoaterHomogenizerMetal DetectorTableting MachineV-Shape Blender
HS Granulator
Film coating
SievingEquipmentMfg Steps
CompressionMetal DetectionHomogenization
Blending
30
Equipment Used
PT/PTFR4PT/PTZ3Erweka/TBH20MT/AX204MT/LP 16
Brand/Model
FriabilatorDisint ApparatusHardness TesterTop Load BalanceMoisture BalanceLOD
EquipmentIPC Testing
Tablet HardnessDisint TimeFriability
Tablet Weights
31Spec # ……Spec # ……Spec # ……Spec # ……Spec # ……Spec # ……Spec # ……Spec # ……Analyt Method
SpecifiedLoss on DryingSpecifiedDisintegration Time
SpecifiedSpecifiedSpecifiedSpecifiedSpecifiedSpecified
Friability
AppearanceLimitsQuality Attributes
DiameterThicknessHardness
Identification
Specifications & Analytical Methods
32
Spec # ……Spec # ……Spec # ……Spec # ……Spec # ……Analyt Method
SpecifiedSpecifiedSpecifiedSpecifiedSpecifiedAssay
LimitsQuality Attributes
Dissolution RateGastric Resistance TestDegradation Product
Content Uniformity
Specifications & Analytical Methods
33
Mixing volume
Foreign mat potential
Challenge study
Premixing (before Wet Granulation)
Mixing method
Mixing speedBlend uniformity
Mixing timeType of machine
RMs SievingBreaking lumpMesh #
Product dissolutionImpact on Quality
Particle SizeDifferent lots
CPPsMfg StepsActive Ingredient
Critical Steps to ValidateSame Source
34End point indicatorAmpere meter
Damp massing, API distribution, torque
Feed RateWater Added
Damp massing, torque
Binder Conc.Binder AmountWet
Granulation
Granulation Time
Impact on QualityLoad sizeMixing Speed
CPPsMfg Steps
Critical Steps to Validate
35
Milling speedFeed rate
Milling (Fitzmill)
Size distribution & shape – Flowability
Screen sizeDrying time
Drying (Oven) Loss on drying (LOD)
Granules size, ease of drying
Impact on QualityMesh #
Drying temp.Type of machine
CPPsMfg Steps
Wet Screening
Critical Steps to Validate
36Mag St sieve #
Final Blending (with Mag Stearate) Blending speed
Blending volumeBlend uniformity, size distribution, flowability, dissolution
Blending time
Blending speed
Blend uniformity, size distribution, flowability
Impact on QualityBlending time
Lub/Dist sieve #
Blending volume
CPPsMfg Steps
Final Blending (without Mag Stearate)
Critical Steps to Validate
37
Dwell timeAssay, content uniformity, dissolution, physical & microbiological properties of tablets
Tableting
IPC dataIPC adjustmentFeeder speed
Hopper level
Blend segregation, degradation product
Impact on QualityMaximum hold time
Comp. force
Tableting speed
CPPsMfg StepsHold Time of Final Blend
Critical Steps to Validate
38
Homo timeAppearance (x10), gastric resistance, DR, microbial count
Coating parametersFilm CoatingLoad size
Coating susp homogenizatn
Appearance (x100), viscosity, microbial
Homo speed
Contamination of metal pieces
Impact on QualityRepeatability tested (PQ)Daily sensitivity
CPPsMfg StepsMetal Detection ( by Detector)
Critical Steps to Validate
39
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
Process Validation (WHO, FDA)
WHO: Search by Google “Supplementary Guidelines on Good Manufacturing Practices (GMP) Validation”FDA: http://www.fda.gov/CDER/GUIDANCE/pv.htm
40
Define CPPs to be Monitored
Geometric dilution200 rpm20 minutes# 20
Process Limits
Premixing (before Wet Granulation) Admixing method
Mixing speedMixing time
RMs Sieving Mesh #CPPsMfg Steps
41
Define CPPs to be Monitored
25 ampAmpere meter5 kgs/minFeed Rate2 kgsWater Added4% PVPBinder Conc.15 kgs15 minutes200 rpm90 kgs
Process Limits
Binder AmountGran TimeMixing SpeedLoad size
CPPsMfg Steps
Wet Granulation
42
Define CPPs to be Monitored
Milling (Fitzmill)
Drying (Oven)
5 kg/minFeed rateMediumMilling speed1.2 mmScreen size15 hrs50-55°CHS Gran4 mm
Process Limits
Drying timeDrying temp.Type of machineMesh #
CPPsMfg StepsWet Screening
43
Define CPPs to be Monitored
24 rpmBlending speed
Final Blending (with Mag Stearate) # 40Mag St sieve #
50-70%Blending volume3 minBlending time# 4024 rpm50-70%30 min
Process Limits
Lub/Dist sieve #Blending speedBlending volumeBlending time
CPPsMfg StepsFinal Blending (without Mag Stearate)
44
Define CPPs to be Monitored
Tableting
50 rpmFeeder speed4K newtonComp. force40-80%30K tab/hr
5 days max
Process Limits
Hopper levelTableting speed
Maximum hold time
CPPsMfg StepsHold Time of Final Blend
45
Define CPPs to be Monitored
10 minHomo time
Film Coating
Coating susp preparation
100.- kgsLoad sizeSee attached
2800 rpm
Must be performed
Coating parameters
Homo speedDaily sensitivity
Process LimitsRepeatability tested (PQ)
CPPsMfg Steps
Metal Detection
46
Attachment: Coating Parameters
47
Quality Attributes in Tablet Specifications
QC Testing
Loss on DryingDisintegration Time
–
Friability
AppearanceIPCQuality Attributes
DiameterThicknessHardness
Identification
48
Quality Attributes in Tablet Specifications
QC Testing
––
–––
(Microbial Count)
AssayIPCQuality Attributes
Dissolution RateGastric Resistance TestDegradation Product
Content Uniformity
49
Identification of CQAs for Tablets
––Identification
Patient
–
––––
–Appearance
–Blend Uniformity → CUProcessProduct
Impact onQuality Attributes(Final Blend, Tablets)
% CompressibilityLoss on DryingMax Hold Time
Size Distribution
Spec
Guida
nce &
Risk
An
alysis
50
––Diameter––Thickness
Patient
––––
–Content Uniformity
–Hardness
––––
ProcessProductImpact onQuality Attributes
(Tablets)
Loss on DryingDisintegration TimeAssay/Dissolution
Friability
Identification of CQAs for Tablets
Spec
ificati
on
Spec
&
Guide
51
–Dissolution Rate
––Maximum Hold Time
–Gastric Resistance Test––LOD → Stability
Patient
–Degradation Product
–
ProcessProductImpact onQuality Attributes
(Film Coated Tablets)
Microbial Count
Identification of CQAs for Tablets
Spec
& G
uide
Guide
52
Max Hold Time
Patient
–––
–Blend UniformityProcessProduct
Impact onCritical Quality Attributes (CQAs)
% CompressibilityLoss on Drying
Size Distribution
Define CQAs to be Tested
53
Define CQAs to be Tested
––Loss on Drying (LOD)
–Assay/Dissolution (Cores)–Content Uniformity (Cores)–Dissolution Rate
–Gastric Resistance Test
Patient
–Degradation Product–
ProcessProductImpact onCritical Quality Attributes
(CQAs)
Microbial Count
54
Tablets (& Capsules/Powders)
Sampling Plan & Acceptance Criteria
55
Sampling/testing plan and acceptance criteria will help demonstrate the Consistency of product dataThe 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
Sampling Plan and Acceptance Criteria
56
Pre-Mixing
Blend Uniformity – see Blend Uniformity Acceptance Criteria for Final Blending
57
Drying
Loss on Drying (LOD): The Acceptance Criterion is based production specification for LODTake at least 3 samples (10 g each) from three different locations throughout the oven chamber
58
Final Blending
Critical Quality Attributes (CQAs) are as follows:Blend UniformitySize Distribution (Sieve Analysis)% CompressibilityLoss on Drying (LOD)Maximum Hold Time
59Thai FDA: Use < 2 mg/unit or < 2%; But it will be harmonized
Mean ± 10% (absolute)
* For product with active: < 25 mg/unit or < 25%; ** if exceeded, use RSD ≤ 5.0% (US FDA/PQRI)
At least 10 samples @ 1-3x at 3 mixing timesSD (n = 10) ≤
3.8% TP**
Blend Uniformity (BU)
Sampling Plan *Acceptance Criteria
Product Parameters
Blend Uniformity:Tablets/Capsules/Powders
60
8.53/8.69 =98.16% TP
8.53291.5724.87Example
Total(mg)Active(mg)115 100% TP
% Target Potency
Composition(%)
Target (Theory)Steps
8.6910Pre-Mix
8.23/8.33 =98.80% TP
8.23292.5124.07Example
8.53/8.69 =98.16% TP
8.53291.5724.87Example
Total(mg)Active(mg)
120
115
100% TP
100% TP
% Target Potency
Composition(%)
Target (Theory)Steps
8.6910Pre-Mix
8.3310Final Blend
Target Potency (TP**)
61
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
62
Inherent Bias (Error)
Sampling bias – segregation during samplingHandling bias – segregation during handlingWeighing bias – segregation during weighing
63
V-Shape Blender(www.ikev.org/haber/bozzone/may31.pdf)
64
Bin Blender(www.ikev.org/haber/bozzone/may31.pdf)
65
36
10≥ 50%
101010
< 25%
66
1025 – < 50%
25 – 150 mg> 150 mg
< 25 mgDose \ Conc.
Establishing Blend Uniformity Acceptance Criteria: Tablets/Capsules
* If exceeded, use RSD ≤ 5.0% (US FDA/PQRI)SD ≤ 2.0% TP3SD* ≤ 3.3% TP6 Mean ± 10%
(absolute)
SD* ≤ 3.8% TP10Acceptance Criteria# of Samples
36
10≥ 50%
101010
< 25%
66
1025 – < 50%
25 – 150 mg> 150 mg
< 25 mgDose \ Conc.
66
< 25 mg & < 25%
< 25 mg & ≥ 25%
≥ 25 mg & < 25%
WVContent Uniformity (CU)
WV
≥ 25 mg &≥ 25%
USP 28: Uniformity of Dosage Units
In USP 27 or earlier, ‘50’ is used in place of ‘25’ mg and %Content Uniformity (CU)Hard Cap
Other CoatFilm Coat
Content Uniformity (CU)Uncoated
< 25 mg or < 25%Dosage Forms
Why Use 25 mg and 25%?
67
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
68
n = number of blend sample
1n,9,9.0F6S
−=
22
21
n,n,9.0 SSF
21=
Calculating SD Limit: Tab/Cap
69
Calculating SD Limit: Tab/Cap
1n,9,1.0F6SD
−
=
SDPI = Standard Deviation Prediction Interval
70
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
71
85 – 120% LA4.2%Mean ± 10% (abs)90 – 110% LA4.2%Mean ± 10% (abs)
Max. SD *AC LimitProduct
SpecificationsAcceptance Criteria (n = 10)
93 – 107% LA85 – 120% LA
3.0%Mean ± 7% (abs)4.2%Mean ± 10% (abs)
90 – 110% LA4.2%Mean ± 10% (abs)Max. SD *AC Limit
Product Specifications
Acceptance Criteria (n = 10)
95 – 105% LA93 – 107% LA85 – 120% LA
Take 10 blend samples of smallest size at 3 mixing times
2.1%Mean ± 5% (abs)* Prediction interval method; if exceeded, use RSD ≤5.0% (US FDA/PQRI)
3.0%Mean ± 7% (abs)4.2%Mean ± 10% (abs)
90 – 110% LA4.2%Mean ± 10% (abs)Max. SD *AC Limit
Product Specifications
Acceptance Criteria (n = 10)
Establishing Blend Uniformity Acceptance Criteria: Powders
72
Prediction Interval (PI) comprisesUpper Prediction Limit (UPL)Lower Prediction Limit (LPL)
Prediction Interval Method
n11.s.txUPL 1n,025.0 ++= −
1011.s.262.2x10x ++=+
s.37.210 = 2.4SD ≤
There is 95% confidence that future test results will fall within mean ± 10% (absolute)
73
Consistently Meet the Specification
xxxxx xx xxx
x
LPL UPLLSL USLPrediction
Interval 95%
LSL & USL = Lower & Upper Specification LimitsLPL & UPL = Lower & Upper Prediction Limits
= Sample mean ± k.SD
74
SD Limits for Powders
75
SD Limits for Powders
76
Comparison of SD Limits
77
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
78
Need for Pre-Blending(www.ikev.org/haber/bozzone/may31.pdf)
79
Scale-Up of Blending(www.ikev.org/haber/bozzone/may31.pdf)
80
1x100 gNormal distributionSieve analysis
* Carr’s Compressibility Index = (bulk volume – tapped volume)*100/bulk volume (Carr, RL, Evaluating Flow Properties of Solids, Chemistry Engineering; 1965, 72: 163 – 168
3x10 gMeet specificationLOD1x50 gRefer guidelines%Compressibility *
Sampling PlanAcceptance Criteria
Critical Quality Attributes (CQAs)
Acceptance Criteria: Final Blend(Other Parameters)
81
LPL > 90% LA, UPL < 110% LA
≤ 4.2%–––RSD
–––Prediction Interval
≤ 3.8% LA*
Mean ± 10% (abs)
Tabs
–
–
Semi-Solids
≤ 4.2% LA*
Pdrs
–
–
LiqsCapsAcceptance Criteria (n=10)BU Limits
Specification Limits: 90 – 110% LA; LPL & UPL: Lower & Upper Prediction Limits; * if exceeded, use ‘RSD’ ≤ 5%
SD
Establishing Bulk Uniformity Acceptance Criteria: Universal
82
32 minutes30 minutes28 minutes
Optimization data will show how 30 minutes comes
A compromised combination of Optimization and Validation requirements (for non-optimized process)
Lot # 2 Lot # 3–
Mixing Time
––
–Lot # 1Blend Sampled at
BPR Mixing Time: 30 minutes
83
32 minutes30 minutes28 minutes
A separate challenging data (e.g. 26, 28, 30, 32, 34 minutes) is required (in dossier) to show how 30 minutes comes
Lot # 2 Lot # 3–
Mixing Time
–––
––Lot # 1Blend Sampled at
BPR Mixing Time: 30 minutes
84
32 minutes30 minutes28 minutes
A separate challenging data (e.g. 26, 28, 30, 32, 34 minutes) is required to show how 28-32 minutes comes
Lot # 2 Lot # 3–
Mixing Time – –
––
–Lot # 1Blend Sampled at
BPR Mixing Time: 28-32 minutes
0
10
20
30
40
50
60
70
80
0 5 10 15 20 25 30 35 40 45 50
Time (min)
%R
elat
ive
Stan
dard
Dev
iatio
n
Left shell
Right shell
Top
Middle
Bottom
Normal Mixing Time (Optimized)
Upper ExtremeLower Extreme
Example to DemonstrateRobustness & Optimization
86
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 BlendingLoss on Drying – see Acceptance Criteria for Drying
87
Tableting
Critical Quality Attributes (CQAs) are as follows:Content UniformityAssayDissolution Rate
88
Thai FDA: Content Uniformity Test– 1st Stage (Not Recommended)
Means ∈ 90 –110% TA (1)
RSD ≤ 6.0%
Weight-Corrected Data
All units ∈ 85 –115% LA
As-is Data
Content Uniformity (CU)
Sampling Plan: 10 x 7’s, Testing Plan: 10 x 3’s(1) – Location mean of 3’s (TA = Target Amount)∈ = Fall within, ∉ = Fall outside
Product Parameters
89
Means ∈ 90 –110% TA
RSD ≤ 6.6%
Weight-Corrected Data
NMT 2 units ∉ 85 –115% LA, all units ∈75 – 125% LA
As-is Data
Content Uniformity (CU)
Testing Plan: 10 x 4’s; Evaluating: 10 x 7’s
Product Parameters
Thai FDA: Content Uniformity Test– 2nd Stage (Not Recommended)
90
Sampling Plan: 10 x 7’s, Testing Plan: 10 x 3’s
RSD ≤ 4.8%RSD ≤ 4.8%
Means ∈ 90 –110% TA
Weight-Corrected Data (BU Data)
NMT c units ∉ 85 –115% LA, all units ∈75 – 125% LA
As-is Data(CU Data)
Content Uniformity (CU): n = 30
c = 1 for tablets; c = 3 for capsules
Product Parameters
Establishing Content Uniformity Test (Modified from US/Thai: 1st Stage; Recommended)
91
RSD ≤ 5.4%RSD ≤ 5.4%
Means ∈ 90 –110% TA
Weight-Corrected Data (BU Data)
NMT c units ∉ 85 –115% LA, all units ∈75 – 125% LA
As-is Data(CU Data)
Content Uniformity (CU): n = 70
Testing Plan: 10 x 4’s; Evaluating: 10 x 7’sc = 1 for tablets; c = 3 for capsules
Product Parameters
Establishing Content Uniformity Test (Modified from US/Thai: 2nd Stage; Recommended)
92
Stage 1: n = 30, P = 4.8; Stage 2: n = 70, P = 5.4
RSD ≤ P%RSD ≤ P%
Means ∈ 90 –110% TA
Weight-Corrected Data (BU Data)
NMT c units ∉ 85 –115% LA, all units ∈75 – 125% LA
As-is Data(CU Data)
Content Uniformity (CU)
Sampling Plan: 10 x 7’s, Testing Plan: 10 x 3’s, 10 x 4’s
c = 1 for tablets; c = 3 for capsules (for both stages)
Product Parameters
Establishing Content Uniformity Test (Summary: Stage 1 & 2)
93
100% LA8.3312010TabletTotal(mg)Active(mg)
% Target Amount (TA)
Composition (%)
Target (Theory)Steps
Weight Corrected (WC) Data
% Target Amount (% TA) = % Target Potency (% TP)
100% LA8.3312010Tablet10.1/10 = 101% LA
8.4911910.1
CU As-is Data
8.49/8.33 =101.92% TA
CU WC Data
Total(mg)Active(mg)% Target
Amount (TA)Composition
(%)Target (Theory)
Steps
94
CU & WC CU Data in MS Excel (Obtained from [email protected])
95
Probability of Falling outside 85 – 115% LA
For RSD < ABOVE, Probability for ‘zero’ unit is increasedThis is in case of RSD = 4.8% (n = 30) or 5.4% (n = 70)
70307030
n
≤ 34.7≤ 33.4≤ 34.7≤ 33.41 unit
≤ 24.5≤ 9.9
––
2 units
≤ 11.3≤ 1.9
––
3 units
2121
Stage #
≥ 24.3≥ 54.5≥ 24.3≥ 54.50 unit
Prob of falling ∉ 85 – 115% LA (%)
Capsule
Tablets
Products
96
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 & weight-corrected data) tests may be acceptableThis is provided that IPC for tableting process is properly carried out
97
PDA Technical Report # 25: Blend Uniformity Analysis: Validation and In-
Process Testing, October 1997To be purchased from www.pda.org
98
Establishing CU RSD Acceptance Limit
Max RSD = 4.8%
99
Max RSD = 4.8%
Establishing CU RSD Acceptance Limit
100
Max RSD = 4.8%
Establishing CU RSD Acceptance Limit
101
Acceptance Region: RSD = 4.8%
Acceptance Region
102
Acceptance Region
Acceptance Region: RSD = 3.5%
103
Max RSD = 5.4%
Establishing CU RSD Acceptance Limit
104
Max RSD = 5.4%
Establishing CU RSD Acceptance Limit
105
Max RSD = 5.4%
Establishing CU RSD Acceptance Limit
106
Acceptance Region
Acceptance Region: RSD = 5.4%
107
Acceptance Region
Acceptance Region: RSD = 4.5%
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USP 28: If Val. RSD ≤ 2%, no CU test but WV is required, cancelled in USP 29
109
Acceptance Limits for Tablet CU Test
110
Meeting limits guarantees, with 95% assurance, that at least 50% of samples tested will pass the USP CU test
4.84.74.64.54.44.34.2
RSD
98.397.897.396.996.696.295.9LL
101.5101.9102.2102.4102.7103.0103.3
UL
4.14.03.93.83.73.63.5
RSD
95.695.395.094.794.494.293.9LL
103.5103.7104.0104.3104.5104.8105.1
UL
105.3105.7106.0106.4106.7107.0107.2
UL
93.693.392.992.692.291.991.7LL
3.43.33.23.13.02.92.8
RSD
Acceptance Limits for Tablet CU Means: n = 30
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Acceptance Limits for Tablet CU Means: n = 30