process validation of solid dosage forms

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


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


Bold with Detailed

9

Define CPPs to be MonitoredDefine Critical Quality Attributes (CQA) to be TestedSampling Plan and Acceptance CriteriaSupporting DataDefinitionsReferencesAppendixAttachments


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 process parameters and their limits

Critical process parameters and limits must be identified


Demonstrate that critical product data meet the specifications (an experiment)


The process when operated within the process limits performs as intended



Demonstrate that critical product data consistently meetthe specifications

Demonstrate that critical product data meet the specifications (an experiment)


The process when operated within the process limits performs as intended

The process does perform consistently as intended


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


↓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)


↓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


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

↓


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


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)


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


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)


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


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


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


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


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


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


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


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(%)


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


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


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


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



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



As-is Data(CU Data)


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 (%)


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%


100

Max RSD = 4.8%


101

Acceptance Region: RSD = 4.8%

Acceptance Region

102

Acceptance Region


103

Max RSD = 5.4%


104

Max RSD = 5.4%


105

Max RSD = 5.4%


106

Acceptance Region


107

Acceptance Region


108

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

111

Acceptance Limits for Tablet CU Means: n = 30

process validation of solid dosage forms

Documents

process validation scheme

process validation rationaleto

reportpreapproved report

copiesvalidation final

single original copy

acceptance criteriato

keptone photocopy

solid dosage formsto