Process Validation - SDF - 1 - FDA PDF

Process Validation:
Solid Dosage Forms

Part I
by
Pramote Cholayudth
GPO, BIOLAB & VALITECH
Tel 0-1932-2374
Email: cpramote2000@yahoo.com
August 22, 2006 1
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 2
Scope of Presentation
Execute Collect &

protocols interpret data

Prepare summary
Write protocols
reports

Develop procedure Review & approve
& specifications reports

Define process & Change & Change

equipment Control 3
Validation Documentation
Requirements
4
Process Validation Protocol Outline
European Medicines Evaluation Agency
Protocol Outline PIC/S EMEA EU WHO

Objective
Scope
Rationale
Personnel Responsibilities
Process Description
Process Flow Chart
Equipment (Process/Lab)
Sampling Plan
Acceptance Criteria 5

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 6

Times Schedules
Batch Analytical Data
Protocol Acceptance Criteria
Supporting Data
Definition
Reference
Appendix
Attachment
7
Objective EMEA: Process Validation Scheme (Note

Scope for Guidance on Process Validation);
www.emea.eu.int/pdfs/human/qwp/084896en.pdf
Rationale
Process Description
Process Flow Chart Bold with
Responsibility Detailed
List of Equipment Used
Product Specifications and Analytical Methods
Define Critical Steps to Validate 8
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
Appendix One photocopy for one batch is
Attachments executed with some notes taken
9
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
10
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)
11
Master Validation Package
(Final Validation Package)
Validation Protocol Original Copy (Pre-
approved) 1 copy
Validation Report Original Copy (Pre-
approved) 1 copy
Validation Protocol Photocopies (Executed)
3 copies
Validation Report Photocopies (Approved) 3
copies
Validation Final Report (Approved) 1 copy 12
Protocol Requirements
13
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
14
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
15
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
16
Rationale Transfer
PV Rationale PV Protocol Rationale
Critical steps are validated Define critical steps to validate
Critical process parameters Define critical process
and limits must be identified parameters and their limits
The process when Demonstrate that critical
operated within the process product data meet the
limits performs as intended specifications (an experiment)
Demonstrate that critical
The process does perform
product data consistently meet
consistently as intended
the specifications
17
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
18
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. 19
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.
20
Process Flow Chart
Critical Process Parameter
CPPs Mfg Steps 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.
21
Process Flow Chart
Time,speed Pre-Mixing IPC Appearance

mix method (HS Mixer) PV Blend uniformity

Time,speed Wet Gran IPC Damp massing

torque (HS Mixer) PV Follow IPC

Mesh #, Wet IPC Gran sizes

type of m/c screening PV Follow IPC
22
Process Flow Chart
Temp, time Drying IPC LOD

batch size (Tray Oven) PV LOD (3 samples)

Screen size Milling (HS IPC Gran shape & size

feed rate Granulator) PV Follow IPC

Time,speed Blending IPC Appearance

(Dist, lub) (V-Blender) PV BU, flow., size dist
23
Process Flow Chart
Max hold Hold Time IPC N/A

time (Bulk Cont.) PV BU, flowability

Speed Tableting IPC Perform IPC

com force (Tab M/C) PV Assay, CU, DR

Sensitivity Metal IPC N/A

check Detection PV N/A (verify SOP)
QC sampling included 24
Process Flow Chart
IPC Appearance
Homo Coating Appearance,

speed, time Susp Prep PV viscosity, microbial
count

Coating par IPC Appearance
Coating
Gastric resistance,
Batch size (Coater) PV
DR, micro count
QC sampling included
25
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.
26
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.
27
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.
28
Equipment Used
Mfg Steps Equipment Brand/Model
Sieving HS Granulator PMS
Wet Granulation HS Mixer/Gran PMS/100 kg
Drying Drying Oven SSS/100 kg
Blending V-Shape Blender PMS/100 kg
Compression Tableting Machine NR/NRT 25
Metal Detection Metal Detector Lock
Homogenization Homogenizer Local
Film coating Film Coater PMS 29
Equipment Used
IPC Testing Equipment Brand/Model
LOD Moisture Balance MT/LP 16
Tablet Weights Top Load Balance MT/AX204
Tablet Hardness Hardness Tester Erweka/TBH20
Disint Time Disint Apparatus PT/PTZ3
Friability Friabilator PT/PTFR4
30
Specifications & Analytical Methods
Quality Attributes Limits Analyt Method

Appearance Specified Spec #
Identification Specified Spec #
Diameter Specified Spec #
Thickness Specified Spec #
Hardness Specified Spec #
Friability Specified Spec #
Loss on Drying Specified Spec #
Disintegration Time Specified Spec # 31
Specifications & Analytical Methods
Quality Attributes Limits Analyt Method

Assay Specified Spec #
Content Uniformity Specified Spec #
Dissolution Rate Specified Spec #
Gastric Resistance Test Specified Spec #
Degradation Product Specified Spec #
32
Same Source
Mfg Steps CPPs Impact on Quality
Active Particle Size Product dissolution
Ingredient Different lots Challenge study
Mesh # Breaking lump
RMs Sieving
Type of machine Foreign mat potential
Mixing time
Premixing Mixing speed
(before Wet Blend uniformity
Granulation) Mixing volume
Mixing method 33
Load size
Damp massing, API
Mixing Speed
distribution, torque
Granulation Time
Wet Binder Amount
Granulation Binder Conc. Damp massing,
Water Added torque
Feed Rate
Ampere meter End point indicator 34
Mesh # Granules size, ease
Wet Screening
Type of machine of drying
Drying temp. Loss on drying
Drying (Oven)
Drying time (LOD)
Screen size
Milling Size distribution &
Milling speed
(Fitzmill) shape Flowability
Feed rate
35
Blending time
Final Blending Blending volume Blend uniformity,
(without Mag size distribution,
Stearate) Blending speed flowability
Lub/Dist sieve #
Blending time Blend uniformity,
Final Blending Blending volume
size distribution,
(with Mag
Blending speed flowability,
Stearate)
Mag St sieve # dissolution
36
Hold Time of Maximum hold Blend segregation,
Final Blend time degradation product
Tableting speed Assay, content
Dwell time uniformity,
Hopper level dissolution, physical
Tableting & microbiological
Comp. force
Feeder speed properties of tablets
IPC adjustment IPC data
37
Metal Repeatability
Contamination of
Detection ( by tested (PQ)
metal pieces
Detector) Daily sensitivity
Coating susp Homo speed Appearance (x100),
homogenizatn Homo time viscosity, microbial
Coating Appearance (x10),
Film Coating parameters gastric resistance,
Load size DR, microbial count
38
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 39
Mfg Steps CPPs Process Limits
RMs Sieving Mesh # # 20
Premixing Mixing time 20 minutes
(before Wet Mixing speed 200 rpm
Granulation) Admixing method Geometric dilution
40
Load size 90 kgs
Mixing Speed 200 rpm
Gran Time 15 minutes
Wet Binder Amount 15 kgs
Granulation Binder Conc. 4% PVP
Water Added 2 kgs
Feed Rate 5 kgs/min
Ampere meter 25 amp 41
Wet Mesh # 4 mm
Screening Type of machine HS Gran
Drying Drying temp. 50-55C
(Oven) Drying time 15 hrs
Screen size 1.2 mm
Milling
Milling speed Medium
(Fitzmill)
Feed rate 5 kg/min
42
Final Blending time 30 min
Blending Blending volume 50-70%
(without Mag Blending speed 24 rpm
Stearate) Lub/Dist sieve # # 40
Final Blending time 3 min
Blending Blending volume 50-70%
(with Mag Blending speed 24 rpm
Stearate) Mag St sieve # # 40 43
Hold Time of
Maximum hold time 5 days max
Final Blend
Tableting speed 30K tab/hr
Hopper level 40-80%
Tableting
Comp. force 4K newton
Feeder speed 50 rpm
44
Repeatability tested
Metal (PQ) Must be performed
Detection
Daily sensitivity
Coating susp Homo speed 2800 rpm
preparation Homo time 10 min
Coating parameters See attached
Film Coating
Load size 100.- kgs
45
Attachment: Coating Parameters
46
Quality Attributes in Tablet
Specifications
Quality Attributes IPC QC Testing
Appearance
Identification
Diameter
Thickness
Hardness
Friability
Loss on Drying
Disintegration Time 47
Quality Attributes in Tablet
Specifications
Quality Attributes IPC QC Testing
Assay
Content Uniformity
Dissolution Rate
Gastric Resistance Test
Degradation Product
(Microbial Count)
48
Identification of CQAs for Tablets
Quality Attributes Impact on

(Final Blend, Tablets) Patient Product Process
Blend Uniformity CU
Guidance & Risk

Size Distribution
Analysis
% Compressibility
Loss on Drying
Max Hold Time
Appearance
Spec
Identification
49

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

(Film Coated Tablets) Patient Product Process
Dissolution Rate
Guide Spec & Guide

LOD Stability
Degradation Product
Maximum Hold Time
Microbial Count
51
Define CQAs to be Tested
Critical Quality Attributes Impact on

(CQAs) Patient Product Process
Blend Uniformity
Size Distribution
% Compressibility
Loss on Drying
Max Hold Time
52
Define CQAs to be Tested
Critical Quality Attributes Impact on

(CQAs) Patient Product Process
Assay/Dissolution (Cores)
Content Uniformity (Cores)
Dissolution Rate
Loss on Drying (LOD)
Degradation Product
Microbial Count
53
Sampling Plan & Acceptance Criteria
Tablets (& Capsules/Powders)
54
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
55
Pre-Mixing
Blend Uniformity see Blend Uniformity

Acceptance Criteria for Final Blending
56
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
57
Final Blending
Critical Quality Attributes (CQAs) are as follows:

Blend Uniformity
Size Distribution (Sieve Analysis)
% Compressibility
Loss on Drying (LOD)
Maximum Hold Time
58
Blend Uniformity:
Tablets/Capsules/Powders
Product Acceptance
Sampling Plan *
Parameters Criteria
Mean 10%
Blend (absolute) At least 10 samples
Uniformity @ 1-3x at 3 mixing
(BU) SD (n = 10) times
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
59
Target Potency (TP**)
Target (Theory) Composition % Target

Steps
Active(mg) Total(mg) (%) Potency
Pre-Mix 10 115 8.69 100% TP
8.53/8.69 =
Example 24.87 291.57 8.53
98.16% TP
Final
10 120 8.33 100% TP
Blend
8.23/8.33 =
Example 24.07 292.51 8.23
98.80% TP
60
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
61
Inherent Bias (Error)
Sampling bias segregation during sampling

Handling bias segregation during handling
Weighing bias segregation during weighing
62
V-Shape Blender
(www.ikev.org/haber/bozzone/may31.pdf)
63
Bin Blender
64
Establishing Blend Uniformity
Acceptance Criteria: Tablets/Capsules
Dose \ Conc. < 25% 25 < 50% 50%
< 25 mg 10 10 10
25 150 mg 10 6 6
> 150 mg 10 6 3
# 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) 65
Why Use 25 mg and 25%?
USP 28: Uniformity of Dosage Units

Dosage < 25 mg or < 25%
Forms 25 mg &
25% 25 mg & < 25 mg & < 25 mg &
< 25% 25% < 25%
Uncoated
WV Content Uniformity (CU)
Film Coat
Other Coat Content Uniformity (CU)
Hard Cap WV Content Uniformity (CU)
In USP 27 or earlier, 50 is used in place of 25 mg and %
66
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
67
Calculating SD Limit: Tab/Cap
2
S1 6
F0.9,n1 ,n2 = S=
2
S2 F0.9,9,n1
n = number of blend sample
68
Calculating SD Limit: Tab/Cap
SDPI = Standard Deviation Prediction Interval
6
SD =
F0.1,9,n1
69
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
70
Establishing Blend Uniformity
Acceptance Criteria: Powders
Acceptance Criteria (n = 10) Product
AC Limit Max. SD * Specifications
Mean 10% (abs) 4.2% 90 110% LA
Mean 10% (abs) 4.2% 85 120% LA
Mean 7% (abs) 3.0% 93 107% LA
Mean 5% (abs) 2.1% 95 105% LA
* 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 There is 95%
UPL = x + t 0.025,n1.s. 1 + confidence that future
n test results will fall
1 within mean 10%
x + 10 = x + 2.262.s. 1 + (absolute)
10
10 = 2.37.s SD 4.2 72
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 73
SD Limits for Powders
74
SD Limits for Powders
75
Comparison of SD Limits
76
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
77
Need for Pre-Blending
78
Scale-Up of Blending
79
Acceptance Criteria: Final Blend
(Other Parameters)
Critical Quality Acceptance
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
80
Establishing Bulk Uniformity
Acceptance Criteria: Universal
Acceptance Semi-
Tabs Caps Pdrs Liqs
Criteria (n=10) Solids
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%
81
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
82
BPR Mixing Time: 30 minutes

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
83
BPR Mixing Time: 28-32 minutes

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
84
Example to Demonstrate
80
Robustness & Optimization
70
Left shell
60
Right shell
%Relative Standard Deviation
Top
50 Middle
Bottom
40
Lower Extreme Normal Mixing Upper Extreme

Time (Optimized)
30
20
10
0
0 5 10 15 20 25 30 35 40 45 50
Time (min)
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
86
Tableting
Critical Quality Attributes (CQAs) are as follows:

Content Uniformity
Assay
Dissolution Rate
87
Thai FDA: Content Uniformity Test
1st Stage (Not Recommended)
Product Weight-
As-is Data
Parameters Corrected Data
RSD 6.0%
Content Uniformity All units 85
(CU) 115% LA Means 90
110% TA (1)
= Fall within, = Fall outside
(1) Location mean of 3s (TA = Target Amount)
Sampling Plan: 10 x 7s, Testing Plan: 10 x 3s

88
Thai FDA: Content Uniformity Test
2nd Stage (Not Recommended)
Product Weight-
As-is Data
Parameters Corrected 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
89
Establishing Content Uniformity Test
(Modified from US/Thai: 1st Stage; Recommended)
Product As-is Data Weight-Corrected

Parameters (CU Data) Data (BU Data)
NMT c units 85
Content Means 90
115% LA, all units
Uniformity (CU): 75 125% LA 110% TA
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)

NMT c units 85
Content Means 90
115% LA, all units
Uniformity (CU): 75 125% LA 110% TA
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
91
(Summary: Stage 1 & 2)

NMT c units 85
Means 90
Content 115% LA, all units
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
92
Weight Corrected (WC) Data
Target (Theory) Composition % Target

Steps
Active(mg) Total(mg) (%) Amount (TA)
Tablet 10 120 8.33 100% LA
CU As-is 10.1/10 =
Data 101% LA
10.1 119 8.49
CU WC 8.49/8.33 =
Data 101.92% TA
% Target Amount (% TA) = % Target Potency (% TP)
93
CU & WC CU Data in MS Excel
(Obtained from cpramote2000@yahoo.com)
94
Probability of Falling outside 85 115% LA
Prob of falling 85 115% LA (%)
Stage
Products n
# 0 unit 1 unit 2 units 3 units
1 30 54.5 33.4
Tablets
2 70 24.3 34.7
1 30 54.5 33.4 9.9 1.9
Capsule
2 70 24.3 34.7 24.5 11.3
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
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 acceptable
This is provided that IPC for tableting process is
properly carried out
96
PDA Technical Report # 25: Blend
Uniformity Analysis: Validation and In-
Process Testing, October 1997
To be purchased
from www.pda.org
97
Establishing CU RSD Acceptance Limit
Max RSD = 4.8%
98
Max RSD = 4.8%
99
Max RSD = 4.8%
100
Acceptance Region: RSD = 4.8%
Acceptance
Region
101
Acceptance
Region
102
Max RSD = 5.4%
103
Max RSD = 5.4%
104
Max RSD = 5.4%
105
Acceptance
Region
106
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

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Process Validation:

Solid Dosage Forms

To review the Process Validation Rationale

Protocol Outline PIC/S EMEA EU WHO

Protocol Outline PIC/S EMEA EU WHO

Protocol Outline PIC/S EMEA EU WHO

Objective EMEA: Process Validation Scheme (Note

Define CPPs to be Monitored

Objective One Batch One Report

Objective Three Batches One Report

To validate the manufacturing process of

This protocol is applied to ProMed Tablets 2

Critical steps are validated

Critical steps are defined and validated

Components of wet mass are dry-mixed in High

Disintegrant and lubricant are sieved through 0.5

Several possible methods of organizing validation are

Validation Coordinator is responsible for (1) providing

Quality Control (QC) is responsible for performing the

Quality Attributes Limits Analyt Method

Quality Attributes Limits Analyt Method

Each critical step of the manufacturing process

Quality Attributes Impact on

Guidance & Risk

Quality Attributes Impact on

Quality Attributes Impact on

Guide Spec & Guide

Critical Quality Attributes Impact on

Critical Quality Attributes Impact on

Tablets (& Capsules/Powders)

Blend Uniformity see Blend Uniformity

Loss on Drying (LOD): The Acceptance Criterion

Critical Quality Attributes (CQAs) are as follows:

Target (Theory) Composition % Target

Eliminate handling and weighing

Sampling bias segregation during sampling

USP 28: Uniformity of Dosage Units

The SD limit will ensure with 90% confidence

SDPI = Standard Deviation Prediction Interval

Blend Uniformity data i.e. blend sample mean

Prediction Interval (PI) comprises

LSL LPL UPL USL

LSL & USL = Lower & Upper Specification Limits

Additive contents e.g. preservative, wetting

Blend Sampled at Lot # 1 Lot # 2 Lot # 3

Blend Sampled at Lot # 1 Lot # 2 Lot # 3

Blend Sampled at Lot # 1 Lot # 2 Lot # 3

Lower Extreme Normal Mixing Upper Extreme

Bulk of final blend is stored (in containers lined

Critical Quality Attributes (CQAs) are as follows:

Sampling Plan: 10 x 7s, Testing Plan: 10 x 3s

Product As-is Data Weight-Corrected

Product As-is Data Weight-Corrected

Product As-is Data Weight-Corrected

Target (Theory) Composition % Target

Prob of falling 85 115% LA (%)

While a batch failing the criterion for blend

Max RSD = 4.8%

Max RSD = 4.8%

Max RSD = 4.8%

Max RSD = 5.4%

Max RSD = 5.4%