Supplementary Training Workshop on Good
Manufacturing Practices (GMP)
MANUFACTURING
PROCESS VALIDATION
Solid Dosage Forms
János Pogány, pharmacist, PhD,
consultant to WHO
Pretoria, South Africa, 28 June 2005
E-mail: pogany@t-online.hu
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WHO GMP and related guides
 WHO good manufacturing practices (GMP):
main principles for pharmaceutical products

Section 4. Qualification and validation
 Supplementary guidelines on good
manufacturing practices (GMP): Validation
(2003) – Draft.
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WHO GMP and related guides
 WHO good manufacturing practices: main principles
for pharmaceutical products – Validation of
manufacturing processes

Good manufacturing practices for pharmaceutical
products. In: WHO Expert Committee on Specifications
for Pharmaceutical Preparations. Thirty-second report.
Geneva, World Health Organization, 1992:14–79 (WHO
Technical Report Series, No. 823).
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ICH guidelines
 PHARMACEUTICAL DEVELOPMENT, Q8,
Draft ICH Consensus Guideline, Released for
Consultation on 18 November 2004, at Step 2 of
the ICH Process
 QUALITY RISK MANAGEMENT, Q9, Draft
ICH Consensus Guideline, Released for
Consultation on 22 March 2005, at Step 2 of the
ICH Process
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PROSPECTIVE
VALIDATION
Pharmaceutical Development
Laboratory scale R + D
Physicochemical and physical
properties of API
Physicochemical
Physical

hygroscopicity
 particle size

solubility
 bulk density (g/100ml)

water content
 flowability

polymorphism
 color, olor, taste

permeability
 consistency
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Equilibrium Moisture Content
At relative humidities (RHs)
<100%, a solid API (that does not
form crystalline compounds with
water) will loose some bound and
all its unbound water until it is in
equilibrium with the surrounding
atmosphere. The sum of both these
moistures is the free moisture of the
API (granules) at the specified RH.
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Rate of Water Absorption at Different RHs
0,45
Lg RH, %
0,40
35%
0,35
55%
75%
0,30
100%
0,25
28
25
22
19
16
13
10
7
4
1
0,20
Lg time, t (3 min. units)
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Solubility of Zidovudine at 25oC
pH
Dissolved material (mg/ml)
3.0
21
4.0
20
5.3
20
6.0
21
7.0
22
Distilled water
20
8.0
21
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Solubility of Artesunate
2005.06.28.
pH
Dissolved API (mg/ml)
1
1,9
5
1,5
6
3,5
7
10,2
8
12,2
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Decomposition of Artesunate
in aqueous solution
Solvent
Water
2
Decomposition
(%)
0
0.1N HCl
2
74
0.1N NaOH
2
100
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Time (h)
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Relationship between Permeability
Coefficient and Octanol-Water Partition
1 Prednisolone
...
3 Dexamethazone
...
9 Dexamethazone-acetate
...
11 Progesterone
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NORVIR (Ritonavir) EPAR/CPMP /527/96
1.
2.
3.
4.
5.
No polymorphism observed at the time of first
submission (only form I : hard capsules and oral
solution registered)
Failure in dissolution during stability studies for hard
capsules
Emergence of form II (contamination of form I)
Production of hard capsules discontinued
Development and registration of soft capsules
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Particle Size
When the solubility of an API is less than 0.1
mg/ml, the optimization of the particle size during
preformulation may be critical to efficacy or
pharmaceutical equivalence. Other researchers
believe that particle size may be critical at a
solubility of 1 mg/ml or less.
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Effect of Particle Size on Dissolution of
Nevirapine tablets
% Drug Dissolved
USP Type II / 0.01N HCl 50 RPM / 900 ml
120
100
80
60
40
20
0
Time (Min)
Nevipan MGS(1024)05 (90%LT81.12)
Nevipan MGS(1024)60B (90%LT30.89)
Viramune 992633B
2005.06.28.
0
0.00
0.00
0.00
10
50.80
80.00
83.30
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20
73.80
92.00
96.60
30
83.98
96.00
97.70
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Screening of Compositions
 Compatibility of an API with the excipients and
the APIs with each other in FDCs is studied in
open system stress stability experiments, e.g., 6080 oC, 100% RH.
 Regulatory stability studies of the final
composition are frequently initiated in the
pharmaceutical R + D laboratory.
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Compatibility of Acetylsalicylic Acid with
Excipients
Time (week)
Talc A
Salicylic acid, %
Talc B
Salicylic acid, %
0
0.10
0.10
4
0.32
5.85
8
0.41
13.00
12
0.80
28.50
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Triomune - WHOPAR
Experimental „studies showed chemical incompatibility for the
lamivudine with stavudine and nevirapine with stavudine
combination. Lamivudine with nevirapine showed no change
indicating that they are compatible. Stavudine was found
incompatible with both the drugs, indicated by the brown
colouration and increase in the impurities.
Therefore it was decided to separate stavudine from the other two
drugs. Hence the formulation was proposed to be bilayered tablet
formulation, where stavudine is in one layer and lamivudine +
nevirapine in other layer. Thus contact of stavudine with the other
two drugs was minimised.”
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Dissolution Test and Profile
 A (discriminating) dissolution test method should
be developed for the final composition of the FPP.
 Limits should be set for each API in fixed-dose
FPPs.
 The dissolution method should be incorporated into
the stability and quality control programs.
 Multipoint dissolution profiles of both the test and
the reference FPPs should be compared.
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Dissolution Profile of Viramune and Generic
Nevirapine Tablets on the Indian Market
% Drug Dissolved
USP Type II / 0.01N HCl 50 RPM / 900 ml
120
100
80
60
40
20
0
Time (Min)
Viramune B.No.992633B
Brand C B.No.C00139
Ranbaxy B.No.(1024)17
2005.06.28.
0
0.0
0.0
0.0
10
83.3
34.3
88.9
20
96.6
51.3
97.6
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30
97.7
61.2
99.2
45
99.7
70.8
99.7
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F2
20
73
% dissolved
Hypothetical Dissolution Profile of a
2-FDC FPP
120
100
80
60
40
20
0
Series1
Series2
Series3
Series4
0
15
30
45
60
minutes
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Pivotal Batches
A tabulated summary of the compositions of the clinical,
bioequivalence, stability and validation FPP batches
together with documentation (batch number, batch size,
manufacturing date and certificate of analysis at batch
release) and a presentation of dissolution profiles must be
provided.
Results from comparative in vitro studies (e.g.,
dissolution) or comparative in vivo studies (e.g.,
bioequivalence) should be discussed when appropriate.
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Excipients – Lactose (L)
Different grade, different physical properties:
 Angle of repose: 32- 47o (Specs.)
 Bulk density: 0.34 – 0.80 g/cm3 (Specs.)
 Bulk density (tapped): 0.41 – 0.95 g/cm3
 Flowability (spray processed): 4.1 g/s (Specs.)

Hygroscopicity: L monohydrate is stable in air at room
temperature. Anhydrous L may absorb humidity.

Moisture content: L monohydrate contains approx. 5%
w/w water of crystallization
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Excipients – Lactose (L)
Solubility in water





1 in 4.63 at 25 oC
1 in 3.14 at 40 oC
1 in 2.04 at 50 oC
1 in 1.68 at 60 oC
1 in 1.07 at 80 oC
Particle size distribution: depends on grade.
Stability: may develop brown colouration (≥ 80% RH)
Incompatibility: APIs with a primary amine group (base
catalysed), aminophylline and amphetamines.
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Surface of a film-coated tablets containing
a high level of a superdisintegrant
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Packaging Materials
 Moisture-impermeable containers: glass ampoules,
vials closed with rubber stoppers and fixed with metal
caps, aluminium/aluminium blisters, high density
polyethylene (HDPE) or glass bottles fitted with metal
metal or HDPE closures, etc.
 Moisture-permeable containers: polyvinyl chloride
(PVC) blisters, low density polyethylene (LDPE)
bottles, HDPE bottles fitted with polypropylene
closures.
 Specifications of packaging materials should include
thickness and permeability coefficient.
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CONCURRENT
VALIDATION
Commitment Batches
Technical pharmacy
 Pharmaceutical production system
(from purchasing API to packaging FP)
 Utility support system (HVAC, water, HPLC, etc.
equipment containing many items)
 Process (tablet making)
 (Unit) operation (granulation, compression)
 Step (sifting, sizing)
 Procedure, method, technique (SOP)
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Causes of variation
 Man (different operators - lack of proper training)
 Machine / equipment (variation of tablet weight)
 Measurement (lack of calibration)
 Method (validated manufacturing methods)
 Material (batch-to-batch variation of the same crystal
form – different crystal forms (ASA)]
 Environment (OoS T and RH in capsule filling)
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4.10 Scientific approach
 „Processes and procedures should be established on the basis
of the results of the validation performed.”
Objectives
 To prove that the tests, measurements, results and
interpretation of formal studies on (manufacturing) processes
and procedures/methods are appropriate and accurate.
 To stabilize new processes (to reduce variability, to increase
batch to batch consistency of quality attributes of products).
 To reduce defect levels (standardize yields).
 To reduce production costs.
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Process approach
CONTINUOUS IMPROVEMENT OF THE QUALITY MANAGEMENT SYSTEM
C
U
S
T
O
M
E
R
S
A
T
I
S
F
A
C
T
I
O
N
Management
responsibility
R
E
Q
U
I
R
E
M
E
N
T
S
Resource
management
Inputs
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Monitoring,
improvement
Manufacture
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Product
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C
U
S
T
O
M
E
R
Measure of variation (spread of data)
68.26%
95.46%
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Mean (average) chart
Abnormal variation of process – special causes
UCL
Upper control limit
average = mean
LCL
Normal
variation
due to
common
causes
Lower control limit
Abnormal variation of process – special causes
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Process capability index, Cp
acceptance limits
Cp =
process capability
Three sigma: Cp =
Six sigma: Cp =
6σ*
6σ*
12σ*
6σ*
UCL - LCL
=
6σ*
=1
=2
σ* ... is the measured standard deviation of the process
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Process capability index, Cpk
UCL - x
Cpk =
3σn
UCL ... upper control limit
x ... mean of the acceptance criteria, target value
σn ... is 50% of the measured standard deviation of the process
Cpk shows the closeness of the process mean to the target value.
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Output of processes for different
Cpk indices
nσn = 3σ
UCL
Cpk
1σ1
m + σ1
-0.166
No. of products
OoS (ppm)
691 464
2σ2
m + 2σ2
0.166
308 536
3σ3
m + 3σ 3
0.5
66 807
4σ4
m + 4σ4
0.833
6 210
5σ5
m + 5σ5
1.166
233
6σ6
m + 6σ6
1.5
3.4
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Objective and result of process control
UCL 1.The process reveals
serious risks and it
N
is not controlled
LCL 2.The process is not
UCL
N
yet controlled but
acceptance criteria
are met
LCL 3.The process is
under control and
UCL
the product has a
N
consistently high
quality
LCL
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Process under control
 Most points fall near the central line (68% within
one σ)
 A few points fall near the control limits (5% in the
third σ)
 Points shold balance on both sides of the mean
 Points should cross the mean line often.
 Points should show a random pattern (no trends,
cycles, clustering)
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4.8-4.9 Protocols and reports
 Validation studies are an essential part of GMP
and should be conducted in accordance with
predefined and approved protocols.
 A written report summarizing the results recorded
and the conclusions reached should be prepared
and stored.
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Process validation protocol/report
 Short description of the process with a summary of the
critical processing steps or critical parameters to be
monitored during validation.
 Additional testing intended to be carried out (e.g. with
proposed acceptance criteria and analytical validation as
appropriate).
 Sampling plan — where, when, how and how many
samples are taken.
 Details of methods for recording and evaluation of results.
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Illustrative variables of wet granulation
Process step
Crystallization
Micronization
Pre-mixing
Wet kneading
2005.06.28.
Control or manipulate
(independent) variables
Particle size
Bulk density
Speed, time, order of
addition
Batch (load) size
Speed
 Impeller
 Chopper
Spraying rate
Volume of binder solution
Granulation time
Measured responses or
output (dependent) variables
Dissolution time
Granulation and granule
variables
Blend uniformity
End-point amperage
 Impeller
 Chopper
Additional solvent volume
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Illustrative variables of wet granulation
Process step
Drying
Sizing
Blending
Control or manipulate
(independent) variables
Inlet air temperature (seasonal
variation)
Drying time (seasonal variation)
Cooling time (if applicable)
Screen type and size
Feed rate
Batch size (sub-batches)
Speed
Blending time
2005.06.28.
Measured responses or output
(dependent) variables
Outlet air temperature
LOD
Moisture content
Granule size distribution
(variation of sub-batches)
Blend uniformity
Bulk density
 untapped
 tapped
Flowability
Yield
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Indentation hardness profiles for tablets
of different shape
Flat
 Shallow convex
 Standard convex
 Deep convex
 Ball-shaped

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Areas most prone to surface erosion for flat, shallow
convex, caplet-shaped and deep convex tablets
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Erosion on the surface of the tablet with
a logo
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Twinning during the coating process for
flat-faced and caplet shaped tablets
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Measurement points of film
thickness across the tablet surfaces
FACE
EDGE
SIDE
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Illustrative variables of compression and
film-coating
Process step
Control or manipulate
(independent) variables
Compression Machine speed
Granule feed rate
Precompression force
Compression force
Punches and dies
Film-coating Inlet air temperature
Inlet air flow
Spray rate
Spray atomizing pressure
2005.06.28.
Measured responses or output
(dependent) variables
Weight variation
Content uniformity
Friability
Hardness
Thickness
Disintegration
Dissolution time and profile
Yield
Outlet air temperature
Tablet-bed temperature
Coat quality
Yield
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Illustrative variables of tablet packaging
Process step
Blistering
Bulk
packing
Control or manipulate
(independent) variables
Machine speed
Machinability of blister material
Forming temperature
Forming pressure
Sealing temperature
Sealing pressure
Tablet counter
Incomplete tablets
Machine speed
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Measured responses or output
(dependent) variables
Leak testing
Appearance
Minimum information is
legible
Yield
Number of tablets
Detection, counting
Pilfer-proof
Labeling
Yield
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4.10 Scientific approach
 Processes and procedures should be established
on the basis of the results of the validation
performed.
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Commitment (validation) batches
 Process validation reports should be submitted in the
application for prequalification.
 Formal studies of production scale batches (not less
than three) are required to identify the critical
variables.
 Provisional equipment control parameters and the
corresponding in-process acceptance criteria must be
deduced from the results of experiments with the
validation batches.
 Critical parameters are to be monitored, non-critical
ones should be tested occasionally.
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RETROSPECTIVE
VALIDATION
Annual Product Review
Annual FPP quality review (1)
 Starting materials used in the product, especially those
from new sources.
 Critical in-process controls and finished product results.
 All batches that failed to meet established specification(s).
 All critical deviations or non-conformances and related
investigations.
 All changes carried out to the processes or analytical
methods.
 Marketing Authorisation variations submitted, or granted,
or refused, including those for third country dossiers.
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Annual FPP quality review (2)
 Results of the stability monitoring programme.
 All quality-related returns, complaints and recalls,
including export only medicinal products.
 Adequacy of previous corrective actions.
 For new marketing authorisations, a review of postmarketing commitments.
 A list of validated procedures and their revalidation
dates.
 A list of qualified equipment, support utility systems
and their requalification dates, including calibration
programmes.
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Case summary of 20 batches (1)
Statistics
Mean
Median
SD
Range
Minimum
Maximum
Conf. level, 95%
Accept. Crit.
2005.06.28.
Av. wt. mg
Dissolution %
Assay %
347,6
346,9
5,2
22.3
337.0
359.3
2.4
99,6
100,0
2.5
10.0
95.6
105.6
1.3
98,2
95.0
103.8
1.0
350±5%
75%, 40'
90-110
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97,5
2.2
8.8
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Case summary of 20 batches (2)
1. Acceptance criteria for assay and dissolution
rate are loose and should be tightened.
2. Potentially critical impurities are not tested.
3. IPC data are not included in the retrospective
analysis of batch records.
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BEST PROCESS
MINIMUM REQUIRED INPUT
MAXIMUM OUTPUT
AT NO COST TO SOCIETY (industrial safety,
labour safety, internal and external environment
protection)
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COSTS OF QUALITY
Visible costs, e.g., waste and
returned goods
Hidden costs, e.g., wrong
decisions, non-competitive
manufacturing process,
low yield, maintenance, idle
machine time, workers attitude,
etc.
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Main points again
 Manufacturing methods are the same in the
innovative and generic industries.
 Pharmaceutical development is a major source of
early identification of critical product and process
parameters.
 Validation batches should be tested extensively to
establish preliminary/tentative IPC parameters.
 Annual product review results in continuous
improvement of products and processes.
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