General aspects Validation of parenterals Validation of tablets component of validation,function of different departments,reasons for validation,shivajirao s jondhle college of pharmacy asangaon,validation of parenterals,validation of tablets,validation priority,vilegave kailash

1. PRESENTED BY…….
Mr. Kailash Vilegave
Department Of Pharmaceutics
Shivajirao S .Jondhle college of
pharmacy Asangaon 421601
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2. Contents
 Introduction
 General aspects
 Validation of parenterals
 Validation of tablets
 References
2

3. DEFINITION
 Validation is attaining & documentation of sufficient
evidence to give reasonable assurance, stating that
equipment or process does & will do what it purports to
do.
According to US FDA
 “validation is establishing documented evidence which
provides a higher degree of assurance that a specific
process , equipment or facility meets its pre determined
specifications & quality characteristics & will consistently
produce a product of standard quality”
3

4. Objective :to manufacture product of requisite
quality with low cost
 Govt regulation
 Assurance of quality
 Cost reduction
4

5. WHEN VALIDATION BEGINS
 Validation should begin in the designing stage for new
facility & pre formulation stage for a new dosage form.
WHO DOES
 In order to have a valid & qualified system it must be
designed by qualified individuals only.
 As it is complex process, it is performed by individuals
with necessary training & experience & who are
themselves previously qualified.
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6. Validation team
Q.A
ENGINERING Q.C
TASK FORCE
LEADER
MAINTENANCE R&D
MFG
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7. Install, qualify & certify plant facility,
Engineering equipment &support systems.
Design, optimize, qualify
R&D manufacturing process with limits &
specifications.
Operate & maintain plant facilities,
Manufacturing equipments ,support systems, process
and strictly follow SOP.
Follow the validation protocol develop
Q.C by Q.A & validate the incoming stock
,in process critical system &final
product.
Establish approvable validation
Q.A protocols &conduct process validation
by monitoring ,sampling ,challenging
the process & equipment.
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8. 1. Large volume parenteral.
2. Small volume parenteral.
3. Ophthalmic, other sterile products & medical devices.
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9.  Analytical test procedures
 Instrument calibration
 Critical support system
 Operators
 Raw materials
 Packaging materials
 Equipment
validation
 Facilities
 Manufacturing process
 Product design
 Utilities & services
 Records & reports
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10. 1. Prospective validation.
2. Retrospective validation.
3. Concurrent validation.
4. revalidation.
Prospective validation
This is validation program executed before
commercialization of a new drug/ formulation,
to make sure that there are no potential
hazards in full scale manufacture of product.
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11.  It is a program chosen for established products whose
manufacturing process are considered stable (i.e. long
history of state control operation).
 This method involves statistical analysis of numerical
data obtained from different batches & then justify
whether the system is qualified or not.
 The data includes
a) MFR,BFR.
b) b) assay values.
c) End product test results.
d) In process data.
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12. Different parameters checked in parenteral.
 pH value.
 Viscosity.
 Density.
 Color & clarity.
 Potency.
 Sterilization parameters.
Different statistical methods are
 Basic statistics (mean , standard deviation, tolerance limit ) .
 Analysis of variance (ANOVA) .
 Regression analysis.
 Cumulative sum analysis.
 Control charting – most advance & useful.
12

13.  This method includes in process monitoring of critical process
steps & end product testing of current production along with
documentation .
 This shows that the manufacturing is in state of control
 The same parameter of retrospective validation are evaluated with
more stress on critical parameters affecting the process .
Revalidation
 This method involves validation of facility which is previously
validated when
1 Change in critical component .
2 Change in critical piece of equipment.
3 Change in facility / plant (design / location ).
4 Significant increased / decease in batch size.
5 Sequential batches fail to meet product / process specifications
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14.  Design & validation of facility
There are four basic steps in validation of
facility
1. Planning
2. Documentation
3. Construction
4. Testing
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15. 1. Planning
 Site selection
 Design staff
 Material flow path
 Room layout
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16. Material flow path
Receiving stores
Component preparation
Aseptic filling
capping
inspection
labeling
quarantine
Release shipping
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17.  Typical room layout:
Salient feature
Double door with interlock system
Positive pressure in sterile area.
Separate entry for material &personal.
Clean room or class-100 room in the filling area.
Entry is done only after gowning
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18. 3. Construction
 Steps involved are:
1. Ground
2. Shell
3. Rooms
4. sewers
5. Ductwork
6. Landscaping
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19.  Its done for
1. Sensitivity
2. Accuracy
3. precision
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20. Air system
Validation is performed mainly in four phases
1. Pre construction phase - - design &engineer air system
2. Construction phase - - all steps of planning are in
place
3. Post Construction phase - - rest phase
4. Post Construction phase - -same test are performed
with machines
HVAC system
Purpose-To provide a specific set of environmental
conditions required for manufacturing process.
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21. HVAC
AIR FILTRATION CONTROL SYSTEM
AIR HANDLING AIR DISTRIBUTION
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22.  Class-100 room: particle count limit 100/cubic foot of 0.5 µm
or larger in size.
 Class- 10,000 room : particle count limit 10,0000/cubic foot
of 0.5 µm or larger in size
Area Absolute Intermediate Pre-filter
preparation optional recommended recommended
washing optional recommended recommended
filling required optional recommended
packaging not required not recommended
recommended
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23.  Hepa filter leak test .
 Temperature control test.
 Humidity control test.
 Air flow uniformity test.
 Pressure control test.
 Particle count test.
 Induction leak test.
 Airborne microbial sampling.
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24.  Different classes of water
CLASS MINERAL MICROBE T.M.REM PYROGE QUALITY
S OVAL N
WELL + + - + I
WATER
POTABLE + CONTRO - + II
L
PURIFIE - CONTRO - + III
D L
W.F.RINS - CONTRO + NIL IV
E L
W.F.I - NIL + NIL V
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25. SAMPLE POINT TEST FREQUENCY
RAW WATER MICROBIAL, cl DAILY
RESIDUAL, TDS,PH
FILTERS MICROBIAL, cl DAILY
RESIDUAL
DISTILLATION /R.O MICROBIAL ,pH CONTINUOUS
EQUIPEMENT
STORAGE TANK MICROBIAL, p H, MULTIPLE TIME IN
PYROGEN, CYCLE
CHEMICALS USP.
DISTRIBUTION MICROBIAL DAIILY
/USAGE POINT PYROGEN , pH
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26. 1.VALIDATION OF GASES : nitrogen, carbon
dioxide, compressed air.
VALIDATION OF GASES INCLUDES 3 STEPS
 Supply of gas (adequate purity & quality)
 Storage conditions
 Distribution network
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27. 2. Validation of steam system
validation of steam generator
 Efficiency.
 Pressure.
 Analysis of condensate.
 Distribution network.
3. Validation of electrical system
main objective is to meet :
 Qualitative specifications. (frequency, voltage,
stability ).
 Quantitative specifications ( load demand).
 Back up system are validated .
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28. VALIDATION OF FILLING
Parenterals are checked for
1. Fill volume
2. Syringe able volume
3. Sterile filling
Monitoring of viable &non viable particles:
 Particle counter
 Strip test
 Reuter centrifugal sample (RCS)
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29.  D-value: time required to reduce the microbial content by
90%i.e.one logarithmic reduction
 F-value: time required to destroyed all spores of suspension when
using a suspension at 121 c
 Z-value: the no of degree required for 1 log reduction in D-value
 N0 –value: No of living organism / defined unit of surface
 Log reduction value: ability of filter in terms of log reduction of
microbial population.
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30.  Biological indicator
 E.g. for steam sterilization-Bacillus stearothermophillus
for dry heat sterilization- Bacillus subtilis var. niger
for ethylene oxide- Bacillus subtilis var. globigli
for ionizing radiation- bacillus pumilis
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31.  Operation condition are 121ºc, 15Psig, for
20 min
1. Qualification & calibration:
Checking, upgrading the unit
2. Selection & calibration of thermocouples
3. Selection & calibration of B.I
4. Heat distribution studies
1. cool spot is find out
2. temp dif should not be more than + 2.5ºc
5. Heat penetration studies
By container mapping studies- in which
thermocouples are introduced at different heights in
the container.
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32.  Its done for
Batch oven & tunnel oven
validation mainly includes
1. Qualification & calibration
2. Selection & calibration of thermocouples
3. Selection & calibration of B.I
4. Air balance determination
5. Heat distribution studies
1. cool spot is find out
2. temp dif should not be more than + 2.5ºc
6. Heat penetration studies
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33. Validation of radiation sterilization
 Major source are cobalt 60, ceasium136 .
 Determine D-values using biological indicator.
 First calculation of dose based on bio –burden.
 Calibration of equipment so that same amount of
radiation is released every time.
 Normal dose for over kill approach is 2.5 Mrad.
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34.  Sources for contamination are
 Skin &hair fragments.
 Droplets from mucous membrane.
 Material deposition due to personal.
 Fibers released from person &equipment.
 Packaging material.
so to maintain aseptic conditions we need something
other thsn hepa filters i.e. SANITIZER
Def- it is defined as a chemical agent that kills microbial
contamination in the vegetative form only.
E.g.; Hypochlorite , phenol ,surfactant etc.
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35.  Membrane filters are cartridges & plates
Physical integrity of filter media is checked by
1. Bubble point test.
2. Bacterial challenge test.
3. Flow rate.
4. Longevity of filter.
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36.  a) INTEGRITY OF RUBBER :
1. Quality
2. Penetratability
3. Fragmentation
4. Water extractive
5. Self-seal ability
 b) INTEGRITY OF GLASS :
There are mainly 4 types of glass
 TYPE I (borosilicate glass ). For (parenterals)
 TYPE II ( treated soda lime glass). (for dry powders)
 TYPE III (soda lime glass).
 TYPE IV (non parenteral glass)
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37. 1. Chemical composition
2. Leaching
3. Powder glass test
4. Water attack test
 C) Leaking tests:
There are mainly two types of leak test:
1. Vacuum dye leak test.
2. Autoclave dye test.
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38.  Validationis a systematic approach to
identifying, measuring, evaluating
,documenting,& reevaluating a series of critical
steps in manufacturing process that require
control to ensure are producible final product.
38

39.  Key elements that form the basis of a
prospective process validation program
1.Definition of the desirable attributes of drug product or
components thereof as well as those characteristics that
are not desired
2. Establishment of limitation or constraints for these
attributes
3. Determination of the controls or testing parameters that
will be measured or tested.
4. Initiation of studies to establish control or boundary limits
for those attributes that influence the product, process
,quality & performance.
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40. It includes validation of both active ingredients& excipients.
Characteristics
particle size, surface area, color, density.
Chemical characteristics- water content residue on ignition &
heavy metals.
Variables:
Flow, blend uniformity, granulation solution/binder uptake
compressibility ,lubricant efficiency
eg;1) Mg sterate (lubricant). Its action depends on particle
size.
2) dyes (color)
variation in material occur depending up on ….
a) Method of transportation chosen,
b) Exposure of material to undesirable conditions (heat and
humidity)
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41.  Steps involved in validation of raw
materials
1. Each raw material should be validated by performing checks
on several batches, preferably 3,from the primary supplier as
well as the alternate supplier .the batches chosen should be
selected to represent the range of acceptable specifications
both high and low
2. Depending on susceptibility of the raw material to ageing
,either physical , chemical or microbial stability assessed .
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42.  Once the samples of raw materials have been selected it should
be used to manufacture a batch of final dosage form it may be
appropriate to manufacture to several lots of final product with
raw material at the low &high ends of the specifications limit .
 The final step of raw material should involve an on –site
inspection of the supplier to review the vendors manufacturing
operations and control procedures
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43.  Analytical criteria must be assessed ……….
1. Accuracy of method
2. Precision of method
3. In –day /out –of-day variation
4. Operator variation.
5. Instrument variation
6. Laboratory variation
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44.  process validation can be defined as means of challenging a
process during development to determine which variables must
be controlled to ensure consistent production of a product or
intermediate.
 Steps in development of validation program :
1. Obtaining test data to determine the numerical range of each
parameter
E.g.: assess the tablet hardness over a series of batches .
2. Establishing specification limits from the test data derived for a
given parameter.
3. Determining how well the specification limit indicates that the
process is under control
4. Certify the equipment operating conditions
Eg: rpm , temp, are within specification limits.
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45.  General tests in process validation are
1. Moisture content
2. Content uniformity
3. Hardness
4. Disintegration & dissolution
5. Friability
6. Weight variation
7. Granulation particle size distribution
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46. A. Tablet composition:
Normal properties
Density
Particle size distribution
Surface area
Flow properties
Moisture content
solubility
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47. B. Process evaluation & selection:
Blending operation
Determine time of un mixing
Characteristics of blend
 bulk density
 Particle size distribution
Color uniformity
C. Wet granulation
1.Evaluation of binder
 Binder concentration
 Solubility in granulating solution
2.Evalution of mixed granulation
3.Evalution of drying
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48. 4. Tablet compression
 Appearance
 Color quality
 Power flow
 Speed of tablet machine
5.Tablet coating
 Evaluate coating procedure in different size pans
 Coating speed
 Amount of material required / application
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49. D. Equipment evaluation
 Blending equipment
 Granulating equipment
 Tablet equipment
 Tablet coating.
49

50. References
Pharmaceutical dosage forms: parenterals medications vol III LACHMAN
LEBERMANN
PHARMACEUTICAL PROCESS VALIDATION BERRY & NASH
Validation of aseptic pharmaceutical process J.P.AGALLOCCO
CARLETON
WWW.GOOGLE.CO.IN.
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