PROCESS VALIDATION- AMPOULES, VIALS, ORAL PREPARATION.

1. PROCESS
VALIDATION
PRESENTED BY- SALMAN LATIF
ROLL NO.-27
M. PHARM
DR. D.Y.PATIL COLLGE OF PHARMACY
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2. CONTENTS
 DEFINITION
 IMPORTANCE
 AMPOULES/VIAL VALIDATION
i. WASHING
ii. FILLING
iii. SEALING
iv. STERILIZATION
v. INSPECTION
vi. PACKAGING
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3. VALIDATION OF OINTMENT & CREAM
i. SAMPLING
ii. TESTING
iii. MOITORING
VALIDATION OF LIQUID ORALS
i. CLASSIFICATION
ii. TESTING
iii. SAMPLING
 VALIDATION REPORT
 REFERENCE
3

4. DEFINITION
› Process validation is establishing document evidence
which provide a high degree of assurance that are
specific process will consistently produce a product
meeting its predetermined specification and quality
characteristics.
› The concept was first proposed by Food and Drug
Administration(FDA) in 1970 in order to improve
quality of pharmaceuticals.
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5. › The definition can be simplified and explained by
three main points:
› Documented evidence
› Assurance
› Consistent Quality
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6. 6

7. IMPORTANCE:
› Assurance of Quality
› Process Optimization
› Safety
› Reduction of Cost
› Compliance
› Time Bound
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8. PROCESS
JUSTIFICATION
› To identify Critical Quality Attributes(CQA)and
Critical Process Parameters(CPP).
› To confirm that overall ampoule/vial filling process
consistently produces the quality finished products.
› To assure that product is sterile after sterilization
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9. VALIDATION
REQUIREMENTS
› Calibration of Equipments
› Cleaning Validation
› Equipment Qualification
› Raw Material Testing Methods
› Change Control
› Training of Operators
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10. PROTOCOL› The protocol should include the critical specifications and operating
› parameters that were identified, such as the following:
› a. Purpose of validation
› b. Operation being validated
› c. Major equipment involved
› d. Components used
› e. Parameters and ranges
› f. Sampling and testing
› g. Acceptance/rejection criteria
› h. Deviations and corrections
› i. Review and approval
› j. Actions to be taken by failure
› k. Responsible personnel and their function
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11. AMPOULES
› The primary packaging material for injectibles is the
ampoules.
› Ampoules may be clear or amber, manufactured
with type I glass, type C form (acc. to ISO 9187-2).
› Ampoules glass must comply with European
Pharmacopoea requirements for type I glass
containers and, if they are manufactured with amber
glass, it should also comply with light transmittance.
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12. Ampoules Washing
› Ampoules’ washing is performed in a rotary washer
machine. This machines CPPs are:-
› Water Temperature– This parameter can influence
the efficiency of the washing;
› Water Pressure– this parameter will influence the
correct and efficient washing of the ampoules;
› Washer Velocity– this parameter can influence the
efficiency of the washing as well as the efficient
processing, as if the washer is too fast, more
ampoules can break on the process 12

13. VIAL WASHING
› Washed by series of water at high pressure and the
pressure should be maintained throughout the
process.
› Pressure less = improper washing.
› Pressure more = breakage.
› Compressed air is used for drying the washed vials
and are moved towards the tunnel.
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14. Ampoules and vials
Depyrogenation
› After washing, the ampoules are continuously conveyed to the
tunnel, sterilized, depyrogenated and then cooled before
being transferred to the filling and sealing station. The key
parameters are:
› 1)Conveyor belt velocity– this parameter can influence the
stability of the ampoules in the tunnel and also the time that
they spend in the tunnel, affecting the exposure to the
sterilization temperature.
› 2)Chamber temperature– the temperature should be high
enough so that the ampoules are efficiently sterilized and
depyrogenated and the value of FH is sufficiently high to
assure the accomplishment of the process.
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15. Filling
› After cooling, the ampoules are directed to the filling
and sealing line. The Filling process can be
influenced by:
› 1)Solution flow– the solution should flow properly in
order to be filled in the ampoules. Filling needles
depend on product flow.
› 2)Volume to fill– The correctness of the volume will
influence the intended use on the dosage form, as it
can influence the dosage uniformity
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16. Sealing
› The sealing process can be influenced by:
› Flame Temperature – the flame will melt the glass
and seal the ampoule. If the flame temperature is
not adequate, the sealing may be compromised.
› Ampoules Height- it is determined by the height
of the flame and will influence the ease of opening.
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17. Sterilization
› Ampoules are now placed in trays and, depending on the
product, may be sterilized in the autoclave by hot steam. This
step assures the use of the finished product.
› Time– This parameter determines the time that the product
remains under the 121ºC temperature. Together with the
temperature it will influence the Fo of the sterilization
process. According to European Pharmacopoeia (EP) the
process should take at least 15 minutes.
› Temperature– This parameter is the key to the sterilization
process, as high temperatures assure the absence of
microorganisms .According to EP it should be at least 121ºC,
unless the process is demonstrated to possess the same
lethality rate.
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18. Visual Inspection
› Visual inspection is performed in an automated machine. The machine
contains a light-transmission double-check system for detecting particles
in ampoules.
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1
•Static Division system
2
•Divides photo-detection system into individual parts,
detection is done from base of ampoule.
3
•Container is spin at specified speed.
4
•Liquid forms a vortex imparts movement of insoluble part
5
•Vial stops , vortex collapses image is projected with
variation in transmitted light is detected.

19. › This machine inspects the following defects: particles,
volume and cosmetic defects in the head of the ampoule.
The inspection process can be influenced by:
› Rotation Speed - this parameter is defined so that it can
optimize the particles to suspend.
› Brake Position -this parameter affects meniscus recovery
and the timing between the end of spin and the
inspection.
› Light Intensity – this parameter defines the intensity of
the light that will illuminate the solution.
› Sensitivity – this parameter defines the threshold of
particle detection, differentiating the signal from the
noise.
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20. Integrity Inspection
› Integrity inspection is performed in an automated
machine by High Voltage Leak Detection (HVLD).
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High voltage is applied to the container.
If crack is present then current will flow through and
detected by the detector.
Difference in the conductivity is measured.

21. Labelling
› Labelling is performed in an automated machine that imprints
the batch number and expiry date on the label, as well as
possesses a sensor that detects the ring code colour and label
presence.
› The parameters that can influence the labelling process are:
› -Label – The correctness of the label placement is essential to
the identification of the product, influencing its quality.
› -Ring quality & quantity – The correctness of the ring colour
code is essential to the identification of the product to be
labelled, as the colour code is exclusive to one product.
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22. › Bar code – The correctness of the bar code is essential
to the correctness of the label that will identify the
product.
› -Batch &Expiry date printing – The correctness of the
printing will allow the correct traceability of the batch.
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23. Packaging
› Packaging is performed in an automated machine that
forms the blister tray, presses the ampoules in the
blister tray and places the trays in the carton box with
the leaflet.
› The parameters that can influence the labelling
process are:
› Leaflet - The correctness of the leaflet (detected by
bar code sensor) and its placement is essential to the
completeness of the packaging.
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24. › Carton Box -The correctness of the carton box
(detected by bar code sensor) and its correct
formation is essential to the correctness of the
packaging.
› Batch & Expiry date printing – The correctness of the
printing will allow the correct traceability of the batch.
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25. To achieve the QTTP, the Finished
Product CQAs should be:
› -Assay;
› - Impurities;
› -Particulate Contamination;
› -Endotoxins;
› -Sterility;
› -Correct identification of product and batch number.
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26. TERMS IN
VALIDATION
STERILITY
TESTING
LEAKAGE
TEST
PYROGEN
TEST
PARTICULATE
EVALUATION
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27. STERILITYTESTING • MEMBRANE
FILTERATION
METHOD
• DIRECT
INOCULATION
METHOD
PYROGENTEST
• LAL TEST
• RABBIT TEST
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28. PROCESS VALIDATION OF
OINTMENT/CREAM FORMULATION
› Why need of process validation for ointment/cream?
› Product bio burden high?
› Multiple component?
› More adequate preservative system?
› All have Newtonian flow behavior?
› History: Zinc oxide rash cream that was heated to a
relatively high temperature solely by the action of rotating
mixing plate.
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29. 29

30. Processes must be validated in
pharmaceutical manufacturing are:
› Cleaning
› Sanitization
› Depyrogenation
› Sterilization
› Sterile filling
› Purification
› Filling, capping, sealing
› Lyophilization 30

31. Validation Protocol
› Written plan describing the process to be validated,
including production equipment.
i. How validation will be conducted
ii. Objective test parameter
iii. Product characteristics
iv. Predetermine specification
v. Factors affecting acceptable result
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32. Components Included in cGMP
Process Validation
› All should be validated.
› Facility
› Environment
› People
› Analytical laboratory
› Raw materials
› Equipment
› Procedures
› Process
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33. Semisolids manufacturing
consideration
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34. 34

35. Unit Operation for semisolid
System
› Five unit operation
› Mixing of liquid
› Mixing of solid
› Mixing of semisolid
› Dispersing
› Milling and size reduction of solid and semisolid
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36. Filling and Packaging
Operation
› The following critical aspects must be evaluated and
controlled during large-scale validation and manufacturing
runs
› Proper control of product temperature to aid product flow
and maintain product consistency before and during filling and
packaging operations
› Proper agitation in holding tanks and filling heads in order to
main product uniformity and homogeneity during filling and
packaging operation
› The use of air pressure and inert atmosphere to achieve
product performance and stability in the primary container.
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37. Product testing
› Validation testing of bulk and finished product must
be based on testing standard release criteria and in
process testing criteria
› Routine QC release testing should be performed on a
routine sample.
› These samples should be taken separately from the
validation samples.
› Validation sampling and testing typically is 3 to 6 time
the usual QC sampling.
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38. Bulk Sampling
› Take 10 sample from the mixture, tank, or during
product transfer to the storage/filling vessel.
› The samples must represent the top, middle and
bottom of the vessel
› If sampling from the mixture/tank using an specific
equipment, samples should be taken immediately adjacent to
blades, baffles, and shafts where product movement during
mixing may restricted.
› The bottom of the tank and any potential dead spots
should be sampled and examined for unmixed material, if
possible
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39. Monitoring Output
› Particle size Consideration- Particle size distribution
for most disperse system should be in the range of 0.2-
20 microns
› Viscosity- The Viscometer- Calibrated to measure the
apparent viscosity of the disperse system at
equilibrium at a given temperature to establish system
reproducibility.
› Content Uniformity-In ointment/cream formulation
are more dependent on particle size, shear rate, and
mixing efficiency in order to attain and maintain
uniformity of the active drug component 39

40. › The average result of 10 individual results must meet the release
limit for assay.
› The usual sample size for testing ranges between 0.5 and 1.5 g per
sample assay.
› Preservative effectiveness-Incorporating a USP antimicrobial
preservative testing procedure or microbial limit test into formal
validation of aqueous dispersion.
› Dissolution Testing- It is primary used as a quality control
procedure to determine product uniformity.
› secondary as a means of assessing the in vivo absorption of the
drug in terms of a possible in vitro/vivo correlation.
› For cream/ointments, the Franz in vitro flow through
diffusion cell has been modified by using silicon rubber
membrane barrier to stimulate percutaneous dissolution unit for
testing purpose
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41. Validation Report
• STANDARD FORMAT
1. Executive summary
2. Discussion
3. Conclusions & recommendation
4. List of attachment
 Topic should be presented in the order in which they appear in
the protocol.
 Protocol deviation are fully explained & justified.
 The report is signed & dated by designated representatives of
each unit involved in water system validation
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42. Liquid orals
› Oral liquids are homogeneous or heterogeneous
liquid preparation.
› Consisting of solution, emulsion or suspension .
› In which one or more medicaments are been
dispersed in suitable vehicle.
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43. CLASSIFICATION
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44. MANUFACTURING OF BIPHASIC
LIQUIDS
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45. Testing of emulsion and suspension
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46. Process Description
› The information given below provides a general description of
the process. Detailed information for the manufacturing will
be supplied separately in the batch manufacturing record.
› DISPENSING OF MATERIAL
› SUGAR SYRUP PREPARATION
› BULK MANUFACTURING
› PH ADJUSTMENT
› VOLUME MAKE UP
› FILTRATION
› WASHING, FILLING AND SEALING
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47. Process validation is concerned
with the following operations
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48. 1.RAW MATERIAL
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49. 2. Monitoring output
I. Appearance
II. pH
III. Viscosity
IV. Specific gravity
V. Microbial count
VI. Content uniformity
VII.Dissolution testing
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50. Sedimentation rate
Resuspendability
Particle size and distribution
Zeta potential measurement
oTest parameter for solution
Clarity
colour
oTest parameters specific for
suspension
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51. oTest parameters specific for emulsion
Dilution test
Conductivity test
Dye solubility test
COCL2 filter paper test
Fluorescence test
oTest for filling and packaging
Leakage test for filled bottle
Cap seal test
Fill volume
Water vapour permeability test
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52. Sampling locations:
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53. › Sampling site: - Top (A), Middle (B), Bottom(C) position; use
the sample tube for A&B and bottom valve for
Position C
› Sampling Qty.: -About 100 ml from each sample site
› Sampling Time: - While mixing is on: - After ____ minutes,
after ____ minutes, After _____ minutes.
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54. Analytical Method Validation protocol
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55. References
› Lieberman H. A. , Rieger M. M. and Banker G. S.
“Pharmaceutical Dosage Forms: Disperse System”
,vol.3; Second Edition,473-511
› R. A. Nash and A. H. Wachter “Pharmaceutical process
validation”; Third edition
› Agalloco James, Carleton J. Fredric “Validation of
Pharmaceutical Processes”; Third edition,417-428
55

56. › Ana Rita Correia Cabaço, A Validation Master Plan for Small
Volume Parenterals, Pg. No. 1-89
› Ronald P. Anjard, SPC chart selection process, Microelectron.
Reliab., Vol. 35, No. II, pp. 1445 1447, 1995 28
› PQRI, Process Robustness – A PQRI White Paper, The official
manazine of ISPE, November/December 2006, Vol.26, No.6 29
› Chien-Wei Wu et al, An overview of theory and practice on
process capability indices for quality assurance, Int.Journ of
Production Economics Volume 117, Issue 2, February 2009,
Pages 338–359 30
› Susan Haigney , QbD in Sterile Manufacturing, Pharmaceutical
Technology Europe, Dec.2013 vol 25 no.12 pp 32
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