Aseptic / sterile- “ A state of control attained by using an aseptic work area and performing activities in a manner that precludes microbiological contamination of the exposed sterile product”

1. STERILE PROCESS OF VALIDATIONSTERILE PROCESS OF VALIDATIONSTERILE PROCESS OF VALIDATIONSTERILE PROCESS OF VALIDATION

2. Contents

3. Introduction
Aseptic / sterile- “ A state of control attained by using an aseptic
work area and performing activities in a manner that precludes
microbiological contamination of the exposed sterile product”
Process Validation- “Process validation is establishing documented
evidence which demonstrate that the manufacturing process will
consistently produce a product meeting its predetermine
specifications and quality Characteristics.”
 Drug product, container, and closure are subject to sterilization
separately, and then brought together.
Validation- is defined as Establishing documented evidence which
provides a high degree of assurance that a specific process will
consistently produce a product meeting its pre-determined
specifications and quality attributes.”

4. Types of process validation
Depending on the time when validation is performed relative to
the production, process validations can be classified as:
A) Prospective
B) Concurrent
C) Retrospective
D) Revalidation

5. Phases in process validation
Phase 1:(Pre-validation qualification phase) which covers all
activities relating to product research and development, formulation
pilot batch studies, scale-up studies, establishing stability conditions
and storage, and handling of in-process and finished dosage forms,
equipment qualification, installation qualification, master production
document, operational qualification and process capacity.
Phase 2: (Process validation phase) It is designed to verify that all
established limits of the critical process parameter are valid and
satisfactory. Products can be produced even under set parameters of
the worst case conditions.
Phase 3: (Validation maintenance Phase) it requires frequent review
of all process related documents, including validation of audit
reports, to assure that there have been no changes, deviations
failures and modifications to the production process and that all
standard operating procedures (SOPs), including change control

6. Purpose of Validation
-Minimize reliance on end product testing.
-To build sterility into a product.
-Increase SAL to all units.
-To provide greater assurance and support of the end product
sterility testing.
Lack of Sterility Assurance
0
10
20
30
40
50
60
'88 '90 '92 '94 '96 '98 '00 '02
Number
of
Recalls
Fiscal Year
-Lack of Sterility Assurance is
the reason for drug recalls in
last 5 years
-Nearly all drugs recalled due to
Lack of Sterility Assurance in
last 20 years were produced via
aseptic processing

7. Aseptic Processing
Essential
Elements
1
2
3
4
5
6
7

8. Manufacturing Environment Facility - Room classification
Class (0.5μ parts/ft3
) ISO Designation WHO Grade
100 5 A
1000 6 B
10000 7 C
100000 8 D
Facility1

9. Four grades of clean areas
Grade D (equivalent to Class 100,000, ISO 8):
• Clean area for carrying out less critical stages in
manufacture of aseptically prepared products eg. handling
of components after washing.
Grade C (equivalent to Class 10,000, ISO 7):
• Clean area for carrying out less critical stages in
manufacture of aseptically prepared products eg.
preparation of solutions to be filtered.
 Grade B (equivalent to Class
1000, ISO 6):
• Background environment for
Grade A zone, eg. clean
room in which laminar flow
workstation is housed.
Class 10,000 cleanroom

10. – Local zone for high risk operations
eg. product filling, stopper bowls,
open vials, handling sterile
materials, aseptic connections,
transfer of partially stoppered
containers to be lyophilized.
– Conditions usually provided by
laminar air flow workstation.
•Grade A (equivalent to Class 100 , ISO 5) :
Class 100 cleanroom

11. Airflow patterns
There are two types of aseptic processing isolators =
1.Closed isolators employ connections with auxiliary equipment
for material transfer. Turbulent flow can be acceptable within
closed isolators
-Gloves, half suits, seals, gaskets and transfer systems should
be covered by P.M. program. Physical integrity test routinely
performed.

12. 2. Open isolators have openings to
the environment from the surrounding
room via overpressure.
Use pressure differential to insure
separation of critical area from
external environment (17.5-50 Pa
0.07-0.20 water gauge)

13. Pressure differentials
 Used to maintain airflow in the direction of higher
cleanliness to adjacent less clean areas
 A minimum of 10-15 Pascals should be maintained
between the aseptic area and an adjacent rooms
with differing cleanroom classifications (doors
open)

14.  HEPA/ULPA filters on ceiling
 Exhaust vents on floor
 Drains in aseptic processing areas are inappropriate
 Airlocks and interlocking doors to control air balance
 Seamless and rounded floor to wall junctions
 Readily accessible corners
 Floors, walls, and ceilings constructed of smooth hard
surfaces that can be easily cleaned
 Limited equipment, fixtures and personnel
 Layout of equipment to optimize comfort and movement
of operators
General Cleanroom Design

15. Material NOT permitted in a Cleanroom
 Fiber-shedding materials such as cardboard and paper
 Cardboard packaging must be removed and items placed into non-
cardboard containers.
 Wood (i.e. wooden pallets)
1. Vacuum all accessible surfaces
2. Wipe surfaces with a cleaning solution
3. Mop floors using a lint free
polyester mops attached to
stainless steel handles

16. 2. Design
Differential Pressure - 10-15 Pascal's
Temperature – 18-20°C
Relative Humidity – 30-60 % RH
Material Flow
-Entry through air lock system or sterilizing ovens or filters.
-Contact plate testing should be done for assurance.

17. Equipment2
Contact sterile materials only with sterile instruments:
-Sterile instruments should be held under Class 100 conditions
between uses and placed in sterile containers
-Operators should not contact sterile products, containers, closures,
or critical surfaces with any part of their gown or gloves
-Equipment includes tanks, centrifuges and dryers is intended to be
sterilize before use.
-The validation program should show the effectiveness of
disinfecting program.
-It also prove that steam is sterilizing all surfaces.
-Heat distribution study should be done to determine the cold spots
where condensate could accumulate.

18. Process3
Process flow of
parenteral
dosage form

19. Process3
- In aseptic processing, each component is individually sterilised,
or several components are combined with the resulting mixture
sterilized.
-Process is validated by simulating the manufacturing process
using microbiological growth medium (media fill)
Process simulation includes formulation (compounding),
filtration and filling with suitable media using the same processes
involved in manufacture of the product modifications must be
made for different dosage formats e.g. lyophilized products,
ointments, sterile bulks, eye drops filled into semi-
transparent/opaque containers, biological products
-Media fill program should include worst case activities.

20. Preparation and Filtration of Solutions
 Solutions to be sterile filtered prepared in a Grade C environment
 If not to be filtered, preparation should be prepared in a Grade A environment with Grade B background (e.g. ointments, creams, suspensions and emulsions)
 Prepared solutions filtered through a sterile 0.22μm (or less) membrane filter into a previously sterilized container
 filters remove bacteria and moulds
 do not remove all viruses or mycoplasmas
 filtration should be carried out under positive pressure
Preparation and Filtration of Solutions (2)
 consideration should be given to complementing filtration process with some form of heat treatment
 Double filter or second filter at point of fill advisable
 Fitlers should not shed particles, asbestos containing filters should not be used
 Same filter should not be used for more than one day unless validated
 If bulk product is stored in sealed vessels, pressure release outlets should have hydrophobic microbial retentive air filters
Preparation and Filtration of Solutions (3)
 Time limits should be established for each phase of processing, e.g.
 maximum period between start of bulk product compounding and sterilization (filtration)
 maximum permitted holding time of bulk if held after filtration prior to filling
 product exposure on processing line
 storage of sterilized containers/components
 total time for product filtration to prevent organisms from penetrating filter
 maximum time for upstream filters used for clarification or particle removal (can support microbial attachment)
Preparation and Filtration of Solutions (4)
 Filling of solution may be followed by lyophilization (freeze drying)
 stoppers partially seated, product transferred to lyophilizer (Grade A/B conditions)
 Release of air/nitrogen into lyophilizer chamber at completion of process should be through sterilizing filter
Prefiltration Bioburden (natural microbial load)
 Limits should be stated and testing should be carried out on each batch
 Frequency may be reduced after satisfactory history is established
 and biobuden testing performed on components
 Should include action and alert limits (usually differ by a factor of 10) and action taken if limits are exceeded
 Limits should reasonably reflect bioburden routinely achieved
Prefiltation Bioburden (2)
 No defined “maximum” limit but the limit should not exceed the validated retention capability of the filter
 Bioburden controls should also be included in “in-process” controls
 particularly when product supports microbial growth and/or manufacturing process involves use of culture media
 Excessive bioburden can have adverse effect on the quality of the product and cause excessive levels of endotoxins/pyrogens

21. Filter integrity
 Filters of 0.22μm or less should be used for filtration of liquids and gasses (if applicable)
 filters for gasses that may be used for purging or overlaying of filled containers or to release vacuum in lyphilization chamber
 filter intergrity shoud be verified before filtration and confirmed after filtration
 bubble point
 pressure hold
 forward flow
 methods are defined by filter manufacturers and limits determined during filter validation
Filter Validaton
 Filter must be validated to demonstrate ability to remove bacteria
 most common method is to show that filter can retain a microbiological challenge of 107
CFU of Brevundimonas diminuta per cm2
of the filter surface
 a bioburden isolate may be more appropriate for filter retention studies than Brevundimonas diminuta
 Challenge concentration is intended to provide a margin of safety well beyond what would be expected in production
 preferably the microbial challenge is added to the fully formulated product which is then passed through the filter
Filter validation (2)
 if the product is bactericidal, product should be passed through the filter first followed by modified product containing the microbial challenge (after removing
any bactericidal activity remaining on the filter)
 filter validation should be carried out under worst case conditions e.g. maximum allowed filtration time and maximum pressure
 integrity testing specification for routine filtration should correlate with that identified during filter validation
Equipment/container preparation and sterilization
 All equipment (including lyophilizers) and product containers/closures should be sterilized using validated cycles
 same requirements apply for equipment sterilization that apply to terminally sterilized product
 particular attention to stoppers - should not be tightly packed as may clump together and affect air removal during vacuum stage of sterilization process
 equipment wrapped and loaded to facilitate air removal
 particular attention to filters, housings and tubing
Equipment/container preparation and sterilization (2)
 CIP/SIP processes
 particular attention to deadlegs - different orientation requirements for CIP and SIP
 heat tunnels often used for sterilization/depyrogenation of glass vials/bottles
 usually high temperature for short period of time
 need to consider speed of conveyor
 validation of depyrogenation (3 logs endotoxin units)
 worst case locations
 tunnel supplied with HEPA filtered air

22. Equipment/container preparation and sterilization (2)
 equipment should be designed to be easily assembled and disassembled, cleaned, sanitised and/or sterilized
 equipment should be appropriately cleaned - O-rings and gaskets should be removed to prevent build up of dirt or residues
 rinse water should be WFI grade
 equipment should be left dry unless sterilized immediately after cleaning (to prevent build up of pyrogens)
 washing of glass containers and rubber stoppers should be validated for endotoxin removal
 should be defined storage period between sterilization and use (period should be justified)
Process Validation
 Not possible to define a sterility assurance level for aseptic processing
 Process is validated by simulating the manufacturing process using microbiological growth medium (media fill)
 Process simulation includes formulation (compounding), filtration and filling with suitable media using the same processes involved in manufacture of the product
 modifications must be made for different dosage formats e.g. lyophilized products, ointments, sterile bulks, eye drops filled into semi-transparent/opaque containers,
biological products
Process Validation (2)
 Media fill program should include worst case activities
 Factors associated with longest permitted run (e.g. operator fatigue)
 Representative number, type, and complexity of normal interventions, non-routine interventions and events (e.g. maintenance, stoppages, etc)
 Lyophilisation
 Aseptic equipment assembly
Process Validation (3)
 Worst case activities (cont)
 No of personnel and their activities, shift changes, breaks, gown changes
 Representative number of aseptic additions (e.g. charging containers, closures, sterile ingredients) or transfers
 Aseptic equipment connections/disconnections
 Aseptic sample collections
 Line speed and configuration
Process Validation (4)
 Worst case activities (cont)
 Weight checks
 Container closure systems
 Specific provisions in processing instructions
 Written batch record documenting conditions and activities
 Should not be used to justify risky practices

23. - Preparation and Filtration of Solutions
- Prefiltration Bio-burden (natural microbial load)
- Filter integrity
- Filter Validaton
- Equipment/container preparation and sterilization
- Process Validation
Aseptic Processing

24. - Duration
-Depends on type of operation
-For conventional operations should include the total filling time.
- Size
-5000 - 10000 generally acceptable or batch size if <5000.
-For manually intensive processes larger numbers should be filled.
-Lower numbers can be filled for isolators.
- Line Speed
-Speed depends on type of process

25. 1st
– eliminate the source of contamination !
2nd
- Reduce the Risk of contamination through:
Sterile barriers
Aseptic technique
Environmental monitoring
Personnel4
3rd
Gowning / Gloves
-Frequent disinfection of gloves shoud done during
operations

26. -Gowning process must be validated.
-Done by Surface Monitoring or microbiological monitoring
(Touch- swab or Contact plates- RODAC Plates) Glove
fingertips into Petri dish containing agar media.
-Change gloves and masks at every working session
-No watches, jewellery and cosmetics
-Eye checks if involved in visual inspection

27. Personnel: Hygiene
 Avoid cleanrooms when ill
 Frequent bathing and shampooing
 Avoid getting sunburned
 Avoid cosmetics such as face powder, hair sprays,
perfumes and aftershave
 Clothing should be clean, nonfrayed and nonlinting
 Avoid smoking
Behavior-Minimize movement: Work slowly and purposefully

28. Control & Verification5
1. Environmental Monitoring
A] Surface monitoring:
Product contact surfaces, floors, walls, and equipment should be
tested on a regular basis.
B] Active air monitoring:
testing of the number of organisms per volume of air sampled.
C] Passive air monitoring
settling plates can be used as qualitative, or semi-quantitative, air
monitors

29. Control & Verification5
1. Environmental Monitoring -Physical
-Particulate matter =
-Differential pressures
-Air changes, airflow patterns
-Clean up time/recovery
-Temperature and relative humidity
-Airflow velocity
The goal of the environmental monitoring program is to provide
meaningful information on the quality of the aseptic processing
environment during production as well as environmental trends and
historical data.
Particulate Air Monitoring
Use of remote systems recommended
in laminar flow areas
“At rest” - production equipment installe
and operating
“In operation” - Installed equipment
functioning in defined operating mode an
specified number of personnel present

30. 2. Personnel Monitoring
-Clothing of appropriate quality:
 Grade D
 hair, beard, moustache covered
 protective clothing and shoes
 Grade C
 hair, beard, moustache covered
 single or 2-piece suit (covering wrists, high neck),
shoes/overshoes
 no fibres/particles to be shed
 Grade A and B
 headgear, beard and moustache covered, masks, gloves
 not shedding fibres, and retain particles shed by operators

31. Environmental Monitoring - Physical
 Particulate matter
 Particles significant because they can contaminate and also carry organisms
 Critical environment should be measured not more than 30cm from worksite, within airflow and during filling/closing operations
 Preferably a remote probe that monitors continuously
 Difficulties when process itself generates particles (e.g. powder filling)
 Appropriate alert and action limits should be set and corrective actions defined if limits exceeded
Environmental Monitoring - Physical
 Differential pressures
 Positive pressure differential of 10-15 Pascals should be maintained between adjacent rooms of different classification (with door closed)
 Most critical area should have the highest pressure
 Pressures should be continuously monitored and frequently recorded.
 Alarms should sound if pressures deviate
 Any deviations should be investigated and effect on environmental quality determined
Environmental Monitoring - Physical
 Air Changes/Airflow patterns
 Air flow over critical areas should be uni-directional (laminar flow) at a velocity sufficient to sweep particles away from filling/closing area
 for B, C and D rooms at least 20 changes per hour are ususally required
 Clean up time/recovery
 Particulate levels for the Grade A “at rest” state should be achieved after a short “clean-up” period of 20 minutes after completion of operations (guidance
value)
 Particle counts for Grade A “in operation” state should be maintained whenever product or open container is exposed
Environmental Monitoring - Physical
 Temperature and Relative Humidity
 Ambient temperature and humidity should not be uncomfortably high (could cause operators to generate particles) (18°C)
 Airflow velocity
 Laminar airflow workstation air speed of approx 0.45m/s ± 20% at working position (guidance value)
Personnel
 Minimum number of personnel in clean areas
 especially during aseptic processing
 Inspections and controls from outside
 Training to all including cleaning and maintenance staff
 initial and regular
 manufacturing, hygiene, microbiology
 should be formally validated and authorized to enter aseptic area
 Special cases
 supervision in case of outside staff
 decontamination procedures (e.g. staff who worked with animal tissue materials)

32. Personnel (2)
 High standards of hygiene and cleanliness
 should not enter clean rooms if ill or with open wounds
 Periodic health checks
 No shedding of particles, movement slow and controlled
 No introduction of microbiological hazards
 No outdoor clothing brought into clean areas, should be clad in factory clothing
 Changing and washing procedure
 No watches, jewellery and cosmetics
 Eye checks if involved in visual inspection
Personnel (4)
 Outdoor clothing not in change rooms leading to Grade B and C rooms
 Change at every working session, or once a day (if supportive data)
 Change gloves and masks at every working session
 Frequent disinfection of gloves during operations
 Washing of garments – separate laundry facility
 No damage, and according to validated procedures (washing and sterilization)
 Regular microbiological monitoring of operators

33. 3. Aseptic Filling Simulations (Media Fills)
 Verification of medium sterility
 Aseptic filling operation
 Challenge unit incubation
 Evaluation of result
Media used:-
 Soybean casein digest media
 Fluid thioglycolate media
Media fill frequency:-
 6 months interval.
 If change in aseptic process
Acceptance criteria:-
 Historically 0.3%(as per WHO)
 0.1% as per Parentral Drug Association. (PDA)

34. Acceptance Criteria
􀂄 Ideally the contamination rate should be zero. However currently the
accepted contamination rate should be less than 0.1 % with a 95 %
confidence level according to the Annex I to the EU/PIC/S Guide to
GMP.
Incubation Temperature
􀂄 It is generally accepted to incubate at 20-25°C for a
minimum of 14 days without having collected data to
support this incubation schedule.
􀂄 It is similarly acceptable for firms who prefer a two
temperature incubation schedule to incubate at 20-25°C
for a minimum of 7 days followed immediately by
incubation at a higher temperature range not to exceed
35°C for a total minimum incubation time of 14 days
Process simulation studies (media fills) are simulating the
whole process in order to evaluate the sterility confidence
of the process.
Process simulation studies include formulation
(compounding), filtration and filling with suitable media.
Simulations are made to ensure that the regular process for
commercial batches repeatedly and reliably produces the
finished product of the required quality. However, each
process simulation trial is unique and so it is not possible to
extrapolate these results directly to actual production
contamination rates.
Where filling takes place over extended periods, i.e.
longer than 24 hours, the process simulation test should
extend over the whole of the standard filling period. In
order to prevent excessively high numbers of units being
filled it is usually acceptable to just run the machine for a
reasonable time, if the validity of the simulation is not
diminished by this procedure.
􀂄 The fill volume of the containers should be sufficient to
enable contact of all the container-closure seal surfaces
when the container is inverted and also sufficient to allow
the detection of microbial growth
Process simulation studies (media fills)
 Media fills should be observed by the QC unit
 Video recording should be considered

35. Finish Product & Testing6
Sterility Testing
Particulate Testing
Container Closure Integrity Testing
Other Final Product/Release
Testing
Stability Testing
Finish Product Testing after Sterilization
􀂄Uniformity of filled volume
􀂄 Perform testing on filled containers.
􀂄Sterility
􀂄 10 samples from each of the beginning and end of the filling run.
Samples must represent all filling nozzles.
􀂄 Visual Evaluation
􀂄 Appearance, Color of solution
􀂄 Other Testing
􀂄 Assay, pH, Density, Pyrogen or Endotoxin etc.
Thesterilitytestcanprovideusefulinformationonthevalidationstatusofasepticpro
ess
Thesterilitytestappliedtothefinishedproductshouldonlyberegardedasthelastina
eriesofcontrolmeasuresbywhichsterilityisassured.Thetestshouldbevalidatedfo
heproduct(s)concerned
Endotoxin: a pyrogenic (fever inducing) substance (e.g. lipopolysaccharide)
present in the bacterial cell wall. Endotoxin reactions range from fever to
death.
 21 CFR 211.167“ For each batch of drug product purporting to be sterile and/or pyrogen-free, there shall be appropriate laboratory testing to
determine conformance to such requirements.”

36. Documentation7
Media Fill Records
Production Batch Records
EM Trend Data
Release Testing Batch Records
Investigation
Response to Excursions
Corrective Actions
Validation Report
􀂄 Validation Team must prepare the report
􀂄 Report must be reviewed and approved by QA.
􀂄 Written Notification or either successful completion or failure of the
process validation must be issued to top management.
􀂄 In case of failure, an investigation must be completed and documented
prior to repeat the validation study
Sterility Testing Investigations
 In the investigation stemming from a negative sterility test consideration should be given to:
 Speciation of the organism
 Record of laboratory results and deviations
 Environmental monitoring of production environment
 Monitoring personnel
 Product Presterilization bioburden
 Production record review
 Manufacturing history

37. Process Validation of Sterile Liquid Products
Validation Team: Production, QC, QA, Engineer,Planner
•To prepare the validation protocol
•Verify the calibration and maintenance status of equipment
•Perform qualification for equipments and system
• Verify change control
• Schedule the validation activities
• Training production operators
• Conduct validation study
• Monitor the critical steps in manufacturing process
• Assure that the approved testing standard is being used
• Evaluate all test results,
• Prepare the validation report.

38. Pre-validation Requirements
•Preventive Maintenance for Facilities and Utilities
• Calibration of Equipment
• Cleaning Validation
• Equipment & System Qualification
• Raw Materials/Components/Test Methods
• Process Justification
• Change Control
• Training operators
All must be proven suitable and reliable for the manufacturing
process before the process can be validated

39. New Product <==> Trial Batch, Development Batch. Transferred Product <==> Products produced at the sending site .Revalidation Product <==> The original
product before revalidation
Type of Process Validation
1 Prospective
o Conducted prior to market the product
2 Concurrent
o Based on information generated during actual
implementation of the process (each batch will be
released separately)
3 Retrospective (Not recommended for sterile product)
O Based on accumulated historical production, testing and
control data
O Generally requires data from 10-30 batches
O Use data only from batches made by the same process
Terminal Sterilization :
Operation whereby the product is sterilized
separately by
autoclave after filled and packaged using
sterilized containers
and closures in critical processing zones.
Aseptic Operation:
Operation whereby the product is sterilized
separately by filtering
through 0.2 μ or less filter, then filled and
packaged using
sterilized containers and closures in critical
processing zones.
Process Justification:
􀂄 To identify critical process steps & process parameter of Mixing
process
􀂄 To determine the suitable Hold time Period
􀂄 To confirm the analytical tests that will have to be performed
􀂄 To define the optimal parameters throughout the overall ampoule
filling process to consistently produce the finished products(filled
ampoules) which meet the established specifications.
􀂄 To assure that the product is sterile after sterilization process
Validation Protocol
A document stating how
validation will be conducted,
including test parameters,
product characteristics,
production
equipment to be used and
decision points on what
constitutes acceptable test
results
Validation Protocol should contain :
􀂄 Title Page, Review/Approval Page
􀂄 Purpose and Overview
􀂄 Equipment List
􀂄 Ingredients and Component List
􀂄 Qualification List of Equipment and System
􀂄 Process Flow Diagram and Description
􀂄 Equipment Critical Process Parameter
􀂄 Process Validation Sampling Plan/Testing
Requirements
􀂄 Acceptance Criteria
􀂄 Stability Requirements
􀂄 Process for evaluation of any deviations occurring
during validation
􀂄 Conclusion
Equipment Critical Process Parameter:
􀂄 Mixing Speed
􀂄 Mixing Time
􀂄 Gas flushing time
􀂄 Type and size of filter
􀂄 Filtering Time and Pressure used
􀂄 Filling Speed
􀂄 Temperature and Duration for Terminal Sterilization
Critical Manufacturing Step
􀂄 Dissolving Step
􀂄 pH adjustment step
􀂄 Final mixing step
􀂄 Filtering Step
􀂄 Filling Step
􀂄 Terminal Sterilization Step
􀂄 Leak Test Step
Changes and Revalidation
􀂄 Change of any of the following may need revalidation
􀂄 Formula Composition
􀂄 Raw Material Source
􀂄 Manufacturing Process
􀂄 Manufacturing Location
􀂄 Equipments
􀂄 Batch Size
􀂄 Testing Specification
Changes
􀂄 Minor: It seems to have no impact on formulation
􀂄 It is not necessary to validate
􀂄 Intermediate : It could have significant impact on formulation
􀂄 Depend on case-by-case (A minimum of 1 trial)
􀂄 Major : It is likely to have significant impact on formulation
􀂄 Revalidation is required (A minimum of 3 trials)
Validation
Minor Change
􀂄 Qualitative inactive excipient change deemed minor by
change control review
􀂄 Process change deemed minor by change control
review
􀂄 Manufacturing location change with in same building,
same equipment, personnel, procedure and utilities are
used
􀂄 Equipment change but same design, configuration
Intermediate Change
􀂄 Process changes, such as mixing times or operating speeds
for solutions.
􀂄 Change in release specification to a tighter limit caused
original validation results to be out of specification
􀂄 Extension of the qualified in process hold time for intermediate
or finished product prior to packaging
􀂄 Equipment change deemed intermediate by change control
review
Major Changes
􀂄 Quantitative or qualitative
formulation change deemed major
by
change control review
􀂄 Inactive excipient or active
ingredient source change deemed
major by change control review
􀂄 Transfer product from on site to
another
􀂄 Significant change in process
􀂄 Equipment change to a different
design, configuration or operating
principle.