Process Validation

Manufacture of
Parenteral Drug Products

Joint CVG/TPD convention

‘Quality by Design’
Design’
October 05,2007

Socrates Nelson
PharmEng Technology Inc.
Disclaimer : The contents of this presentation are my personal opinion and does not reflect either the policy or the practice of my company.

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 Manufacture of 1mg/ml
Dexamethasone Inj. 10ml
Raw material Packaging
Dexamethasone base components
Polyethylene Glycol Glass vials 10ml
Benzyl alcohol Rubber stoppers
Ethanol
Sterilization &
Aseptic Processing

Bulk Filling
manufacturing Operation

Packaging &
Labeling
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 Raw materials
(Processes involved)
• Selection & Qualification
• Set raw material specifications
• Supplier selection & audit
• Routine testing & release of RM

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 Packaging components
(Processes involved)
Glass vials
•Cleaning/washing
Cleaning/washing
•Sterilization
Sterilization (dry heat)
Sterility assurance (10–6)
–Sterility
•Depyrogenation
Depyrogenation
Endotoxin reduction (10–3)
–Endotoxin
Rubber stoppers
•Cleaning/washing
Cleaning/washing
•Siliconization
Siliconization
•Sterilization
Sterilization
(Autoclaving)
– Sterility Assurance (10–6)
•Depyrogenation
Depyrogenation
– Endotoxin reduction (10–3)
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 Bulk Manufacturing
(Processes involved)
• Bulk manufacturing process
• Bulk bio-
bio-burden limit
• Bulk holding time
• Bulk sterilization (Steam/Filtration)

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 Filling Operation
(Processes involved)
• CIP /SIP of the filling line
• Filling process
– Fill Volume
– Head space
– Particulates

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 Packaging operation

• Container/closure integrity
– Dye ingress
– Microbial ingress

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 Labeling Operation
• Label integrity
– Adherence strength
– Printing ink strength & durability
– Lot number & expiry date
• Vision systems

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 Stability studies
• Broaching study
• Freeze /thaw study
• Photo stability
• Stress testing
- Temperature stability
(Storage conditions)
- Humidity requirements

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 Shelf life & Expiry

• Accelerated study
• Long term study

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 Not to mention

• Qualification (IQ/OQ/PQ) of all the

manufacturing & testing equipment
– Including calibrations & maintenance
• Validation of all the test methods

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 All instruments calibrated
All equipments qualified
All test methods validated
All processes validated

Is the Quality of the Product

Assured?
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 No, it is not !
• The initial qualification of the equipment
& validation of the processes are only a
stamp at that moment in time on the life
cycle of the products.

• Assurance comes from the proof that all

equipments are maintained at the state
they were qualified and all processes are
regularly controlled in the validated state.

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Aseptic Processing

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 Introduction
Aseptic processing
The ability of personnel to manipulate
sterile preparations/products and sterile
packaging components in a way that
excludes the introduction of viable
microorganisms.

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How is aseptic processing
achieved?
•Development
Development of Cleanroom
environment & maintenance
•Personnel
Personnel that are qualified and
trained in cleanroom operation
•Validation
Validation of the processes

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 Cleanroom

Definition -
Room in which the concentration of airborne particles is
controlled, and which is constructed and used in a
manner to minimize the introduction, generation, and
retention of particles inside the room, and in which other
relevant parameters, e.g. temperature,humidity, and
pressure, are controlled as necessary

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 Cleanroom Classification
Airborne Particulate Cleanliness Classes*
Class Name Particles equal to or larger than 0.5um
SI U .S. C USTOMARY (m3 ) (ft3 )
M1 10 O.2 8 3
M1 .5 1 3 5 .3 1
M2 100 2 .8
M2 .5 10 353 10
M3 1000 2 8 .3
M3 .5 100 3530 100
M4 10000 283
M4 .5 1000 35300 1000
M5 100000 2830
M5 .5 10000 353000 10000
M6 1000000 28300
M6 .5 100000 3530000 100000

*Adapted from US Federal Standard 209E, September 11, 1992 -- “Airborne particulate
cleanliness classes in cleanrooms and clean zones.”

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 Cleanroom Classification cont . . .
Technical Committee 209 of the International Organization for
Standardization (ISO/TC209) has proposed the following eleven
(11) documents as the Clean room Standards:
ISO 14644-1: Classification of air cleanliness
ISO 14644-2: Cleanroom testing for Compliance
ISO 14644-3: Method for Evaluating & Measuring Cleanrooms &
Associated controlled environment
ISO 14644-4: Cleanroom Design and Construction
ISO 14644-5: Cleanroom Operation
ISO 14644-6: Terms, Definition & Units
ISO 14644-7: Enhanced Clean Devices
ISO 14644-8: Molecular Contamination
ISO 14698-1: Bio-contamination: Control General Principles
ISO 14698-2: Bio-contamination: Evaluation & Interpretation of Data
ISO 14698-3 Bio-contamination: Methodology for Measuring Efficiency of
Cleaning Inert Surfaces.

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 Cleanroom Classification
ISO AIRBOURNE PARTICULATE CLEANLINESS CLASSES

Class Number of Particles per Cubic Meter

0.1 um 0.2 um 0.3 um 0.5 um 1 um 5 um

ISO 1 10 2 ¡¡ ¡¡ ¡¡ ¡¡
ISO 2 100 24 10 4 ¡¡ ¡¡
ISO 3 1,000 237 102 35 8 ¡¡
ISO 4 10,000 2,370 1,020 352 83 ¡¡
ISO 5 100,000 23,700 10,200 3,520 832 29
ISO 6 1,000,000237,000 102,000 35,200 8,320 293
ISO 7 ¡¡ ¡¡ ¡¡ 352,000 83,200 2,930
ISO 8 ¡¡ ¡¡ ¡¡ 3,520,000 832,000 29,300
ISO 9 ¡¡ ¡¡ ¡¡ 35,200,000 8,320,000 293,000

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 Cleanroom environment

• Design of cleanrooms
• Air handling systems (HVAC)
• HEPA/ULPA filters
• Cleanroom utilities
• Cleanroom certification
• Maintenance of cleanrooms

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 Cleanroom design
The following to be considered
Cleanroom surfaces
iCleanroom
Cleanroom layout
iCleanroom
Cleanroom equipment
iCleanroom
Clean Rooms Procedures
iClean
Product issues
iProduct

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 Air Handling System (HVAC)
25% Outdoor Air Intake
through pre-filter 30-60% 75-95% Pre-HEPA Filter
. intermediate filter
FAN MIXING BOX FAN

Heating /Cooling and

Dehumidification 75% Re-circulated Air

Terminal HEPA Filter 99.97%

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 HEPA/ULPA filters

HEPA is an acronym for

‘High Efficiency Particulate Air’

ULPA is an acronym for

‘Ultra Low Penetration Air’

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 HEPA filters
• HEPA filters are throwaway, extended-
extended-
medium, dry-
dry-type filter in a rigid frame having
a minimum particle-
particle-collection efficiency of
99.97% for 0.3 µm and larger, and a
maximum clean-
clean-filter pressure drop of 2.54
cm water gauge (0.249 kPa), when tested at
rated airflow capacity (85 L/min).
- IES-RP-CC001, HEPA and ULPA Filters.

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 ULPA filters

• ULPA filters are a throwaway, extended-

extended-
medium, dry-
dry-type filter in a rigid frame having
a minimum particle-
particle-collection efficiency of
99.999% for particles 0.12um and larger.
- IES-RP-CC001, HEPA and ULPA Filters.

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Common air contaminants
Human Hair…………………… 70-100 microns
Human Sneeze………………… 10-100 microns
Pet Dander……………………. 0.5-100 microns
Pollen…………………………... 5-100 microns
Spores from Plants……………... 6-100 microns
Mold……………………………... 2-20 microns
Smoke…………………...………. 0.1-1 microns
Dust Mite Debris………..……… 0.5-50 microns
Household Dust…………………. 5-100 microns
Skin Flakes…………..…………. 0.4-10 microns
Bacteria……………………….... 0.3-10 microns

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 Cleanroom Utilities
Cleanroom Steam
Plant Steam manufactured by boiler
using city water
Pure Steam manufactured by steam
generator using purified water
Water
Compressed Air

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 Cleanroom Certification
ISO 14664-
14664-2:2000(E): Specifications for testing and
monitoring to prove continued compliance with ISO
14644-
14644-1
Normative Test
Airborne Particle Count (cleanroom classification)
iAirborne
Airflow Velocity / Air Volume Tests
iAirflow
Room Pressure Differential Test
iRoom
Optional Tests in Annex A
HEPA filter installation leak (integrity) tests
iHEPA
Airflow visualization (smoke video)
iAirflow
Recovery
iRecovery
Containment Leakage
iContainment
Other Tests - Temperature, Humidity, Light and Noise Level

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 Cleanroom Certification
HEPA Filter Leak (Integrity) Testing
These tests are performed to confirm that the HEPA or
ULPA filter system is properly installed by verifying the
absence of bypass leakage in the installation, and that the
filters are free of defects and small leaks. The tests are
particularly important for cleanrooms and clean zones
classified at < ISO class 5 or M 3.5 (Class 100 or cleaner)

• Reference-
Reference- IES-
IES-RP-
RP-CC006.2 (Contamination Control Division Recommended
Practice O06.2

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 Cleanroom Certification
HEPA Filter Leak (Integrity) Testing
Results
i The leaks <0.01% are acceptable
i Record all leaks that exceed 0.01% of the upstream
challenge concentration and should be repaired
Repair
i HEPA filters may be repaired, providing:
- The size of the repair does not block or restrict
more than 3% of the filter’s face area
- The lesser dimension of any repair does not
exceed 3.8 cm (1.5 in.)

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 Cleanroom Certification
Air Flow Velocity/Volume
Normally a air velocity of 90 ft/min
± 20% is adequate.

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 Cleanroom Certification
Air Changes
The air changes can be calculated by taking the total
volumes divided by room volume and reported as air
changes per hr.
Not less then 20 air changes per hour are acceptable.

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 Cleanroom Certification
Air Pressure Differential
Acceptance criteria
- A pressure differential of at least 0.05
inch of water (with all door closed)
relative to adjacent area is acceptable

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 Cleanroom Certification
Air Flow Visualization (Smoke
Smoke Testing)
Testing
Performed in order to assure that
the unidirectional flow of HEPA filtered air is not
ithe
compromised
the air moves in a downward direction away
ithe
from the work surfaces
Air flow patterns don’t present a contamination
iAir
risk
itoto detect dead spots

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 Cleanroom Certification
Temperature / Humidity
Performed to demonstrate the capability of the
cleanroom air handling system to maintain air
temperature and humidity.
Temperature
Range 22 + 2 oC
iRange
Humidity
i<< 45% RH is recommended
Range 40% to 60% RH
Monitored on a continuous on-
on-going basis

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 Cleanroom Certification
Airborne Particle Counts
Acceptance for Airborne Particle Counts
The average particle concentration at each
iThe
sample location should fall below the class
limit
The mean of of these averages should fall
iThe
at or below the class limit with 95% upper
confidence level (UCL)

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 Cleanroom Environment
Microbial control
Environmental Monitoring Program
h Establishment of Sampling Plan & Site
h Testing Methods
h Testing Devices
h Testing Frequencies
h Action / Alert Limits
h Follow Up & Identification

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 Environmental Monitoring
Program
A program capable of detecting an
adverse drift in microbiological
conditions in a timely manner and
would allow for meaningful and
effective corrective actions.

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Environmental Monitoring

•Testing
Testing Methods
•Testing
Testing Frequency
•Setting
Setting of Alert & Action limit
•Microbial
Microbial Identification
•Deviations
Deviations
•Follow
Follow-
Follow-Up & Corrective Action

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Cleanroom Maintenance
Cleaning & Sanitization
Cleanroom Behavior
Formal Training Program
Qualification Program

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Validation of Aseptic Processing
Involves all of the following –
• Qualification & Maintenance of well designed HVAC system
• Initial & periodic Certification of Cleanrooms & HEPA filters
• Validated Cleaning & Sanitization procedures
• Validated sterilization of Bulk & Packaging Components
• Validated state of Utility systems (Water, Comp. Air etc.)
• Maintaining trained & qualified cleanroom personnel
• Good record of environmental monitoring & trending.
• An excellent track record of Investigations & CAPA system.

• Process Simulation (Media fills)

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 Process Simulation (Media fills)
Objective
The intent of a process simulation study is to
demonstrate that the aseptic processing
employed for the manufacturing of sterile
products, with its day to day normal activities
and interventions, does indeed result in a
sterile product.

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 Process Simulation (Media fills)
The media fill collectively evaluates the
adequacy of the following:
i Disinfecting Techniques
i Transfer of sterile material
i Training of personnel
i Cleanroom Environmental Control
i Aseptic assembly
i Aseptic techniques & behavior

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 Process Simulation (Media fills)
Initial Validation
iInitial
Minimum of three consecutive successful
runs
Routine re-
iRoutine re-validation
Minimum re-
iMinimum re-test frequency should be twice per
year per operator shift or team, for each process
line.
Every 6 months (FDA Draft & ISO13408-
iEvery ISO13408-1)

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Process Simulation (Media fills)
Planned Interventions
Routine manipulation & Setup
• Volume adjustment
• Torque adjustment

• Addition of components (plugs, caps & bottles)

• Touching filling needles with glove hand

• Shift changes, breaks and gown change (when applicable)

• Manual weight checks

•Any routine changeover during aseptic fill

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Process Simulation (Media fills)
Planned Interventions performed during MF
Worse case interventions
• Clean up of spill
• Simulation of mechanical adjustment, stoppages or transfer
• Long storage of components in the hoppers
• Including multiple shifts or maximum hrs of continuous
processing
• Consideration of temperature and humidity set point extremes
• Maximum number of operators and their activities

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Process Simulation (Media fills)
Planned Interventions
Worse case interventions (continued)
• Using the minimum processing speed for the container with
the largest opening and vice versa
• Number and type of filters or Filtration train
• Maximum number of operators
• Maximum activity
• Maximum number of aseptic connection that may be
performed in a single production run.

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Process Simulation (Media fills)

Number of units to be filled

The number of units filled should be relevant to production
batch size which allowed to detect a 0.1% contamination
with 95% CL

For small batch sizes, the number of units filled should be

actual batch size with no positive

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Process Simulation (Media fills)

Volume to be filled
the volume should be normal production fill volume
where possible. In the case of high volume containers,
a lesser quantity may be used, provided the steps are
taken to ensure wetting of all the inner surfaces of the
container and any closure, by the medium
The fill volume of TSB - filled unit during incubation
must be large enough to facilitate growth of
microorganisms.

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Process Simulation (Media fills)
Media Fill Rejects
All units filled should be incubated (including cosmetics
rejects i.e. low volume, black spec) with the exception of
leakers or potential leakers
• Crooked caps,

• Cracked vials or caps

• Low torque

• deformed container

• Units failed on-

on-line leak test

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Process Simulation (Media fills)
Incubation Time
All filled units should be incubated immediately
iAll
after filling and leak-
leak-testing, for a total period of
not less than 14 days.
Incubation Temperature
the incubation temperature should be 30 to 35
ithe
oC. The incubation temperature should be

carefully monitored and maintained throughout

the incubation period (TPP).

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Process Simulation (Media fills)

In-
In-process microbiological monitoring
Operators’ qualification (glove /gown testing)
iOperators’
Surface monitoring (pre & post media Fill)
iSurface
Quantitative Air sampling (before & during
iQuantitative
media fill)
Settling Plate monitoring
iSettling
Particulate monitoring
iParticulate
Microbial identification
iMicrobial

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Process Simulation (Media fills)
Acceptance Criteria
1. Media Growth Promotion

i the prepared bulk media should be clear so as to allow

the observation of any evidence of growth following
incubation.
i media used in evaluation must pass the USP growth
promotion test where a challenge with between 10-
10-100
organism per container must show the growth
characteristics of the organism

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 Process Simulation (Media fills)
Acceptance Criteria
“Any contaminated units should be considered objectionable
and investigated”
2. Recommended criteria for state of control are as follows:
i For < 5,000 units filled – No contaminated units.
One contaminated unit – Investigation & Revalidation
i For 5,000 to 10,000 units filled -
One contaminated unit – Investigation & consideration for
Revalidation
Two contaminated units - Investigation & Revalidation
i For > 10,000 units filled -
One contaminated unit – Investigation
Two contaminated units - Investigation & Revalidation

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Process Simulation (Media fills)
Invalidation of Media fill
In validation of a media fill run should be a
rare occurrence

A media fill run should be aborted only under

circumstances in which written procedures
require commercial to be equally handled

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Process Simulation (Media fills)
Revalidation

If an assign able cause is found for a process
or area, only one process simulation is
required for re-
re-qualification after correcting
the cause

If no root cause is found for process

simulation failure, three consecutive
successful process simulation runs required.

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Process Simulation (Media fills)

Revalidation
Repeat media fill must use the same equipment,
same operators, same line, same process,
container /closures, same interventions with the
exception of correcting the root cause.

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?

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Thank you

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