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.

Manufacture of 1mg/ml

Dexamethasone Inj. 10ml

Raw material

Packaging
components

Dexamethasone base
Polyethylene Glycol
Benzyl alcohol
Ethanol

Glass vials 10ml

Rubber stoppers

Sterilization &
Aseptic Processing
Filling
Operation

Bulk
manufacturing
Packaging &
Labeling

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

Packaging components
(Processes involved)
Glass vials

Rubber stoppers

Cleaning/washing
Cleaning/washing
Sterilization
Sterilization (dry heat)

Cleaning/washing
Cleaning/washing
Siliconization
Siliconization
Sterilization
Sterilization
(Autoclaving)

Sterility
Sterility assurance (106)

Depyrogenation
Depyrogenation
Endotoxin
Endotoxin reduction (103)

Sterility Assurance (106)

Depyrogenation
Depyrogenation
Endotoxin reduction (103)

Bulk Manufacturing
(Processes involved)
Bulk manufacturing process
Bulk biobio-burden limit
Bulk holding time
Bulk sterilization (Steam/Filtration)

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

Packaging operation
Container/closure integrity
Dye ingress
Microbial ingress

Labeling Operation
Label integrity
Adherence strength
Printing ink strength & durability
Lot number & expiry date

Vision systems

Stability studies
Broaching study
Freeze /thaw study
Photo stability
Stress testing
- Temperature stability
(Storage conditions)
- Humidity requirements
9

Shelf life & Expiry

Accelerated study
Long term study

10

Not to mention
Qualification (IQ/OQ/PQ) of all the
manufacturing & testing equipment
Including calibrations & maintenance

Validation of all the test methods

11

All instruments calibrated

All equipments qualified
All test methods validated
All processes validated
Is the Quality of the Product
Assured?
12

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

14

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.

15

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

16

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

17

Cleanroom Classification
Airborne Particulate Cleanliness Classes*
Class Name
SI
M1
M1 .5
M2
M2 .5
M3
M3 .5
M4
M4 .5
M5
M5 .5
M6
M6 .5

Particles equal to or larger than 0.5um

U .S. C USTOMARY
1
10
100
1000
10000
100000

(m3 )
10
3 5 .3
100
353
1000
3530
10000
35300
100000
353000
1000000
3530000

(ft3 )
O.2 8 3
1
2 .8
10
2 8 .3
100
283
1000
2830
10000
28300
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.

19

Cleanroom Classification
ISO AIRBOURNE PARTICULATE CLEANLINESS CLASSES
Number of Particles per Cubic Meter

Class

0.1 um

0.2 um

0.3 um

0.5 um

1 um

5 um

ISO 1

10

ISO 2

100

24

10

ISO 3

1,000

237

102

35

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

20

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

21

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

22

Air Handling System (HVAC)

25% Outdoor Air Intake
through pre-filter 30-60%

75-95% Pre-HEPA Filter

.
FAN

MIXING BOX

FAN

intermediate filter

Heating /Cooling and

Dehumidification

75% Re-circulated Air

Terminal HEPA Filter 99.97%

23

HEPA/ULPA filters
HEPA is an acronym for
High Efficiency Particulate Air
ULPA is an acronym for
Ultra Low Penetration Air

24

HEPA filters
HEPA filters are throwaway, extendedextendedmedium, drydry-type filter in a rigid frame having
a minimum particleparticle-collection efficiency of
99.97% for 0.3 m and larger, and a
maximum cleanclean-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.

25

ULPA filters
ULPA filters are a throwaway, extendedextendedmedium, drydry-type filter in a rigid frame having
a minimum particleparticle-collection efficiency of
99.999% for particles 0.12um and larger.
- IES-RP-CC001, HEPA and ULPA Filters.

26

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

27

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

Water
Compressed Air

28

Cleanroom Certification
ISO 1466414664-2:2000(E): Specifications for testing and
monitoring to prove continued compliance with ISO
1464414644-1

Normative Test
iAirborne
Airborne Particle Count (cleanroom classification)
iAirflow
Airflow Velocity / Air Volume Tests
iRoom
Room Pressure Differential Test

Optional Tests in Annex A

iHEPA
HEPA filter installation leak (integrity) tests
iAirflow
Airflow visualization (smoke video)
iRecovery
Recovery
iContainment
Containment Leakage
Other Tests - Temperature, Humidity, Light and Noise Level

29

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)

ReferenceReference- IESIES-RPRP-CC006.2 (Contamination Control Division Recommended

Practice O06.2

30

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 filters face area
- The lesser dimension of any repair does not
exceed 3.8 cm (1.5 in.)

31

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

32

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.

33

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

34

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

35

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

36

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

37

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

38

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.

39

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

40

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

41

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)

42

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.

43

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

44

Process Simulation (Media fills)

iInitial
Initial Validation
Minimum of three consecutive successful
runs
iRoutine
Routine rere-validation
iMinimum
Minimum rere-test frequency should be twice per
year per operator shift or team, for each process
line.
iEvery
Every 6 months (FDA Draft & ISO13408ISO13408-1)

45

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

46

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

47

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.

48

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

49

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.

50

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 onon-line leak test

51

Process Simulation (Media fills)

Incubation Time
iAll
All filled units should be incubated immediately
after filling and leakleak-testing, for a total period of
not less than 14 days.
Incubation Temperature
ithe
the incubation temperature should be 30 to 35
oC. The incubation temperature should be
carefully monitored and maintained throughout
the incubation period (TPP).

52

Process Simulation (Media fills)

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

53

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 1010-100
organism per container must show the growth
characteristics of the organism

54

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

For 5,000 to 10,000 units filled One contaminated unit Investigation & consideration for
Revalidation
Two contaminated units - Investigation & Revalidation

For > 10,000 units filled One contaminated unit Investigation

Two contaminated units - Investigation & Revalidation

55

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

56

Process Simulation (Media fills)

Revalidation

If an assign able cause is found for a process

or area, only one process simulation is
required for rere-qualification after correcting
the cause
If no root cause is found for process
simulation failure, three consecutive
successful process simulation runs required.

57

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.

58

?
59

Thank you

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