1. Critical GMP Validations for Drugs / BiologicsⅡ
Chung Keel Lee, Ph.D.
Special Advisor to the Minister, MFDS
Advisor, WHO
Adjunct / Invited Professor, KU / EWU
President, ISPE Korea
July 23, 2013

2. Parametric Release
Release or approval of a process step, such as a sterilization cycle, by physical parameters measured during the process without confirmation by laboratory testing.
Parametric release can only be used if the processing step and measurement of physical parameters have been validated.

3. Current Good Manufacturing Practice(CGMP)
Validation
Aseptic Filling/Closing Activities
T. HEPA
T. HEPA
Freeze
-Dryer
Laminar Flow Hood with HEPA
Machine
Room
Aseptic Filling Room
Vial/Stopper Preparation Room
Air-lock

4. Validation Filling validation via simulated media-fill
Growth promotion test of the medium
Positive control
Environmental monitoring
Fill volume measurement
Rocking the filled vials before incubation
Vial/Stopper washing, sterilization and depyrogenation
Personnel involvement in filling validation

5. Validation Water for Injection system & its operation
After all the equipment & piping has been verified
as installed correctly & working as specified,
Initial phase
Develop operation parameters, cleaning / sanitization procedures & frequencies
Sampling / Testing:
Daily for 2-4 weeks
At each step in purification process
At each point of use
Develop SOPs for WFI operation

6. Validation Water for Injection system & its operation Second phase
Sampling / Testing
Same as in Initial phase
For additional 2-4 weeks
Prove consistent water quality in compliance with SOPs

7. Validation Water for Injection system & its operation Third phase
Sampling/Testing
Routine frequencies
WFI: daily for a minimum of one point of use tested
weekly for all points of use tested
Over a long period of time : full year
Check seasonal variation
Validation of WFI is completed when a full year’s data are obtained.
Final validation report signed by operation & QA persons
Prove that seasonal variation in feed water does not adversely affect water quality.
Acceptance criteria

8. Validation Cleaning processes : General Validation protocol
Sampling procedures
Analytical methods
Sensitivity of methods
Acceptance criteria
Revalidation
Responsible persons for validation study
Responsible persons for approving study
Validation report
SOP’s detailing the cleaning processes

9. Validation Cleaning processes : Evaluation
Cleaning processes between batches of the same product
Validation not required
“Visibly Clean”
Equipment design
In the large equipment with CIP system sanitary type piping without ball valves should be used.
The length of time between the end of processing and each cleaning step
The drying of residues affects cleaning efficiency.
Equipment should be dried before storage.

10. Validation Cleaning processes : Evaluation Analytical methods Sampling
Determine the specificity & sensitivity.
Sampling
Direct surface sampling (swab method)
Indirect sampling (rinsing)
Efficiency of recovery
Acceptable limit of residues
Ensure the limit is scientifically justifiable.

11. Validation Cleaning processes : Establishment of limits
NMT 10ppm of any product will appear in another product.
NMT 0.1% of the normal therapeutic dose of any product will appear in the maximum daily dose of the following product.
No quantity of detergent residue should be visible on the equipment after cleaning.

12. Validation Cleaning processes : Establishment of limits
For certain allergenic ingredients, penicillins, cephalosporins, potent steroids & cytotoxics
the limit should be below the limit of detection
by best available analytical methods.
In practice dedicated plants are used.

13. Validation A process is considered validated if :
Validated support system
Justified sampling plan for the product
The process & product meeting specifications
No deviations indicating a lack of process or product control
Consistency of the process : meeting predetermined specifications

14. Sequence of Validation
Support systems/processes
HVAC, WFI/PW, Steam, Compressed air, Dust collection ∙∙∙∙
Cleaning, Sterilization, Depyrogenation, Decontamination ∙∙∙∙
Manufacturing Processes
Critical production processes impacting on :
Product quality
Reproducibility of the process
Parameters
Range of variability
Sampling
Testing via validated methods
Consistency : 3 consecutive batches (full production scale)

15. Laminar Flow Hoods (LFH)
Laminar flow vs. Turbulent flow
Laminar flow hoods
Clean bench (booth)
Biological safety cabinet
Class Ⅰ
Class Ⅱ type A1
Class Ⅱ type B1
Class Ⅱ type B2
Class Ⅱ type A2
Class Ⅲ

16. Note : O = protected , X = not protected
Protection
Product O X
Personnel X O
Environment X O
Clean Bench
BSC Class Ⅰ
BSC Class Ⅱ type A1
Do type B1
Do type B2
Do type A2
BSC Class Ⅲ
Note : O = protected , X = not protected

17. Biological Safety Cabinet
Class I BSC
A = front opening
B = work surface
C = window
D = exhaust plenum
E = HEPA filter

18. Biological Safety Cabinet
The Class II BSC
(Type A1)
A = blower
B = rear plenum
C = supply HEPA filter D = exhaust
E = sash
F = work surface

19. Biological Safety Cabinet
The Class II BSC
(Type B1)
A = blowers
B = supply HEPA filters
C = sliding sash
D = positive pressure plenums
E = additional supply HEPA filter
or back pressure plate
F = exhaust HEPA filter
G = negative pressure exhaust
plenum
H = work surface

20. Biological Safety Cabinet
The Class II BSC
(Type B2)
A = storage cabinet
B = work surface
C = sliding sash
D = lights
E = supply HEPA filter
F = exhaust HEPA filter
G = supply blower
H = control panel
I = filter screen
J = negative pressure plenum

21. Biological Safety Cabinet
The Class II BSC
(Type A2)
A = front opening
B = sliding sash
C = light
D = supply HEPA filter
E = positive pressure plenum
F = exhaust HEPA filter
G = control panel
H = negative pressure plenum
I = work surface

22. Biological Safety Cabinet
The Class III BSC
A = stand
B = glove ports
C = O-ring for attaching arm-length
gloves to cabinet
D = sash
E = supply HEPA filter
F = exhaust HEPA filter
(note: the second exhaust HEPA filter
required for Class III cabinets is not
shown in this diagram)
G = double-ended autoclave or pass-
through box
(note: a chemical dunk tank may be
installed which would be located
beneath the work surface with access
from above.)

23. LFH(HEPA filter) Testing
Testing and certification
HEPA-filtered air velocity measurement
Leak test using DOP or PAO (Emery 3004)
Particle count
Air flow pattern
Testing frequency
1×/ 6 months

24. LFH(HEPA filter) Testing
Supply airflow velocity measurement
At 6-12inches from the filter face
At work level : 0.45±20% m/sec
m2 → minimum 4 measuring points
At least 1point/each filter outlet

25. LFH(HEPA filter) Testing
Filter leak test (DOP or PAO)
DOP challenge : 20-80μg/l
Polydispersed aerosol of 0.1~3.0μ(m) (mean: 0.3~1.0μ)
Acceptable criteria : ≤ 0.01% leak
Repair (IEST)
Area(filter) : ≤ 3%
Dimension : ≤ 1.5 inches
Filter scanning
At 1-2 inches from the filter face
With the speed of ≤ 1-2 inches/sec
Sampling rate : ≥ 1 ft3/min