Cleaning_Validation of Clean Room Facility.ppt

Cleaning_Validation of Clean Room Facility.ppt

1. BE WELL
Bart van Osch
MSD bv Haarlem, the Netherlands
Vacsera / Egypt MoH
Cairo Jan 30, 2014
Setting up a good Cleaning
Validation Concept

2. 2
Steps in a cleaning validation plan
Design the Cleaning Process
Design the Validation Approach
Prepare the validation studies (protocols)
Other considerations
Maintaining validated state
 capture considerations in Cleaning Validation
Program, Validation Master Plan or Project Plan
Introduction – cleaning – validation – prepare – other – maintaining

3. 3
Structure of the validation program
Introduction – cleaning – validation – prepare – other – maintaining
Study 1
Validation
protocol
Study 2
Validation
protocol
Study 3
Validation
protocol
Cleaning Validation Program
Validation Master Plan
Cleaning Validation Program
Revalidation or regular review

4. 4
Manual or CIP: different considerations
Method standardization !!!
Method
Times
Tools
Training
Regular monitoring/re-
testing most important
Technical design !!!
Nozzles
Automation
Worst case spots
Control on utilities
Initial validation most
important
Introduction – cleaning – validation – prepare – other – maintaining
Manual CIP

5. 5
Potent Compounds (toxic, sensitizing, antibiotics)
Dedicated equipment where possible
Check Lower Detection Limit !
Often long cleaning with detergents
Spill procedure might need validation
Introduction – cleaning – validation – prepare – other – maintaining
!! Operator safety often equally important to cross-
contamination !!

6. 6
Dedicated equipment
Establish Dirty Hold Time
Establish max campaign length based on stability of active
and inactive compounds
Consider accepting visually clean
Introduction – cleaning – validation – prepare – other – maintaining

7. 7
Validation tests
Rinse sample testing
Tracers / Colorants
Visual Residue Level
Microbial testing
Swab testing
Matrixing
Introduction – cleaning – validation – prepare – other – maintaining

8. 8
Rinse sample testing
Use only as test in addition to swabbing
Gives an ‘average’ rather than worst case spots
Might miss dead spots
Only works with near 100% recovery rate
Gives quick and ‘easy’ insight in cleaning behavior
Perfect experimenting in method design
Sometimes your only option for difficult-to-reach places
(example: interior of mass flow meter)
Introduction – cleaning – validation – prepare – other – maintaining

9. 9
Tracers and Colorants
Use only as test in addition to swabbing
Need to proof that the agent is cleaned away after test
Perfect for quick and easy (visual!) experimenting in
method design.
Introduction – cleaning – validation – prepare – other – maintaining

10. 10
Visual Residue Level
Approach:
Apply series of contamination levels with actual
product(s) to actual surface material(s); determine which
contamination level is still clearly visible. If VRL <
Acceptable Residue Level, than visual inspection is
preferred method of cleaning validation
 Still need to take validation approach: do not ‘clean
until visually clean’ as normal operating procedure.
 Requires high accessibility of equipment: angle of
inspection/lighting is critical
 some visual examination should be part of every
cleaning validation
Introduction – cleaning – validation – prepare – other – maintaining

11. 11
Microbial testing
Sterile processes: Broth Fill Trials is very powerful test
Include maximum sterile processing time, max dirty/clean
hold times, all relevant manual interventions, exact copy of
process (all piping).
Non-sterile / dry: if Water Activity is low: might not be an
issue (see USP General Information Chapter 1112)
Non-sterile / wet: Risk Assessment needed to evaluate
product characteristics.
Growth promoting, growth inhibiting or bactericidal? Not only
cleaning procedure but also operating conditions are
important: humans are primary source of contamination!
Introduction – cleaning – validation – prepare – other – maintaining

12. 12
Swab testing
Analytical method optimized (extraction solvent!!)
Recovery optimized (swab type, wetting agent, #swabs,
surface area)
Swabber trained: consider ‘swabber certification’!
Swab SOP
Swab surface area aid (25 cm
2
window)
Intermediate storage: cover, max time
Accessibility: create swab accesses?
Set all conditions to worst case
Introduction – cleaning – validation – prepare – other – maintaining

13. 13
Matrixing or bracketting
Select worst case:
Previous product (lowest solubility)
Previous product (lowest ADI)
Next product (highest MDD) For calculating limits
Next product (lowest batch size)
Locations
Equipment (highest surface; worst surface type)
 Cleaning validation programs often use matrixing, but:
matrixing tightens the limits !
Introduction – cleaning – validation – prepare – other – maintaining

14. 14
Limits or ARL: Acceptable Residual Level
1.Healthbased limit: never allow more than lowest clinically
relevant amount of previous product in next product
ref 1
2.Industry standard: should always be possible to clean
<100µg/25cm
2
3.Industry standard: should aim for <10 PPM carry over in
next batch, if feasible
ref 2
Apply most stringent of ARL1, ARL2 and ARL3.
Allow for some flexibility with respect to ARL3
Introduction – cleaning – validation – prepare – other – maintaining

15. 15
Limits Swabs (mg / swab)
ARL1 =
 SB and MDD both in active compound weight or both in units
ARL2 = 0.1 mg/25cm
2
ARL3 =
 SB in total kg batch size
ADI * SB * Area * Recovery
MDD * SSA
10 * SB * Area * Recovery
SSA
Introduction – cleaning – validation – prepare – other – maintaining

16. 16
Limits Rinse (mg / L)
ARL1 =
 SB and MDD both in active compound weight or both in units
ARL2 = 100 µg/25cm
2
ARL3 =
 SB in total kg batch size
ADI * SB * RinsedArea
MDD * SSA * RinseVolume
10 * SB * RinsedArea
SSA * RinseVolume
Introduction – cleaning – validation – prepare – other – maintaining

17. 17
Analytical methods
Existing analytical methods often need considerable re-
designing to accommodate for low concentrations
Be aware of lower detection limit!
Change of solvents is often the clue to success
Determine the recovery percentage for every compound
under study and for every surface type; example test
requirements: >40% and reproducible within ±3% for 5
replicates
Separate qualification of swabbers is great value for
money; pay attention to both accuracy and reproducibility
Introduction – cleaning – validation – prepare – other – maintaining

18. 18
Roles and Responsibilities
in typical Pharm company
Manufacturing: plan validation time, perform cleaning for
validation purposes, keep on standardizing and improving
cleaning processes (SOP’s, change control)
Quality: validate analytics, perform sampling, perform
analyses, review&approve protocol upfront,
review&approve report after validation, release equipment
back to manufacturing
Technical: Write validation protocol, lead validation, write
validation report.

19. 19
Other considerations
Campaign length or cleaning frequency
Might be irrelevant based on good scientific judgment
Dirty Hold Time
always important for cleanability
Clean Hold Time
Might be irrelevant based on good scientific judgment
Introduction – cleaning – validation – prepare – other – maintaining

20. 20
Maintaining the matrix
Change control procedures should include cleaning
validation assessment when changes are made to:
Equipment (contact area, surface material, cleanability)
Products (ADI, MDD, solubility)
Batch size
Clean or dirty hold times
Campaign length
Cleaning methods (times, tools, order, automation,
detergents, temperature, …)
Introduction – cleaning – validation – prepare – other – maintaining

21. 21
Revalidation program
For manual processes at least annual assessment
Any changes missed (see previous slide)
Confirmation batch to assess prolonged consistency of
cleaning activity
For automated CIP not necessary if change control is
robust
Introduction – cleaning – validation – prepare – other – maintaining

22. 22
Questions?
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Thank you!

23. 23
References to slide 14
1.Conine, David, Bruce Naumann, Lawrence Hecher,
setting health based residue limits for contaminants in
pharmaceuticals and medical devices, Quality
Assurance: Good Practice, Regulation and Law, Vol I,
No. 3 (June 1992), pp 171-180
2.Fourman, Gary and Michael Mullen, Determining
cleaning validation acceptance limits for pharmaceutical
manufacturing operations, Pharmaceutical Technology,
(April 1993) pp. 54-60

24. 24
Equation elements from slides 15 and 16
ADI = Acceptable Daily Intake (mg/day)
= lowest clinically relevant dose OR 0.1% therapeutic dose
SB = Smallest Batch size of next product
(see footnote for Unit of Measure)
Area = Swab area, usually 25 cm
2
Recovery = Percentage divided by 100%,
should be within 0.40 - 1.00
MDD = Maximum Daily Dose (units per day of
next product; worst case: lowest dose)
SSA = Shared Surface Area (cm
2
)
RinsedArea = (cm
2
)
RinseVolume = Volume of final rinse (L)

25. 25
Public documents provided on paper
Cleaning validation guideline from Health Canada
(recommended as most practical and complete guidance
by any of the regulatory bodies)
USP <1112>: provides rationale for reduced or eliminated
microbial testing based on water activity
FDA inspection guide on cleaning validation