Objectives

Systems-Based Inspections  Describe cleaning processes and

for Cleaning Validation approaches
 Identify various techniques utilized
FDA DG 230 to measure the effectiveness of
July 20, 2017 cleaning processes
New Orleans, LA  Identify documents associated with
Destin A. LeBlanc
cleaning validation processes
Cleaning Validation Technologies  Identify significant issues and typical
www.cleaningvalidation.com problems with cleaning validation
1 2

Cleaning Critical cleaning?

 Definition: The process of  Critical cleaning must be validated
removing potential contaminants  Cleaning between products
from process equipment such that  Focus on product contact surfaces
the equipment can be safely used  Significant indirect product contact
surfaces
for subsequent product  Applies to drug products and APIs
manufacture  Dedicated equipment
 Focus for this presentation is  Documented evidence of effectiveness
process equipment, not cleanroom  Also address cleaning agent and
cleaning bioburden
3 4

Non-critical cleaning? Life Cycle Approach

 Validation not required for non-critical  Stage 1: Process Design (and
cleaning Development)
 Floors, walls, outside of vessels  Stage 2: Process Qualification
 Still have cleaning SOP
 Utilities, equipment, facility
 Residues on such surfaces are addressed by
containment procedures and personnel  Process Performance qualification (PPQ)
practices  Stage 3: Continued Process Verification
 Only loosely adherent residues can become (or maintenance of state of control, or
airborne for cross-contamination
 For highly hazardous actives, may evaluate
validation maintenance)
as part of a overall risk assessment  Based on FDA Process Validation
 Some API intermediate steps (ICH Q7) guidance
5 6

Cleaning Validation/LeBlanc/FDA DG 230 July 20, 2017 1

 Paradigm change Cleaning validation
 Companies moving to “lifecycle”  Documented evidence (reports)
approach
 High degree of assurance (data)
 Legacy products will be in traditional
paradigm  Consistency (traditionally multiple
 But -- PQ runs)
 Design and development has always been  Predetermined quality attributes (of
done equipment)
 Monitoring and control after validation
runs has always been done
For repeated cleaning processes
 So, don’t be afraid to ask for it Throughout life cycle
7 8

Cleaning verification Systems-Based?

 Documented evidence  Inspection starts with higher level
 High degree of assurance documents to determine if appropriate
practices are specified
 For unique or non-repeatable events
 Moves to lower documents as
 Quality attributes may be evaluated appropriate to confirm compliance with
later depending on next product higher level documents
For clinical products cleaning,  SOPs (cleaning and cleaning validation)
infrequent production, cleaning  Rationales
after maintenance or deviations  Protocols and protocol reports
One time  Batch records
9
 Validation maintenance documents 10

Differences PV vs. CV Differences PV vs. CV (2)

 Analytical values  Sampling

PV has a goal for conc. of active PV based on statistics –
(for example); want a narrow uniformity throughout batch and
range () from batch to batch
CV has limits for active (for CV based on worst cases – swab
example) that firm wants to be sample locations most likely to
below (<) have higher levels of residues
(difficult to clean)
11 12

Cleaning Validation/LeBlanc/FDA DG 230 July 20, 2017 2

 Differences PV vs. CV (3) Cleaning process

 Processes  Cleaning agent

For production process, each  Cleaning parameters
manufacturing process is more or  Cleaning method
less unique  ALL three are critical for defining
and controlling the cleaning process
For cleaning process, firms prefer  Addressed initially in design phase, but
to use one cleaning process for all may be modified based on info from
qualification and validation maintenance
manufactured products phase

13 14

Cleaning agent options Cleaning parameters

 Organic solvents  Time (3 aspects)
e.g., methanol Time before cleaning
 Water Time of cleaning steps
 Commodity chemicals (aqueous) Time after cleaning
e.g., caustic, phosphoric acid  Action (agitation or impingement)
 Detergents  Chemistry (includes concentration)
Surfactants  Temperature
Formulated aqueous cleaners
15 16

Cleaning parameters (cont.) Application methods

 Water quality  Objective of application method is

to contact the cleaning solution
 Rinsing with ALL the surfaces to be
 Soil condition cleaned to meet the requisite
Dried during manufacture cleaning parameters
Dried during dirty hold time  Time

 Soil levels (amount on surfaces)  Action

 Temperature
17 18

Cleaning Validation/LeBlanc/FDA DG 230 July 20, 2017 3

 How apply Common steps
 Static immersion  Pre-rinse
 Fill tank with water to slowly dissolve
 Water or solvent to remove bulk of
 Agitated immersion
residue
 CIP (Clean In Place)
 Wash step
 Automated parts washer
 Like home dishwasher  Utilizes cleaning agent or detergent
 Ultrasonic  Rinse
 Use of sound waves to remove particles  May include a final rinse with purer
 Manual grade of solvent or water
 Solvent reflux
 Drying and storage
 Boil with organic solvent like methanol
19 20

CIP parts Manual cleaning

 Types
CIP supply line with spray ball

Chemical
Wipe
Soak
supply
Chemical
feed
CIP Vessel to be Brush
Tanks Skid Cascade cleaned
Heat
down
sidewalls
Spray
exchanger
CIP pump Combinations of above
Probes

CIP return line with return pump

21 22

Manual issues Measuring effectiveness

 Control through…
 More detail in SOP  Key aspects
Disassembly Setting residue limits
Cleaning agent preparation Analytical techniques
Specific cleaning actions
Rinsing Sampling techniques
Drying
Reassembly
Storage
 Training/qualifying of operators
23 24

Cleaning Validation/LeBlanc/FDA DG 230 July 20, 2017 4

 Residues measured Key aspect of CV
 How selected?  “Intersection” of two products
 Should be based on what cleaned,  Product just manufactured- good
how cleaned, and effects on next cleaning to remove residues to
product acceptable level
 Minimum is usually active, cleaning  Product subsequently manufactured-
“acceptable level” is based on possible
agent, and bioburden
contamination of this product
 Others that may be important
 Must always evaluate effects on
 Endotoxin
subsequently produced product
 Degradants or byproducts
25 26

Residue limits How low?

 For actives  May contain measurable residues, but no
 Traditional approach is dose-based contaminants
calculation  A “contaminant” is an “unacceptable”
 Newer approach is “health based limit” residue
 ADE: acceptable daily exposure  Any residue must…
 PDE: permitted daily exposure  be medically safe
 not affect product quality
 For compounds without dose (such as  be reasonably avoidable
detergents), use ADI (acceptable  leave equipment visually clean
daily intake) based on toxicity  Last four points in FDA’s Q&A on CGMP
information (LD50) 27
(6/8/2015) 28

Overall dose-based equation Other considerations

(0.001)(min.dose Act.A) (B.S.) (S.A.)  For highly hazardous actives
(max.dose Prod.B)(S.S.A.)(S.E.A.) (allergens, cytotoxics, actives
with reproductive concerns, etc.)
Where  May set limit based on LOD (limit
B.S. = minimum batch size Prod.B
of detection) of analytical technique
using best available procedure, OR
S.A. = sampled area  May dedicate equipment, OR
S.S.A. = shared surface area  May set limit on ADE or PDE using
S.E.A. = solvent extraction amount the specific highly hazardous
property (substitute for 0.001
(For finished drug product manufacture) minimum daily dose of active in
29
equation in previous slide) 30

Cleaning Validation/LeBlanc/FDA DG 230 July 20, 2017 5

 Other considerations (2) Limit for microbes
 For highly hazardous actives, may  Limits based on scientifically justified
want to look at other modes of
potential contamination (these are not carryover calculations usually result in
strictly process equipment cleaning impractically high values
validation, but may be addressed by  Most will default to limit of 25-50 CFU
risk analysis) per 25 cm2 (1-2 CFU/cm2) for non-
 Non-product contact surfaces (from dusts sterile manufacture
that become airborne, settle on surfaces,
become airborne again, and contaminate  For rinse water (non-sterile
next product) manufacturing), default to Purified
 Containment practices (including HVAC) Water specifications
 Room cleaning practices
 Operator practices, garments 31 32

Visual cleanness Analytical method

 Include visual inspection  Is it a direct measure of
 Complements rinse and/or swab
residue?
sampling
 Key is to not have cleaning residues  Is LOD/LOQ appropriate for
left behind limit in analytical sample?
 Issues  Both specific and non-specific
 Background variations
methods may be used
 Rouge - may be indicative of a
maintenance problem, but generally not
a cleaning problem 33 34

Specific method Specific method (2)

 Unequivocally measure target  Potential problems with specific
residue in the presence of methods
expected possible interferences  Interference from cleaning agent or
cleaning process by-products
 Examples: HPLC, UPLC, UV,
ELISA  Active degraded in cleaning process so
that residues are degradants, not
intact active
 If degrades and use specific method for
active, will always be non-detectable
 Addressed in method design and
35
development 36

Cleaning Validation/LeBlanc/FDA DG 230 July 20, 2017 6

 Non-specific methods Why TOC acceptable?
 Measure any species with a  Residue limit is NOT goal
certain response  Goal is to be below limit
 Most common is TOC (Total  If treat all measured Carbon as
Organic Carbon) if it were from the target
 See FDA’s Q&A on cGMP for residue (worst case), AND it is
below the acceptance limit, can
Drugs, May 2005 for issues in
have assurance that residue is
proper use below limit
37 38

Analytical method validation Sampling methods

 Generally done for cleaning validation
 “Swab” sampling
 LOD/LOQ
 Accuracy - closeness to true value Sometimes called “direct”
 Precision - closeness among measurements sampling
 Range
 Linearity  “Rinse” sampling
 For cleaning verification mode in clinical Sometimes called “indirect”
manufacture, may have simpler analytical
method validation (pass/fail test, for sampling
example)

39 40

Swabs Swabbing SOP

 Advantages  Specify swab (supplier and part no.)
 Can focus on “worst-case” locations  Specify surface area to be swabbed
(usually 25-100 cm2)
 Mechanical means of removing
 Specify wet or dry (& solution, if wet)
substances
 Specify template (if used)
 Issues  Specify number of swabs
Interferences from swab  Specify swab pattern
Swabbing is a manual procedure  Specify vial
 Specify swab transport
Access to sampling sites  Specify blanks/controls
41 42

Cleaning Validation/LeBlanc/FDA DG 230 July 20, 2017 7

 Swabs Pressure effects




43 44

Template vs. "Eyeball” Swab sampling locations

 Template more consistent Most difficult-to-clean locations

 But template less useful on “non-flat”  Good practical common sense
 Non-flat surfaces are generally going  Prior experience
to be the worst-case locations that Sites for non-uniform
require the eyeball method contamination
 My preference: Rather than training
 Different materials
on both methods, spend more time on
training on eyeball method, since this  Functional locations
will be on most critical surfaces
45 46

Rinse sampling “Rinse” sampling

 Definition: Using a solvent to  Advantages
contact all surfaces of sampled  Sample “inaccessible” locations
item to quantitatively remove target  Provides overall picture
residue  Issues
 Solvent can be water, water with  Solubility of residue in rinse solution
pH adjusted, or organic solvent  Need to relate amount in rinse
 Must contact all surfaces sample to potential contamination of
next product
 Residue measured in collected
sample
47 48

Cleaning Validation/LeBlanc/FDA DG 230 July 20, 2017 8

 Recovery studies Swab recovery schematic
 Recovery study - swabs & rinse
 Procedure
 Spike coupon with known amount 1.Spike control diluent directly
 Remove in swab or simulated rinse procedure control
 For swab, desorb standard
solution 2a. Spike
 Analyze sample
coupon
 Done at or below surface acceptance limit 2b. Swab coupon test
 In method validation or separate study 2c. Extract
swab
49 50

Acceptable recovery Challenges

>80% is good  For PPQ runs
 Process conditions (within normal
>50% is okay process conditions)
<50% is questionable  Different operators for manual
cleaning
Caution: May use recovery
 Bioburden
factor to correct measured  Dirty hold time
analytical value or acceptance  Clean hold time
limit (but not both)  Under life cycle approach, may be
51
addressed in design/development 52

Dirty hold time Dirty hold time (2)

 What?  What do?
 Time between end of manufacture and
Specify a maximum hold time in
beginning of cleaning cleaning SOP
 Why? Challenge worst-case condition in
 Manufactured product may be harder validation (at least one run at
to clean (dries, bioburden growth) maximum if not addressed in
 Issues design/development)
 Sometimes cleanability does NOT
change with time (e.g., dry products)
53 54

Cleaning Validation/LeBlanc/FDA DG 230 July 20, 2017 9

 Clean hold time Clean hold time (2)
 What?  What done?
 Time from end of cleaning to beginning  Specify maximum hold time in SOPs
of manufacture  For extended storage, dry equipment (as
 Sometimes called expiry period part of cleaning SOP)
 For extended storage, seal/wrap
 Why?
equipment appropriately
 Equipment may become recontaminated
 Measure residues before and after
during storage (bioburden, dust) storage (may be in separate protocol)
 Issues  Usually are measuring bioburden and
 If dry and sealed, should not be visual cleanness
recontaminated 55  Criteria is change from baseline 56

Grouping strategies Grouping conditions

 Grouping  Conditions to meet for product

By product (soil)
grouping
Similar product type
By equipment
In same equipment train
 Also called matrixing, family
Identical cleaning process
approach, bracketing
Cleaning agent
 Rationale Cleaning method
Simplify amount of validation work Process parameters
57 58

Representative product Representative limit

 Representative: most difficult  Residue limit selection

to clean Lowest limit among group
 Basis of selection OR
Historical Validate most difficult to clean
Solubility data (at its limit) and most “toxic”
(product with lowest limit)
“Point system” based on several
factors
Lab/pilot study 59 60

Cleaning Validation/LeBlanc/FDA DG 230 July 20, 2017 10

 Equipment grouping Grouping conditions
 Must be similar type
 Look for rationales for:
 Identical equipment (identical for
cleaning purposes) Forming groups
 May involve simple equipment of Selecting worst case
different sizes Selecting residue limits
 Example: 300L, 500L and 1000L tanks
 Alternatives --
 Validate separately largest & smallest
sizes
 Validate together testing extremes
61 62

CV maintenance Monitoring objective

 Monitoring  Different companies may use the word

 Change control “monitoring” differently
 For me, routine monitoring is done
 Deviations
every cleaning event initially, and then
 Training and retraining perhaps on a reduced schedule
 Continuing control  Collect data to determine process
 Note: “revalidation” is control
disappearing from FDA lexicon  Monitoring alert/action levels generally
more stringent than limits in protocol
63 64

Monitoring during routine cleaning Regular review

 May monitor key control parameters  Repeat of PPQ run on any significant
 Time(s) change
 Temperature(s)  On a “regular” basis (such as yearly)
 Cleaning agent concentration evaluate consistency based on
 Pressure  Monitoring data
 Change control data
 May monitor key indicators of control
 Deviations
 Rinse water TOC or conductivity
 Quality records
 Visual examination  Training
65 66

Cleaning Validation/LeBlanc/FDA DG 230 July 20, 2017 11