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Cleaning Validation with TOC
• Jamie Thompson, EMEA Applications Specialist, GE Analytical Instruments
• Guidelines on how to use TOC (Total Organic Carbon) for documenting this type of
cleaning process control and how to subsequently manage documentation
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Agenda
• Background
• Non-specific methods have advantages
• TOC for Cleaning Design, Cleaning Validation and Continuous Verification
• Key parts of the regulations
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History
1993 – Lots of guidance based on Barr Labs Decision
1998 – TOC introduced to industry via pharmacopeias
2004-2006 – cGMP’s for the 21st Century, Process Analytical Technology (PAT)
2011 – New Process Validation Guidance
2012-2013 – PDA Technical Reports – Cleaning Validation
INSA 4 / 14
Cleaning is important since 1993
Your firm has not cleaned and maintained equipment at appropriate intervals to
prevent contamination that would alter the safety, identity, strength, or quality of the
drug product [21 C.F.R. § 211.67(a)].
For example, your firm has not successfully validated the cleaning process used for
cleaning non-dedicated manufacturing equipment. Your firm does not have
assurance that the cleaning processes effectively clean the equipment to
prevent contamination of drug products with cleaning agents and cleaning
agent carryovers from previously manufactured products. Please ensure your
cleaning validation studies place special emphasis on “worst case/hardest to clean”
drug products or components to assure cleaning is effective in all equipment used
for manufacturing drug products. Also, take into account for attributes that may
affect cleaning (e.g., solubility, viscosity, percent solids) and the cleaning
parameters (e.g., wash times, temperature, and pH) intended to be used during
routine cleaning. All analytical methods should be validated for measuring
these attributes. Source: http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2012/ucm327498.htm
INSA 5 / 14
Non-product specific methods for CV
• “Can Total Organic Carbon (TOC) be acceptable method for detecting residues of
contaminants in evaluating cleaning effectiveness?”
http://www.fda.gov/Drugs/GuidanceC
omplianceRegulatoryInformation/Guid
ances/ucm124777.htm#TOC
INSA 6 / 14
Is TOC acceptable for CV?
• “Yes. Since the publication of the inspection guide on cleaning validation in 1993, a
number of studies have been published to demonstrate the adequacy of TOC in
measuring contaminant residues.
• TOC or TC can be an acceptable method for monitoring residues routinely and for
cleaning validation and verification…”
• Monographs
• Guidance (e.g. PDA Technical Reports 29 & 49)
• Industry
• No audit warning letters
INSA 7 / 14
Analyser & Method Qualification
Specificity
Linearity
Range
Accuracy
Precision
LOD
LOQ
Robustness
Recovery
Calibration
TOC AIQ (IQ/OQ/PQ)
USP <1058>
Yes
Yes
Yes
Yes
Yes
Yes (Analyser)
Yes (Analyser)
Yes
N/A
Yes
AMV
ICH Q2R1
-
Yes (Compound)
-
Yes (Compound)
Yes (Compound)
Yes (Sampling method)
Yes (Sampling method)
Yes (in addendum 2)
Yes
N/A
INSA 8 / 14
Total Organic Carbon (TOC)
Inorganic carbon: Carbon dioxide, Hydrogen carbonate and Carbonate
Organic carbon: Covalently bonded carbon
Total organic carbon: A measure of all the organic carbon in a sample
API Excipient Cleaning Agent Degradant
e.g. Ibuprofen e.g. Caffeine e.g. Surfactant e.g. Protein fragment
INSA 9 / 14
Organics CO2 TOC
1. Oxidise 2. Detection
UV Membrane conductometric
Persulphate
Organic (R) → CO2 + H2O
R-N → H2O + H+ + NO3-
R-P → H2O + H+ + H2PO4-
N-S → H2O + H+ + HSO4-
R-Cl → H2O + H+ + Cl-
INSA 10 / 14
Advantages of TOC for CV
• “Non-product specific methods are now considered more stringent – they provide more
data on contamination than HPLC.”
http://www.ivtnetwork.com/article/methodology-assessing-product-inactivation-during-cleaning-part-ii-setting-
acceptance-limits
API + Excipients + Cleaning Agents
+Degradants + Cleaning Process By-
products = Contamination
Specific method
Non-specific method
Microbiological method
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Sampling
• Rinse
• Swab
• Off-line
– Rinse
– Swab
• At-line
– Rinse
– Swab
• On-line
– Rinse
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TOC Analysis
TOC method Sample method Rinse Swab Results
Lab Grab samples Y Y Paper / Electronic
At-line Grab samples Y Y Paper / Electronic
On-line On-line Y N Directly into PLC/SCADA
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1
4
Design Phase
• TOC plays a major role during the design phase with a focus on 1) the intended use of the production equipment, 2) cleaning agents & compounds, 3) sampling and sampling locations, 4) recovery studies, 5) limits, 6) analytical instrument qualification, and 7) method validation.
Validation Phase
• TOC* sampling is utilized to during the performance qualification (PQ) of production equipment including steps to verify the cleaning process parameters (TACT) are designed and capable of meeting predetermined limits.
Continued Verification Phase
• TOC* sampling is utilized to verify that the cleaning process is still within the validated state through routine monitoring or product change over sampling.
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Design Phase
• Typical parts of the Design Phase
• Production Equipment
• Cleaning Agents & Compounds (Cleanability study)
1. Cleanability study (pre-validation test)
2. Lab samples
3. Analysis
4. Results typically stored by lab / validation
• Sampling of Equipment (Swab and/or Rinse)
• Acceptance criteria for Equipment (Limits)
• AIQ (USP <1058>)
• Recovery Testing (Sampling method)
• Analytical Method Validation of TOC (ICH Q2R1)
INSA 17 / 14
Qualification (Validation) Phase
• Does the cleaning process work for the manufacturing process?
• Samples taken from production equipment
• Samples typically sent to the lab
• Analysis
• Results generated in lab and stored in lab system (paper, LIMS)
• Results typically entered onto CV Report
INSA 18 / 14
Cleaning Process
VALIDATION
Remember a process needs to be
measured for effectiveness…
Every Cleaning Process needs TACT!
T – Temperature
A – Action
C – Cleaning Agent Concentration
T - Time
Sample
Rinse or Swab
Analyze Report
Flush/Vacuum
Cleaning Agent
Flush
Final Rinse
Batch Cleaning
Process
“Equipment released for next batch”
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Continued Verification Phase
• Does the cleaning process work continue to work for the manufacturing process?
• Samples taken from production equipment
• Samples typically sent to the lab
• Analysis
• Results generated in lab and stored in lab system (paper, LIMS)
• Results onto Revalidation Report / Equipment Use Record / Verification Report
INSA 20 / 14
Cleaning Process
Every Cleaning Process needs TACT!
T – Temperature
A – Action
C – Cleaning Agent Concentration
T - Time
Sample
Rinse or Swab
Analyze Report
Flush/Vacuum
Cleaning Agent
Flush
Final Rinse
Batch Cleaning
Process
“Equipment released for next batch”
VERIFICATION
Is the process still working effectively
as validated?
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Limits example
MAC = ADI x Batch Size
Max Daily Dose ADI =
LD50 x 80 kg
SF (e.g. 1,000) Equipment =
MAC
Total Surface Area
Swab = Equipment x Swab Area Swab Sample = Swab
Vial Volume Rinse Sample =
MAC
Working Volume
Swab Sample for TOC = Swab
Vial Volume Rinse Sample for TOC =
MAC
Working Volume x % Carbon x % Carbon
or
or
Only carry out the calculation if
the Acceptable Residue Limit is
less than 10 ppm!!!!!
1. This is an example. Refer to PDA Technical Report 29 and 49 for further guidance
2. Key points: Safety factor depends on route of administration, different limits possible for
rinse and swab, you can use a % carbon for TOC for a compound
INSA 22 / 14
New limits guidance
EU Annex 15 Qualification and Validation
• 9.5 Limits for the carry over of product residues should be based
on a toxicological evaluation to determine the product specific
permitted daily exposure (PDE) value.
EMA Guidance on PDE
•
• F1: Factor for extrapolation between species
• F2: Factor for variability between individuals
• F3: Factor for repeat-dose toxicity studies of short duration
• F4: Factor may be applied in cases of severe toxicity
• F5: Factor may be applied if the no-effect level was not established
INSA 23 / 14
Regulations - Validation
• EU: Eudralex Vol 4, Annex 15 Qualification and Validation
• Cleaning validation should be performed in order to confirm the effectiveness of a
cleaning procedure
• US: Drugs 21 CFR 211.67(a), Dietry Suppliments 21 CFR 111.27(d)
• Equipment must be cleaned at appropriate intervals
• US: Medical Devices 21 CFR 820.70
• Procedures to prevent contamination of equipment or product by substances that could
reasonably be expected to have an adverse effect on product quality.
• ICH Q7
• Cleaning validation is to demonstrate a cleaning process must consistently clean the
equipment to a predetermined limit
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Regulations - Verification
• Eudralex Vol 4, Annex 15 Qualification and Validation
• Facilities, systems, equipment and processes should be periodically evaluated to verify
that they are still operating in a valid manner.
• ICH Q7
• Cleaning procedures should be monitored at appropriate intervals after validation to
ensure that these procedures are effective when used during routine production
INSA 25 / 14
Summary
• TOC is acceptable and an effective tool for all 3 phases of process validation
• TOC is non-specific and can detect contamination of API, excipients, degradants,
cleaning agents and contamination
• Non-specific methods (TOC) are good for equipment release whereas specific methods
are more applicable to product release
INSA 26 / 14
Thank you and questions
• LinkedIn: Cleaning Validation Re-Imagined
