RISK-BASED

CLEANING VALIDATION

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AGENDA
• Applying QRM to Cleaning Validation
• Regulatory Basis
• Scope of Cleaning Validation within Process Validation Lifecycle
• Stage 1: Cleaning Process CQAs, CPPs
• Developing Risk-Based Cleaning CQAs and Carryover Limits
• Developing Risk-Based Cleaning CPPs
• Stage 2a: Cleaning Equipment Design, C&Q
• QRM-Based Design, C&Q of Cleaning, Client Equipment, Utilities
• Stage 2b: Cleaning PPQ (CV)
• Cleaning Process-Related Prerequisites
• Product- and Equipment-Related Prerequisites
• Sampling/Testing Prerequisites
• Operational Prerequisites
• Stage 3: Cleaning CPV
• Q&A
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Applying QRM to Cleaning Validation

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REGULATORY BASIS
Risk-Based Cleaning Validation

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CLEANING VALIDATION: REGULATORY BASIS

• ISPE Guide: Cleaning Validation Lifecycle (2020):

Applications, Methods, and Controls
• Introduction:
• “Cleaning validation is a requirement of the biotechnology, biological, pharmaceutical,
diagnostics, medical device, nutraceutical, and in some cases cosmetic industries.
Regulatory agencies expect the development and validation of a compliant cleaning
program. This critical activity ensures that the risks of contamination, product carryover, and
cross-contamination are controlled, minimized, and monitored to safeguard patient safety
and product quality.”
• EU EudraLex, Volume 4, Annex 15 (2015):
EU Guidelines for GMPs for Medicinal Products for Human and Veterinary Use
• Cleaning Validation:
• “Documented evidence that an approved cleaning procedure will reproducibly remove the
previous product or cleaning agents used in the equipment below the scientifically set
maximum allowable carryover level.”

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RISK-BASED CLEANING VALIDATION: REGULATORY BASIS

• US FDA Report (2004):

Pharmaceutical Development for the 21st Century – A Risk-Based Approach
• Innovation, QRM/Quality Systems, Risk-Based Approaches, Critical Areas, State of
the Art Science
• US FDA Guidance for Industry (2011):
Process Validation: General Principles and Practices
• QRM/Quality Systems, Risk-Based Decisions, Criticality as a Continuum, Control
Commensurate with Risk, Less Reliance on Terminology
• EU EudraLex, Volume 4, Annex 15 (2015):
EU Guidelines for GMPs for Medicinal Products for Human and Veterinary Use
• Control of Critical Aspects, QRM Approach, Risk Assessment Basis/Justification for
Qualification/Validation

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SCOPE OF CLEANING VALIDATION
Cleaning Validation within the context of the Process Validation Lifecycle

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 SCOPE OF CLEANING VALIDATION LIFECYCLE

• Cleaning Process Validation Lifecycle

• Stage 1: Process Design (ICH Q8)
• Output: Product and Process Knowledge (PPK) (CQAs, CPPs), Process Requirements
• Stage 2a: Facility, Utility System, Equipment (FSE) Design, C&Q
• Input: PPK, Process Requirements
• Output: Qualified systems
• Stage 2b: Process Performance Qualification (PPQ)
• Input: Qualified FSE systems
• Output: Validated cleaning process
• Stage 3: Continued Process Verification (CPV) (ICH Q10)
• Input: Validated cleaning process
• Output: Lifetime cleaning process validated state / state of control

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 SCOPE OF CLEANING VALIDATION LIFECYCLE

• Cleaning Process Validation

Lifecycle
• Stage 1: Process Design
• Stage 2: Process Performance
Qualification (PPQ)
• Stage 3: Continued Process
Verification (CPV)

ISPE Guide: Cleaning Validation Lifecycle, Figure 1.3

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 SCOPE OF CLEANING VALIDATION LIFECYCLE

• Stage 1: Process Design

• Develop Cleaning PPK • Outputs: Cleaning PPK
• Complete Residue Characterization • Cleaning process CQAs, CPPs
• Select Cleaning Agents • Developed cleaning process “Basis
• Determine Process Parameters and of Design”
Criticality • Product/Equipment Cleaning Risk
• Select Cleaning Methods Assessments
• Review Equipment Design • Carryover Limits
Considerations
• Acceptance Criteria
• Define & Justify Cleaning Limits
• Select Analytical & Microbial Methods
• Identified Methods
• Define Sampling Methods & Conduct • Identified Sampling Methods,
Recover Studies Recovery
• Define Acceptance Criteria
• Conduct Small-Scale Studies

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 SCOPE OF CLEANING VALIDATION LIFECYCLE

• Stage 2: Cleaning PPQ

• Design, Deliver (C&Q) • Outputs:
• Complete Equipment Qualification • Qualified Systems
• Process Performance Qualification • Cleaning Systems
• Validate Analytical & Microbial Methods • CIP/COP Skids
• Define Validation Strategy, # of Runs • Client Equipment
• Define Sampling Plan • Vessels, Piping, Transfer Panels,
• Define Visual Inspection Criterion etc.
• Write SOPs • Validated Cleaning Process
• Write Cleaning Validation Protocol • Cleaning Validation Master Plan
• Train Personnel • CV Protocol(s) / Report(s)
• Execute Cleaning Validation Protocol(s) • Established Cleaning Procedures
• Complete Cleaning Validation Reports • Controlled Cleaning Cycles/Recipes

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 SCOPE OF CLEANING VALIDATION LIFECYCLE

• Stage 3: Cleaning CPV

• Continued Process Qualification • Outputs:
• Monitor Cleaning Process Performance • Maintain Validated Cleaning
• Conduct Periodic Reviews of Cleaning Process
Process State of Control • Routine/Continuous Monitoring
• Evaluate Changes via Change Control • Change Management / Risk
• Determine: Is Cleaning Process in a Assessment
State of Control? • New Product Introduction
• Yes: Iterate CPV Activities • New Equipment Introduction
• No: Investigate and Determine • Periodic Assessments
Appropriate Corrective Action
• Process Re-design
• Process Re-qualification

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CLEANING AND QRM
Cleaning as application of QRM

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RISK-BASED CLEANING VALIDATION
ICH Q9: QRM Process

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 RISK-BASED CLEANING VALIDATION

• What is Risk Assessment?

• The identification of hazards and the analysis and evaluation of risks
associated with exposure to those hazards. (ICH Q9)
• Risk Identification:
• What might go wrong?

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RISK-BASED CLEANING VALIDATION

But: risk to what, exactly?

• Risk to product quality

Quality of which product?

• Prior Batch (batch immediately prior to cleaning)?
• Next Batch (batch immediately after cleaning)

Risk of what hazard?

• Cross-contamination / adulteration

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 RISK-BASED CLEANING VALIDATION

• What is Risk Assessment?

• The identification of hazards and the analysis and evaluation of risks
associated with exposure to those hazards. (ICH Q9)
• Risk Identification:
• What might go wrong?
• Risk Analysis:
• Risk – combination of the Probability of Occurrence and Severity of a harm:
• Probability of Occurrence: What is the likelihood that it will go wrong?
• Severity: What are the consequences if it goes wrong?
• Sometimes considered:
• Probability of Detection: What is the likelihood that a failure will be detected?
• Risk Evaluation:
• Is the identified level of risk acceptable?

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 RISK-BASED CLEANING VALIDATION

• What is Risk Control?

• Decision making to reduce and/or accept risks. (ICH Q9)
• Often performed concurrently with Risk Assessment
• Risk Reduction: Processes for mitigation or avoidance of quality risk
• Decrease Probability of Occurrence (or Severity)
• Increase Likelihood of Detection

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RISK-BASED CLEANING VALIDATION

So: cleaning is a risk reduction strategy!

How does cleaning reduce risk?

• Reduce occurrence: minimize product carryover
• Increase detection: increase routine monitoring

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 RISK-BASED CLEANING VALIDATION

• What is Risk Control?

• Decision making to reduce and/or accept risks. (ICH Q9)
• Often performed concurrently with Risk Assessment
• Risk Reduction: Processes for mitigation or avoidance of quality risk
• Decrease Probability of Occurrence (or Severity)
• Increase Likelihood of Detection
• Risk Acceptance: A decision to accept risk.
• Level of evaluated risk, or residual risk following Risk Control, is acceptable (sr. mgmt.
defines)
• Risk cannot always be completely eliminated, mitigated, or avoided
• Risk Control Strategy
• Collective processes implemented to mitigate or avoid unacceptably-high quality risk,
and to ensure residual risk meets a defined level of acceptability.
• Design Controls, Alarms, Procedural Controls
• The amount of effort used for risk control should be proportional to the significance of the
risk.

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Stage 1:
Cleaning Process CQAs, CPPs (TACT)

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PROCESS VALIDATION STAGE 1
Developing Cleaning Process CQAs

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 RISK-BASED CLEANING VALIDATION

• Stage 1: Cleaning Process Design

• Cleaning Process Critical Quality Attributes (CQAs):
• (Next Batch) Product Purity, Product Safety
• Residue Removal / (Prior Batch) Product Carryover

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PROCESS VALIDATION STAGE 1
Developing Risk-Based Carryover Limits

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 RISK-BASED CLEANING VALIDATION

• Developing Carryover Limits

• Residue Assessment (Carryover to Next Batch):
• Residue Sources
• Final drug product and raw materials (API, excipients) (Prior Batch)
• Intermediates, solvents, process aids (Prior Batch)
• Particulates, Bioburden, Endotoxin (Prior Batch)
• Detergents, product residue degradants (Cleaning Process)
• Residue Hazard Determination Factors (Prior Batch):
• Pharmacologic:
• Highly potent, highly toxic, allergenic
• Appearance/Consumer:
• Adversely impacts appearance, taste, smell, etc.
• Process:
• Inhibits (next batch) process (e.g. inhibits/interferes with chemical reactions)
• Cleaning/removal difficulty

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 RISK-BASED CLEANING VALIDATION

• Developing Carryover Limits

• Regulatory Basis
• US FDA Guide to Inspections – Validation of Cleaning Processes
• "FDA does not intend to set acceptance specifications or methods for determining
whether a cleaning process is validated... The firm's rationale for the residue limits
established should be logical based on the manufacturer's knowledge of the materials
involved and be practical, achievable, and verifiable.“
• "Some limits that have been mentioned by industry representatives in the literature or in
presentations include analytical detection levels such as 10 PPM, biological activity
levels such as 1/1000 of the normal therapeutic dose, and organoleptic levels such as
no visible residue.“
• "The objective of the inspection is to ensure that the basis for any limits is scientifically
justifiable.“
• "...unlike product residues, it is expected that no...detergent levels remain after
cleaning. Detergents are not part of the manufacturing process and are only added to
facilitate cleaning during the cleaning process. Thus, they should be easily removable.“
• "When the cleaning process is used only between batches of the same product (or
different lots of the same intermediate in a bulk process) the firm need only meet a
criteria of, "visibly clean" for the equipment. Such between batch cleaning processes do
not require validation."

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 RISK-BASED CLEANING VALIDATION

• Developing Carryover Limits

• Regulatory Basis
• EU Annex 15 (10.5)
• "Limits for the carryover of product residues should be based on toxicological
evaluation.
• The justification for the selected limits should be documented in a risk assessment
which includes all the supporting references.
• Limits should be established for the removal of any cleaning agents used.
• Acceptance criteria should consider the potential cumulative effect of multiple items
of equipment in the process train.“

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 RISK-BASED CLEANING VALIDATION

• Developing Carryover Limits

• Quantitative
• Safety-Based (Toxicological): Maximum Safe Carryover (MSC)
• Daily Exposure (EU Annex 15 / ISPE Risk MaPP)
• Acceptable Daily Exposure (ADE) / Permissible Daily Exposure (PDE)
• ISPE: Health-Based Exposure Limits (HBEL)
• Therapeutic Dose (PIC/S)
• NMT 0.1% (1/1,000th) of therapeutic dose
• Process Capability/Control: Maximum Allowable Carryover (MACO)
• Cleaning Process State of Control
• NMT 10 ppm
• Qualitative
• Organoleptic
• Visual Inspection
• “No visual residue detected”, “Visually clean and dry”, etc.

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 RISK-BASED CLEANING VALIDATION

• Developing Carryover Limits

• Quantitative Limit Calculations
• [MSC]: Safety-Based Limit (Toxicological) (mass)
• Daily Exposure (ADE/PDE)
• [PDEPB]: ADE/PDE (Prior Batch) (mass/day)
• [MBSNB]: Minimum Batch Size (Next Batch) (mass)
• [MTDNB]: Maximum Therapeutic Dose (MTD) (Next Batch) (mass/day)

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 RISK-BASED CLEANING VALIDATION

• Developing Carryover Limits

• Quantitative Limit Calculations
• [MSC]: Safety-Based Limit (Toxicological) (mass)
• Therapeutic Dose (NMT 0.1% of therapeutic dose)
• [MTDPB]: Maximum Therapeutic Dose (Prior Batch) (mass/day)
• [MBSNB]: Minimum Batch Size (Next Batch) (mass)
• [MTDNB]: Maximum Therapeutic Dose (Next Batch) (mass/day)

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 RISK-BASED CLEANING VALIDATION

• Developing Carryover Limits

• Quantitative Limit Calculations
• [MACO]: Process Capability/Control Limit (mass)
• Cleaning Process State of Control (NMT 10 ppm)
• [MBSNB]: Minimum Batch Size (Next Batch) (mass)

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 RISK-BASED CLEANING VALIDATION

• Developing Carryover Limits

• Qualitative Limit Determination
• Organoleptic
• Visual Inspection (No visual residue detected)
• Observation of residue = failure
• FDA “dirty pot” analogy
• Can be correlated to recovery results/limits under certain conditions
• Known limit of visual detection (mass/area) (coupon studies)
• Limit of visual detection (mass/area) ≤ quantitative recovery limit (mass/area)
• Operator qualification for visual detection

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PROCESS VALIDATION STAGE 1
Developing Cleaning Process CPPs

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 RISK-BASED CLEANING VALIDATION

• Stage 1: Cleaning Process Design

• Cleaning Critical Process Parameters (CPPs) (TACT):
• Time:
• Cleaning Times (Flush/Cleaning/Blowdown Steps)
• Hold Times (Dirty Hold / Clean Hold)
• Action:
• Flow Rates, Pressure, Agitation
• Concentration:
• Detergents (acid/base concentration/conductivity), Residues
• Temperature:
• Detergent efficacy, protein denaturing

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 RISK-BASED CLEANING VALIDATION

• Stage 1: Cleaning Process Design

• Cleaning Critical Process Parameters (CPPs) (TACT):
• Time (Cleaning Times):
• Flush/Cleaning/Blowdown Steps
• Longer flush time = more cleaning
• Pre-rinses, between-detergent rinses, final rinse steps
• Detergent cleaning (caustic and/or acidic) steps
• Post-rinse air blowdown steps
• “The solution to pollution is dilution”

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 RISK-BASED CLEANING VALIDATION

• Stage 1: Cleaning Process Design

• Cleaning Critical Process Parameters (CPPs) (TACT):
• Time (Hold Times):
• Regulatory Basis
• FDA Guide to Inspections – Validation of Cleaning Processes
• "Always check for the presence of an often critical element in the documentation of the
cleaning processes; identifying and controlling the length of time between the end of
processing and each cleaning step... the drying of residues will directly affect the
efficacy of a cleaning process.“
• "...microbiological aspects of equipment cleaning should be considered. This consists
largely of preventive measures rather than removal of contamination once it has
occurred. There should be some evidence that the routine cleaning and storage of
equipment does not allow microbial proliferation. For example, equipment should be
dried before storage, and under no circumstances should stagnant water be allowed to
remain in equipment subsequent to cleaning operations."
• EU Annex 15 (10.8)
• "The influence of the time between manufacture and cleaning and the time between
cleaning and use should be taken into account to define dirty and clean hold times for
the cleaning process."

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 RISK-BASED CLEANING VALIDATION

• Stage 1: Cleaning Process Design

• Cleaning Critical Process Parameters (CPPs) (TACT):
• Time (Hold Times):
• Dirty Hold Time (DHT)
• Time from previous batch process end to begin of cleaning process
• Longer DHT = greater cleaning difficulty (residue drying)
• Typically a practical limit to DHT effect on cleaning difficulty
• Clean Hold Time (CHT)
• Time from cleaning process end to begin of next batch process begin
• Storage conditions contribute
• Longer CHT = greater risk of soiling (ambient particulates)
• Longer CHT = greater risk of biogrowth (standing water from cleaning process)
• Mitigation for exceeding CHT: typically WFI rinse or re-clean

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 RISK-BASED CLEANING VALIDATION

• Stage 1: Cleaning Process Design

• Cleaning Critical Process Parameters (CPPs) (TACT):
• Action:
• Flow Rates, Pressure, Mechanical Action
• Flow Rate (stagnant, laminar, turbulent) / Pressure
• Higher flow rate/pressure = more cleaning
• Mechanical Action (agitation, vibration, manual scrubbing, etc.)
• Higher action = more cleaning

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 RISK-BASED CLEANING VALIDATION

• Stage 1: Cleaning Process Design

• Cleaning Critical Process Parameters (CPPs) (TACT):
• Concentration:
• Detergents
• Concentration
• Higher concentration = more cleaning
• Conductivity
• Higher conductivity = more cleaning
• Acid/Base (pH / Ionic Strength)
• Higher ionic strength = more cleaning
• Some residues react differently to acidic vs caustic detergents
• Detergent Components / Viscosity / Density
• Can influence solubility of residues, contact time, anti-foam, etc.

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 RISK-BASED CLEANING VALIDATION

• Stage 1: Cleaning Process Design

• Cleaning Critical Process Parameters (CPPs) (TACT):
• Concentration:
• Residues
• Concentration
• Higher concentration = more to clean
• Acid/Base (pH / Ionic Strength)
• Some residues react differently to acidic vs caustic detergents
• Residue Components / Viscosity / Density
• Greater Viscosity/Density = less soluble (harder to clean)

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 RISK-BASED CLEANING VALIDATION

• Stage 1: Cleaning Process Design

• Cleaning Critical Process Parameters (CPPs) (TACT):
• Temperature:
• Cleaning efficacy, protein denaturing
• Cleaning Efficacy
• Higher temperature = increased solubility (usually)
• Higher temperature = increased detergent efficacy (usually)
• Protein Denaturing
• Higher temperature can denature proteins, creating harder-to-clean residues
• Typical mitigation: ambient temperature water flush to start cleaning process

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 RISK-BASED CLEANING VALIDATION

• Stage 1: Cleaning Process Design

• Cleaning Critical Process Parameters (CPPs) (TACT):
• Design Space / Cycle Optimization (Coupon Studies):
• Single-Parameter Experiments
• Vary one CPP at a time
• More parameters investigated = more studies
• Often, Time, Concentration, and Temperature are investigated
• Used to determine which variables have greatest impact on cleaning
• Multiple-Parameter Design of Experiment
• Multivariate investigation of CPP interaction
• Develop multi-parameter design space
• Cleaning process CPP operating ranges established
• Optimize cleaning process
• Combination of lowest temperature, detergent concentration
• Optimal (shortest) overall cleaning cycle duration (time)

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Stage 2a:
Cleaning Equipment Design, C&Q

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 RISK-BASED CLEANING VALIDATION

• Cleaning Equipment Design, C&Q

• Regulatory Basis
• US FDA Guide to Inspections – Validation of Cleaning Processes
• “Examine the design of equipment, particularly in those large systems that may
employ semi-automatic or fully automatic clean-in-place (CIP) systems since they
represent significant concern. For example, sanitary type piping without ball valves
should be used. When such nonsanitary ball valves are used, as is common in the
bulk drug industry, the cleaning process is more difficult.
• EU Annex 15 (10.4)
• "Validation should consider the level of automation in the cleaning process. Where
an automatic process is used, the specified normal operating range of the utilities
and equipment should be validated."

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RISK-BASED CLEANING VALIDATION
Applying QRM Concepts to Cleaning Process Equipment Qualification
Critical Quality Attribute (CQA):
Applies to the product.
Origin: Product and Process Knowledge (PPK) Risk to Product Quality = failure to meet CQA

Critical Process Parameter (CPP):

Applies to the process.
Origin: Product and Process Knowledge (PPK) and Risk Assessment Process Risk = failure to maintain CPP
(RA)

Critical Aspect (CA):

Applies to a process system (equipment, utility, facility).
Risk Control Strategy = CAs collectively mitigate
Origin: Risk Assessment (RA) unacceptable risk to product quality

Critical Design Element (CDE):

Applies to a process system design element (component, process control, alarm, etc.).
Origin: Critical Aspects (CA) and System Design Definition Verification Strategy = CDEs tested to verify
installation/operation fit for intended use

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PROCESS VALIDATION STAGE 2A
Cleaning Equipment Qualification (CIP Skid, COP, etc.)

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RISK-BASED CLEANING VALIDATION
Relationship Between CQA, CPP, CA, and CDE

Step Cleaning
Process
System CIP Skid

CQAs Product Purity, Product Safety

PPK
CPPs Time, Action, Concentration, Temperature (TACT)

Risk Failure
Failure to control TACT. CQA impact: Insufficient Cleaning, Adulterated/Unsafe Product
Assessment Modes

Risk Control CAs Control, Monitoring, and Alarming of TACT

Risk Review CDEs CIP Skid TACT components, CIP loop monitoring, etc.

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PROCESS VALIDATION STAGE 2A
Client Equipment Qualification (Vessels, Piping, etc.)

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RISK-BASED CLEANING VALIDATION
Relationship Between CQA, CPP, CA, and CDE

Step Cleaning
Process
System Client Equipment (Vessels, Piping, etc.)

CQAs Product Purity, Product Safety

PPK
CPPs Product Contact Surfaces Non-Additive, Non-Reactive, Non-Absorptive
Cleaning Agent/Water Coverage

Risk Failure Failure to control MOC/Coverage.

Assessment Modes CQA impact: Insufficient Cleaning, Adulterated/Unsafe Product

Risk Control CAs MOC Design, Control of Cleaning Agent/Water Coverage

Risk Review CDEs Materials of Construction, Sprayball Coverage, etc.

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PROCESS VALIDATION STAGE 2A
Support Utility Equipment Qualification (WFI, PW USP, etc.)

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 QRM-Based Integrated C&Q
Applying QRM to Integrated C&Q Process Deliverables

Step Cleaning
Process
System WFI Storage, Distribution

CQAs Water Meets Specifications for WFI, USP

PPK Product Contact Surfaces Non-Additive, Non-Reactive, Non-Absorptive

CPPs Drainability
Cleanability
Additive/reactive/absorptive MOC. CQA impact: Chemical (TOC/Cond/pH Failure)
Risk Failure Not Drainable. CQA impact: Microbial (Bioburden/Endotoxin) Failure
Assessment Modes
Not Cleanable. CQA impact: Chemical/Microbial Failure
Design of Materials of Construction
Risk Control CAs Hygienic Vessel/Piping Design
Design and Control of Cleaning/Coverage
316L Stainless Steel Vessel
Risk Review CDEs Conical Vessel Bottom
Spray Ball, Control and Monitoring of CIP Supply Flow

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Stage 2b:
Cleaning PPQ / Cleaning Validation (CV)

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PROCESS VALIDATION STAGE 2B
Cleaning Process-Related Cleaning PPQ (CV) Prerequisites

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 RISK-BASED CLEANING VALIDATION

• Cleaning Process-Related Prerequisites

• Cleaning Cycle Development/Optimization
• CPPs (TACT)
• CIP Recipes
• Equipment Hold Times
• Dirty/Clean Hold Times (DHT, CHT)
• Cleaning Paths/Loads
• CIP: Client Equipment Cleaning Circuits
• COP: Load Configurations
• Rinse Volume Determination
• Calculation of rinse recovery limits
• Calculated from CIP recipe parameters for final rinse (flow rate/time)

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 RISK-BASED CLEANING VALIDATION

• Process Risk Assessment

• Points to Consider:
• Severity
Rating Examples
Severity
5 4 3 2 1
Bacteriostatic / low
Dry manufacturing Dry processing water activity Pre-use Pre-use
Microbial Concerns
processing step step sanitization step sterilization step
Process material
Patient Proximity Filling Formulation Final Purification Initial Purification Fermentation

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 RISK-BASED CLEANING VALIDATION

• Process Risk Assessment

• Points to Consider:
• Probability of Occurrence
Rating Examples
Probability
5 4 3 2 1
Cleaning Process
Manual Semi-Automated Automated
Reproducibility
Cleanability Moderately hard to
Difficult to clean Easy to clean
(Due to Process) clean
Deviations Due to cleaning Due to cleaning No known cleaning
(Cleaning Failures) process failure system failure failures
Age of CV > 20 years 16 – 20 years 11 – 15 years 6 – 10 years < 5 years
CV Results
Above 51% of limit 21 – 50% of limit 10 – 20% of limit Below LOQ Below LOD
(worst-case)
Historical Routine
Historically outside Variable trending Consistent trending
Monitoring Trend
of sigma history within sigma
Data

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PROCESS VALIDATION STAGE 2B
Product-Related Cleaning PPQ (CV) Prerequisites

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 RISK-BASED CLEANING VALIDATION

• Product-Related Prerequisites
• Product Carryover Limits
• Product Solubility Studies
• Lab/Coupon Studies (Phase 1 Process Design/TACT)
• Solubility in proposed detergents
• Products, intermediates, degradants, etc.
• Product Risk Assessment and Grouping

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 RISK-BASED CLEANING VALIDATION

• Product Risk Assessment

• Regulatory Basis
• EU Annex 15 (10.10)
• "Where a worst case product approach is used as a cleaning validation model, a
scientific rationale should be provided for the selection of the worst case product
and the impact of new products to the site assessed. Criteria for determining the
worst case may include solubility, cleanability, toxicity, and potency."

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 RISK-BASED CLEANING VALIDATION

• Product Risk Assessment

• Critical Quality Attributes (Next Batch):
• Product Purity
• Residue (Prior Batch) Removal / Product (Prior Batch) Carryover (to Next Batch)
• Relative Batch Size, Prior Batch to Next Batch
• Product Safety
• Toxicity, Potency (Prior Batch)
• Residue Risk Factors (Prior Batch):
• Solubility:
• Less soluble = higher risk
• Toxicity/Potency:
• More toxic/potent = higher risk
• Cleanability:
• Less cleanable = higher risk

WHEN YOU NEED TO MEET A HIGHER STANDARDTM 60

 RISK-BASED CLEANING VALIDATION

• Product Risk Assessment

• Residue Risk Assessment (Prior Batch):
• Raw Materials:
• Solubility x Toxicity x Cleanability (sum, product, weighted, etc.)
Raw Material Rating
Raw Material
Description Solubility Toxicity Clean Risk Factor #

Raw Material 1 2 3 5 25
Raw Material 2 2 2 1 4
Raw Material 3 2 2 1 4
Raw Material 4 2 1 1 3
Raw Material 5 2 1 1 3
Raw Material 6 2 3 1 5
Raw Material 7 1 3 1 4
Raw Material 8 1 1 5 10
Raw Material 9 3 2 1 5
Raw Material 10 2 2 5 20
Raw Material 11 1 3 1 4
Raw Material 12 1 3 1 4
Raw Material 13 2 3 1 5
Raw Material 14 1 2 1 3
Raw Material 15 1 3 1 4

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 RISK-BASED CLEANING VALIDATION

• Product Risk Assessment

• Residue Risk Assessment (Prior Batch):
• Solutions:
• Normalized risk from component raw materials
RM Risk Normalized
Solutions Amount % Comp.
Score Risk Score
Solution 1 4.800
Raw Material 3 4.2% +/- 0.5 4.20% 3 0.126
Raw Material 4 5.8% +/- 0.5 5.80% 3 0.174
Raw Material 5 90% 90.00% 5 4.500

Solution 2 4.798
Raw Material 3 4.7% +/- 0.5 4.70% 3 0.141
Raw Material 6 5.4% +/- 0.5 5.40% 3 0.162
Raw Material 7 89.9% +/- 2 89.90% 5 4.495

Solution 3 3.158
Raw Material 1 2.8% +/- 0.5 2.80% 3 0.084
Raw Material 3 7.8% +/- 0.5 7.80% 0 0.000
Raw Material 8 11.0% +/- 1.5 11.00% 3 0.330
Raw Material 9 39.2% +/- 1 39.20% 4 1.568
Raw Material 10 39.2% +/- 1 39.20% 3 1.176

WHEN YOU NEED TO MEET A HIGHER STANDARDTM 62

 RISK-BASED CLEANING VALIDATION

• Product Risk Assessment

• Residue Risk Assessment (Prior Batch):
• Product Formulations:
• Normalized risk from component raw materials
Normalized
Worst Case % Risk Normalized Product
Product Family Raw Material / Solution Blends
Composition Score Risk Risk
Product
Number
Solution 1 33.00% 2 0.66

Product Family 1 Product 1a Raw Material 1

Caustic pH Adjustment Reagent 1
67.00%
0.00%
8
0
5.36
0.00
6.02
Acidic pH Adjutment Reagent 1 0.00% 0 0.00
Raw Material 3 2.10% 2 0.04
Raw Material 5 2.50% 2 0.05
Solution 3 65.40% 0.017 0.01
Product Family 2 Product 2a Solution 4
Raw Material 10
30.00%
0.05%
5
4
1.50
0.00
2.21
Caustic pH Adjustment Reagent 1 0.01% 0 0.00
Acidic pH Adjutment Reagent 1 0.00% 0 0.00
Raw Material 4 5.50% 2 0.11
Solution 2 20.00% 4.8 0.96
Solution 3 74.40% 0.021 0.02
Product Family 3 Product 3a Solution 4 0.10% 4 0.00 1.09
Caustic pH Adjustment Reagent 1 0.00% 0 0.00
Acidic pH Adjutment Reagent 1 0.00% 0 0.00
Raw Material 7 20.00% 0.73 0.15
Raw Material 8 10.00% 2 0.20
Raw Material 9 2.50% 2 0.05
Raw Material 1 49.40% 0.021 0.01
Product Family 4 Product 4a Solution 6 18.00% 30 5.40 4.11
Solution 7 0.10% 0.8 0.00
Caustic pH Adjustment Reagent 1 0.01% 0 0.00
Acidic pH Adjutment Reagent 1 0.01% 0 0.00

WHEN YOU NEED TO MEET A HIGHER STANDARDTM 63

 RISK-BASED CLEANING VALIDATION

• Product Risk Assessment

• Points to Consider:
• Severity
Rating Examples
Severity
5 4 3 2 1
Residue Type Product Excipient Buffers

Product Type Low HBEL Rx OTC Nutritional Cosmetic

HBEL ≤ 1 g/day ≤ 10 g/day ≥ 100 g/day

Stability of API Stable 25% degraded 50% degraded 75% degraded 100% degraded

Admin. Route Intravenous Oral Topical

Cleaning Agent Formulated Commodity Water

Dry mfg. Bacteriostatic / low Pre-use Pre-use
Microbial Dry processing
processing water activity sanitization step sterilization step
Patient Proximity Filling Formulation Final Purification Initial Purification Fermentation

WHEN YOU NEED TO MEET A HIGHER STANDARDTM 64

 RISK-BASED CLEANING VALIDATION

• Product Risk Assessment

• Points to Consider:
• Probability of Occurrence
Rating Examples
Probability
5 4 3 2 1
Soil Type Pastes Solids Liquids
Cleanability Moderately hard to
Difficult to clean Easy to clean
(Due to Solubility) clean
Bacteriostatic or
Ambient process Hot process water Caustic and/or
low water activity SIP / sanitization
Microbial Load water (WFI/PW) (WFI/PW) cleaning acidic cleaning
prior to use
cleaning solutions solutions solutions
Process material

WHEN YOU NEED TO MEET A HIGHER STANDARDTM 65

 RISK-BASED CLEANING VALIDATION

• Product Risk Assessment

• Residue Risk Assessment (Prior Batch):
• Worst-case product determination
• Products ranked by risk

Product Family Worst-Case Product Risk, Normalized

Product Family 1 Product 1a 6.02

Product Family 4 Product 4a 4.11
Product Family 2 Product 2a 2.21
Product Family 3 Product 3a 1.09

WHEN YOU NEED TO MEET A HIGHER STANDARDTM 66

 RISK-BASED CLEANING VALIDATION

• Product Grouping
• Product Family
• Related products (same/similar API, etc.)
• Product component-based risk-assessment
• Family represented by worst case product
• Product Bracketing
• Product Risk Assessment (Toxicity x Cleaning Difficulty)
• Group Constraint
• Lowest Recovery Limit

WHEN YOU NEED TO MEET A HIGHER STANDARDTM 67

 RISK-BASED CLEANING VALIDATION

• Product Grouping
• Product Bracketing
A B C Strategy:
• One product group:
1. Test Product C Using Product A Limit
• Two product groups:
1. Test Product B Using Product A Limit
2. Test Product C Using Product C Limit
Toxicity

• Two product groups:

1. Test Product A Using Product A Limit
2. Test Product C Using Product B Limit

Difficulty to Clean

WHEN YOU NEED TO MEET A HIGHER STANDARDTM 68

PROCESS VALIDATION STAGE 2B
Equipment-Related Cleaning PPQ (CV) Prerequisites

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 RISK-BASED CLEANING VALIDATION

• Equipment-Related Prerequisites
• Equipment Qualification
• Process equipment to be cleaned (CIP client equipment)
• CIP skid
• Support utilities (WFI, PW USP, etc.)
• Equipment risk assessment
• Including sampling methods, tests
• Equipment grouping
• Including sampling locations
• Equipment surface area calculations
• Calculation of (swab/rinse) recovery limits
• Equipment hold times
• Dirty/Clean Hold Times (DHT, CHT)

WHEN YOU NEED TO MEET A HIGHER STANDARDTM 70

 RISK-BASED CLEANING VALIDATION

• Equipment Risk Assessment

• Critical Quality Attributes (Next Batch):
• Product Purity, Product Safety
• Equipment Risk Factors:
• Materials of construction:
• Additive/reactive/absorptive, surface finish
• Soil buildup:
• Equipment geometry/functionality
• Hot spots:
• Difficult to clean / poor cleaning coverage
• Site criticality:
• Disproportionate contamination potential
• Cleaning process:
• Automated, semi-automated, manual

WHEN YOU NEED TO MEET A HIGHER STANDARDTM 71

 RISK-BASED CLEANING VALIDATION

• Equipment Risk Assessment

E
A B C D

Material of Construction
Clean
MOC Soil Buildup Hot Spot Critical Site
Process

Surface Area
Risk
State of
Rating
Volume
Material of Promoted by Hard to Disproportionate

Units

Units
Unit Equipment New / Fixed / Cleaning control of
ID Construction Geometry / Clean / Poor Contamination
Operation Type Legacy Portable Process cleaning
Affinity/Risk Functionality Coverage Potential
process type

3 = High 3 = High 3 = High 3 = High 3 = Manual

2 = Moderate 2 = Moderate 2 = Moderate 2 = Moderate 2 = Semi-Auto AxBxCxDxE
1 = Low 1 = Low 1 = Low 1 = Low 1 = Automatic
[Functional Area]
0

WHEN YOU NEED TO MEET A HIGHER STANDARDTM 72

 RISK-BASED CLEANING VALIDATION

• Equipment Risk Assessment

Sample Sample for Sample for Sample for
Sample?
Availability? Product? Detergents? Micro?
Risk Rating
Equipment Sampling area large Conductivity / pH
Unit Operation ID Include in CV TOC sampling for Bioburden / Rationale
enough for all sampling for
Type sampling plan?
residues?
product residues?
cleaning agents?
Endotoxin sampling?

AxBxCxD Yes / No Yes / No Yes / No Yes / No Yes / No

[Functional Area]
0
0
0
0
0
0
0
0
0

WHEN YOU NEED TO MEET A HIGHER STANDARDTM 73

 RISK-BASED CLEANING VALIDATION

• Equipment Risk Assessment

• Points to Consider:
• Severity
Rating Examples
Severity
5 4 3 2 1
Equipment Use Shared Dedicated

Equipment Contact Product Excipient Buffers

Patient Proximity Filling Formulation Final Purification Initial Purification Fermentation

WHEN YOU NEED TO MEET A HIGHER STANDARDTM 74

 RISK-BASED CLEANING VALIDATION

• Equipment Risk Assessment

• Points to Consider:
• Probability of Occurrence
Rating Examples
Probability
5 4 3 2 1
Complex geometry Simple geometry Complex geometry Simple geometry Simple geometry
and high number of and high number of with low number of with low number of with no internal
Equipment Design
internal internal internal internal components,
components components components components except valve

WHEN YOU NEED TO MEET A HIGHER STANDARDTM 75

 RISK-BASED CLEANING VALIDATION

• Equipment Grouping
• Regulatory Basis
• EU Annex 15 (10.1)
• "Where similar types of equipment are grouped together, a justification of the
specific equipment selected for cleaning validation is expected."

WHEN YOU NEED TO MEET A HIGHER STANDARDTM 76

 RISK-BASED CLEANING VALIDATION

• Equipment Grouping
• Equipment Family
• Related equipment (vessels, etc.)
• Related design
• Functionality, materials of construction, size/capacity
• Family represented by worst case equipment
• Equipment Grouping
• Operational brackets (volume, piping length, etc.)
• Similar unit operation (role in process)
• Shared cleaning process (CIP, recipe, cleaning agents)
• Equipment risk assessment
• Group Constraint
• Worst-case sampling locations

WHEN YOU NEED TO MEET A HIGHER STANDARDTM 77

PROCESS VALIDATION STAGE 2B
Cleaning Process-Related Cleaning PPQ (CV) Prerequisites

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 RISK-BASED CLEANING VALIDATION

• Sampling-Related Prerequisites
• Sampling Methodology by Validation Activity
• Cleaning process validation vs cleaning verification
• Sampling Methods
• Visual, Swab/Rinse, Online
• Sample Testing Methodology
• Sample Locations
• Visual inspection, residue analysis
• Specific vs general analyte (e.g. TOC), Microbial/Endotoxin
• Swab Recovery Studies
• Calculation of swab recovery limits
• Coupon studies: ideal: ≥ 80% (> 50% may require further evaluation)
• Rinse Recovery Studies
• Calculation of rinse recovery limits
• Coupon studies: ideal: ≥ 80% (> 50% may require further evaluation)

WHEN YOU NEED TO MEET A HIGHER STANDARDTM 79

 RISK-BASED CLEANING VALIDATION

• Sampling Methodology by Validation Activity

• Regulatory Basis
• US FDA Guide to Inspections – Validation of Cleaning Processes
• "Constant retesting and resampling can show that the cleaning process is not
validated since these retests actually document the presence of unacceptable
residue and contaminants from an ineffective cleaning process."
• EU Annex 15
• “Repeated cleaning and retesting until acceptable residue results are obtained is
not considered an acceptable approach.“ (10.2)
• “It is recognized that a cleaning validation programme may take some time to
complete and validation with verification after each batch may be required for some
products… There should be sufficient data from the verification to support a
conclusion that the equipment is clean and available for further use.”

WHEN YOU NEED TO MEET A HIGHER STANDARDTM 80

 RISK-BASED CLEANING VALIDATION

• Sampling Methods
• Regulatory Basis
• US FDA Guide to Inspections – Validation of Cleaning Processes
• "A negative result may also be the result of poor sampling technique..."
• EU Annex 15
• "A visual check for cleanliness is an important part of the acceptance criteria for
cleaning validation. It is not generally acceptable for this criterion alone to be used.
Repeated cleaning and retesting until acceptable residue results are obtained is not
considered an acceptable approach.“ (10.2)
• "Sampling should be carried out by swabbing and/or rinsing or by other means
depending on the production equipment.” (10.12)

WHEN YOU NEED TO MEET A HIGHER STANDARDTM 81

 RISK-BASED CLEANING VALIDATION

• Sample Testing Methodology

• Regulatory Basis
• US FDA Guide to Inspections – Validation of Cleaning Processes
• Dirty Pot Analogy: "In the evaluation of cleaning a dirty pot, particularly with a dried out
residue, one does not look at the rinse water to see that it is clean; one looks at the
pot.”
• "...it is not acceptable to simply test the rinse water for water quality (does it meet the
compendia tests) rather than test it for potential contaminates."
• "Any indirect test method must have been shown to correlate with the condition of the
equipment. During validation, the firm should document that testing the uncleaned
equipment gives a not acceptable result for the indirect test."
• EU Annex 15
• "If it is not feasible to test for specific product residues, other representative parameters
may be selected, e.g. total organic carbon (TOC) and conductivity.“ (10.6.2)
• "The risk presented by microbial and endotoxin contamination should be considered
during the development of cleaning validation protocols.“ (10.7)
• "Cleaning validation protocols should specify or reference the locations to be sampled,
the rationale for the selection of these locations and define the acceptance criteria.“
(10.11)

WHEN YOU NEED TO MEET A HIGHER STANDARDTM 82

 RISK-BASED CLEANING VALIDATION

• Recovery
• Regulatory Basis
• US FDA Guide to Inspections – Validation of Cleaning Processes
• "The firm should challenge the analytical method in combination with the sampling
method(s) used to show that contaminants can be recovered from the equipment
surface and at what level, i.e. 50% recovery, 90% recovery, etc."
• EU Annex 15 (10.12)
• “Recovery should be shown to be possible from all product contact materials
sampled in the equipment with all the sampling methods used."

WHEN YOU NEED TO MEET A HIGHER STANDARDTM 83

 RISK-BASED CLEANING VALIDATION

• Testing-Related Prerequisites
• Establishment of Inspection/Recovery Limits
• Visual inspection
• Safety-based carryover limits, swab/rinse recovery limits
• Test Method Validation
• Organoleptic (visual)
• Compendial/non-compendial (residue/rinse analysis)

WHEN YOU NEED TO MEET A HIGHER STANDARDTM 84

 RISK-BASED CLEANING VALIDATION

• Developing Recovery Limits

• Quantitative Recovery Limit Calculations
• [SRL]: Swab Recovery Limit (mass)
• [MSC]: MSC/MACO (mass)
• [SA]: Equipment (Sample Site) Swab Surface Area (area)
• Standard swab area: 25 cm2 or 100 cm2
• [SSA]: Equipment (Process) Shared Surface Area (area)
• Total equipment surface area shared by prior/next batch processes
• [%SR]: Percent Swab Recovery (%)
• Determined through lab coupon soiling studies

WHEN YOU NEED TO MEET A HIGHER STANDARDTM 85

 RISK-BASED CLEANING VALIDATION

• Developing Recovery Limits

• Quantitative Recovery Limit Calculations
• [RRL]: Rinse Recovery Limit (mass/volume)
• [MSC]: MSC/MACO (mass)
• [SA]: Equipment Rinse Surface Area (area)
• [RV]: Equipment Rinse Volume (volume)
• [SSA]: Equipment (Process) Shared Surface Area (area)
• Total equipment surface area shared by prior/next batch processes
• [%RR]: Percent Rinse Recovery (%)
• Determined through lab coupon soiling studies

WHEN YOU NEED TO MEET A HIGHER STANDARDTM 86

PROCESS VALIDATION STAGE 2B
Operational Cleaning PPQ (CV) Prerequisites

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 RISK-BASED CLEANING VALIDATION

• Operational Prerequisites
• Cleaning Procedures
• Fully automated (CIP skid), semi-automated, manual
• Sampling procedures
• Visual inspection, swab/rinse sampling, online sampling
• Operator training
• CIP operation, cleaning process
• Operator qualification
• Visual inspection

WHEN YOU NEED TO MEET A HIGHER STANDARDTM 88

Stage 3:
Cleaning Continued Process Verification
(CPV)

WHEN YOU NEED TO MEET A HIGHER STANDARDTM 89

PROCESS VALIDATION STAGE 3
Application of QRM to Cleaning Continued Process Verification (CPV)

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RISK-BASED CLEANING VALIDATION
ICH Q9: QRM Process

WHEN YOU NEED TO MEET A HIGHER STANDARDTM

 SCOPE OF ISPE BASELINE GUIDE VOLUME 5

• Cleaning Continued Process Verification

• Purpose
• Maintain state of control of the cleaning process
• Maintain and support validated state of the cleaning process

WHEN YOU NEED TO MEET A HIGHER STANDARDTM 92

 SCOPE OF ISPE BASELINE GUIDE VOLUME 5

• Scope Within Process Validation Lifecycle

• Routine/Continuous Monitoring
• Cleaning Process
• Routine monitoring of cleaning process acceptance and release
• Trending of cleaning process endpoints (conductivity, TOC)
• Cleaning Equipment
• Maintenance/trending of TACT parameters within design space
• Client Equipment
• Routine monitoring of visual inspection (residues, rouge, damage)
• Utilities
• Routine monitoring and trending of compendial specification conformance
• Manufacturing Processes
• Routine monitoring of product impurity OOS
• Routine monitoring of product sterility OOS

WHEN YOU NEED TO MEET A HIGHER STANDARDTM 93

 SCOPE OF ISPE BASELINE GUIDE VOLUME 5

• Scope Within Process Validation Lifecycle

• Change Management (New Product/Equipment Risk Assessment)
• Regulatory Basis
• "Where a worst case product approach is used as a cleaning validation model, a
scientific rationale should be provided for the selection of the worst case product
and the impact of new products to the site assessed. Criteria for determining the
worst case may include solubility, cleanability, toxicity, and potency.“ (EU Annex 15,
10.10)
• New Product (and Equipment) Introduction
• Perform the same product/equipment risk assessment
• Product: Solubility, Toxicity/Potency, Cleanability
• Equipment: MOC, soil buildup, hot spots, site criticality, cleaning process
• Does new product/equipment fit within existing Groups?
• Does new product/equipment represent new worst case?
• Cleaning Validation decision based on risk assessment

WHEN YOU NEED TO MEET A HIGHER STANDARDTM 94

 SCOPE OF ISPE BASELINE GUIDE VOLUME 5

• Scope Within Process Validation Lifecycle

• Periodic Assessments
• Trending of CQAs, CPPs
• Historical data or real-time/online monitoring
• Conductivity, TOC
• TACT parameters within design space
• Qualified state of process systems
• Cleaning equipment (CIP skid, COP, etc.), client equipment, utilities (WFI, PW USP)
• Review of OOS, Deviations, CAPA
• Cleaning process, manufacturing process where cleaning is implicated
• Review of change control
• New product(s) or equipment introduced to established cleaning program

WHEN YOU NEED TO MEET A HIGHER STANDARDTM 95

DISCUSSION
Questions?

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BIBLIOGRAPHY

• US FDA Report (2004):

Pharmaceutical Development for the 21st Century – A Risk-Based Approach
• US FDA Guidance for Industry (2011):
Process Validation: General Principles and Practices
• US FDA Guide to Inspections (1993):
Validation of Cleaning Processes
• EU EudraLex, Volume 4, Annex 15 (2015):
EU Guidelines for GMPs for Medicinal Products for Human and Veterinary Use
• ISPE Guide (2020):
Cleaning Validation Lifecycle – Applications, Methods, and Controls
• PDA Technical Report 29 (Revised 2012):
Points to Consider for Cleaning Validation
• PDA Technical Report 49 (2010):
Points to Consider for Biotechnology Cleaning Validation
• ASME BPE (2016):
Bioprocessing Equipment

WHEN YOU NEED TO MEET A HIGHER STANDARDTM

PRESENTER

• Chip Bennett, PMP

• Associate Director, Global C&Q, CAI
• Lead SME: CQV Program Development
• SME: QRM, Aseptic Manufacturing, Cleaning Validation, OPM
• Pharma/CQV since 2000
• Contact:
• [email protected]
A Project Manager and Senior Validation Engineer, Chip is a PMI® Certified Project Management Professional
(PMP) with 20 years of experience in the pharmaceutical and regulated non-pharmaceutical industries and with
expertise in risk-based verification, aseptic manufacturing, cleaning validation, quality systems, and owner project
management. Chip is responsible for developing and implementing Quality Risk Management (QRM) based
Commissioning and Qualification programs and projects, with a focus on assessing and training clients regarding
development, implementation, and transition to risk-based approaches.

WHEN YOU NEED TO MEET A HIGHER STANDARDTM 98

 Project | People | Process | Facility | Quality

WHEN YOU NEED TO MEET A HIGHER STANDARDTM