Cleaning Process Development and Validation

1
Cleaning Process Development and Validation

• June 16, 2006
• Brian Kim
• VP of Quality
• Tanox, Inc.

2
Part I
3
Regulatory/Compliance Overview

• Applicable regulations and requirements
• 21 CFR 211.65 a)
• Equipment . surfaces which contact components,
  in-process materials, or drug products shall not
  be reactive, additive or absorptive..
• 21 CFR 211.67
• Equipment and utensil . cleaned, maintained, and
  sanitized at appropriate intervals to prevent or
  contamination that would alter the safety,
  identity, strength, quality, or purity

4
Regulatory/Compliance Overview

• 21 CFR 211.182
• Written cleaning Procedure
• Cleaning and use log
• Cholestyramine Resin USP recall due to the low
  level contamination with intermediates and
  degradants after reuse of recovered solvents from
  pesticide production increased FDA awareness.
  

5
Regulatory/Compliance Overview

• Guidance
• Guide to Inspection for Validation of Cleaning
  Processes. FDA, 1993
• ICH Q7A, GMP for Pharmaceutical Active Ingredients

6
Regulatory/Compliance Overview

• FDA 21 Century Risk-Based Quality System
  Initiative
• Define critical product attributes and control of
  critical processes (Process Capacity) to ensure
• SAFETY, PURITY, EFFICACY, QUALITY
• Design Quality into processes
• Science-based risk management
• Real time QA

7
Cleaning Validation Overview

• Objectives
• Assurance of product purity, safety, efficacy and
  quality
• Prevention of product cross contamination by
  byproduct, residual product, microbial residue
  and residual detergent
• When cleaning validation is required
• Introduction of new equipment/product
• Manufacturing/cleaning process changes
• Raw material/cleaning agent changes

8
Cleaning Validation Overview

• Good system design
• Comprehensive Master Validation Program
• Effective cleaning process development
• Adequate analytical technique
• Justifiable acceptance criteria product
  specific (How Clean is Clean?)
• Continuous data monitoring and evaluation
• Acceptance criteria adjustment as necessary

9
Cleaning Validation Overview

• Routine review of deviations, excursions and
  change control related to cleaning process
  parameters, equipment, and materials
• Re-validation as required
• Define what and how to revalidate
• Define when to revalidate
• Application of validation lifecycle management

10
Cleaning Validation Overview

• Cleaning Validation Lifecycle Management

New product/Equipment
Evaluation of Cleaning Parameters
Cleaning Cycle Development
Validation Master Plan
Regular Data Review
(Re)Validation (IQ/OQ/PQ)
Routine Testing
11
Cleaning Cycle Development

• Elements to consider
• Design/Construction complexity of equipment
• Characteristics of residuals/product to clean
• Cleaning agents
• Type of cleaning process (Automated vs. Manual)
• Manufacturing process
• Analytical methods and their sensitivity

12
Equipment Design/Construction for Effective
Cleaning

• Adequate design/structural complexity and
  configuration
• Material and Surface
• Non-Reactive and cleanability
• Compatibility with detergents
• Stage of Manufacturing Process
• Upstream
• Down stream Increased Risk
• Drug product

13
Equipment Design/Construction for Effective
Cleaning

• Structural/design complexity
• Size and process piping configuration for CIP
• Potential dead leg/space
• Adequate turbulence
• Adequate slope
• Nozzle design and locations
• Branch piping orientation

14
Equipment Design/Construction for Effective
Cleaning
Instrument Tee for CIP L/D lt1.5
D
L
Adequate turbulence (Flow rate) for CIP
5 ft/sec
½ ft/sec
5 ft/sec
15
Equipment Design/Construction for Effective
Cleaning
CIP Return
CIP Return
Bad
Good
16
Equipment Design/Construction for Effective
Cleaning
Branch piping orientation
Up
Parallel
Down
Good Design
Bad Design
17
Characteristics of Products

• Understand (Bio)chemical characteristics of
  Product(s)
• Product matrix
• Type of active molecule (e.g., protein, DNA,
  peptide, small molecule)
• Excipients/Process related components
• Product matrix is a critical element for
• Cleaning process design
• For the determination of a detergent and process
  parameters

18
Characteristics of Products

• Physicochemical characteristics
• Solubility with medium (e.g., water, organic
  solvent)
• Reactivity is a critical element for the
  determination of process parameters
• Degree of a reaction with a detergent or medium
  at different conditions.
• Degradants
• Chemical state
• Liquid
• Semi-solid
• Solid

19
Characteristics of Products

• Microbe static property
• Critical for detergent selection
• Toxicity/Pharmacological potency
• Critical for acceptance criteria
• Potential product and/or component degradants
  after reaction with a detergent
• Critical for acceptance criteria

20
Cleaning Agent Selection

• Selection of a Cleaning Agent
• Depending on the particular type of chemicals
  (soils) to remove considering
• Chemical/Physical nature of the molecule (soil)
  to remove
• Reactivity
• Physicochemical characteristics of the molecule
• Chemical state of soils

21
Cleaning Agent Selection

• Type of Detergent

22
Cleaning Agent Selection

• Biological soils alkaline
• Blending of other cleaning components with
  alkaline detergent enhances cleaning effects.
• Builders the group of complexing agents that
  enhance the cleaning effect and the effect of
  surfactant
• EDTA, polyphosphate, NTA, citrates

23
Cleaning Agent Selection

• Surfactants several types based on the ion
  characteristics of the active group
• Anionic, cationic, non-ionic and amphoteric
• Anionic and Non-ionic used as components for
  detergent
• Cationic and amphoteric used in the formulations
  of disinfectants for their microcidal effect
• Surface tension capillary action

24
Cleaning Agent Selection

• Complexing agents complexing with minerals and
  inorganic components
• Sequestering agent prevention of scale
  formation (crystallization of water hardness)
• May reduce the need for acid cleaning following
  the base cleaning
• Deformers
• Oxidizing agents H2O2
• Corrosion inhibitors - Silicates

25
Cleaning Agent Selection
Removed Soil
80 70 60 50 40 30 20 10 0
Cleaning agent Builder Surfactant
Single cleaning agent
Surfactant
Builder
0 2 4 6
8 10 12
14
Cleaning Time (mins)
26
Cleaning Agent Selection

• Application parameters for cleaning agents
• Type of cleaning agent
• Depending on the type of soils to remove
• Concentration
• Effectiveness
• EHS consideration
• Temperature
• Contact time

27
Cleaning Process Development

• Selection of Cleaning Process
• Automated vs. Manual
• Automated CIP and/or COP
• Consistency and reproducibility
• Readily validatable
• Better process control
• Manual
• Inconsistency
• Hard to validate
• Inadequate for most of the state-of-the-art
  facilities

28
Cleaning Process Development

• Consider
• Historical cleaning data (trending)
• Previous validation data if available
• Complexity and delicacy of manufacturing
  equipment
• Level of facility automation
• Cleaning cycle development
• CIP or COP design and capacity
• Nature of soils

29
Cleaning Process Development

• Complexity and delicacy of equipment
• Nature of product contacting surface
• Sequence
• Critical parameters
• Legging time between the end of equipment use and
  cleaning
• Temperature
• Pressure
• Volume
• Process time

30
Cleaning Process Development

• Types of CIP (Clean-in-place)
• Portable CIP
• Simple control and non re-circulation
• Multiple-Tank Re-use CIP
• Separate tanks for detergents (Acid, Base) and
  washing solution (e.g., water)
• Re-circulation and re-use of detergents and
  washing solution
• May not be adequate for biopharmaceutical in
  terms of prevent cross contamination (e.g., viral
  contamination)

31
Cleaning Process Development

• Single and multiple-tank single use CIP
• Appropriate for Biopharmaceuticals
  re-circulation
• Relatively easy for validation but depending on
  number of pumps, valves, and the complexity of
  cycle
• High degree of cycle flexibility
• No re-use of cleaning agent for
  biopharmaceuticals
• Validation is depending on the complexity of the
  cleaning sequence.

32
Cleaning Process Development

• COP (Clean-out of place)
• Used for miscellaneous fittings and parts out of
  the main equipment (disassembly)
• A single open tank for rinsing and washing
• Re-circulation of detergent using a detergent
  feed pump
• Appropriate cycle development

33
Cleaning Process Development

• Automated CIP system components and functions
• Temperature sensors
• Two for re-circulation system cleaning
  solution supply and return monitoring
• Temperature is a primary indicator of cleaning
  cycle performance
• Conductivity sensors
• Detergent conc. monitoring
• Conductivity a primary indicator of cleaning
  cycle performance

34
Cleaning Process Development

• pH sensors
• Monitoring of rinsing efficacy
• CIP supply flow sensors
• Flow rate and totalization are directly related
  to contact time
• Magnetic flow sensors not recommended because
  of inability to sense non-conductive fluid
• CIP supply pressure sensors
• Indicator of spray device performance and
  solution contact time

35
Cleaning Process Development

• CIP vessel level sensors
• Indirect indicator of performance of the system
• Return flow switch
• Conductance based probe
• Prevention of inadvertent events such as
  mis-connection of supply and return circuits
  product contamination
• Spray device
• Fixed and rotating

36
Safety
Part II
Purity
Efficacy
37
Cleaning Process Development

• Sequence development
• Pre-rinse piping and equipment to be cleaned by
  pressure washing
• End point
• Total volume or time
• On-line turbidity, conductivity or return flow
• Must be drained or to kill-tank

38
Cleaning Process Development

• Detergent washing
• Acid or alkali depending on the type of soil
• Continuous feed
• Endpoint
• Volume or time
• Must be drained
• Soaking with detergent as necessary
• Chromatography system

39
Cleaning Process Development

• Post rinse and drains
• To remove residue after pre-rinse and detergent
  washing
• Continuous flow and drain
• Usually not heated
• Neutralization wash and drain
• Endpoint total volume and/or elapse time
• Final rinse and drain
• Endpoint total volume and/or elapse time, pH,
  conductivity

40
Cleaning Process Development

• Parameter and range determination
• Factoring experimental design (example)

41
Cleaning Process Development

• Study approach
• Coupon study
• Same materials as manufacturing equipment
• Equivalent surface treatment
• Experimental run
• Worst case approach
• Residues to be cleaned
• Equipment surface
• Appropriate sampling and analytical methods

42
Cleaning Process Development

• Sampling
• Direct surface sampling
• Selection of
• Appropriate sample dissolving medium
• Sample container
• Sampling material(s)
• Swab Interference by adhesive, Variability

• Swabbing unidirectionally with a
• new wet swab for each direction

• Wet swab and finish with a dry swab

43
Cleaning Process Development

• Rinse water sample
• Dilution effect
• Unreliable, inconsistent recovery
• Visual inspection

44
Cleaning Process Development

• Analytical Methods
• Depending on the types of analytes
• Proteins
• Organic compounds
• Inorganic compounds
• Other biological contaminants
• Adversary agents
• Mycoplasma, virus
• Residual host bacteria

45
Cleaning Process Development

• Type of analytical methods
• Specific
• Multi-product equipment
• Potent product
• Toxic or potent degradants or contaminants
• Non-specific
• Broad application
• Holistic evaluation
• Selection of methods based on the nature of
  analytes

46
Cleaning Process Development

• Development of specific method(s) requires longer
  time
• Matrix of the material for method development
  should be the representative of the cleaning
  sample.
• Inhibitory or enhance effects of the sample
  matrix must be evaluated and appropriate sample
  preparation and method should be developed.
• Sensitive and specific

47
Cleaning Process Development

• Selection of appropriate method(s) is a key for
  successful cleaning validation
• Routine and validation
• Methods must be validated for
• Sensitivity (LOD/LOQ)
• Specificity
• Precision
• Accuracy

48
Cleaning Process Development

• Examples of methods widely used in
  biopharmaceutical cleaning process

49
Cleaning Process Development

• Use methods in combination
• Validation and routine cleaning sample analysis
• Test intended routine cleaning samples during the
  validation study and establish co-relationship
  between specific and non-specific sample test
  results. Use the ratio as a correction factor
  during the routine cleaning sample analysis if
  the results show relative difference in a
  consistent manner.

50
Cleaning Validation

• Validation Approach
• Development of Validation Master Plan to
  describe
• Objective, scope, references, responsibilities
• Nature of products (dosage form and therapeutic
  areas) all products
• Manufacturing process
• Include equipment list
• Cleaning system and process for each type of
  equipment

51
Cleaning Validation

• Validation Strategy
• Multi-use vs. dedicated equipment
• Individual vs. group vs. matrix
• Scope of use vs. configuration
• Each product basis vs. worst case approach
• Define the worst case or group
• Provide a scientifically sound justification if
  chosen (e,g., degree of difficulty in cleaning,
  toxicity)
• List of Equipment and qualification status
• Equipment PIDs
• Cleaning system (e.g., CIP) qualification (I/OQ)
  status

52
Cleaning Validation

• Analytical method selection and validation
  requirements
• Recovery study requirements recovery factor
• Determination of sampling methods
• Lot requirements for validation
• Documentation requirements
• Protocol
• Reports
• Raw data
• Re-validation requirements and frequency
• Validation project planning (Generic)

53
Cleaning Validation

• Cleaning Validation Prerequisites
• Ensure that all cleaning process equipment are
  adequately qualified.
• Draft a cleaning SOP based on the development
  study.
• Prepare PID for each piece of equipment and
  define sampling locations and/or methods.
• Ensure that analytical methods are validated.

54
Cleaning Validation

• Conduct a recovery study per type of equipment
  construction material.
• Protocol driven
• Report recovery factor for each type of
  equipment construction material
• Define acceptance criteria.
• Justification must be established.
• Develop a detailed plan and responsibilities.

55
Cleaning Validation

• Recovery study
• Recovery rate is directly related to the
  condition of equipment surface and sampling
  technique.
• Define appropriate sampling methods and
  techniques.
• Recovery factor must be reflected on the residue
  calculation during the cleaning validation.

56
Cleaning Validation

• Considerations for recovery study
• Coupons and other materials
• Representative of all types of equipment (316L
  SS, Glass, plastic)
• Same surface treatment (e.g., electropolishing)
• Sampling materials
• Sample container
• Sampling methods
• Spiking solution preparation
• Simulated cleaning sample
• Concentration should be at a level of acceptance
  acceptance criteria

57
Cleaning Validation

• Spiking and spiked coupon handling procedures
• Clean coupons before spiking
• Simulate actual cleaning condition
• Allow the spiked solution to be on the coupon the
  maximum time as cleaning time limit is defined
  the SOP.
• Evenly spike the solution on the defined area of
  the coupon.
• The coupon spiking area should be an equal to the
  actual sampling area on the actual equipment.

58
Cleaning Validation

• Coupon arrangement
• Coupon to be arranged to have areas or separate
  coupons for
• Background blank
• Control spiking sample prep solution
• Sample spiking area
• Sampling
• Protocol and report
• Define expected acceptance criteria
• Example 60 120 RECOVERY
• The recovery factor
• Spiked value/recovered value

59
Cleaning Validation

• Acceptance Criteria Approach
• Visually cleanliness
• Prerequisite of cleaning acceptance.
• Cannot be an acceptance criterion alone.
• Cleaning capability
• Statistical analysis of historical cleaning data
• Product specific data
• Non-specific data (e.g, rinse water TOC) to be
  evaluated based on the worst case (toxicity)
  residual.
• Data should be analyzed from the toxicity and
  dosage level perspective

60
Cleaning Validation

• Maximum daily dose based carryover
• lt0.001 of any contaminant in maximum daily dose
  of the subsequent batch (3 factors)
• 10 of maximum daily dose inactive
• 10 of maximum daily dose safety factor
• 10 of maximum daily dose cleaning capability
• Toxicity based carryover
• Toxicity data based criterion safety factor (1
  10 of the toxicity) is applied to the toxicity.
• Applicable to detergent, sanitizing agent and
  cross-contaminating product.

61
Cleaning Validation

• The lowest value to be chosen as acceptance
  criteria.
• Process capability to remove contaminants must be
  considered.
• Apply different criteria to different
  manufacturing process step considering down
  stream impurity/contaminant removal capacity.
• The most stringent criteria to finished product
  manufacturing.
• Justification must be clearly documented.

62

Cleaning Validation

• Acceptance criteria should include
• Number of batches (consecutive)
• Sample test time limit
• Cleaning time limit (number of hours after
  production)
• Deviation handling
• Allowed contaminant level per swab area or per
  volume of sample

63
Cleaning Validation

• Analytical Method Application
• Non-specific method for the equipment at the
  manufacturing step where the process material
  matrix is complicated
• Upstream Process (except viral particles)
• Cell culture/fermentation media
• By products
• Cell debris
• Nucleic acid
• Assumption- the value represent the worst (the
  most toxic) substance

64
Cleaning Validation

• Contaminant specific (product specific) method
  should be applied to multi-product down stream
  equipment and finished product manufacturing
  equipment
• Rinse solution (water) test shall be performed
  along with specific test
• Rinse water test results are correlated to the
  product specific test results and use the value
  as a routine cleaning specification.

65
Cleaning Validation

• Cleaning procedure should be drafted or
  established before validation
• Validation protocol should include
• Description of manufacturing process
• Cleaning procedure refer to SOP
• Sampling requirements
• Test methods
• Include PID of equipment to define sampling
  location

66
Cleaning Validation

• Report
• Main document for inspection
• Briefly describe equipment, sampling, recovery
  result, acceptance criteria
• Clearly state results
• Recommendation for routine cleaning sample test
  and specification
• Appendix calculations

67
Changeover

• Unique to multi-product facility
• In addition to cleaning of dedicated and
  non-dedicated equipment
• Removal of any remaining prior product or batch
• Cleaning and sanitization of production area
  surface
• Removal of any disposable equipment and supplies
• QA clearance review and approval

68
Re-validation Requirements

• Define in the Validation Master Plan
• Historical data based evaluation
• Full re-validation when
• Frequent OOS, deviations
• Equipment change
• New product introduction
• Manufacturing process change
• Major component change

69
Re-validation Requirements

• Minimum re-validation when data show effective
  cleaning process
• Report should include historical data to support
  the minimum re-validation approach