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Cleaning validation
Presented by Marc Fini
21 May, 2013
Slide 2 © PharmOut 2013
What is cleaning validation?
Cleaning validation is documented evidence that the cleaning process can effectively and reproducibility clean equipment to a pre-defined acceptable level.
Slide 3 © PharmOut 2013
What does CLEAN mean?
Oxford Dictionary definition:
• To be free from dirt, marks, or unwanted matter
Slide 4 © PharmOut 2013
Types of cleaning
Clean in Place (CIP)
• Skid
• WFI System
• Recirculation
Clean out of place
• Equipment washer
• Loading patterns
Manual Cleaning
• Brushes
• Procedural
• Operator
Slide 5 © PharmOut 2013
Cleaning agents
Solvent:
• A substance, usually a liquid, capable of dissolving another substance
Water (WFI, RO, Municipal Supply)
Ethanol or other organic solvents
Detergent solutions
Acidic or Caustic Solutions
Placebos
Slide 6 © PharmOut 2013
Cleaning agents
Solute:
• A substance dissolved in another substance, usually the component of a solution present in the lesser amount.
API
Excipients
Cleaning Agents
Degradation Products
Solvents
Intermediates
Slide 7 © PharmOut 2013
Cleaning modes of action
Physical
• High Pressure Spray
• High Velocity Flow
• Scrubbing
• Vacuuming
Slide 8 © PharmOut 2013
Cleaning modes of action
Chemical
• Solubility
• Emulsification
• Wetting
• Chelation
• Dispersion
• Hydrolysis
• Oxidation
“Like dissolves Like”
Slide 9 © PharmOut 2013
Examples of critical process parameters
Temperature
Pressure
Flow
Contact Time
Cleaning Agent Concentration
Dirty Hold Time
Clean hold conditions
Slide 10 © PharmOut 2013
Examples of critical quality attributes
Visual detection
Cleaning Agent Residues
Product Residues
Microbiological residue limits
Drainability/drying
Conductivity/resistivity
Slide 11 © PharmOut 2013
Performing cleaning validation
1. Create a Cleaning Validation Team
2. Write a Cleaning Validation Master Plan
3. Collect Information
4. Group products
5. Set limits
6. Group equipment
7. Determine Sampling Sites
Slide 12 © PharmOut 2013
Performing cleaning validation
8. Select Analytical Method
9. Perform Recovery Studies
10. Perform an Engineering Study
11. Perform the Cleaning Validation Study
12. Write a Validation Summary Report
13. Implement Cleaning Procedures
14. Monitoring
Slide 13 © PharmOut 2013
Create a team
Cross-functional/departmental team:
• Quality Assurance
• Operations/Manufacturing
• Engineering & Maintenance
• Validation
• Research and Development (R&D)
• Medical Affairs
• Regulatory Affairs
Slide 14 © PharmOut 2013
Cleaning validation master plan
Documents the rationale and important aspects of the cleaning validation program:
Purpose and Scope
Responsibility
Validation Approach
Risk Assessment
Acceptance Criteria
Assessment for the Removal and Toxicity of Drug Product Formulation Excipients
Slide 15 © PharmOut 2013
Cleaning validation master plan
Validation for the removal of Cleaning agents
Defining Equipment Train for Cleaning Validation
Equipment Train Surface Area Calculation
Product Grouping
Equipment Bracketing
Selection of Sampling Sites
Validation of 'Dirty' Holding Periods
Validation of 'Clean' Holding Periods
Single use Components
Dedicated Equipment
Slide 16 © PharmOut 2013
Cleaning validation master plan
Analytical Methodology
Development of Analytical Methods
Product Specific versus Product Non-Product Specific Analytical Methods
Sensitivity Requirements for Cleaning Validation Samples
Recovery Studies
Sampling Methodology for Cleaning Verification and Cleaning Validation
Monitoring Program
Slide 17 © PharmOut 2013
Cleaning validation master plan
Data Collection
Deviations & Deficiencies Handling
Change Control
Reporting
Protocol Execution
Validation Summary Reports (VSR)
Routine Monitoring
Slide 18 © PharmOut 2013
Collect information about the products
• Dosage, toxicity, concentrations
• Excipients, degradants and impurities
• Material compatibility/interactions
• Solubility in water and in the cleaning agent
• Stability of product
• Difficulty of cleaning
Slide 19 © PharmOut 2013
Collect information about the equipment
• Define the equipment train and sequence in which equipment is used
• Materials of Construction
• Surface Finish
• Geometry (hard to reach areas)
• Surface Area
• Disassembly and Assembly Requirements
• Condition and suitability of equipment
Slide 20 © PharmOut 2013
Collect information about the process attributes
• Product list including media, buffers and non-routine cleaning agents
• Batch sizes
• Cleaning procedures
• Cleaning agents
• Cleaning temperature requirements
• “clean” and “dirty” holding times
Slide 21 © PharmOut 2013
Collect information
This is the most difficult and time consuming part of any cleaning validation program, but if the information is complete and accurate it will prove to be highly beneficial at later stages of
the validation process.
Slide 22 © PharmOut 2013
Group products
If possible, group products and select a worst-case or representative product by considering:
Solubility – in water and proposed cleaning agent(s)
Therapeutic dose
Toxicity (e.g. LD50)
Affinity to certain materials of construction
Interaction with product which will follow on?
Equipment train
Product characteristics
Class of drug
Slide 23 © PharmOut 2013
Group products
Whilst this can significantly reduce the validation effort, ensure that each product
selection is documented, scientifically justified and defendable in an audit situation.
Slide 24 © PharmOut 2013
Calculate limits
Limits and acceptance criteria should be:
Practical Verifiable Achievable Scientifically
Sound
Slide 25 © PharmOut 2013
Calculate limits
MAC =MDD x SF x MBS
LDD
MAC = Maximum Allowable Carryover
MDD = the minimum daily dose of the active of cleaned product
SF = Safety Factor, which is typically 0.001 or 1/1000
MBS = the Minimum Batch Size of the next product
LDD = the largest daily dose of the next drug product to be manufactured in the same equipment
Slide 26 © PharmOut 2013
Calculate limits
.
10 mg
10 µg
10 µg
Largest Daily Dose 2 units
Minimum Batch Size 50,000 units
1/1000 Safety Factor
Minimum Daily Dose
Slide 27 © PharmOut 2013
Calculate limits
Example:
• MDD (Product A) = 10 mg
• Safety Factor = 1/1000 or 0.001
• MBS (Product B) = 50,000 units
• LDD (Product B) = 2 units
• Surface Area (Equipment Train) = 75,000 cm2
MAC (µg/cm2) = 10 x 0.001 x 50,000
2 x 75,000
= 3.3 µg/cm2
Slide 28 © PharmOut 2013
Calculate limits
Other methods to calculate limits:
• Using LD50 and modifying factor (determined by toxicologist)
• Default limits such as 10 ppm
LD50 = 50% lethal dose of the target residue in an animal, typically in mg/kg of body weight
10 ppm = 10 mg of residue per litre of next batch
Slide 29 © PharmOut 2013
Calculate Limits: Visually clean
• Visually clean acceptance criteria may be considered appropriate for dedicated equipment however possible degradants and bioburden need to be considered.
• Equipment should always be inspected when dry
• Minimum visual limit should be established in terms of amount
Slide 30 © PharmOut 2013
Group equipment
• Same design but differs only in size
• It may be acceptable to only validate the largest and smallest of each item (e.g. vessels?).
• Dedicated and shared equipment
• Same material of construction
Slide 31 © PharmOut 2013
Group equipment
As with the product grouping, ensure that each equipment grouping is scientifically justified and
defendable in an audit situation.
Slide 32 © PharmOut 2013
Determine sampling sites
A Riboflavin or Fluoroscein study to determine hard to clean area
Representative surface with respect to different materials of construction
Role in process likely to lead to build-up or difficult to clean areas
Hot spots i.e. locations that are considered hard to clean or have complex geometries
Critical sites i.e. locations that may disproportionately contribute residue to the next process (e.g. filling needles )
Slide 33 © PharmOut 2013
Select analytical method
New analytical methods should typically occur concurrently with the development of new products.
Methods should be product specific
Non-specific methods may be used if it is not possible or practical to use a specific method
Method must be sensitive enough
Method must be appropriately validated particularly in the expected residue limit working range
Slide 34 © PharmOut 2013
Select analytical method
Specific Non specific
• HPLC • Total Organic Carbon
(TOC)
• GC/MS • Conductivity
• UV/Vis • pH
Slide 35 © PharmOut 2013
Recovery Studies
• The recovery studies should ordinarily be performed in conjunction with the development of the analytical methods
• Recovery studies are performed to establish the effectiveness of the sampling technique
• Should be done for all product contact surfaces, e.g. stainless steel, plastics, glass, gaskets and hoses
• Usually carried out in the laboratory using coupons to simulate the product contact surface
Slide 36 © PharmOut 2013
Recovery method
Swab Recovery
• Generally 70% recovery required
• Less than 50% recovery needs a justification
• Typically 15-30% RSD between samples acceptable
Slide 37 © PharmOut 2013
Recovery studies
Rinse Recovery
• Should be treated the same as swabs.
• Used for sampling areas that can’t be reached by swabs. For example, transfer lines.
• Innovative ways may be required when applying or collecting rinsate.
Slide 38 © PharmOut 2013
Perform an engineering study • It is very important that the cleaning process capability is well
understood before any validation takes place.
• Develop a cleaning validation protocol and report to document findings.
Validation should not be a learning exercise but a verification of what is already known about your process.
Slide 39 © PharmOut 2013
Perform the cleaning validation study
Once the cleaning validation plans and protocols have been prepared and approved, it is time to execute it.
Ensure the protocol and procedures to be validated are being followed correctly.
Preparation and pre-determined acceptance criteria are crucial in achieving a successful cleaning validation outcome.
Ensure that any deviations or exceptions/ observations are captured via an exception reporting system.
Slide 40 © PharmOut 2013
Validation summary report
At the conclusion of the validation exercise, a validation summary report will bring together all the aspects of the validation and allow conclusions to be
drawn regarding the suitability of the cleaning programme and overall compliance with the
validation plan.
Slide 41 © PharmOut 2013
Implement the cleaning method
Once all the cleaning validation is complete and approved then its time to implement the cleaning system into the production process.
It is not acceptable to use a cleaning process that has not been adequately validated.
Ensure implemented method is consistent with validation and has not been changed in the process.
Slide 42 © PharmOut 2013
Monitoring
Once the cleaning process is validated revalidation is generally not required providing the process is appropriately managed by a change control system
Review of the cleaning methods can be done during annual product reviews
Routine monitoring of equipment can be done on a rotating basis
Slide 43 © PharmOut 2013
Common deficiencies Unsuitable equipment (Surface finish or poorly maintained e.g. diaphragm valves and surface of tanks)
Scientifically unsound justifications for product and equipment groupings
Cleaning methods does not consider critical process parameters (temperature or contact time)
Cleaning methods are not followed or reflect actual validation
Control and lifespan of gaskets and silicone hosing
Removal of cleaning agents unvalidated
Incorrect limits set