Cleaning validation

Presented by Marc Fini

21 May, 2013

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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.

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What does CLEAN mean?

Oxford Dictionary definition:

• To be free from dirt, marks, or unwanted matter

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Types of cleaning

Clean in Place (CIP)

• Skid

• WFI System

• Recirculation

Clean out of place

• Equipment washer

• Loading patterns

Manual Cleaning

• Brushes

• Procedural

• Operator

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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

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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

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Cleaning modes of action

Physical

• High Pressure Spray

• High Velocity Flow

• Scrubbing

• Vacuuming

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Cleaning modes of action

Chemical

• Solubility

• Emulsification

• Wetting

• Chelation

• Dispersion

• Hydrolysis

• Oxidation

“Like dissolves Like”

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Examples of critical process parameters

Temperature

Pressure

Flow

Contact Time

Cleaning Agent Concentration

Dirty Hold Time

Clean hold conditions

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Examples of critical quality attributes

Visual detection

Cleaning Agent Residues

Product Residues

Microbiological residue limits

Drainability/drying

Conductivity/resistivity

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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

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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

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Create a team

Cross-functional/departmental team:

• Quality Assurance

• Operations/Manufacturing

• Engineering & Maintenance

• Validation

• Research and Development (R&D)

• Medical Affairs

• Regulatory Affairs

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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

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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

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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

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Cleaning validation master plan

Data Collection

Deviations & Deficiencies Handling

Change Control

Reporting

Protocol Execution

Validation Summary Reports (VSR)

Routine Monitoring

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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

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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

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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

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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.

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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

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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.

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Calculate limits

Limits and acceptance criteria should be:

Practical Verifiable Achievable Scientifically

Sound

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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

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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

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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

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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

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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

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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

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Group equipment

As with the product grouping, ensure that each equipment grouping is scientifically justified and

defendable in an audit situation.

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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 )

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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

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Select analytical method

Specific Non specific

• HPLC • Total Organic Carbon

(TOC)

• GC/MS • Conductivity

• UV/Vis • pH

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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

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Recovery method

Swab Recovery

• Generally 70% recovery required

• Less than 50% recovery needs a justification

• Typically 15-30% RSD between samples acceptable

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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.

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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.

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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.

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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.

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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.

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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

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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