Principles of Cleaning Validation

Chris Appleby Global Quality Operations

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Overview

Purpose and Scope Approach Cleaning process development Acceptance Criteria Instructions and Records Protocol and Report Validation Maintenance
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Purpose and Scope of Cleaning Validation

The objective of cleaning validation is to prove that the equipment is consistently cleaned from product, detergent and microbial residues to an acceptable level, to prevent possible contamination and crosscontamination.

Test until clean is not considered an appropriate alternative to cleaning validation

Applies to major and minor product contact equipment

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Cleaning Validation Approach

Equipment Cleaning Validation is typically based on: Product Matrix (Grouping) Approach

perform validation using the most difficult to clean product(s) produced in an Equipment Train in which all the products use the same cleaning procedure (i.e., Worst Case product); perform validation of the cleaning procedure for each product produced in an equipment train.

Individual Product Approach

Validation should consist of three consecutive, successful executions of the cleaning procedure.
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Cleaning Validation Approach (cont.)

Selection of the most difficult to clean product in a group of products usually includes consideration of at least the following:
Solubility of residues in the cleaning agents Potency and toxicity of the API Difficulty to remove excipients Cleaning process parameters Cleaning history

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Cleaning Process Development

Cleaning process development should be documented and should include:

Equipment to be cleaned Materials required to be cleaned (in-process materials; API; raw materials; cleaning and sanitizing materials; solvents; microorganisms) What residues will be tested for, sampling locations, sampling methods and analytical methods Proposed Cleaning methodology

cleaning parameters and ranges; extent of equipment disassembly; extent of manual cleaning required, cleaning agents and rationale for selection

Determination of appropriate cleaning interval

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What Residues to Test For?

Actives:

If several active ingredients are processed in a single piece of equipment, a marker active, an indicator active can be selected based on its solubility in the cleaning agent, potency, previous production experience, and R&D studies. The removal of excipients can either be confirmed through analytical testing but is normally by visual inspection. The approach followed should be stated along with training requirements for individuals performing visual inspection. An indicator compound can be selected for analysis based on the recommendation of the cleaning agent manufacturer. Determined based on science and risk
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Excipients:

Cleaning Agents:

Microbial Residues:

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Sampling Methods

Validated Sampling Methods must be used to determine residue levels after cleaning changeover, before and during cleaning validation. Direct surface sample (e.g. swab)

Historically a primary sampling method for validation when feasible.

Rinse sample (Indirect sampling)

Allows sampling of a large surface, of areas that are inaccessible or that cannot be routinely disassembled provides an overall picture.

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Analytical Methods

Analytical methods used for cleaning validation must be validated

Suitable methods that are sensitive and specific should be used where possible

The detection limit for each analytical method should be sufficiently sensitive to detect the established acceptable level of the residue or contaminants, e.g. active ingredients, degradants, cleaning agents. Methods may include HPLC, GC. Also total organic carbon (TOC), pH, conductivity; ultraviolet (UV) spectroscopy; and enzyme-linked immunosorbent assay (ELISA).

Validation of the method should consider the reproducibility, linearity, specificity, detection limit, and swab and surface recovery.
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Recovery Studies

Recovery studies evaluate quantitative recovery of residue from both the surface to be sampled and the sampling method.

The minimum recovery criteria for each surface type should be determined.

Recovery values of 50% or greater are considered acceptable for rinse or swab methods of sampling.
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Sample Site Selection

Determine the product contact surface areas that are most difficult to clean (worst case). Consider:

composition of the equipment (e.g. glass or steel) location (e.g. blades, tank walls or fittings)
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Sample Site Selection

Critical areas, i.e. those hardest to clean, should be identified, particularly in large systems that employ semi-automatic or fully automatic clean-in-place systems. The basis for selecting each site should be justified. Sampling locations may be depicted on a schematic diagram or photograph.

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Validation Acceptance Criteria

Limit calculation for therapeutic materials typically considers:

Lowest value by comparison of Dose and Toxicity Maximum Allowable Residues (MARs) and Wt % default limits. Safety Factors ranging from 1/100th to 1/1000th

Residue Acceptability Limits (RALs) for swabs should be calculated using the sum of product contact surface areas of common equipment items/units between product A and B.

Where there is more than one equipment configuration, the largest total surface area should be used in the limit calculation

For multi-product equipment using a matrixing approach, the minimum calculated limit for all product combinations should be used Where applicable, limits for non-therapeutic materials should be based on toxicity

e.g. cleaning agents

Acceptable Daily Intake (ADI) approach to limit determination, per draft ISPE Cleaning Good Practice Guideline is being considered.
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Surface Area Calculations

An accurate surface area can be calculated for each piece or section of equipment

practical estimates are acceptable.

This can be done with manufacturer's drawings but should be confirmed by field measurements.

It is advisable to include the calculations with a schematic diagram of the equipment.

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Equipment holding times

Maximum allowable time intervals between Use and Cleaning should be evaluated

If this time period potentially impacts the ability to clean the equipment then the time period should be specified.

Maximum allowable time intervals between the Completion of Cleaning and Next Use should be evaluated.

If this time period potentially impacts the cleaning status of the equipment then the time interval should be specified and validated.
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Cleaning Instructions and Records

Equipment Cleaning Instruction and Records should include the following parameters:

Cleaning and sanitizing agents used (concentration and amounts) Quality of water/solvent used Equipment disassembly/re-assembly requirements Temperature and pressure parameters Flow rates for washes/rinses Start/end times for each step Volume/weight and number of rinses
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Cleaning Instructions and Records (cont.)

Tools/utensils employed Agitation, recirculation and/or reflux Draining and drying Identification/inspection of dead-legs Method for indicating equipment cleaning status Verification of cleaning (incl. visual) Method for protecting clean equipment from contamination Maximum time intervals between use and cleaning (if any)

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Cleaning Validation Protocol

The Cleaning Validation Protocol should include, or reference, the following:

Approval page with approval signatures and date of final approval Cleaning Procedure/Instruction-Records to be validated Products addressed by the protocol Description of equipment Residue materials to be removed Cleaning and sanitizing materials to be used

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Cleaning Validation Protocol (cont.)

Campaign lengths, if applicable Cleaning critical process parameters Analytical Methods Microbiological test methods (if any) Sampling plans, including rationale for the selection of specific Sites identified for sampling Sampling methods Acceptance criteria

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Cleaning Validation Report

A Validation Report referencing the relevant protocol(s) should discuss the results from the execution of the protocol and should be approved. The report should include or reference:

A list of products and equipment included in the cleaning validation study; Validated parameters and ranges; Cleaning procedures used. Summary of the results obtained Analysis of the results Summary and resolution of any deviations observed Report conclusions Recommendations or corrective actions needed; Attachments (including raw data or summary of raw data).

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Training & Qualification

Personnel responsible for equipment cleaning operations and validation sampling must be trained and qualified Training records should be maintained

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Periodic Review

Validated cleaning procedures should be subject to a Periodic Review to verify that they continue to operate in a validated state

The results of the periodic review should be documented, reviewed, and approved. The review may result in the need for additional studies (e.g., supplemental validation or Revalidation)

The documentation review should consider, but is not limited to the following:

Major changes Impact of cumulative changes Significant deviations, including investigations of failures, deviation frequencies and reasons Performance Trends SOPs, and training

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Periodic Review Frequency

A risk-based review schedule may be used, based on the criticality of the process and the impact on product quality, efficacy and regulatory compliance of the process.

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Change Control

Planned and Unplanned Changes with potential to affect validated cleaning practices should be addressed by established change control and/or investigation procedures. Examples of planned changes include:
Configuration of equipment or equipment assembly; Change in minimum lot size; Change in product mix produced in the equipment

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Other Questions and Comments?

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