Cleaning Processes and Validation

Ensures process residues/cleaning agents are reduced to acceptable levels prior to manufacture of the next product/process in the same equipment.

Evaluated and verifies changes to cleaning procedures and systems

Provide on-going assurance that cleaning procedures are in a state of control.

Assesses new product/process for general cleanability in lab prior to intro into GMP production environment.

Ensures cleaning procedures are adequate for new products, processes, and/or new equipment during intro into GMP equipment/production area.

Cleaning procedures for process contacting surfaces of equipment in commercial production must be designed, validated and reviewed during ongoing monitoring.

Cleaning Process Validation Lifecycle

Continued verification of CP stage 3

CP Performance Qualification Stage 2

CP Design stage 1

Building & Capturing Process Knowledge[/Understanding]
Bench Scale Analysis
DOE (Design of experiment) and Design Space
Establishing a strategy for Process Control
Critical cleaning process parameters
Cleaning control strategy

Statistical Process Control Charting
Monitoring Program/Periodic Review
New Product Risk Review

Design and Qualification of equipment/utilities
Design of equipment for cleanability
Process Performance Qualification
Cleaning Process Robustness
Data Collection and Evaluation
Statistical Analysis
Margin of Safety Measurement

Building cleaning process knowledge to establish a strategy for process control prior to start of validation.

Protocols, executions and summary write up

ongoing monitoring, cleaning validation maintenance, ongoing process verification, trending and assessing data, improving the process and control of variation, periodic review, change control, and revalidation.

Cleaning validation is not required:
Investigational Medicinal Products (IMP)
Small Molecules Drug Substance
Non-product contacting parts

Cleaning validation must provide documented evidence that the cleaning processes employed consistently:

  • control carryover of process residues
  • cleaning/sanitizing agents
  • foreign matter to a level within predetermined acceptance criteria
  • Does not allow microbial proliferation

E.g. Solutions made in vessels for process use (raw material charges, washes, buffers) must be cleaned for removal of the prior material and cleaning agent

Unknown analytical peaks discovered during analysis of cleaning sampled must be assessed/quantified/compared to relevant acceptance criteria

Test until clean involves cleaning, sampling and testing with repetition until acceptable residue limit is attained.

Analytical acceptance criteria SOP-0115304

Cleaning Procedure: ensure all process contacting parts are adequately cleaned and stored.
Procedures include automated, semi-automated or manual.

Cleaning SOPs:

  • Clear & detailed cleaning steps
    -Specific requirements for hard to clean locations
    -Cleaning surface areas with less than turbulent conditions must include appropriate actions.
  • Holding times of equipment, condition and location, before and after cleaning
  • when/where samples must be taken for on-going monitoring with acceptance criteria

Cleaning records:
must be kept for equipment with unique identification numbers

  • equipment identification number
  • person who carried out the cleaning
  • when cleaning was performed
    - SOPs used to perform cleaning process
    The actual cleaning parameters achieved (e.g. time, results, recipe performed, alarm conditions)
  • The product that was previously processed on the equipment being cleaned.

systems

CIP/COP

Auromated cleaning systems

tanks, filter housings

piping, heat exchnagers

Less than turbulent conditions

equi. with unique identification numbers

Cleaning performed by automated systems must be recorded in an equipment logbook, batch records or in the automation system.

Cycle Development:
Cleaning procedure development is an intrinsic part of manufacturing process development and incorporates a comprehensive, systematic and risk based approach.
If the developed process requires specific cleaning procedure, product technology transfer must include cleaning knowledge/details of cleaning procedure.

Cleaning & Sanitation agents:
solvents/detergents used for cleaning or bioburden reduction.
cleaning/sanitization agents slected during cycle development/rationale for selection should be documented.

  • Establish limits that cleaning /sanitizing agent does not have effect on product/manufacturing process.
    Evaluate compatibility of cleaning/sanitizing agent with equipments MOC.
  • Composition of cleaning agent.

Sanitizing agents

Hyderogen Peroxide

Cleaning Validation:
Based on scientific sound assessment of following
-design of equiment to be cleaned (MOC/Surface finish)
-Process residues/cleaning agents to be removed

  • Cleaning procedue; analytical method determiniation
    hold times/storage conditions
  • hard to clean locations
  • Equi/product groupings
    -# of replicate runs

"Mock Soiling"
Minimum number of 3 runs required for validation GSP008


Single use equipment (Plastic tubing, bags, filters)
Dedicated equipment (single-product

  • maybe quality driven due to difficultly to clean; gummy residues etc.
  • Cross contamination risk reduced

Multi-Product Equipment
Manufacture more than one material

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Manual cleaning rpocedures must be validated
New product introduction
Product Chnageover

  • residues from one product are reduced b4 intro another product

Cleaning Validationmust be documented
reports on the acceptability of cleaning procedures must be approved by the quality unit
Cleaning Validation master plan
Equipment Qualification

  • Manu equipment must be designed for effective & consistent cleaning
  • process contacting surface finished
    "Equipment Grouping"

GSP33: Equipment grouping: Family, modular, bracket, Matrix, cross-site, worst-case

Product grouping:

  • potency and dosage of product
  • toxicity
  • concentration or amount of process residue
  • chem/phys properties of process residues
    Processing time (process step and campaign length)
  • results from lab challenge studies
  • cleaning experience within roche network