Cleaning Validation for Bio-pharmaceutical & Medical Device

2020-06-18T08:22:02+00:00June 18th, 2020|

1. Background
The definition of “clean” is free from dirt, soil or impurities (chemical/microbial).
The cleaning process intend to remove dirt, impurities and soil in addition to decontamination of the equipment.
In case that reuse of the production equipment is required (for the same product or for different products) – Cleaning Validation should be performed.
There are many new disposable manufacturing equipment such as single use mixers that are in use mostly in the Bio-pharmaceutical industries, that theoretically will enable us to avoid cleaning validation activities.
The main reason for Cleaning Validation execution is to protect the patient health, by preventing product / device contamination with high/unsafe levels of product residues, chemical, physical and microbial contaminants that will affect the Quality, efficacy, purity and safety for drug product on one hand and Quality/safety for Medical Device on the other.
Cleaning process should be performed in order to protect a product or Medical Device from contamination (and cross contamination).
Cleaning Validation is defined as documented evidence that the process of cleaning is consistently capable of cleaning to predetermined level of cleanness.
Cleaning verification is defined as process that demonstrates that a cleaning process that meets pre- defined acceptance criteria per a single occasion.
Cleaning verification is common for clinical batch manufacturing and in cases of low contamination and cross contamination risk levels.
In addition to cleaning, the hold time (dirty/clean) of the equipment should be covered as well as part of the Cleaning Validation process.
The dirty hold time of equipment defined as the maximum time the equipment can be left soiled after production usage and before cleaning.
The clean hold time of equipment defined as the maximum time the equipment clean status can be maintained after cleaning process and before production usage.

2. Discussion
Cleaning Validation is a prolonged and costly process. There are several types of cleaning techniques which are popular in the Bio-pharmaceutical and Medical Devices industries:
• Manual cleaning
• Soaking / immersion
• Agitated immersion
• Spray / jet washing
• Ultrasonic bath
• Clean in place (CIP)
• Clean out of place (COP)

The cleaning efficacy will be influenced from “TACT” parameters related to the cleaning (process/utilities/materials) such as:
Time
Action (immersion, agitation, scrubbing, spraying etc.)
Concentration/Chemistry/Coverage
Temperature

Cleaning Validation should be performed after the cleaning method was tested and established. Usually it will be performed post cleaning studies (in case of a new facility/equipment/process) and/or Validation of the existing cleaning procedure (in case of existing facility/process).
Cleaning agents usage is very useful for cleaning process. It should be included in the Cleaning Validation for cleaning agent residuals after cleaning/ in the next product.
In order to achieve the Cleaning Validation challenges, when we define new process equipment for purchasing in the URS (User Requirements Specifications), a sanitary design should be defined in the URS. We have to meet the GMP principles for process equipment in order to assure an effective cleaning and storage methods that will meet the acceptance criteria defined in the Cleaning Validation protocols.

3. Grouping
In order to avoid validating all piece of equipment in production floor for cleaning, a grouping strategy should be defined in the Validation Plan, prior to Cleaning Validation protocols writing.
A grouping strategy defined as a method of grouping equivalent equipment (based on IQ and OQ) together to reduce the number of validations required. The grouping strategy should be based on cleaning materials, cleaning method and technology, cleaning parameters, product to be cleaned and engineering characteristics of the equipment (size, shape, materials of content, geometry etc.)

4. Sampling techniques
For Cleaning Validation, in addition to visual inspection (“Organoleptic method”) which is a regulatory requirement, there are direct and indirect sampling techniques.
Direct sampling locations (“Hard to clean locations”) should be identified as part of the “coverage trial” study which is usually a part of the Installation Qualification and Operational Qualification stages, or will be supplied by the manufacturer of the process equipment.
Sampling techniques should be supported by recovery studies. Recovery study provides documented evidence that any residue present on a product contact surface can be recovered by the sampling method that will be in use.
All the analytical and microbial analysis methods should be validated before the Cleaning Validation project initiation.
In order to support the Validation results, background control and positive control samples should be taken.
Acceptance criteria are defined as objective evidence that demonstrate that the methodology of the protocol was achieved and in order to confirm the validity of the cleaning process. Acceptance criteria should be also based on MACO calculations (Maximum Allowable Carry Over). The MACO value is maximum limit of product that can theoretically be carried over to the next batch, without leading to the next product being adulterated.
Common cleaning process tests as part of Cleaning Validation can include Conductivity, TOC, pH, Endotoxin, Bioburden and other tests, based on the dosage form, product, contaminants and Risk Assessment.

5. Validation
Validation of the process equipment and cleaning system (CIP, washers, water systems, clean rooms, SIP etc.) should be completed prior to Cleaning Validation (Installation Qualification, Operational Qualification and Performance Qualification).
Worst case scenario should be defined and implemented as part of the Cleaning Validation and the clean hold time Validation.
Typically, three consecutive successful Cleaning Validation runs should be completed in order to reach the validity of the equipment.
After Cleaning Validation completion, it is very important to assure validated state will be maintained in the future. In case the validated state will not be maintained, it may impact the product quality and the patient safety.
An effective GMP and Quality Systems are essential factor in the Cleaning Validation life cycle, dealing with issues such as:
• Change Control
• Corrective And Preventive Actions
• Preventive maintenance
• Product annual review
• Deviation management
• Calibration
• Risk Assessment

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