Cleaning Validation for Bio-pharmaceutical & Medical Device

2020-08-05T13:44:54+00:00July 7th, 2020|

Background

The definition of “clean” is free from dirt, soil or impurities (chemical/microbial).
Cleaning processes are intended to remove dirt, impurities and soil in addition to decontaminating equipment.
If reuse of production equipment is required for the same product or for different products, then cleaning validation should be performed.
There are many new disposable manufacturing equipment items such as single use mixers that are used in the biopharmaceutical industries which theoretically enable us to avoid cleaning validation activities.
The main reason for performing cleaning validation is to protect patient health by preventing contamination of pharmaceutical products or medical devices by high or unsafe levels of product residues, or chemical, physical or microbial contaminants, that could affect the quality, purity, safety or efficacy of a product.

Cleaning processes should be performed 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 a predetermined level of cleanliness.
Cleaning verification is defined as a process that demonstrates that a cleaning process consistently meets predefined acceptance criteria.
Cleaning verification is common for clinical batch manufacturing and in cases where the risk of contamination or cross contamination is low.
In addition to cleaning, the hold time (dirty/clean) of the equipment should be included as part of the cleaning validation process.
Dirty hold time of equipment is defined as the maximum time the equipment can be left soiled after production use and before cleaning.
Clean hold time of equipment is defined as the maximum time the clean equipment can be maintained after the cleaning process and before use for production.

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Discussion

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

Cleaning efficacy is influenced by the “TACT” parameters related to the cleaning (process/utilities/materials):
Time
Action (immersion, agitation, scrubbing, spraying etc.)
Concentration/Chemistry/Coverage
Temperature

Cleaning validation should be performed after a cleaning method is tested and established. Usually cleaning validation is performed as post-cleaning studies, in the case of a new facility, equipment or process, and/or during validation of an existing cleaning procedure for an existing facility or process.
The cleaning agents used should be considered in the cleaning validation, including testing for cleaning agent residuals after cleaning or in the product next manufactured with the same equipment.

In order to meet cleaning validation challenges, prior to purchasing new process equipment, a sanitary design should be defined in the equipment URS (User Requirement Specifications). We must apply GMP principles to process equipment to assure that effective cleaning and storage methods are used to meet the acceptance criteria that are defined in the cleaning validation protocols.

Grouping

In order to avoid validating every single piece of equipment on the production floor for cleaning, a grouping strategy may be defined in the validation plan, prior to writing the cleaning validation protocols.
A grouping strategy is defined as a method of grouping together similar or equivalent equipment (based on IQ and OQ) to reduce the number of validations required. A grouping strategy should be based on cleaning materials, cleaning methods and technologies, cleaning parameters, products to be cleaned and engineering characteristics of the equipment (size, shape, materials or content, geometry, etc.)

Research and development

Consultancy in a variety of areas including design, research labs and clean rooms, development technologies, investor business presentations, regulatory strategy, market analysis, clinical trial protocols, GLP, GCP, ISO 17025, calibration, CMC, professional training.

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Design and engineering

Designing factories, clean rooms and laboratories, engineering documentation, certification, technology selection, process engineering, and validation with a combination of theoretical knowledge, practical experience, and in-depth understanding of the biometrics regulation and principles and in accordance with the GxP principles.

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Consultancy in manufacturing plant design, development and engineering of manufacturing processes, selecting the most appropriate technology, process gable, technology transfer, GMP, process improvement, utilization optimization and improvement, employee training and equipment validation, systems, production processes and cleaning.

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GXP, Quality Validation

Advises, establishes, accompanies and upgrades systems of various types of quality management, executes GMP trainings and courses, assimilates the company’s GxP principles, ISO 13485, assures quality and prepares for global regulatory audits while conducting risk analysis and evaluation, equipment, systems, software, testing methods, manufacturing processes. And cleanliness until successfully audited.

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Regulation and registration

Regulatory consulting and drug registration, EMC, CE Mark, nutritional and cosmetic supplements in Israel and worldwide, building a smart regulatory strategy, helping to prepare documents and requirements in a professional manner, in a short time, outlining the product, shelf life and graphics, import certifications and meetings with regulatory bodies and up to approval .

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Digital healthcare consulting, software development and medical applications in accordance with 21CFR part 11 / Annex 11 / HIPAA / GDPR requirements, ISO 13485/27001/27799, CE marking, Risk Assessment, and software validation and control systems up to marketing approval.

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Sampling techniques

In addition to visual inspection (an “organoleptic” testing method) which is a regulatory requirement, there are other direct and indirect sampling techniques for cleaning Validation.
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 (IQ) and operational qualification (OQ) stages, or will be supplied by the manufacturer of the process equipment.
Sampling techniques should be supported by recovery studies. Recovery studies provide documented evidence that any residue present on a product contact surface can be recovered by the sampling method that will be used.
All analytical and microbial analysis methods should be validated before initiating a cleaning validation project.
Background control and positive control samples should be taken to support the validation results,.
Acceptance criteria are defined as objective evidence that demonstrates that the methodology of a protocol was achieved and can confirm the validity of the cleaning process. Acceptance criteria should be also based on MACO (maximum allowable carry over) calculations. The MACO value is the maximum amount 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, and should be selected based on the dosage form, product, contaminants and risk assessment.

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Validation

Validation (IQ/OQ/PQ) of process equipment and cleaning systems such as CIP, washers, water systems, clean rooms, SIP, etc., should be completed prior to cleaning validation.
The worst-case scenario should be defined and implemented (or simulated) as part of the cleaning validation and the clean hold time validation.
Typically, three consecutive, successful cleaning validation runs should be completed to be assured of the validity of the process or equipment.
After cleaning validation is completed, it is very important to assure that the validated state will be maintained in the future. If the validated state is not maintained, it may adversely impact the product quality or patient safety.
Effective GMP and quality systems are essential factors in the cleaning validation life cycle, and deal with issues such as:
• Change control
• Corrective and preventive actions (CAPA)
• Preventive maintenance
• Product annual review
• Deviation management
• Calibration
• Risk assessment
• Validation review

Bio-Chem has been advising biomedical companies for more than 13 years.
Contact us for medical device and cleaning validation.
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