CLEANING VALIDATION SERVICES

Clean-In-Place (CIP) Validation Services

Additionally, BPV specialises in Clean-in-Place (CIP) Validation. Our engineers validate CIP procedures to meet regulatory requirements, ensuring consistent and uniform results.

Clean-in-Place (CIP) is a method of cleaning the interior surfaces of process equipment, vessels, and piping without disassembly. This automated cleaning process involves the circulation of cleaning, rinsing, and sanitising solutions through the system, ensuring efficient and thorough cleaning.

With a deep understanding of the advantages of CIP systems— such as the repeatability of the cleaning process and time savings from not disassembling components— we verify and document that cleaning, rinsing, and sanitising solutions are effectively delivered to the interior contact surfaces of process piping, vessels, mixers, fillers, blenders, fermenters, and other equipment within a processing system.

Cleaning Validation provides documented evidence to demonstrate manufacturing cleaning processes effectively, reproducibly and robustly remove product and extraneous residues from manufacturing equipment to pre-defined acceptable safe levels

Cleaning Validation is a regulatory requirement as described within EudraLex Annex 1, Chapter 15 Qualification and Validation and FDA Process Validation: General Principles and Practices (2011).

EudraLex Volume 4, Annex 1 (2022) has highlighted the requirement to adopt an holistic approach to contamination and cross contamination. The authors state that all personnel within the supply chain  are responsible for the quality, efficacy and safety of the finished product.

To this end, within the Pharmaceutical industry all stakeholders  are accountable for preventing contamination and cross contamination of products. With the objective to  maintain  product  characteristics, i.e., Critical Quality Attributes: Identity, Purity, Strength, Potency and Sterility.

Further industry guidance is provided ISPE Cleaning Validation Lifecycle, PDA TR29: Cleaning Validation and PDA TR49 Points to Consider: Biotechnology Cleaning Validation.

Cleaning Validation utilises a risk based approach as defined in ICH Q9 Quality Risk Assessment, where worst case challenging equipment, products and processes receive the highest level of focus. Therefore reducing validation effort for less challenging /lower risk equipment, products and processes.

Due to the complexity of Cleaning Validation activities it is expected that for every site the cleaning validation approach shall be bespoke, compliant to current legislation and regulations and provide assurance for patient safety, product quality and efficacy.

Regulatory Compliance

Cleaning validation is a regulatory requirement for all pharmaceutical and many life science manufacturers operating in a cGXP environment. It is essential to demonstrate compliance with relevant legislation, for example MHRA (Orange Guide) EU (EudraLex), FDA (21 CFR) and HPRA. All medicinal products and medical devices manufacturers must provide documented assurance that equipment cleaning processes are effective, robust and reproducible.

Compliance with current legislation protects companies from potential enforcement actions following regulatory inspections.

Patient Health and Safety

A properly validated cleaning process is essential to safeguard patient health and safety. It ensures that residual traces of previous products, manufacturing residues or cleaning agent residues meet acceptance criteria, (below maximum safe carryover limits).

Product Integrity and Quality

Cleaning validation upholds the integrity and quality of pharmaceutical and healthcare products, ensuring no unwanted residues interfere with the safety, stability, or efficacy of medicines or devices. This consistent assurance of quality supports manufacturers in delivering safe products to market and maintaining high consumer and regulatory trust.

Cost Efficiency and Risk Reduction

Validated cleaning procedures help to mitigate the risk of costly incidents such as batch failures, contamination investigations, and product recalls. By identifying any weaknesses early, companies can avoid significant financial losses and production downtime.

Traceability and Documentation

Cleaning validation is fully documented, providing a clear and auditable record of cleaning effectiveness. This traceability is crucial for Regulatory inspections and internal quality audits, allowing manufacturers to demonstrate that their procedures are compliant, are capable of maintaining product critical quality attributes and  provide assurance of patient safety.

The cleaning validation process has adopted the Process Validation lifecycle approach, using a holistic and risk based approach to ensure products, equipment and processes receive the most appropriate level of validation effort.

The objective for cleaning validation is to assess through quantitative, semi-quantitative and qualitative methods the removal of product and manufacturing residues to predetermined acceptable limits.

Cleanliness is determined through organoleptic/visual observations , analytical and microbiological assays against baseline values.

Visually? There is a risk for highly potent Active Pharmaceutical Ingredients  where the safe carryover limit is not visible to the naked eye. Therefore visually clean cannot be used as a sole criterion to release cleaned equipment for further processing/next batch.

Analytically?,  there is a risk that analytical assays are not suitably sensitive to detect product residues. Or that sampling is not effective or sampling is not collected from worst case locations, thus the results from analytical assays may not be reliable.

Microbiologically?,  may be difficult to determine where a  Pharmaceutical raw material is  sourced from a culture of bacteria and due to the inherent nature of the fermentation process,  mask the contaminant and therefore may not be detected during sampling.

Visual cleanliness is established through laboratory based visual residue limit studies, A cohort of trained operators visually inspect spiked coupons of representative equipment  materials (e.g., stainless steel, borosilicate glass,  PTFE surfaces) against a control non-spiked coupon.

The objective is to determine the minimum concentration of product that can be seen using the naked eye in normal manufacturing environmental lighting conditions. The Visual Residue Limit is essential when determining whether a cleaning process can be validated using visual inspection as the sole criterion for routine cleaning.

Quantitative analysis using direct surface swab analysis and rinse water (grab samples or fixed volume) is used to demonstrate equipment surfaces are sufficiently clean to safe limits.

Direct surface swabs are collected from equipment surface worst case locations (as demonstrated through riboflavin/fluorescein coverage studies).

Final rinse water samples are collected either as grab samples from the final rinse cycle or as a fixed volume. The sample results represent the surface area of the equipment (and pipework) that is in direct contact with the rinse water.

There are three routinely used analytical assays:

• Total Organic Carbon (TOC) analysis, this is non-specific it provides a result for all organic sources of residues, including microbiological.
• High Performance Liquid Chromatography (HPLC) a specific assay for individual products/residues and thus requires extensive validation activities to ensure the assay is suitably sensitive and robust to detect specific signals within a sample.
• Conductivity – essential to demonstrate cleaning agent removal to predetermined acceptable safe limits. Conductivity may also be an indicator of increased levels metallic ions within a system, indicative of surface breakdown/rouging.

Semi-quantitative assay using Total Viable Count by membrane filtration method and in the case where the final rinse water uses WFI, quantitative endotoxin analysis (LAL).

Direct surface swabs may also be used to collect samples from product surfaces, such as filling needles. The swabs are streaked over the surface of agar plates and incubated for a predefined temperature and duration.

Microbiological analysis is used for Clean Hold Time studies (DHT) where the time between the end of cleaning and next use is tested to demonstrate the equipment is stored correctly to prevent microbiological proliferation.

The development, qualification, validation and verification of manufacturing equipment cleaning processes is essential to prevent contamination and cross contamination from one product pr batch to subsequent product or batch.

The removal of residues is scientifically calculated to demonstrate any carryover does not  exceed the maximum safe carryover limit from the previous batch to subsequent. It must be acknowledged that 100% residual removal is not guaranteed and thus a safe limit is required to provide assurance of patient safety, product quality and efficacy.

There are three cleaning processes, offering differing levels of automation, assurance of product and residue removal and risk to next batch Critical Quality Attributes.

• CIP – fully automated using fixed cycles.
• COP- automated using fixed cycles, but involves manual intervention for loading and unloading of equipment items, medium risk due to correct loading and selection of correct cleaning cycle.
• Manual Cleaning- no automation, inherently variable outcomes, verified only.

Clean-In-Place (CIP) is a method of cleaning product contact surfaces of process equipment, vessels, and piping without disassembly. This automated cleaning process involves the circulation of rinse water and cleaning agent solutions through the  system, ensuring efficient cleaning and removal of residues to maximum safe carryover limits.

Clean Out of Place (COP) cleaning methods utilise parts washers to clean disassembled equipment items or small parts. The cleaning process and load/s are validated to provide assurance of effectiveness, robustness and reproducibility.

BPV provides comprehensive cleaning validation services tailored to meet the rigorous requirements of the pharmaceutical, biotech, and medical device sectors. Our validation protocols are designed to ensure cleaning processes are repeatable, compliant, and scientifically justified. We work closely with you to develop robust validation strategies that align with your product risk profile and facility setup.

Our cleaning validation services include preparing detailed validation protocols, executing swab and rinse sampling, residue limit calculation, and full analytical reporting.

Our cleaning validation services include:

• Writing and executing cleaning validation protocols
• Determination and justification of cleanliness limits
• Support in the development of analytical testing methods for trace contaminants
• Design and execution of sampling techniques for chemical and microbial residues
• Optimisation of cleaning cycles for process equipment and cleaning processes
• Preparation of detailed summary reports
• Customised training programmes on cleaning validation best practices and regulatory compliance

We serve a broad range of GMP-regulated industries including pharmaceuticals, biotechnology, and medical device manufacturing. Our experience spans both small molecule and biologic manufacturing environments, as well as facilities producing high-potency or cytotoxic compounds.

No matter your specific industry or sector, feel free to get in touch with us today. Our team are here to support your specific compliance needs.

To take advantage of our team’s expertise in process validation, you can reach out to us today to discuss your needs or request a quote by either filling in our online form, sending us an email at [email protected], or calling us on 01293 405147.

Bio Products Validation Ltd (BPV) was established to offer the best level of validation services within the UK and Ireland life science industry. With a dedicated team of validation engineers and consultants, BPV’s team has provided services to the life science industry since 2005.

As a company, our engineers have over 20 years of experience working on a variety of validation projects, small and large, across the pharmaceutical and life science sectors. We understand that every company’s needs are different, so we will work with you to achieve your desired goals and outcomes efficiently.

Our experienced validation engineers can reduce your project timelines and overall costs by streamlining your processes and we can quickly scale our resources to meet your changing demands. BPV is a trusted name in the industry; our team is fully versed in cGMP and GxP regulations and boasts an unwavering commitment to excellence and customer satisfaction which truly sets us apart.