What is Cleaning Validation in the Pharmaceutical Industry?
By: Gerry Creaner B.Chem Eng and Donagh Fitzgerald B.Prod Eng. Last Updated: Feb 2023
What is Cleaning Validation?
Cleaning validation is a process used in the pharmaceutical, biotech, and medical device industries to provide documented evidence that equipment and facilities are properly cleaned and sanitized (with an approved cleaning procedure) before being used for the production of drugs or medical devices.
Pharmaceutical products and active pharmaceutical ingredients (APIs) can be contaminated by other pharmaceutical products or APIs, by cleaning agents, by micro-organisms or by other materials (e.g. air-borne particles, dust, lubricants, raw materials, intermediates, auxiliaries). In many cases, the same equipment may be used for processing different products.
To avoid contamination, adequate cleaning procedures are critical. Cleaning procedures must strictly follow carefully established and validated methods of execution. This applies equally to the manufacture of pharmaceutical products and active pharmaceutical ingredients. In any case, manufacturing processes have to be designed and carried out in a way that contamination is reduced to an acceptable level.
The objective of the Cleaning Validation is the confirmation of a reliable cleaning procedure so that the analytical monitoring may be omitted or reduced to a minimum in the routine phase.
Take me to:
- 5 Steps to Cleaning Validation
- Why is Cleaning Validation Necessary?
- What are the FDA and the EMA Guidelines?
- Where is Cleaning Validation Used?
- What Type of Sampling Methods are Used?
- What Types of Cleaning Methods are Used?
- What is contained in a Cleaning Validation Protocol?
- Microbiological Aspects
- Analytical Methods
- Establishment of Limits
5 Steps to Cleaning Validation
Cleaning Validation at its simplest level can be broken into the following steps
Step 1: Develop a cleaning validation protocol:
The first step is to develop a protocol that outlines the cleaning procedures, including the cleaning agents, equipment, and personnel involved. The protocol should also include the acceptance criteria for the cleaning validation process.
Step 2: Conduct a risk assessment
Before cleaning validation begins, a risk assessment should be conducted to identify potential sources of contamination. This will help to determine which areas of the facility require the most attention during the cleaning process.
Step 3: Clean and sanitize the facility
The next step is to follow the cleaning protocol and thoroughly clean and sanitize all equipment and surfaces. This should be done by trained personnel and in accordance with the cleaning agent’s manufacturer’s instructions.
Step 4: Conduct testing
Once the cleaning process is complete, samples should be taken from various areas of the facility and tested to ensure that the acceptance criteria have been met. The samples should be analyzed for the presence of any contaminants and the results should be documented.
Step 5: Review the results
The final step is to review the results to ensure that the facility meets regulatory guidelines and industry standards for cleanliness and sanitation and make any necessary adjustments to the cleaning protocol. The cleaning validation process should be repeated on a regular basis to ensure that the facility remains in compliance with regulatory guidelines.
Why is Cleaning Validation Necessary?
Cleaning validation is necessary because it helps to ensure the safety and efficacy of the products being produced. Equipment and facilities are often used to produce multiple products, and if the equipment is not properly cleaned and sanitized between production runs, it can lead to cross-contamination. This can lead to product defects, recalls, or even harm to patients.
Cleaning validation also helps to ensure compliance with regulatory guidelines. Both the pharmaceutical and medical device industries are heavily regulated, and facilities are required to follow strict guidelines for cleanliness and sanitation to prevent contamination. Cleaning validation helps to demonstrate that the facility is in compliance with these guidelines and is taking the necessary steps to prevent contamination.
Cleaning Validation Guidelines
Most regulatory agencies and industry bodies publish guidelines on how to conduct cleaning validation. Their principles could be summarized as follows:
- Cleaning validation should be a part of a pharmaceutical company’s overall quality system and it should be based on a scientific rationale.
- A risk assessment should be conducted to identify potential sources of contamination.
- The cleaning process should be validated to ensure that it is effective in removing these contaminants.
- Cleaning validation should be performed on a regular basis and the results should be documented and kept on file.
1) Food and Drug Administration (FDA)
- FDA Cleaning Validation Guideline from CFR 211.67
- Here is a link to the entire code. 21 CFR Part 211
- Inspection References: Guide to inspections validation of cleaning processes
- Questions & Answers on Current Good Manufacturing Practices—Equipment
2) European Medicines Agency (EMA)
3) Pharmaceutical Inspection Co-operation Scheme (PIC/S)
- Cross-contamination in shared facilities – PI-043-1
- Guideline on Setting HBEL for use in risk identification in the manufacture of different medicinal products in shared facilities
4) World Health Organization (WHO)
5) International Society For Pharmaceutical Engineering (ISPE)
- Baseline Guide Vol 7: Risk-Based Manufacture of Pharma Products 2nd Edition
- Cleaning Validation Lifecycle – Applications, Methods, and Controls ISPE Cleaning Validation Guideline
6) Parenteral Drug Association (PDA)
- PDA Technical Report 29: Points to Consider for Cleaning Validation PDA TR 29
- PDA Technical Report 49: Points to Consider for Biotechnology Cleaning Validation
7) American Society For Testing and Materials (ASTM)
Where is Cleaning Validation Used?
Normally only cleaning procedures for product contact surfaces of the equipment need to be validated. Consideration should be given to non-contact parts into which product may migrate. For example, seals, flanges, mixing shaft, fans of ovens, heating elements etc. Cleaning procedures for product changeover in the case of marketed products should be fully validated.
Generally, in the case of batch-to-batch production, it is not necessary to clean after each batch. However, cleaning intervals and methods should be determined.
Several questions should be addressed when evaluating the cleaning process. For example:
- At what point does a piece of equipment or system become clean?
- What does visually clean mean?
- Does the equipment need to be scrubbed by hand?
- What is accomplished by hand scrubbing rather than just a solvent wash?
- How variable are manual cleaning processes from batch to batch and product to product?
- What is the most appropriate solvent or detergent?
- Are different cleaning processes required for different products in contact with a piece of equipment?
- How many times need a cleaning process be applied to ensure adequate cleaning of each piece of equipment?
Cleaning procedures for products and processes which are very similar, do not need to be individually validated. It is considered acceptable to select a representative range of similar products and processes concerned and to justify a validation programme which addresses the critical issues relating to the selected products and processes. A single validation study under consideration of the “worst case” can then be carried out which takes account of the relevant criteria. This practice is termed “Bracketing”.
At least three consecutive applications of the cleaning procedure should be performed and shown to be successful in order to prove that the method is validated.
Raw materials sourced from different suppliers may have different physical properties and impurity profiles. Such differences should be considered when designing cleaning procedures, as the materials may behave differently.
Control of change to validated cleaning procedures is required. Revalidation should be considered under the following circumstances:
- Re-validation in cases of changes to equipment, products or processes.
- Periodic Re-validation at defined intervals.
Manual methods should be reassessed at more frequent intervals than clean-in-place (CIP) systems.
It is usually not considered acceptable to “test until clean”. This concept involves cleaning, sampling and testing, with repetition of this sequence until an acceptable residue limit is attained. For the system or equipment with a validated cleaning process, this practice of “test until clean” should not be required. The practice of “test until clean” is not considered to replace the need to validate cleaning procedures.
What Type of Sampling Methods are Used?
There are two methods of sampling that are considered to be acceptable, direct surface sampling (swab method) and indirect sampling (use of rinse solutions). A combination of the two methods is generally the most desirable, particularly in circumstances where accessibility of equipment parts can mitigate against direct surface sampling.
- Direct Surface Sampling – The suitability of the material to be used for sampling and of the sampling medium should be determined. The ability to recover samples accurately may be affected by the choice of sampling material. It is important to ensure that the sampling medium and solvent are satisfactory and can be readily used.
- Rinse Samples – Rinse samples allow the sampling of a large surface area. In addition, inaccessible areas of equipment that cannot be routinely disassembled can be evaluated. However, consideration should be given to the solubility of the contaminant. A direct measurement of the product residue or contaminant in the relevant solvent should be made when rinse samples are used to validate the cleaning process.
What Types of Cleaning Methods are Used?
The type of cleaning method chosen will depend on the specific equipment and facility being cleaned, the product being produced, and the potential sources of contamination. These include:
- Manual cleaning: Manual cleaning involves using cleaning solutions and tools such as brushes, sponges, and cloths to clean equipment and surfaces by hand. They all have the inherent advantage of low capital costs and the inherent disadvantage of higher variability. When done right, they can be very effective. Manual methods of cleaning also allow operators some degree of immediate feedback on their cleaning performance. The types of manual cleaning covered are:
- Sink brushing
- Equipment brushing
- Ultrasonic cleaning: Ultrasonic cleaning involves using high-frequency sound waves to agitate cleaning solutions and remove contaminants from equipment and surfaces.
- High-pressure spraying: High-pressure cleaning involves using high-pressure water jets to remove contaminants from equipment and surfaces.
- Steam cleaning: Steam cleaning involves using high-pressure steam to remove contaminants from equipment and surfaces.
- CIP (Clean-in-place) cleaning: CIP cleaning involves using a cleaning solution that is circulated through equipment and surfaces, and then drained out, without the need for disassembly.
- COP (Clean-out-of-place) cleaning: COP cleaning involves disassembling equipment and cleaning the parts separately, usually in a tank or vessel, using cleaning solutions and sometimes mechanical or ultrasonic cleaning devices.
What is contained in a Cleaning Validation Protocol?
- The objective of the validation process. This section provides the objectives and an overview of the cleaning validation process and its purpose, including a summary of the regulatory requirements.
- Scope: This defines the scope of the cleaning validation, including the equipment, surfaces, and systems that will be cleaned, and the products that will be produced on them.
- Responsibility: This section outlines the roles and responsibilities of the personnel involved in the cleaning validation process.
- The interval between the end of production and the beginning of the cleaning procedures.
- Cleaning procedures to be used for each product, each manufacturing system or each piece of equipment.
- Sampling plan: This section outlines the sampling plan, including the number of samples to be taken, the locations to be sampled, and the sampling methods to be used.
- Analytical methods: This section describes the analytical methods to be used to test the samples, including the detection limits, precision, and accuracy of the methods.
- Acceptance criteria: This section defines the acceptance criteria for the cleaning validation, including the maximum allowable levels of contaminants.
- Record keeping: This section outlines the procedures for maintaining records of the cleaning validation, including the documentation of all cleaning procedures, sampling and testing results, and any deviations or corrective actions taken.
- Other products, processes, and equipment for which the planned validation is valid according to a “bracketing” concept.
- When Re-validation will be required.
Do note that the contents of the protocol will vary depending on the specific facility and equipment being cleaned, and the products being produced.
The Cleaning Validation Protocol should be formally approved by the Plant Management, to ensure that aspects relating to the work defined in the protocol, for example personnel resources, are known and accepted by the management. Quality Assurance should be involved in the approval of protocols and reports.
A Final Validation Report should be prepared. The conclusions of this report should state if the cleaning process has been validated successfully. Limitations that apply to the use of the validated method should be defined (for example, the analytical limit at which cleanliness can be determined). The report should be approved by the Plant Management.
The cleaning process should be documented in an SOP.
Records should be kept of cleaning performed in such a way that the following information is readily available:
- the area or piece of equipment cleaned
- the person who carried out the cleaning
- when the cleaning was carried out
- the SOP defining the cleaning process
- the product which was previously processed on the equipment being cleaned
The cleaning record should be signed by the operator who performed the cleaning and by the person responsible for Production and should be reviewed by Quality Assurance.
Operators who perform cleaning routinely should be trained in the application of validated cleaning procedures. Training records should be available for all training carried out.
It is difficult to validate a manual, i.e. an inherently variable/cleaning procedure. Therefore, operators carrying out manual cleaning procedures should be supervised at regular intervals.
The design of the equipment should be carefully examined. Critical areas (those hardest to clean) should be identified, particularly in large systems that employ semi-automatic or fully automatic clean-in-place (CIP) systems.
Dedicated equipment should be used for products which are difficult to remove (e.g. tarry or gummy residues in bulk manufacturing), for equipment which is difficult to clean (e.g. bags for fluid bed dryers), or for products with a high safety risk (e.g. biologicals or products of high potency which may be difficult to detect below an acceptable limit).
The existence of conditions favourable to the reproduction of microorganisms (e.g. moisture, temperature, crevices and rough surfaces) and the time of storage should be considered. The aim should be to prevent excessive microbial contamination.
The period and when appropriate, conditions of storage of equipment before cleaning and the time between cleaning and equipment reuse, should form part of the validation of cleaning procedures. This is to provide confidence that routine cleaning and storage of equipment does not allow microbial proliferation.
In general, equipment should be stored dry, and under no circumstances should stagnant water be allowed to remain in equipment subsequent to cleaning operations.
The efficiency of cleaning procedures for the removal of detergent residues should be evaluated. Acceptable limits should be defined for levels of detergent after cleaning. Ideally, there should be no residues detected. The possibility of detergent breakdown should be considered when validating cleaning procedures.
The composition of detergents should be known to the manufacturer. If such information is not available, alternative detergents should be selected whose composition can be defined. As a guide, food regulations may be consulted. The manufacturer should ensure that he is notified by the detergent supplier of any critical changes in the formulation of the detergent.
The analytical methods should be validated before the Cleaning Validation Study is carried out.
The analytical methods used to detect residuals or contaminants should be specific for the substance to be assayed and provide a sensitivity that reflects the level of cleanliness determined to be acceptable by the company.
The analytical methods should be challenged in combination with the sampling methods used, to show that the contaminants can be recovered from the equipment surface and to show the level of recovery as well as the consistency of recovery. This is necessary before any conclusions can be made based on the sample results. A negative result may also be the result of poor sampling techniques.
Establishment of Limits
The pharmaceutical company’s rationale for selecting limits for product residues should be logically based on a consideration of the materials involved and their therapeutic dose. The limits should be practical, achievable and verifiable.
The approach for setting limits can be:
- Product specific Cleaning Validation for all products,
- Grouping into product families and choosing a “worst case” product,
- Grouping into groups of risk (e.g. very soluble products, similar potency, highly toxic products, difficult to detect).
Carry-over of product residues should meet defined criteria, for example, the most stringent of the following criteria:
- No more than 0.1% of the normal therapeutic dose of any product will appear in the maximum daily dose of the following product,
- No more than 10 ppm of any product will appear in another product,
- No quantity of residue should be visible on the equipment after cleaning procedures are performed. Spiking studies should determine the concentration at which most active ingredients are visible,
- (For certain allergenic ingredients, penicillins, cephalosporins or potent steroids and cytotoxics, the limit should be below the limit of detection by best available analytical methods. In practice, this may mean that dedicated plants are used for these products.
One cannot ensure that the contaminate will be uniformly distributed throughout the system. It is also an invalid conclusion to make the assumption that a residual contaminant would be worn off the equipment surface uniformly or that the contamination might only occur at the beginning of the batch.
In establishing residual limits, it may not be adequate to focus only on the principal reactant since chemical variations (active decomposition materials) may be more difficult to remove.
About the Authors
Senior Lecturer with GetReskilled
Gerry Creaner has over 30-years of experience in the Life Sciences Manufacturing industry across a range of technical, managerial and business roles. He established a very successful engineering consultancy prior to founding GetReskilled, an online education and learning business, with offices in Singapore, Ireland and Boston (USA), focussed on the manufacture of safe and effective medicines for the public.
He is also a founding Director of two Singapore based philanthropic organizations, the Farmleigh Fellowship and the Singapore-Ireland Fund, both of which deepen the well established and historical Singapore – Ireland relationship and deliver long-term benefits to both countries.
Gerry has an undergraduate degree in Chemical Engineering (UCD, 1980) and an MSc (Management) from Trinity College Dublin (2003) and is currently doing research for his Ph.D.
Head of Marketing & Product Development
Donagh looks after the marketing and product development including the training and pedagogical elements of our programs and makes sure that all GetReskilled’s users can have a great online learning experience. Donagh has lived and worked in many countries including Ireland, America, the UK, Singapore, Hong Kong and Japan where he managed to pick up the language. Donagh has also served as the Program Manager for the Farmleigh Fellowship based out of Singapore.
Donagh holds Degrees in Production Engineering and Mechanical Engineering from South East Technological University, Ireland.