Cleaning Validation

What is cleaning Validation

Cleaning validation is the methodology used to assure that a cleaning process removes chemical and microbial residues of the active, inactive or detergent ingredients of the product manufactured in a piece of equipment, the cleaning aids utilized in the cleaning process and the microbial attributes.

OR

Cleaning validation is a procedure of establishing evidence that cleaning processes for manufacturing equipment prevents product contamination. Cleaning validation should be properly documented to demonstrate Current Good Manufacturing Practice (CGMP) for finished pharmaceuticals.

Why is it needed

Cleaning validation is required because Active Pharmaceutical Ingredients (APIs) cross contaminated with chemical residues and microbes can compromise patient safety. Ineffective cleaning processes not only lead to more downtime and batch failures, but it also result in FDA rejection and costly fines due to drug adulteration.

FDA Guidelines

While the U.S. Food and Drug Administration (FDA) has yet to release cleaning validation guidelines for pharmaceutical firms, they provide a reference material for the inspections regularly carried out by investigators and other FDA personnel. In the document, FDA generally expects:

• Written standard operating procedures (SOPs) for equipment cleaning processes that address different scenarios (e.g. one process for different batches, different processes between product changes, etc.)

• Written cleaning validation procedures, including who is responsible for performing and approving the validation study, the acceptance criteria, and when re-validation will be required
• Written cleaning validation protocols for the inspection of each equipment that address common issues (e.g. sampling procedures, analytical methods, etc.), conducting the validation according to the protocols and documenting its results
• Data-supported, management-approved, and final cleaning validation report stating whether or not the cleaning process for a specific piece of equipment or manufacturing system is valid

The U.S. (FDA) has strict regulations about cleaning validation. For example, FDA requires firms to have written general procedures on how cleaning processes will be validated. Also, FDA expects the general validation procedures to address who is responsible for performing and approving the validation study, the acceptance criteria, and when revalidation will be required. FDA also require firms to conduct the validation studies in accordance with the protocols and to document the results of studies. The valuation of cleaning validation is also regulated strictly, which usually mainly covers the aspects of equipment design, cleaning process written, analytical methods and sampling. Each of these processes has their related strict rules and requirements. Acceptance criteria for cleaning validation protocols considers limits for chemicals and actives, limits for bio burden, visually cleanliness of surfaces, and the demonstration of consistency when executing the cleaning procedure. Regarding the establishment of limits, FDA does not intend to set acceptance specifications or methods for determining whether a cleaning process is validated. Current expectations for setting cleaning limits include the application of risk management principles and the consideration of Health Based Exposure Limits as the basis for setting cleaning limits for actives. Other limits that have been mentioned by industry include analytical detection levels.

EVALUATION OF CLEANING VALIDATION

Examine the design of equipment, particularly in those large systems that may employ semi-automatic or fully automatic clean-in-place (CIP) systems since they represent significant concern. For example, sanitary type piping without ball valves should be used. When such nonsanitary ball valves are used, as is common in the bulk drug industry, the cleaning process is more difficult.

When such systems are identified, it is important that operators performing cleaning operations be aware of problems and have special training in cleaning these systems and valves. Determine whether the cleaning operators have knowledge of these systems and the level of training and experience in cleaning these systems. Also check the written and validated cleaning process to determine if these systems have been properly identified and validated.

In larger systems, such as those employing long transfer lines or piping, check the flow charts and piping diagrams for the identification of valves and written cleaning procedures. Piping and valves should be tagged and easily identifiable by the operator performing the cleaning function. Sometimes, inadequately identified valves, both on prints and physically, have led to incorrect cleaning practices.

Always check for the presence of an often critical element in the documentation of the cleaning processes; identifying and controlling the length of time between the end of processing and each cleaning step. This is especially important for topicals, suspensions, and bulk drug operations. In such operations, the drying of residues will directly affect the efficiency of a cleaning process.

Whether or not CIP systems are used for cleaning of processing equipment, microbiological aspects of equipment cleaning should be considered. This consists largely of preventive measures rather than removal of contamination once it has occurred. There should be some evidence that routine cleaning and storage of equipment does not allow microbial proliferation. For example, equipment should be dried before storage, and under no circumstances should stagnant water be allowed to remain in equipment subsequent to cleaning operations.

Subsequent to the cleaning process, equipment may be subjected to sterilization or sanitization procedures where such equipment is used for sterile processing, or for nonsterile processing where the products may support microbial growth. While such sterilization or sanitization procedures are beyond the scope of this guide, it is important to note that control of the bioburden through adequate cleaning and storage of equipment is important to ensure that subsequent sterilization or sanitization procedures achieve the necessary assurance of sterility. This is also particularly important from the standpoint of the control of pyrogens in sterile processing since equipment sterilization processes may not be adequate to achieve significant inactivation or removal of pyrogens.

Procedure and Documentation

Examine the detail and specificity of the procedure for the (cleaning) process being validated, and the amount of documentation required. We have seen general SOPs, while others use a batch record or log sheet system that requires some type of specific documentation for performing each step. Depending upon the complexity of the system and cleaning process and the ability and training of operators, the amount of documentation necessary for executing various cleaning steps or procedures will vary.

When more complex cleaning procedures are required, it is important to document the critical cleaning steps (for example certain bulk drug synthesis processes). In this regard, specific documentation on the equipment itself which includes information about who cleaned it and when is valuable. However, for relatively simple cleaning operations, the mere documentation that the overall cleaning process was performed might be sufficient.

Other factors such as history of cleaning, residue levels found after cleaning, and variability of test results may also dictate the amount of documentation required. For example, when variable residue levels are detected following cleaning, particularly for a process that is believed to be acceptable, one must establish the effectiveness of the process and operator performance. Appropriate evaluations must be made and when operator performance is deemed a problem, more extensive documentation (guidance) and training may be required.

Determine the specificity and sensitivity of the analytical method used to detect residuals or contaminants. With advances in analytical technology, residues from the manufacturing and cleaning processes can be detected at very low levels. If levels of contamination or residual are not detected, it does not mean that there is no residual contaminant present after cleaning. It only means that levels of contaminant greater than the sensitivity or detection limit of the analytical method are not present in the sample. The firm should challenge the analytical method in combination with the sampling method(s) used to show that contaminants can be recovered from the equipment surface. This is necessary before any conclusions can be made based on the sample results. A negative test may also be the result of poor sampling technique (see below). 

There are two general types of sampling that have been found acceptable. The most desirable is the direct method of sampling the surface of the equipment. Another method is the use of rinse solutions.

1. Equipment Design
2. Cleaning Process Written
3. Analytical Methods
4. Sampling

 Advantages of direct sampling are that areas hardest to clean and which are reasonably accessible can be evaluated, leading to establishing a level of contamination or residue per given surface area. Additionally, residues that are “dried out” or are insoluble can be sampled by physical removal. A disadvantage of rinse samples is that the residue or contaminant may not be soluble or may be physically occluded in the equipment. measurement of the residue or contaminant has been made for the rinse water when it is used to validate the cleaning process. For example, it is not acceptable to simply test rinse water for water quality (does it meet the compendia tests) rather than test it for potential contaminates.

Monitoring – Indirect testing, such as conductivity testing, may be of some value for routine monitoring once a cleaning process has been validated. This would be particularly true for the bulk drug substance manufacturer where reactors and centrifuges and piping between such large equipment can be sampled only using rinse solution samples. Any indirect test method must have been shown to correlate with the condition of the equipment. During validation, the firm should document that testing the uncleaned equipment gives a not acceptable result for the indirect test.

However, it is generally accepted in the pharmaceutical industry that there are two types of sampling methods for cleaning validation: direct and indirect.

• Direct sampling for cleaning validation is also known as the swab method, where a sterile material is systematically rubbed across a surface to be analyzed for the presence of residue.
• Indirect sampling for cleaning validation is often referred to as rinse sampling, where a solvent like water is rinsed in a specific area of clean surface and tested for traces of contaminants.

Types of Cleaning Methods:

While the total number of cleaning methods used in pharmaceutical cleaning validation has yet to be completely determined,the most types so far and it generally includes the following:

• Clean-in-place Method – normally using fixed or rotating spray devices with a wash tank, recirculation pump, and associated piping
• Clean-out-of-place Method – often used for automated parts washing through cabinet or tunnel washers with cleaning, rinsing, and drying cycles
• Immersion Method –  either agitated, where a cleaning agent in a process vessel is mechanically stimulated to achieve a cleaning effect, or static, where the process vessel is merely soaked with the cleaning agent
• Ultrasonic Washing – typically works better for intricate parts such as filling needles as it involves a tank equipped with ultrasonic transducers to induce cavitation
• High-pressure Spraying – serves to dislodge any residues on the surface through high-pressure, continuous, and directed water or cleaning solution
• Manual Cleaning – usually the most difficult cleaning method to validate; includes three most common techniques: wiping, sink brushing, and equipment brushing

Acceptance Criteria

Accurately setting the acceptance criteria for the limit in cleaning validation is crucial to determine the results of the study. To better evaluate whether or not cleaning methods are effective, cleaning validation acceptance criteria can be generally categorized into three various testing parameters:

• Physical Criterion: a visual inspection of the equipment should reveal that there are no particulate matters or residues.

• Chemical Criterion: no more than 10 ppm (parts per million) of a product should be detected in another product and/or no more than 0.1% of the normal therapeutic dose of a product should appear in the maximum daily dose of another product
• Microbial Criterion: no more than 20 CFU (colony-forming units) for bacterial counts, no more than 2 CFU for molds, and/or no more than 25 CFU/25cm2 of contaminants in a sample

Pharmaceutical Terms and Their Definitions

Cleaning validation in the pharmaceutical industry mostly entails certain jargons that manufacturing personnel should be familiar about. Here are twelve of the most common abbreviations related to pharmaceutical cleaning validation and what they mean:

• CGMP – Current Good Manufacturing Practice
• API – Active Pharmaceutical Ingredient
• ADE – Acceptable Daily Exposure
• PDE – Permitted Daily Exposure
• MACO – Maximum Allowable Carry Over
• NOEL – No Observed Effect Level
• LOEL – Lowest Observed Effect Level

• NOAEL – No Observed Adverse Effect Level
• LOAEL – Lowest Observed Adverse Effect Level
• LOQ- Limit of Quanititation
• LOD – Limit of Detection
• LD – Lethal Dose

Is cleaning validation required for dedicated equipment?

Yes, as long as any piece of equipment or manufacturing system is used in the production, processing, packing, or holding of drug products, cleaning validation is required. Moreover, the FDA inspects the cleaning process especially for dedicated equipment (e.g. fluid bed dryer bags) because they can be more difficult to clean and the likelihood of contamination can be higher.

When should cleaning validation be done?

Even when federal regulations do not specify exactly how often cleaning validation should be done, the FDA enforces Section 211.67a of Current Good Manufacturing Practice for Finished Pharmaceuticals to address the matter:

“Equipment and utensils shall be cleaned, maintained, and, as appropriate for the nature of the drug, sanitized and/or sterilized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements.

In other words, the FDA expects equipment cleaning at the necessary frequency to prevent drug adulteration. Regularly performing cleaning validation is useful for determining how often equipment should be cleaned as required by law. More importantly, it is essential in verifying if cleaning processes are actually effective in preventing contamination.

As a general guide or starting point, cleaning validation should be conducted for the initial qualification of a manufacturing process or equipment.

five more instances when cleaning validation should be done:

• when there is a critical change in equipment cleaning procedures.
• when there is a critical change in drug formulation.
• when there is a significant change in the equipment.
• when there is a change in a cleaning process.
• when there is a change in a cleaning agent.

How is the worst case selected in cleaning validation?

This srticle published in the Brazilian Journal of Pharmaceutical Sciences reported that their calculation of a worst case index (WCI) was based on drug solubility, difficulty of equipment cleaning, and occupancy of products in the production line. Refer to the solubility factor table below for more information:

Descriptive term	Solubility (S) in water (ppm)	Classification	Score fs
Highly soluble	S > 1,000,000	High Solubility	3
Easily soluble	100,000 < S < 1,000,000
Soluble	33,000 < S < 100,000
Sparingly soluble	10,000 < S < 33,000	Moderate Solubility	2
Slightly soluble	1,000 < S < 10,000
Very slightly soluble	100 < S < 1,000	Low Solubility	1
Practically insoluble or insoluble	S < 100

Can each equipment cleaning process be clearly understood?

Effective cleaning validation clearly defines:

• the solubility of the materials to be removed;
• the design and construction of the equipment and surface materials to be cleaned;
• the safety of the cleaning agent;
• the ease of removal and detection,
• the product attributes;
• the minimum temperature and volume of cleaning agent and rinse solution; and
• manufacturer’s recommendations.

Operational, validation, and laboratory personnel should understand all decontamination steps, process residue details, hold times, and worst cases related to the equipment and product. Quality managers should regularly evaluate acceptable limits, soiling conditions, and incoming raw material inspection.

What systems and procedures are in place to ensure regulatory compliance?

The FDA inspects pharmaceutical manufacturers to verify compliance with relevant regulations, such as Section 211.67 (Equipment Cleaning and Maintenance). Some of its provisions include:

• Protection of clean equipment from contamination prior to use
• Inspection of equipment for cleanliness immediate before use
• Maintenance, cleaning, sanitizing, and inspection record-keeping

Establishing and implementing practical steps to make sure that baseline requirements are met can also enable pharmaceuticals to adequately prepare for FDA inspections. Use preparedness checklists and conduct internal audits to address the different types of FDA inspections.