Cleaning validation in the manufacturing of ointments poses some challenges that differ from those that come with many traditional solid oral dosage forms. Ointments, creams and gels contain waxes, oils, hydrocarbons, fatty materials, emulsifiers, polymers and active ingredients of poor water solubility. Although cleaning may seem visually effective, residues can still remain in places that are hard to clean like the shafts of agitators, blades of scrapers, corners of the vessel, valves, ports of discharge, transfer pipes and seals.
That is why methods of cleaning validation in ointment making should be using a combination of visual checking, sampling that is scientifically justified, and advanced analysis. It is not enough just to prove that the equipment is clean. The study should prove that it is possible to effectively clean the equipment with the help of the approved cleaning methods so that product residues and cleaning agents effectiveness and if necessary appearance of microbes can be brought to acceptable level.
The level of difficulty in cleaning depends greatly on the characteristics of the product being produced. Thus, a water-soluble cream can be cleaned with the use of water, while an ointment with petrolatum, mineral oil or waxes may require certain temperature, cleaning methods, mechanical action, and sequence of cleaning steps.
One thing I always check when analyzing a validation process is dirty hold time. If the leftover material is being held on the equipment for many hours or overnight, removing it becomes a much harder task. Therefore, the validation process has to simulate the possible worst-case situations for cleaning.
It is mentioned in the FDA guidance related to cleaning validation inspections that the dirty hold time is one of the main aspects that should be taken into account when it comes to ointments and other similar operations when the product gets dry and is not easy to remove anymore.
Factors for the product selection process should include:
The reasoning behind the selection should be documented based on Quality Risk Management principles instead of selecting the product based on its batch size only.
Attention must be paid also to:
The validation protocol should, for example, point to the worst places and the representative locations where most contaminated areas could potentially occur.
The method itself used for swabbing should also be proved to be effective. Recovery studies should show that the swab and the solvent used can actually recover residue from the surface of the equipment.
This is a very important point. "Undetected" laboratory results do not mean much if the method used for sampling fails in recovering residue.
Direct surface sampling is mentioned in FDA guidance as an important technique.
However, for ointments, careful consideration of rinse solvent is needed. An oily or waxy residue may not be dissolved properly in the rinse medium, which means that a rinse sample that looks clean will not necessarily guarantee that the surface of the equipment is clean.
While the FDA acknowledges that rinse sampling can be used in big or hard-to-reach areas, it does indicate its drawbacks when speaking about residues that are either not soluble or kept on the surface of the equipment.
As a result, combination of swab sampling and rinse sampling means more reliable results than performing rinse sampling alone.
If possible, a specific analysis for the active ingredient is likely to produce the best results. Depending on the formulation method as well as validation methods used, other methods could include TOC, detergent-specific testing and/or other validated analytical method.
The method should have sufficient sensitivity in light of the acceptance limit set and provide appropriate specificity, accuracy, precision and sensitivity.
As stated in FDA's Q7A guideline, cleaning validation procedure should indicate the equipment to be used, cleaning procedures, cleaning levels, sampling and appropriate analytical method.
Because of this, cleaning validation should include microbiological control in cases that correlate with the product, the equipment and the manufacturing process used. The equipment must be properly dried and protected once the cleaning process is completed.
This becomes especially relevant when there is a waiting period between batches when production equipment is not in use. A surface may look clean from a chemical point of view but poses biological risks if water gets to accumulate in storage and viable microbes proliferate.
Action Points for a QA Department During Validation Review
In terms of QA, validating the cleaning process involves looking beyond just the final residue statistics. The validation process is intended to prove the reproducibility of the cleaning process itself.
Questions to Consider Include:
Risk assessment → Selecting the situation with the greatest risk → Specifying the cleaning process → Developing/validating the analytical technique → Conducting the study to evaluate the cleaning process → Executing the delivery of treatment → Evaluating the findings → Compiling an official report → Carrying out the regular monitoring.
In the procedure for cleaning, key parameters such as concentration of the cleaning product, temperature and time of cleaning process, duration of cleaning and rinsing of the equipment, as well as the drying mode, must be established. In addition, rectification process should be described in detail to ensure accuracy of actions of personnel.
Subsequently, any variations in the formula, equipment, cleaning agents and parameters, as well as manufacturing processes, should be evaluated through a post-change control process to reveal whether additional cleaning validation, if needed, will be required.
For the QA department the most crucial question is not whether the samples have passed the test; the most relevant question is whether the study gives the necessary proof that the process of cleaning can achieve required level of cleanliness under realistic extreme conditions of manufacturing.
Why Ointment Equipment Requires a Different Cleaning Strategy
Equipment that produces ointments often works with hot containers, high-shear mixers, homogenizers and systems for scraping. During this process, the product may create a uniform thin layer over big stainless-steel areas.The level of difficulty in cleaning depends greatly on the characteristics of the product being produced. Thus, a water-soluble cream can be cleaned with the use of water, while an ointment with petrolatum, mineral oil or waxes may require certain temperature, cleaning methods, mechanical action, and sequence of cleaning steps.
One thing I always check when analyzing a validation process is dirty hold time. If the leftover material is being held on the equipment for many hours or overnight, removing it becomes a much harder task. Therefore, the validation process has to simulate the possible worst-case situations for cleaning.
It is mentioned in the FDA guidance related to cleaning validation inspections that the dirty hold time is one of the main aspects that should be taken into account when it comes to ointments and other similar operations when the product gets dry and is not easy to remove anymore.
Choosing the Worst-Case Ointment
The cleaning validation method does not require testing for each product if it is possible to choose appropriate products using a scientific approach, i.e. bracketing or grouping.Factors for the product selection process should include:
- Solubility of the product in the cleaning medium
- Concentration and potency of the active ingredient
- Toxicological properties
- Composition of the formulation
- Adhesiveness of the material to the surface of machines
- Presence of waxes, oils or other polymers
- Thermal properties
- Past cleaning history
- Level of difficulty for removing the residue
The reasoning behind the selection should be documented based on Quality Risk Management principles instead of selecting the product based on its batch size only.
Important Methods for Cleaning Validation
1. Visual Inspection
Visual examination has significance in cleaning validation. The inspection of critical product-contact areas must be done by inspectors or operators in according to certain lightening or viewing conditions.Attention must be paid also to:
- Blades and shafts of the stirrer
- Walls and bottoms of vessels
- Screeding arrangements
- Components of the homogenizer
- Gaskets and valves
- Hoses for the transfer
- The equipment for filling
- Difficult zones and places hard to get to
2. Swab Sampling
Swab sampling plays a great role when it comes to ointments equipment since it provides direct evidence from the respective surfaces of the equipment.The validation protocol should, for example, point to the worst places and the representative locations where most contaminated areas could potentially occur.
The method itself used for swabbing should also be proved to be effective. Recovery studies should show that the swab and the solvent used can actually recover residue from the surface of the equipment.
This is a very important point. "Undetected" laboratory results do not mean much if the method used for sampling fails in recovering residue.
Direct surface sampling is mentioned in FDA guidance as an important technique.
3. Rinse Sampling
Rinse sampling is a technique employed when direct swabbing is not possible, for instance in case of internal transfer lines, closed systems, or hard-to-reach surfaces.However, for ointments, careful consideration of rinse solvent is needed. An oily or waxy residue may not be dissolved properly in the rinse medium, which means that a rinse sample that looks clean will not necessarily guarantee that the surface of the equipment is clean.
While the FDA acknowledges that rinse sampling can be used in big or hard-to-reach areas, it does indicate its drawbacks when speaking about residues that are either not soluble or kept on the surface of the equipment.
As a result, combination of swab sampling and rinse sampling means more reliable results than performing rinse sampling alone.
4. Specific Analysis
The analysis used to test for residue being analyzed should be chosen in accordance with the type of contaminant being analyzed.If possible, a specific analysis for the active ingredient is likely to produce the best results. Depending on the formulation method as well as validation methods used, other methods could include TOC, detergent-specific testing and/or other validated analytical method.
The method should have sufficient sensitivity in light of the acceptance limit set and provide appropriate specificity, accuracy, precision and sensitivity.
As stated in FDA's Q7A guideline, cleaning validation procedure should indicate the equipment to be used, cleaning procedures, cleaning levels, sampling and appropriate analytical method.
Do Not Ignore Microbiological Cleaning Controls
Manufacturing emulsions can introduce microbiological risks if the formulations contain water and provide environments in which microbes can thrive.Because of this, cleaning validation should include microbiological control in cases that correlate with the product, the equipment and the manufacturing process used. The equipment must be properly dried and protected once the cleaning process is completed.
This becomes especially relevant when there is a waiting period between batches when production equipment is not in use. A surface may look clean from a chemical point of view but poses biological risks if water gets to accumulate in storage and viable microbes proliferate.
Action Points for a QA Department During Validation Review
In terms of QA, validating the cleaning process involves looking beyond just the final residue statistics. The validation process is intended to prove the reproducibility of the cleaning process itself.
Questions to Consider Include:
- Was the justification of the worst-case product scientifically sound?
- Did the sampling include the hardest parts of the cleaning process?
- Is the hold time that was used for cleaning operations accurate and reflective of real-life conditions?
- Is there proof of the proper concentration of the cleaning agent?
- Was temperature and cleaning time controlled and monitored?
- What about the performance of the hand scrubbing?
- Were the studies on recovery rates conducted?
- Is the residue limit supported by scientific data?
- Were deviations identified and analyzed to check for potential deviations?
- Have any repeated cleaning attempts occurred during the validation process?
A Practical Approach for Ointment Cleaning Validation
The approach to this process will generally involve the following steps:Risk assessment → Selecting the situation with the greatest risk → Specifying the cleaning process → Developing/validating the analytical technique → Conducting the study to evaluate the cleaning process → Executing the delivery of treatment → Evaluating the findings → Compiling an official report → Carrying out the regular monitoring.
In the procedure for cleaning, key parameters such as concentration of the cleaning product, temperature and time of cleaning process, duration of cleaning and rinsing of the equipment, as well as the drying mode, must be established. In addition, rectification process should be described in detail to ensure accuracy of actions of personnel.
Subsequently, any variations in the formula, equipment, cleaning agents and parameters, as well as manufacturing processes, should be evaluated through a post-change control process to reveal whether additional cleaning validation, if needed, will be required.
For the QA department the most crucial question is not whether the samples have passed the test; the most relevant question is whether the study gives the necessary proof that the process of cleaning can achieve required level of cleanliness under realistic extreme conditions of manufacturing.
Get ready to use editable Validation Protocols in MS-Word FormatView List
No comments:
Post a Comment
Please don't spam. Comments having links would not be published.