Cleaning validation in pharma manufacturing.
When you thinking of doing cleaning validation of an equipment or a procedure adapted for cleaning, first question you should ask is that is the cleaning validation planed in the validation master plan? If not it’s not late to do that.
Along with cleaning validation most important work needs to be done is dirty equipment hold time study as well as clean equipment hold time study should be done.
Many pharma company don’t do hold time study for dirty equipment and cleaned equipment, this is not proper approach, during cleaning validation itself, hold time study for dirty equipment and cleaned equipment should be done.
Cleaning validation in pharma industry can be defined as “process of establishing through documentary evidence that the cleaning method adapted is capable of maintaining the cleanliness of the equipment so as to prevent the cross contamination from earlier product manufactured in the equipment and to comply with the Good manufacturing guidelines used by regulatory agencies life US FDA, WHO, CDISCO, UKMHRA. TGA, ETC.
It is a mandatory part and responsibility of pharma manufacturing facilities to adapt methods for cleaning during regular production runs, with these adapted cleaning methods it should be assured that no cross contamination of a product occurs in other products.
Good manufacturing practices guidelines have not mentioned any limit for cleanness and traces levels for cleaning agent and previous product. Which means that after cleaning there should not be any traces of a product remaining in the equipment. Neither should there be any microbial load which will be a risk of contamination of product with microbial contamination.
As per GMP guidelines, the minimum carries over limit is not given.
LOD 50 and not more than 0.1% of the daily dose of a drug fundamentals are not required by Food and Drugs administration, rather it is manufacturers data for establishing the safety of the product being manufactured with the adapted cleaning methodology.
Therefore, a cleaning validation process is run through exhaustive five levels which is also called a life cycle approach towards cleaning validation.
1) Design a cleaning procedure.
2) Test the developed procedure for its workability.
3) Validate the cleaning procedure on the three consecutive batches.
4) Monitor the contaminant residue after every cleaning and evaluate the cleaning procedure.
5) If any improvisation is required, do it at an appropriate stage through a change management system.
Above is a simple explanation of the lifecycle approach for conducting cleaning validation.
Following questions should be answered to know the technical aspects of cleaning validation in the pharma industry.
1) Design a cleaning procedure.
Q: Why design a cleaning procedure?
A: There are many products with different behaviour during cleaning, some products traces don’t get removed easily they require special treatment with base or acid, therefore a detergent or cleaning agent it self when included with such acid or bases work better. This when combined with a robust cleaning process procedure it yields satisfactory results consistently.
2) Test the developed procedure for its workability.
Q: Why to test the workability of cleaning procedure?
A: It’s required for Analytical Method Validation for traces and cleaning agents identification.
3) Validate the cleaning procedure on the three consecutive batches.
Q: Why to use three consecutive batches for cleaning validation?
A: Always first batch falls short for one or the other thing, time required for first batch is always greater than subsequent batch. Second batch is done with all learnings and experiences from first batch.
Third batch then confirms that the results obtained from second batch during validation are similar to third batch. Thus repeatability is confirmed.
4) Monitor the contaminant residue after every cleaning and evaluate the cleaning procedure.
Q:Why Monitor the residue levels after doing cleaning in routine batches?
A:It’s requirements of monitoring products validation cleaning validation through out it’s life cycle.
5) If any improvisation is required, do it at an appropriate stage through a change management system.
Q:Why to do changes in validated procedure?
A:To incorporate the best procedure and learnings from ongoing process and as part of improvisation.
When we try to answer these questions we get the perfect answers for what is at the heart of the requirement of cleaning validation in the pharma industry.
Minimum Allowable carry over limit of previous product: MACO.
The presence of previous product in the traces after cleaning is basically not expected rather it is not allowed as per the good manufacturing practices guidelines. At the same time cleanness is required to be verified for microbial load on the equipment. In MACO the A stands for allowable, it doesn’t mean it is allowed. It is allowed after consideration of risk assessment and establishment of the safety and purity of the product manufactured after adapting the said cleaning procedure.
What is NOEL: NOEL is a concentration of previous products active pharmaceutical products concentration which when included in the next product even after cleaning will not produce any lethal effect on the health of individual, in other words it the limit of concentration beyond which the concentration of previous drug products AIPs if included in next product will be toxic.
NOEL = (LD50 X BODY Weight)/2000 where 2000 is a constant derived from toxicology chronic exposure study.
Minimum carry over limit is calculated based on three criteria’s,
1) Health-based exposure limit (HBEL) 2) therapeutic dose, toxicological, 3) 10-ppm approaches 4) NOEL
1)MACO by health based exposure limit = HBEL \ MBS x MDD
2)MACO by NOEL = (NOELX Batch size in milligram)/ (Daily dose of the productx1000)
3) MACO BY THERAPEUTIC DOSE = Smallest dose of the earlier product x Batch size of earlier product Safety factor/ Largest daily dose of next product.
Microbial load limit for cleaning validation
During cleaning validation, the present microbial load even if it is with in the limit, the microorganism must be separated.and indented, that is which bacteria or fungus is there in the load, if more types of colonies are present those too must be separated and microorganism must be identified, this will help during making decision for disinfection process and decontamination of the manufacturing area, for sterile drug products.
10 PPM criteria for visible residues after cleaning:
Most of the molecules do not exert any untoward effect in such concentration as 10 ppm of previous products active ingredient, most of the APIs are considered safer.
Why is the LD 50 Value of product considered during cleaning validation?
LD 50 Value is a measure of toxicity if a pharmaceutical product having lower LD 50 is considered as most risky, and taken for evaluation in cleaning validation. If these products are cleaned with an adapted cleaning procedure, it is considered safe for other products with higher LD50 than the lowest one taken for cleaning validation study.
Q: Why is a product with API with lowest solubility in water preferred for cleaning validation study?
A: Cleaning is done with water and soap or any approved cleaning agent, therefore the drug molecule which is not soluble in water will not get removed from surface of equipment and may contaminate other product, therefore a cleaning procedure that can remove lowest soluble or water insoluble drug molecule from surface of equipment will also be able to clean other drug molecules which may be soluble in water.
Q: What is the criteria for compliance for visible cleanness in cleaning validation?
A: After cleaning there should not be any visible uncleaned surface or surface with dirt.
Q: What is the method for assessing cleaning of equipment that is not visible directly, how to do assessment of the cleaning of that part of equipment?
A: In such events where swab test or visual observation is not possible, surfaces which are not accessible are rinsed with purified filtered water and examined visually and analytically for traces of previous product or residues of cleaning agent.
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