2. CONTENT
• Importance of microbial residue control
• Changes in microbial residues
• Microbial residue reduction
• What is measured for acceptance criteria?
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3. IMPORTANCE OF MICROBIAL
RESIDUE CONTROL
The rationale for considering microbiological contamination as part of a
cleaning program is that microbiological quality is of concern for all products.
At a minimum, the absence of certain enteric organisms in the cleaned
equipment is a must for all products.
For biotechnology manufacturing involving microbial cells, the presence of
species other than the one desired for manufacturing purposes may interfere
with productivity and quality.
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4. CONT…
The issue of microbiological contamination of cleaned equipment for sterile products
may also be related to endotoxin levels in the subsequently manufactured product.
Additional concerns are the possible effects of microbes on the stability of the drug
product or perhaps on the bioavailability of the drug active.
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5. CHANGES IN MICROBIAL RESIDUE
• Microbial residues are different from chemical residues.
• Chemical residues generally are transferred unchanged to the subsequently
manufactured product.
• As pointed out in the FDA guidance document, there may be microbial
proliferation after the cleaning step (and during storage), which may
considerably change the level of microbial residues.
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6. CONT…
• On the other hand, there may be microbial death on cleaned, dried equipment
that significantly lowers the bioburden transferred to the subsequently
manufactured product.
• The main issue is that levels of microbial residues present at the end of cleaning
are not as relevant as levels of microbial residues that are present at the
beginning of manufacture of the next product.
• The key point is that microbial residues may change during storage of the
cleaned equipment
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7. CONT…
• If the product is a dry product with a water content of < 0.6 percent, it is
generally accepted that microbes will not grow in such products.
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8. MICROBIAL RESIDUE
REDUCTION
• Effective cleaning by itself can in most cases
produce equipment that will have acceptable
microbial residue levels.
• Effective cleaning in this case generally means
cleaning with a hot solution of a highly alkaline
or acidic cleaning agent containing surfactants,
which also remove the chemical residues that are
present in the system.
• The purpose of the acidity or alkalinity is to
produce a cleaning environment that is hostile to
microorganisms. The same is true for using an
elevated temperature (generally above 60°C) to
produce an environment hostile to microbes.
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9. CONT…
• It is important that the cleaning process also remove the chemical residues
present; significant amounts of chemical residues left behind may serve as
microbial traps, which prevents the destruction or removal of the microorganism
during the cleaning process.
• A proper design and engineering of the equipment is necessary to eliminate
locations where microorganisms can hide and proliferate. These are generally
the same locations that may cause problems with chemical residues, including
dead legs and crevices.
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10. WHAT IS MEASURED FOR
ACCEPTANCE CRITERIA?
• The acceptance criteria preferably include a specification of restricted organisms
(that is, those that should not be present at all, such as enteric organisms) and a
specification of the maximum number of CFUs per swab or contact plate.
• The maximum number acceptable in the cleaned equipment should be based,
on the contribution of microbial load to the subsequently manufactured product
or to the bioburden for the subsequent sterilization process.
• In selecting acceptable limits for cleaning validation acceptance criteria, one
possibly could view these numbers as extremely high; in most cases, one would
never have equipment contaminated at those levels.
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11. CONT…
• The action/alert limits measured as part of routine monitoring will be
significantly below the acceptance criteria for cleaning validation purposes. This
is to be expected.
• The action/alert limits are initially established as tentative limits based on
prequalification testing. As more data are obtained from routine monitoring,
these action/alert limits may be revised.
• The action/alert levels for monitoring purposes are designed to provide an early
warning of possible changes in the system through a review of trend data.
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12. CONT…
• This contrast between validation acceptance criteria and routine monitoring
limits is important for chemical monitoring as well as for microbial monitoring.
• It should also be noted that microbial testing for cleaning validation usually
focuses on bacterial or mold/yeast contamination.
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13. CONCLUSION
• Control measures in manufacturing may include limiting bioburden:
i. In raw materials (and on equipment in direct contact with these).
ii. In packaging components
iii. In manufacturing environment
iv. On product-contact surfaces
• The purpose of microbiological consideration in cleaning validation is to control
microbial bioburden within an acceptable level.
• Cleaning of cleanroom surfaces & cleaning of process equipment – have distinct
regulatory and technical focus.
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14. REFERENCES
1. Validated Cleaning Technologies for Pharmaceutical Manufacturing_Destin A.
LeBlanc(2000, Informa Healthcare)
2. Microbiological Aspects of Cleaning Validation; Dr. Tim Sandle
https://www.pharmig.org.uk/en/wp-content/uploads/2019/05/10.10-10.50-
Tim-Sandle-Microbial-Cleaning-Validation-frkkgor55kfiodug.pdf
3. Microbiological Cleaning Method Validation; Fergus O’Connell
https://cdnmedia.eurofins.com/apac/media/489871/raci-capsig-
microbiological-cleaning-method-validation-16-aug-2017.pdf
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