Suez Total Organic Carbon - March 2020 - 10

The example process information on Minimum Batch Size (MBS), safety
factor, and average patient mass (kg body weight) are as follows:

The example illustrates that when starting with defensible clinical
reference values, the MAC value for Epinephrine in Diazepam is 1.46
mg/dm2. When TOC technology is deployed for a cleaning validation
process, based on MAC and sampling method, the TOC limit for
Epinephrine in Diazepam is determined to be 21.5 ppm.

With this information, the MAC value of Epinephrine into Diazepam
(MACA in B) can be calculated.

conclusion
Based on recent guidance from the FDA, the life cycle approach should
be considered best practice when implementing a cleaning validation
process. The life cycle approach calls for continuous monitoring and
updating to the design, qualification, and verification of the cleaning
validation process. When choosing an analytical method to measure

The MAC value must now be converted to a product limit by considering
the sampling method. In this example, the method is swabbing a 1
dm2 area inside a tank. The active surface area of the tank is 80% of
the total based on the fill level of the tank.

the effectiveness of the cleaning validation process, it should be noted
that specific methods, looking at a single API, do not comply with the
best practice recommendation as changes in other non-quantified
contaminants will go unnoticed.
Nonspecific methods, such as TOC, comply with the best practice
recommendation by measuring the total contaminants in the cleaning
process rather than just a specific API. Degradants, excipients, and
cleaning residues are just a few potential contaminants that are not
captured in a specific method, such as HPLC, but are captured in a
nonspecific method, such as TOC.
This chapter demonstrates that the determination of acceptance
criteria limits for TOC in cleaning validation can be easily calculated and

The TOC vial volume of 40 mL is also known. Since the sampling
method is swabbing, the swab will be broken off in the vial; therefore,
the final product limit concentration for Epinephrine is as follows:

defended when starting from justifiable clinical reference values. This,
in conjunction with the US FDA best practices for cleaning validation,
highlights a few of the many appealing aspects driving industry leaders
to adopt TOC analysis for cleaning validation on a large scale.

References
1.

Guidance for Industry, Process Validation: General Principles
and Practices. FDA, 2011, https://www.fda.gov/media/71021/

With the product limit established, the TOC limit can be determined by
the percent carbon in the chemical formula for Epinephrine, C9H13NO3.

download
2.

DSSTox (FDAMDD) FDA Maximum (Recommended) Daily Dose
Database. Pub Chem BioAssay Database, Record for AID
1195, https://pubchem.ncbi.nlm.nih.gov/bioassay/1195

3.

Guidance on Aspects of Cleaning Validation in Pharmaceutical
Ingredient Plants. APIC Publications, APIC.cefic.org,
https://apic.cefic.org/pub/APICCleaningValidationGuideupdateSeptember2016-final.pdf

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https://www.fda.gov/media/71021/download https://www.fda.gov/media/71021/download https://pubchem.ncbi.nlm.nih.gov/bioassay/1195 http://APIC.cefic.org https://apic.cefic.org/pub/APICCleaningValidationGuide-updateSeptember2016-final.pdf https://apic.cefic.org/pub/APICCleaningValidationGuide-updateSeptember2016-final.pdf

Suez Total Organic Carbon - March 2020

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