Suez Total Organic Carbon - March 2020 - 8

application note

calculating maximum
allowable carryover (MAC)
for cleaning validation
The United States Food and Drug Administration (FDA) released
guidance for current Good Manufacturing Process (cGMP) validation
in January 2011.1 Within that guidance, the traditional approach of
process validation has been replaced with a life cycle approach as the
best practice recommendation. The life cycle approach is broken into
three stages: Design, Qualification, and Verification. The three stages
are no longer viewed as static steps but rather dynamic stages to be
constantly reviewed and updated during the lifetime of the process.
This new direction for process validation applies directly to cleaning
validation (CV) as well.

A key question for any cleaning validation process is how to establish

The traditional objective of any pharmaceutical manufacturing
cleaning process is to remove or reduce the Active Pharmaceutical
Ingredient (API), degradants, excipients, and cleaning agent residues.
This is important to ensure product integrity and patient safety.

process is that each manufacturing process is unique. Raw materials,

practical, achievable, verifiable, and scientifically defensible acceptance
criteria limits. This chapter presents a framework for how to establish
acceptance criteria limits using TOC to comply with FDA best practice
guidance for the life cycle approach to cleaning validation.

know your process
One of the many challenges to implementing a cleaning validation
process flow diagrams, manufacturing procedures, run rates,
Minimum Batch Size (MBS), and order of operations are a just a few
of the factors that can affect cleaning processes. Additionally, how
each manufacturer cleans and how each manufacturer measures
also present unique challenges to implementing a cleaning validation
process. These factors are not addressed in this application brief but
must be understood prior to calculating MAC.

product change over
The need for determining MAC for a given product stems from the
practice of product change over in a production facility. Product
change over, just as it sounds, occurs when a vessel is emptied of one
product (Product A) and then refilled with a different product (Product
B), as shown in Figure 1. The MAC value is how much of Product A
With the new life cycle approach to process validation, the traditional
practice of measuring a single API with a specific method does not
elicit the necessary process understanding and, therefore, is no
longer compliant with US FDA best practice guidance. As a nonspecific
method, Total Organic Carbon (TOC) analysis measures both product
and process related residues as a function of their carbon containing
properties. TOC analysis provides efficient feedback necessary to
continuously evaluate the validated state of the cleaning process and,
therefore, is compliant with FDA best practice guidance.

8

can safely be present in Product B without any danger to the patient.

A

A

B
A

B+A

Figure 1. Product change over from A to B illustrating carryover of A
into B.
Suez Total Organic Carbon - March 2020

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