Water Technologies & Solutions

application note

calculating maximum allowable carryover (MAC)

for cleaning validation
The United States Food and Drug Administration (FDA) A key question for any cleaning validation process is
released guidance for current Good Manufacturing how to establish practical, achievable, verifiable, and
Process (cGMP) validation in January 2011.1 Within that scientifically defensible acceptance criteria limits.
guidance, the traditional approach of process validation This application brief presents a framework for how
has been replaced with a life cycle approach as the best to establish acceptance criteria limits using TOC to
practice recommendation. The life cycle approach is comply with FDA best practice guidance for the life
broken into three stages: Design, Qualification, and cycle approach to cleaning validation.
Verification. The three stages are no longer viewed as
static steps but rather dynamic know your process
stages to be constantly reviewed
One of the many challenges to implementing a
and updated during the lifetime
cleaning validation process is that each
of the process. This new
manufacturing process is unique. Raw materials,
direction for process
process flow diagrams, manufacturing procedures,
validation applies directly
run rates, Minimum Batch Size (MBS), and order of
to cleaning validation (CV)
operations are a just a few of the factors that can
as well.
affect cleaning processes. Additionally, how each
The traditional objective manufacturer cleans and how each manufacturer
of any pharmaceutical measures also present unique challenges to
manufacturing cleaning process implementing a cleaning validation process. These
is to remove or reduce the Active factors are not addressed in this application brief but
Pharmaceutical Ingredient (API), must be understood prior to calculating MAC.
degradants, excipients, and cleaning agent residues.
This is important to ensure product integrity and patient product change over
safety.
The need for determining MAC for a given product
With the new life cycle approach to process validation, stems from the practice of product change over in a
the traditional practice of measuring a single API with a production facility. Product change over, just as it
specific method does not elicit the necessary process sounds, occurs when a vessel is emptied of one
understanding and, therefore, is no longer compliant product (Product A) and then refilled with a different
with US FDA best practice guidance. As a nonspecific product (Product B), as shown in Figure 1. The MAC
method, Total Organic Carbon (TOC) analysis measures value is how much of Product A can safely be present
both product and process related residues as a function in Product B without any danger to the patient.
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.
Figure 1: Product change over from A to B illustrating
carryover of A into B.
reference values in developing acceptance criteria Two common sampling methods are:
1. collecting a swab sample from inside the tank
MAC calculations start by identifying clinical reference
2. collecting a rinse grab sample
values for each product. These may include, but are not
limited to, Therapeutic Daily Dose (TDD), Acceptable
Product Limit from Swabbing
Daily Intake (ADI), Lethal Dose for 50% of population
(LD50), or Permitted Daily Exposure (PDE). Clinical If sampling involves swabbing a specified area in the
reference values may be found in literature or online, tank, the target value may be calculated using the
including PubChem DSSTox FDA Maximum Daily Dose MAC value, assuming an even, homogenous API
Database (DSSTox FDAMDD).2 Regardless of the deposition throughout the active surface area.
citation source for starting reference values, they must
be scientifically defensible. Starting reference values in
this application brief originate from DSSTox FDAMDD.
Product Limit from Rinse
MAC from TDD
If sampling involves collecting a final rinsate from the
When determining MAC from TDD, the current product
tank, the MAC value is converted into a concentration
in the tank (Product A) and the next product in the tank
(mg/L) based on final rinse volume.
(Product B) must be known (see Figure 1). The known
identity of both products allows identification of a
defensible starting clinical reference value. Depending
on what types of compounds Product A and B are, a
different Safety Factor (SF) in the calculation is used product limit to TOC limit
based on the risk assessment of those compounds.3 A
Specific product limits are not directly transferrable
typical safety factor value is 1000.3
to a TOC method. The specific product limit,
depending on the sampling method, can be converted
to a TOC limit by multiplying by relative mass
percentage of carbon from the chemical formula of
MAC from LD50 the product.
As with TDD, when determining MAC from LD50, the When a specific method limit has been previously
current product in the tank (Product A) and the next calculated, converting from the specific cleaning
product in the tank (Product B) must be known (see validation method, such as HPLC, to a nonspecific
Figure 1). Next, calculate the No Observed Effect Limit method, such as TOC, can be achieved using the
(NOEL) using the LD50 reference value for Product A. percentage carbon in the chemical formula. For
Then, calculate MAC from the derived NOEL value. example, if a specific API limit for HPLC is established
Please note that the denominator value of 2000 in the at 10 ppm and the percentage carbon is 50%, the TOC
NOEL equation is an empirical constant referenced in limit would be 5 ppm.
literature.3
example using TDD
In this example, Product A is Epinephrine and
Product B is Diazepam. The clinical reference values
are as follows2:

MAC to product limit

A MAC value alone is not sufficient to release
equipment for use. Once MAC has been determined, the The example process information on Minimum Batch
value must be converted into an actual product limit (in Size (MBS), safety factor, and average patient mass
ppm). The product limit accounts for the sampling (kg body weight) are as follows:
method with the MAC value.

300 00112 EN Rev. D

 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
With this information, the MAC value of Epinephrine
process, based on MAC and sampling method, the
into Diazepam (MACA in B) can be calculated. TOC limit for Epinephrine in Diazepam is determined
to be 21.5 ppm.

conclusion
Based on recent guidance from the FDA, the life cycle
approach should be considered best practice when
The MAC value must now be converted to a product
implementing a cleaning validation process. The life
limit by considering the sampling method. In this
cycle approach calls for continuous monitoring and
example, the method is swabbing a 1 dm2 area inside a
updating to the design, qualification, and verification
tank. The active surface area of the tank is 80% of the
of the cleaning validation process. When choosing an
total based on the fill level of the tank.
analytical method to measure 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
The TOC vial volume of 40 mL is also known. Since the a specific API. Degradants, excipients, and cleaning
sampling method is swabbing, the swab will be broken residues are just a few potential contaminants that
off in the vial; therefore, the final product limit are not captured in a specific method, such as HPLC,
concentration for Epinephrine is as follows: but are captured in a nonspecific method, such as
TOC.
This application note demonstrates that the
determination of acceptance criteria limits for TOC in
cleaning validation can be easily calculated and
defended when starting from justifiable clinical
reference values. This, in conjunction with the US
FDA best practices for cleaning validation, highlights
With the product limit established, the TOC limit can be a few of the many appealing aspects driving industry
determined by the percent carbon in the chemical leaders to adopt TOC analysis for cleaning validation
formula for Epinephrine, C9H13NO3. on a large scale.
References
1. “Guidance for Industry. Process Validation: General Principles and
Practices.” U.S. FDA Pharmaceutical Quality/Manufacturing Standards
(CGMP),fda.gov,
www.fda.gov/downloads/drugs/guidances/ucm070336.pdf. Accessed 10
Sept. 2017.
2. “DSSTox (FDAMDD) FDA Maximum (Recommended) Daily Dose
Database.” Pub Chem BioAssay Database, Record for AID 1195,
ncbi.nlm.nih.gov, https://pubchem.ncbi.nlm.nih.gov/bioassay/1195.
Accessed 10 Sept. 2017.
3. “Guidance on Aspects of Cleaning Validation in Pharmaceutical
Ingredient Plants.” APIC Publications, APIC.cefic.org,
http://apic.cefic.org/pub/apic_cleaning_validation_2014.pdf. Accessed
10 Sept. 2017.

Find a contact near you by visiting www.sieversinstruments.com and clicking on “Contact Us.” 300 00112 EN Rev. D
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