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Rizwan Sharnez
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“New Perspectives on Cleaning” is an ongoing series shorter cycles and higher success rates for cleaning
of articles dedicated to cleaning process development, operations. It also facilitates the utilization of simpler
validation, and monitoring. This column addresses and more cost-effective non-specific assays, such as
scientific principles, strategies, and approaches associ- total organic carbon and conductivity. Part I of this
ated with cleaning that are faced in everyday work series applied this approach to samples for surface
situations. analysis. Part II deals with the application of this
Reader questions, comments, and suggestions are approach to rinse samples.
requested for future discussion topics. These can
be submitted either to column coordinator Rizwan INTRODUCTION
Sharnez at rsharnez@amgen.com or to managing edi- The maximum acceptable carryover (MAC) criterion
tor Susan Haigney at shaigney@advanstar.com. is used to set cleaning validation acceptance limits
for multiproduct (shared) equipment. It is based on
SUMMARY a worst-case mass balance (WCMB) for the previously
The maximum acceptable carryover (MAC) criterion manufactured product (1). The WCMB approach is
is widely used to set cleaning validation acceptance based on the conservative assumption that all the
limits for multiproduct equipment. The conventional residual contaminant in the cleaned equipment will
approach for setting cleaning validation limits based carryover into the next batch that is manufactured
on the MAC criterion results in acceptance criteria in that equipment.
that are much more stringent than necessary. This In Part I of this series we described how the con-
often results in cleaning validation limits that are ventional approach for setting MAC-based clean-
impractical to achieve and, in some instances, well ing validation limits is far more conservative than
below the limit of quantitation of the analytical the worst-case scenario that is physically possible
method. (2). This results in acceptance criteria for surface
In this series we describe strategies for setting ratio- analysis (e.g., swab samples) that are much more
nal MAC-based limits for multiproduct equipment. stringent than necessary. The resulting cleaning
The limits are used to justify more reasonable accep- validation limits are often impractical to achieve
tance criteria for cleaning validation. This results in and, in some instances, well below the limit of quan-
[
ABOUT THE AUTHORS
For more Author
Rizwan Sharnez, Ph.D., is principal engineer at Amgen, Colorado. He has more than 15 years of experi-
information,
ence in the pharmaceutical industry. He may be reached by e-mail at rsharnez@amgen.com. Angela To
go to
has a Bachelors degree in chemical engineering. Laura Klewer is senior engineer at Amgen, Colorado
gxpandjvt.com/bios
and has more than 10 years of experience in the pharmaceutical and biotech industries.
MS, i = MAC AB (V T/∑) (i=1-N) [Equation 3] final rinse is (MS, i + M R, i), and so the rinse recovery
factor for A (RRF) can be expressed as:
Where, MS, i, the mass of A on the surface of the ith
circuit, is the maximum allowable carryover of A for RRF = M R, i/(MS, i + M R, i) [Equation 1c]
the ith circuit. Note that by definition, ∑ MS, i = MAC AB.
Also, M R, i, the mass of A in the effluent rinse for Note that unlike the conventional approach, the
the ith circuit, is given by, proposed approach accounts for the mass that is
removed by the final rinse. As shown below, this
M R, i = V i • Ci [Equation 4] results in higher acceptance criteria for the rinse
samples.
Where V i is the volume of the final rinse for the ith
circuit, and Ci is the concentration of the previous Substituting for MS, i and M R, i from Equations 3 and
product A in V i. When MS, i is given by Equation 3, 4a, respectively, into Equation 1c gives:
Ci becomes the acceptance criterion for the ith circuit
(ACi), and Equation 4 becomes: ACi = (MAC AB/V T) [RRF/(1- RRF)] [Equation 5c]
M R, i = V i • ACi [Equation 4a] In Equation 5c, ACi represents the acceptable limit
of A in the rinse for the ith circuit (i.e., the acceptance
Conventional Approach criterion for the ith rinse sample).
The conventional approach is based on the premise
that MS, i, defined by Equation 3, is the mass of A on the Because the RHS of Equation 5c is independent of
surface of the ith circuit before the final rinse step. Thus, i, the subscript i can be dropped. Thus,
in accordance with Equation 1, the rinse recovery factor
for A (RRF) can be expressed as: ACP = (MAC AB/V T) [RRF/(1- RRF)] [Equation 5d]
RRF = M R, i/MS, i [Equation 1b] Where the subscript P denotes the proposed
approach.
Substituting for MS, i and M R, i from Equations 3 and The above analysis indicates that the rinse volume-
4a, respectively, gives: weighted approach results in a uniform acceptance
criterion for all the rinse samples. This results in
RRF = ACi • V T/MAC AB [Equation 4b] the highest possible acceptance criterion that can
be justified for rinse samples (4). Thus, the rinse
In Equation 4b, ACi represents the acceptable limit volume-weighted approach represents an optimal
of A in the rinse for the ith circuit (i.e., the acceptance solution for deriving the acceptance criteria for rinse
criterion for the ith rinse sample). Thus, samples.
Table: Acceptance criterion (AC) for final rinse the approach described here can be extended to other
samples as a function of the RRF. Subscripts applications, such as the carryover of cleaning agents.
P and C denote proposed and conventional
approaches, respectively.
RRF (%) ACP/ACC REFERENCES
→ 100 → infinity 1. Fourman, G. L., and M. V. Mullen, “Determining Clean-
ing Validation Acceptance Limits for Pharmaceutical
90 10
Manufacturing Operations,” Pharmaceutical Technology
80 5 14 (4): 54-60, 1993.
70 3.33 2. Sharnez, R., “Strategies for Setting Rational MAC-based
60 2.5 Limits: Part I-Reassessing the Carryover Criterion,”
50 2 Journal of Validation Technology, p. 71-74, Winter 2010.
3. Sharnez, R. and Klewer, L., “Parametric Release for
25 1.33
Cleaning Part I: Process Characterization,” Journal of
→0 →1
Validation Technology, Summer 2009.
4. Sharnez, R., Unpublished results. JVT
CONCLUSION
MAC-based acceptance criteria for cleaning validation ACKNOWLEDGEMENTS
are derived with the assumption that all the residual The authors would like to thank Sushil Abraham for
mass of the previously manufactured product A that helpful suggestions and support.
is on the cleaned surfaces of the equipment train
will carryover into the next batch of B. This repre- SUBSCRIPTS
sents a worst-case scenario from the standpoint of C Conventional
contamination. i Cleaning Circuit Number
The conventional approach for setting MAC-based P Proposed
limits for rinse samples is far more conservative than R Rinse
the worst-case scenario that is physically possible. This S Surface
results in acceptance criteria that are much more strin- T Total
gent than necessary. The resulting cleaning validation
limits are often impractical to achieve or significantly ARTICLE ACRONYM LISTING
below the LOQ of the analytical method. A Product A
The proposed approach is based on a realistic AC Acceptance Criteria
worst-case mass balance, and provides more rea- API Active Pharmaceutical Ingredient
sonable acceptance criteria for rinse samples. For a B Product B
rinse recovery of 90%, limits based on the proposed BB,MIN Smallest batch size of B
approach are shown to be about an order of magni- DB,MAX Largest (worst-case) dose of B
tude higher than those based on the conventional LOQ Limit of Quantitation
approach. An important benefit of justifying higher M Mass
cleaning validation limits is that complex product- MAC Maximum Acceptable Carryover
specific assays can be replaced by relatively simple MAC AB Maximum Acceptable Carryover of A into a
and more cost-effective non-specific assays, such Manufacturing Batch of B
as TOC or conductivity. It also can be leveraged N Total Number of Cleaning Circuits
to develop more efficient cleaning cycles to reduce PSA Product-Specific Assay
cleaning validation failures. PSIA Product-Specific Immunoassays
The analyses presented in this series are based on RRF Rinse Recovery Factor
the carryover of one product into another (i.e., cross- SF Safety Factor
contamination of multiproduct equipment); however, TDMIN,A Minimum Therapeutic Dose of A
the underlying principles for converting MAC-based TOC Total Organic Carbon
limits to acceptance criteria for cleaning validation V Volume
samples are the same for most contaminants, and so WCMB Worst-Case Mass Balance