ABSTRACT
The characterization and validation of equipment cleanliness are key requirements for biopharmaceutical facilities to assure
that the cleaning process can meet predetermined cleanability criteria consistently and reproducibly. For a multi-product
facility, the cost of performing such process characterization at large-scale could be substantial. This article describes
how a robust bench-scale model can be used to characterize the key operating parameters of the cleaning process. A scale-down
model that evaluates the cleanability of various protein drug products on stainless steel coupons was used to explore the
process performance over a wide design space. The bench-scale cleaning model is also a useful tool for comparing the cleanability
of various products and for developing new cleaning cycles.
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The design space concept as introduced by the International Committee on Harmonization (ICH) for a unit operation can be defined
as the linkage between the input variables or process parameters and critical quality attributes.1 Characterizing the design space involves understanding these linkages and identifying variables and ranges within which
consistent quality can be achieved. For the cleaning process, the design space can be considered the interactions among various
operating parameters (e.g., temperature, soilant, cleaning agent concentration, dirty hold time) and their effect on performance
parameters such as residual soil levels at the end of the cleaning process.
Drug product processing involves various process parameters that can affect the safety, quality, efficacy, and purity of the
final dosage form.2 Cleaning processes also can have a direct effect on the critical quality attributes of a product by means of contaminant
carryover through product contact equipment surfaces. Regulatory expectations call for biopharmaceutical companies to have
a sound, documented cleaning validation approach that uses effective and consistent cleaning and keeps the carryover below
the acceptable limits.3–5 Such an approach warrants a cleanability assessment before the introduction of a new product into the manufacturing equipment.
Bench-scale cleaning studies are a useful model to evaluate the relative cleanability of new products with very low material
requirements, well in advance of technology transfer to the manufacturing facility.6–9
Bench-scale models also provide the benefit of performing cleaning evaluations under controlled simulated conditions, thereby
offering a useful tool to characterize the process design space.
There are several elements of cleaning process characterization, control, and validation including, but not limited to, cleaning
cycle, equipment, sampling techniques, analytical assays, and acceptance criteria.5,7,10 This article focuses on the characterization of the cleaning process with respect to process parameters. A bench-scale model
is used to evaluate four different protein drug product formulations over a wide range of operating conditions. Both single
parameter and cross interaction among different operating conditions are studied to fully characterize the design space associated
with the cleaning process. Results show that temperature and cleaning agent concentration are strongly coupled, and different
protein products behave differently with respect to their cleanability because the process conditions are varied. The work
also provides useful insights into the development of an optimized cleaning cycle for biopharmaceuticals.
CLEANING PROCESS
In a typical cleaning process, cleaning agents such as alkaline and acidic reagents are used at elevated temperatures in combination
with mechanical action to achieve removal of protein soilants from equipment surfaces. A combination of water and caustic
acid rinses is used to achieve the desired level of cleanability needed to ensure minimal product carryover to the next product
lot. A hot alkaline wash is considered the critical cleaning step in which conditions of high pH and high temperature are
used to remove the protein by degrading it into smaller fragments, and to solubilize any hydrophobic residues.
A cleaning cycle relies on two pathways for soilant removal from equipment surfaces.9,11 The first pathway is the physical removal commonly achieved through mechanical action resulting from the convective action
of the fluid flow. The efficacy of this mechanism is governed by the soil–surface interactions and the extent of adhesion.
The second mechanism uses chemical interaction between the cleaning agents and the protein soils such as protein degradation,
solubilization, wetting, and emulsification to remove the soilant from the surface.11 There are various inputs to the cleaning process that affect these cleaning mechanisms and thereby the overall performance
of the cleaning cycle. These key operating parameters include the temperature of the cleaning solution, the concentration
of the cleaning agent, the strength of the mechanical action, and contact time with the cleaning agent. In addition, other
factors such as soil type, dirty hold time (i.e., how long the soiled equipment is held before cleaning), material of construction
(stainless steel, glass, Teflon), and surface finish also affect the cleanability of the equipment.
