Cleaning validation is a critical consideration in the pharmaceutical industry. Inadequate cleaning can result in contamination
of drug products with bacteria, endotoxins, active pharmaceuticals from previous batch runs, and cleaning solution residues.
Such contaminants must be reduced to safe levels, both for regulatory approval and to ensure patient safety.
Regulatory agencies worldwide require validation of pharmaceutical cleaning processes. None, however, offer a specific formulation
for validation. Cleaning processes vary according to the nature of the drug being produced, the type of equipment being used,
and whether equipment is dedicated or multi-use, among other variables. Thus, a one-size-fits-all validation strategy is impossible.
A validated pharmaceutical cleaning process must use principles that are scientifically sound and reproducible. It is the
pharmaceutical company's responsibility to set acceptance criteria and to explain the scientific basis for those limits to
the regulatory authorities.
Companies must have written standard operating procedures (SOPs) in place that detail the cleaning processes used for individual
pieces of equipment or systems. Validation protocols also must describe each operator's responsibilities, and include details
of acceptance criteria and timelines or circumstances for revalidation. Protocols should contain sampling procedures, analytical
methods and their sensitivities, and descriptions of methods and materials, including cleaning agents used in all processes.
Instructions should be included for disassembly and reassembly of equipment when necessary, removal of previous batch identification,
protection of equipment from contamination before use, and inspection of equipment immediately before use, as well as maximum
time lapse permitted between the end of a production process and the start of cleaning procedure.1
In addition, pharmaceutical companies must provide the regulatory authorities with a validation report, approved by management,
which demonstrates the effectiveness of the cleaning process. The report must include data indicating that residues specific
to the drug product and process in question are reduced to acceptable levels by the cleaning process.
Such regulatory scrutiny of cleaning processes means that pharmaceutical companies must carefully consider the cleanability
of new equipment and to the systems already in place for cleaning existing equipment.
Construction material should be a primary consideration in selecting equipment and establishing cleaning protocols. Equipment
should not be reactive, additive, or adsorptive with the process materials that contact them. Materials such as seals, valves,
gaskets, hoses, or tank surfaces that come in contact with drug products cannot cause contamination. Possible interactions
of equipment materials with cleaning products must also be examined.
Other things to consider for equipment design include difficult- to-clean areas such as piping, connections, and valves. Surfaces
should be smooth and the system should have no dead legs where sediment can settle. Piping and instrumentation diagrams can
identify problem areas.
Depending on the drug product being manufactured, different cleaning methods and analyses may be required. First one must
identify the substances to be removed. The chemical and physical properties of the residues determine the best method to remove
these from equipment surfaces. Some characteristics to consider include solubility, hydrophobicity, and reactivity. In addition,
removal of the cleaning agent will have to be demonstrated, so its composition must be known.
CASE STUDY: A CHROMATOGRAPHY COLUMN
The following example details cleaning protocols for a chromatography column. While some specifics may vary, the procedures
will apply to cleaning most pharmaceutical equipment.
Cleanability — Considerations for New Equipment