PROCESS LIFECYCLE VALIDATION - Risk Management Applications in Pharmaceutical and Biopharmaceutical Manufacturing - page 213

validation [33]. Unlike cleaning development studies on a commercial scale,
which require large amounts of material, small-scale cleaning studies can be per-
formed with very low material requirements and well in advance of technology
transfer to the manufacturing facility. They also provide the benefit of perform-
ing cleaning evaluations under controlled simulated conditions, thereby offering a
useful tool to characterize the cleaning process. However, small-scale data should
be verified at the commercial scale. Authors observed that cleaning without any
detergent could be as effective in some instances (such as buffer tank), thereby
eliminating the risk of product contamination by residual detergent.
Absence of a risk-based approach makes the validation unnecessarily complex
and/or time consuming. Finally, the extent of revalidation after a change should
be justified on the basis of the risks associated with the change.
The following are some of guidances/references related to QRM application
in CV:
• Product grouping can be accomplished through RAs [6]. Worst-case prod-
ucts, equipment, or limits can be determined on the basis of solubility,
potency, toxicity, difficulty of detection, cleaning behavior, etc. Determining
the most-difficult-to-clean product (i.e., worst-case product) from a group of
products should involve a risk ranking based on cleaning behavior, history,
and solubility.
• Cleaning limits and sampling locations should be determined on the basis
of RA [10]. For example, limits could be based on risk for potential car-
ryover, toxicity, detectability, past history, safety factors, etc. For sampling
locations, areas or equipment could be ranked or classified on the basis
of severity/impact to product quality (e.g., nature of operation, toxicity,
extent and impact of contamination), likelihood of occurrence (e.g., possi-
bility of contamination), detectability (capability to detect, inspect), or any
combination of these three elements.
• Level of containment based on severity (i.e., toxicology, acceptable daily
intake, hazardous nature of the compound(s)) and the frequency (degree
of exposure) of contamination of drug product and/or manufacturing
personnel [34]. Contamination and cross-contamination issues may be
directly related to CV and would be good areas for use of a risk-based
approach [14].
8.10.1 Equipment Dirty Hold Time in Cleaning Validation
There is little guidance on how to establish or extend equipment hold times
in CV, other than three commercial-scale validation experiments. Using a risk-
based approach is one possibility. For example, a site producing multiple products
used an FMEA to establish the number of experiments required for establishing
the dirty equipment hold time (DEHT). Severity, occurrence, and detection were
defined on a scale of 1-10 (Table 8.10). RPN (severity × occurrence × detection)