PDA's New Technical Report for Biotech Cleaning Validation - The authors encourage biotech manufacturers to consult PDA Technical Report No. 49 for a detailed perspective on current practices and issu


PDA's New Technical Report for Biotech Cleaning Validation
The authors encourage biotech manufacturers to consult PDA Technical Report No. 49 for a detailed perspective on current practices and issues in biotech cleaning validation.

BioPharm International
Volume 24, Issue 3, pp. 26-34


Another key part of a cleaning-validation program is appropriate sampling methods for the equipment surfaces and for the nature of the study, including the analytical methods used. The principles for sampling methods for biotech manufacture are not fundamentally different from those for sampling in nonbiotech cleaning validation. Sampling methods discussed in Technical Report No. 49 include "direct surface" sampling (e.g., using a fiberoptic probe), swabbing, rinse-water sampling, and placebo sampling. In practice, sampling for biotech manufacture may more likely involve rinse samples because much of the equipment is hard-piped and not readily accessible for swab sampling. Furthermore, some biotech companies like to use mock runs or blank runs (i.e., a type of placebo sampling) to provide an accurate picture of total carryover throughout the entire process of bulk active manufacture.

Table 5
Sampling recovery studies for biotech cleaning validation are not different in principle from sampling recovery studies in nonbiotech cleaning validation. However, residues used for spiking surfaces for recovery studies in biotech cleaning validation may include not only the bulk active, but also soils representative of early-stage harvesting steps. Furthermore, these recovery studies represent worst cases, in that residues actually sampled in cleaning-validation qualification protocols are actually degraded fragments of the active, which, being smaller in molecular weight and more polar, should be easier to remove in a sampling recovery study using water as the solvent. Table V provides some of the important considerations for choosing the sampling method for cleaning.


A key part of the validation life cycle for any system is maintaining the validated state on an ongoing basis. Any change in the validated state of a cleaning process might detract from the quality, safety, and purity of manufactured products. Tools for validation maintenance covered in Technical Report No. 49 include change control, risk-based periodic monitoring, and data trending review. Training and retraining for manual cleaning processes are also significant because they are the primary mechanisms for obtaining consistency in manual cleaning processes.

For biotech and nonbiotech cleaning validation, actual values for residues (e.g., in rinse-water samples) are significantly below the acceptance criterion limit. The reason is that most manufacturers design their cleaning processes with a reasonable margin of safety so that any samples taken during qualification protocols or during routine maintenance will pass the acceptance criteria with a good margin of safety (e.g., a robust cleaning process is designed). Therefore, the fact that actual residue values are significantly below acceptance limits should not by itself be a reason for making qualification protocol limits more stringent. This situation is often addressed by establishing action or alert levels for residues for routine monitoring samples. Routine monitoring results above such action or alert levels provide an indication of a possible change in the cleaning process, thus requiring an investigation into the cause.

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