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

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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

DEGRADATION EFFECTS

A key consideration in bioprocessing is that the active ingredient is usually degraded by cleaning processes that involve hot, aqueous, alkaline cleaning solutions. Although this degradation is a key mechanism of the cleaning process, and in many cases is required to remove denatured proteins from surfaces, it affects various elements of cleaning validation. For example, after a cleaning process, the active ingredient itself should not be present on cleaning surfaces; if residues are present, they may exist as degradation products of the active ingredient. Also, a specific analytical method for the active ingredient is not usually an appropriate analytical technique to determine whether the cleaning process is effective. These effects are discussed in more detail in Technical Report No. 49.

ANALYTICAL METHODS

Because of the degradation of the active ingredients in the cleaning processes for biotech manufacture, the most common practice is to use TOC as the analytical procedure to indicate the removal of the active. TOC also measures other sources of organic carbon, including media, cellular materials, detergents, and organic process materials. If total protein is used as a nonspecific analytical method for the active, that method may measure various protein species. Other methods, such as conductivity, may be used for the cleaning agent.

The appropriate analytical methods must be validated. Typically, validation involves principles from the International Conference on Harmonization's Q2 (R1) (4). Although degraded fragments of the active ingredient are measured in a cleaning-validation protocol, analytical method validation is typically performed with the bulk active itself because this typically reflects the worst case.

ACCEPTANCE LIMITS FOR ACTIVES


Table 4
Personnel demonstrate the effectiveness and consistency of a cleaning procedure by showing that the cleaning process can reduce the amounts of potentially adverse residues to acceptable levels. For nonbiotech applications, limits for the active ingredient are typically established using a carryover calculation, which is based on the safety or toxicity of the active ingredient. For the manufacture of biotech products, however, that approach only works for fill–finish manufacture, where it is assumed that all measured organic carbon comes from the active ingredient (a worst-case assumption).

Table IV provides a list of the methods that can help set limits for the various cleaning applications (1). Limits for cleaning validation generally contain a measure related to the active protein or other major component of interest, a measure related to the cleaning agent, a measure related to bioburden levels, a measure related to endotoxin levels, and a requirement that the equipment be visually clean. In addition, if the active protein or other process components raise specific toxicity concerns (e.g., cytotoxicity, allergenicity, or reproductive hazards), the manufacturer's toxicology or pharmacology groups may determine whether limits should be modified or whether dedicated equipment is needed.

That approach does not work for limits for the active ingredient in bulk active manufacture. If the carryover limits are calculated using the entire equipment train's surface area, the limits are extremely low. If the active ingredient were undegraded after the cleaning process, it might be possible to measure the active ingredient using a specific analytical technique, such as enzyme-linked immunosorbent assay (ELISA). When the carryover limit for the active is converted to a TOC value, it typically is below a quantifiable TOC value for a swab or rinse value. That quantifiable value is close to 100 or 200 ppb carbon because of the background subtraction (i.e., the correction for the blank values).

A further complicating factor is that in the manufacture of the bulk active, residues left after earlier cleaning steps (e.g., until the first purification-process step) may be removed by subsequent purification processes, such as chromatographic purification. Therefore, consistent with ICH Q7, the cleaning of these earlier steps may not be critical for the carryover of residues to the final bulk active (5). Only a few literature references document the degradation of specific drug active proteins during the cleaning process. However, the literature contains ample evidence that proteins generally will degrade in hot, alkaline cleaning solutions. Although not well documented, this effect further mitigates the concern about carryover of residues in bulk active manufacture.

For these reasons, limits for the manufacture of bulk actives in biotech are generally established based on industry standard practice of about 5–10 ppm TOC for upstream processes and 1–2 ppm for downstream processes for any analytical sample, whether a swab sample or a rinse sample. The industry needs to provide more scientific rationales and data to support that practice, and such improvements in support documentation have started to occur.


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