Cleaning Validation Articles

Introducing new compounds into a pharmaceutical manufacturing facility can pose ongoing challenges to a facility’s cleaning validation program. Some discussions have described how a cleaning validation program can be conducted (1–2). Several programs have used a worst-case approach to validating a cleaning program (3–8).Approaches for determining the worstcase soil have included evaluating which residue was the last to rinse from the manufacturing vessel (3), using a product grouping strategy (4–6), assessing the relative toxicological properties of the formulation components (7), and relying on the practical cleaning experience of the formulators and equipment cleaners (8). Once a worst-case soil has been validated, however, introducing a new compound requires determining whether this compound is a new worst case.

This is a continuation of last month’s Cleaning Memo. In that Cleaning Memo I discussed the criticality of cleaning for primary packaging equipment.

That this is important is evident from the fact that the principle involved (non-uniform contamination of the next batch) is mentioned in the FDA cleaning validation guidance. This month I will focus on issues related to limits and worst-case challenges. As discussed last month, one issue that makes primary packaging equipment critical is that it is possible that residues on some or all surfaces of the primary packaging equipment may preferentially transfer to a small portion (such as the first portion) of the next product packaged. It would be prudent to set limits based on this worst-case assumption (that transfer of residues can preferentially occur into a small portion of the next batch).

Sometimes I am asked about cleaning validation for packaging equipment, and the thought behind the question appears to be that this is not a critical cleaning process and therefore doesn’t require cleaning validation. While it is true that effective cleaning of some packaging equipment may be much easier to achieve, it is not necessarily true that the effectiveness of such cleaning is non-critical.
 
Before I discuss the topic, let’s make sure of some definitions. By packaging equipment I am referring to primary packaging equipment, usually of a finished drug product. That includes such examples as liquids being filled into vials and then capped, and tablets being filled into bottles and then capped.

A common question in training seminars is “How do I deal with unknown peaks in HPLC analysis?” My first answer is a facetious one: “Try TOC; there are no unknown peaks in TOC!” However, TOC is not without its problems. To directly answer the question about unknown peaks in HPLC analysis, the first attempt should be to clarify the question. By unknown peaks, we are talking about unknown peaks in the HPLC samples taken in the cleaning validation protocol itself.
 
The first attempt should be a preventive one. That is accomplished by trying to identify in the HPLC analytical development all possible “unknown” substances.

cross contamination with active ingredients is a real concern. The Code of Federal Regulations (CFR) states that "Equipment and utensils shall be cleaned, maintained, and sanitized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official, or other established requirements" (1). Cleaning validation is required in the pharmaceutical field to avoid potential clinically significant synergistic interactions between  armacologically active chemicals (2). Since the issuance of the US Food and Drug Administration's "Guide to Inspection of Validation of Cleaning Process" in July 1993 (3), cleaning validations have received increasing attention.Validation is required not only for manufacturing sites, but also for the sampling- filling suite in research and development.