PQRI Case Study (5): Nonsterile Facility Cleaning Requirements

The following case study on nonsterile facility cleaning requirements is the fifth of eight in a series put together by the Product Quality Research Institute Manufacturing Technical Committee (PQRI–MTC) risk-management working group. The series is meant to advance the understanding and application of the International Conference on Harmonization (ICH) Q9 Quality Risk Management guideline by providing actual examples of risk-management assessments used by the bio/pharmaceutical industry. The introductory article explaining the history and structure of the series, as well as the first case study on defining design space, appeared in the July 2011 issue of Pharmaceutical Technology (1). The second study addressed functional equivalence for equipment replacement, and the third addressed facility biocontainment and inactivation; they appeared in the August, September, and October 2011 issues, respectively (2, 3, 4).

Effective cleaning of nonsterile finished pharmaceutical manufacturing areas is a key component of GMPs aimed at protecting product from extraneous matter, microbiological contamination, and product cross-contamination. Such protection is commonly accomplished by designing facilities, cleaning procedures and frequencies, which effectively take into consideration the activity in the area to be cleaned, the product's microbial susceptibility, and the inherent dust-generation properties of the process. In general, cleaning procedures must be effective in visually removing product residues, extraneous matter and other soil from manufacturing, packaging and warehousing areas. Manufacturing areas should be inspected on a periodic basis and practices should be modified as necessary to ensure areas are maintained in an appropriately clean manner.

In this case study, the firm used risk-management tools to help define and drive a minimum consistency in cleaning practice and frequency across multiple nonsterile finished pharmaceutical manufacturing departments and operating sites. Prior to conducting the risk-assessment exercise, confirmation was made to ensure that core guidance and consistent practices were already in place for cleaning agent selection, cleaning and storage methods for cleaning tools (e.g., mops), and for facility drain and disinfection practices, all of which are fundamental aspects of facility-cleaning practices not addressed by this case study.

Risk question and assessment method

The risk question developed for the subject case study is: What is the required level and frequency for cleaning a nonsterile finished pharmaceutical GMP manufacturing area?

Table I: Prioritization table.

Excluded from the scope of this analysis are antibiotics and potent compounds (e.g., steroids and hazardous compounds) which generally present an additional level of exposure and/or cross-contamination concerns and warrant additional cleaning efforts. This analysis is specific to facility cleaning and excludes cleaning of equipment.

The effort first required the compilation of empirical information to gather and organize the risk inputs. The risk tool selected for this purpose was a prioritization table (see Table I). After prioritization, a qualitative analysis was performed, based on the product-risk prioritization and the process and facility design attributes. The risk tool used was a decision tree (see Figure 1).

Figure 1: Decision tree.

Risk identification and analysis

The purpose of the risk assessment was to help prioritize cleaning efforts based on actual process conditions and specific product needs. Risk prioritization considerations for this analysis included: a review of key product characteristics, such as inherent microbial inhibitory and susceptibility characteristics as well as dust potential (based on historical experience); the review of key process and facility-design attributes, such as use of open versus closed manufacturing equipment; the use of dedicated versus multiproduct operations; and the use of cross-contamination barriers (e.g., physical barriers, heating, ventilation, and air conditioning).

A team of industry microbiology subject matter experts worked to categorize cleaning options and developed the prioritization schematic shown in Table I. The table is used by manufacturing and quality heads to first identify the applicable GMP area (e.g., manufacturing, packaging); the applicable product category (e.g., microbial susceptible and/or dust generating); and the minimum requirements regarding what to clean (e.g., floors, benches) and how to clean (e.g., vacuum, sweep, disinfect).

After developing the prioritization table, a qualitative analysis was performed based on the product-risk prioritization (i.e., product categories) and the process and facility design controls. Subject-matter experts were consulted to develop the decision tree shown in Figure 1, to determine minimum frequency for areas identified as "green" (i.e., requires a minimum cleaning frequency) in the prioritization table (see Table I). The decision tree is used by local department heads to define the minimum frequency for cleaning, based on the specific risks associated within their respective operations (see Figure 1).

Risk control

In this case study, risk as reduced by applying a structured and standardized approach to determine minimum facility cleaning requirements. The frequency was predicated on good scientific principles and an understanding of the facility design, process characteristics (e.g., historical dust generating capabilities), and product susceptibility (e.g., inherent microbial inhibition, water content). Risk was further mitigated by routine facility audits to ensure that cleaning choices and frequencies are sufficient for maintaining facilities in a GMP-compliant state.

Risk communication and documentation

The risk analysis was reviewed by a senior level quality standards committee to gain alignment on operating principles, risk analysis, and risk controls. The resulting tools of the analysis (i.e., the prioritization table and decision tree) are now codified in a company quality guidance document. The quality guidance is used to establish local standard operating procedures for execution at the shop-floor level. Training is performed against the operating procedure and training records are periodically audited for compliance.

Risk review

As part of the firm's standard practice for the ongoing maintenance of quality guidances, the subject risk analysis (defined as part of the company guideline on facility cleaning) is reviewed by subject matter experts on a periodic basis to ensure that the assumptions and decisions remain valid and justified.

Ted Frank is with Merck & Co; Stephen Brooks, Kristin Murray,* and Steve Reich are with Pfizer; Ed Sanchez is with Johnson & Johnson; Brian Hasselbalch is with the FDA Center for Drug Evaluation and Research; Kwame Obeng is with Bristol Myers Squibb; and Richard Creekmore is with AstraZeneca.

*To whom all correspondence should be addressed, at kristin.murray@pfizer.com

Reference

1. T. Frank et al., Pharm. Technol. 35 (7), pp. 72–79.