ABSTRACT

A cleaning process should remove materials such as media, buffers, storage solutions, cell culture fluids, cell debris, non-active pharmaceutical ingredient, and formulations and concentrations of active pharmaceutical ingredients. Manufacturing and cleaning equipment must be designed for effective and consistent cleaning to avoid cross-contamination and the cleaning processes must be verified as effective. Part 1 of this article provided background on cleaning validation and the associated regulations, cleaning methods, validation strategy, and new product introduction. Part 2 covers Genentech's grouping strategy, validation samples, acceptance criteria, clean hold time, training, change control, and revalidation.

Cleaning validation refers to establishing documented evidence providing a high degree of assurance that a specific specific cleaning process will produce consistent and reproducible cleaning results that meet a predetermined level. A cleaning program can be divided into three phases: cleaning process and cycle development, cleaning validation, and maintenance. The program begins with equipment design evaluation such as sanitary equipment, sprayball, rinse water, and compatibility of construction materials with product and cleaning solutions, followed by cleaning process development and cleanability studies. Cleaning validation must be performed using a pre-approved protocol. Selection of appropriate sampling to demonstrate that residues are removed to an acceptable level is vital for the success of cleaning validation. In addition, use of sampling techniques such as recovery study for swab and rinse and thorough visual inspection can reduce the number of samples required for cleaning validation. Ongoing monitoring, change control, and revalidation constitute the maintenance program. This article covers Genentech's grouping strategy, validation samples, acceptance criteria, clean hold time, training, change control, and revalidation.

To simplify cleaning validation, similar equipment may be grouped into equipment families. These families are based on equipment design, construction material, geometry, complexity, functionality, or cleaning procedure. Such families involve only the equipment for manufacturing similar products that are cleaned by the same or similar cleaning processes. Grouping may apply to equipment that is cleaned by an automated clean-in-place (CIP) process, a semi-automated CIP process, a manual cleaning process, or an automated parts washer. Grouping into equipment families must be justified and documented.

Grouping may involve separately validating the extremes of a group (for example, the largest and smallest portable tanks in a group), or it may involve testing only the worst case in a group (for example, the most difficult to clean transfer line). The following are some examples of equipment families: bracketed equipment, identical equipment, small equipment or parts cleaned manually, and small equipment or parts cleaned in an automated parts washer. Bracketed equipment such as portable stainless steel tanks, fermentors, glass vessels, transfer lines, filler parts, and glass carboys may vary in scale. Identical equipment such as lyophilizers, 400-liter fermentors, transfer pumps, and 120-liter freeze-thaw tanks, are of the same scale.

Equipment that is validated individually and not as a family, because of significant differences in design and cleaning processes, is called unique equipment or unique systems. Examples of unique equipment include large-scale harvest cell culture systems, centrifuge systems, and chromatography systems.

GROUPING OF PRODUCTS

Cleaning following the manufacture of products may be validated for individual products or may be validated by product group. Grouping by products includes considerations of potency, toxicity, and cleaning difficulty. Products in groups must be manufactured using the same equipment categories and cleaned by the same or similar cleaning processes. Chemical and physical properties of ingredients (including excipients) must be considered when grouping by products; excipients may be more difficult to clean.

Cleaning following the manufacture of buffers, media, and similar indirect product-contacting surfaces may be validated individually or by product group. Acceptable validation of extreme or worst case constitutes acceptable validation for all group members. Grouping must be justified and documented.