Cleaning Validation for Biopharmaceutical Manufacturing at Genentech, Inc. Part 1 - Best practices from Big Biotech, including how to handle new product introductions. - BioPharm International


Cleaning Validation for Biopharmaceutical Manufacturing at Genentech, Inc. Part 1
Best practices from Big Biotech, including how to handle new product introductions.

BioPharm International
Volume 21, Issue 2


The cleaning processes for product-contact surfaces for all products manufactured in GMP equipment must be demonstrated to be effective. Product-contact surfaces are surfaces that make direct contact with product or materials introduced into equipment as part of the normal manufacturing process by their very design. Indirect-product-contact surfaces (such as buffer tanks), where there is a significant risk of residues on surfaces contaminating a subsequently manufactured product, also undergo cleaning validation.

To demonstrate the effectiveness of a cleaning process, the process is challenged. This challenge involves at least three consecutive successful cleaning process runs, after which residues are measured and results are compared to predetermined acceptance criteria.

Mock soiling is also used. Mock soiling refers to the soiling of equipment by a process other than routine manufacturing that creates a dirty equipment state equivalent to that following routine manufacturing. Mock soiling of equipment for validation purposes can be performed when equipment is not available for manufacturing soiling. Mock soiling procedures must be adequately described to simulate normal manufacturing processes.

Cleaning validation includes the establishment of dirty hold times and clean hold times. Dirty hold time is the amount of time between the end of the use of the equipment and the start of equipment cleaning. Clean hold time is the amount of time between the completion of the equipment cleaning and the next cycle of use. Cleaning processes are challenged for maximum dirty hold times during cleaning validation runs.

For clinical products, infrequently made products, or infrequently used equipment, a cleaning verification approach may be used in lieu of cleaning validation.

Single-use product-contact equipment (used once and then discarded) is excluded from cleaning validation. Single-use items include beakers, pipettes, weigh boats, silicone tubing, sample tubes, storage bags, and normal-flow filtration filters.

Product-dedicated refers to equipment that is used for a single product and then is removed as part of changeover procedures. Product-dedicated items, such as chromatography resins and tangential-flow filtration membranes, are used with one product only. The requirement for residues in dedicated equipment may differ from that for residues in equipment used for multiple products; nevertheless, the cleaning of product-contact surfaces of dedicated equipment requires cleaning validation. The validation of product-specific resin and membrane cleaning is captured in process validation protocols.

Multi-use equipment may be used to process one or more products or media components. At Genentech, the main emphasis of the equipment cleaning validation program is on multi-use equipment, because this equipment type has the highest risk of process contamination (run-to-run or product-to-product).


Before introducing a new product into equipment used for manufacturing a marketed product, a cleanability study is performed to determine the effectiveness of the cleaning process, using the new product on similar equipment surface types. The new product introduction (NPI) method has two purposes: to avoid cross-contamination of commercial products, and to collect development data on new products.

The cleanability study is divided into two parts: the laboratory-scale study, and the representative-scale runs. The cleanability study starts with an evaluation of the characteristics of the product and soiling at laboratory scale to determine the effectiveness of the rinse, swab, and visual inspection methods. Results of the laboratory-scale study are verified at representative scale. Representative-scale runs include three successful consecutive cleaning runs, conducted on equipment used for marketed products, which include sampling and analysis for residues, and comparison to predetermined acceptance criteria.

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