Biopharmaceutical 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. A cleanability study is essential before introducing a new product
into the manufacturing equipment. Part 1 of this article provides background on cleaning validation and the associated regulations,
cleaning methods, and the validation strategy. It also describes Genentech's approach for new product introduction using laboratory-scale
and representative-scale studies. Part 2 will cover the other aspects of the cleaning validation program such as grouping
strategy, validation sampling, acceptance criteria, change control, and revalidation.
Cleaning validation refers to establishing documented evidence providing a high degree of assurance that a 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 should
begin with equipment design evaluation and cycle and process development that includes, but is not limited to, the following:
sanitary equipment design, selection of final rinse water, approved equipment specifications that address an evaluation of
the compatibility of construction materials with product and cleaning solutions, sprayball design optimization, cleaning process
design studies, cleaning sample assay validation, suitability of sampling, and recovery studies for assay and sampling methods.
Without these design and development activities, validation could potentially lead to unnecessary troubleshooting and cleaning
The cleaning process should remove materials such as media, buffers, storage solutions, cell culture fluids, cell debris,
non-active pharmaceutical ingredients containing placebos, and formulations and concentrations of drugs or active pharmaceutical
ingredients (API). Selection of appropriate sampling to demonstrate that residues have been removed to an acceptable level
is vital for the success of cleaning validation.
At Genentech, Inc., design and cleaning-cycle development is considered a prerequisite for cleaning validation. The purpose
of cleaning validation at Genentech for biopharmaceuticals is to:
- Assess a new product or new equipment for cleanability before cGMP production.
- Ensure that cleaning procedures are adequate for cleaning new products or new equipment.
- Ensure that residues after cleaning of equipment are reduced to an acceptable level before the manufacture of the next run
or the next product in the same equipment.
- Provide ongoing assurance that the validated cleaning procedures are in a state of control through monitoring and periodic
- Evaluate and validate changes to cleaning processes, other manufacturing processes, and equipment to maintain these validated
cleaning processes in a state of control.
Cleaning validation is driven by regulatory expectations to ensure that residues from one product will not carry over and
cross-contaminate the next product. An effective cleaning program starts with appropriately designed equipment and cleaning
processes, followed by validation and maintenance. The following are some good manufacturing practice (GMP) cleaning validation
requirements for the biopharmaceutical industry.
US Food and Drug Administration 21 CFR Part 211: Current GMP for Finished Pharmaceuticals
§ 211.63 Equipment design, size, and location:
Equipment used in the manufacture, processing, packing, or holding of a drug product shall be of appropriate design, adequate
size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance.1
§ 211.67 Equipment cleaning and maintenance:
(a) 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. (b)(3)(5) Protection of clean equipment from contamination before use.1
§ 211.182 Equipment cleaning and use log:
A written record of major equipment cleaning, maintenance, . . . and use shall be included in individual equipment logs that
show the date, time, product, and lot number of each batch processed.1