Basic European Union GMP Requirements for Medicinal Products
EudraLex, volume 4, Medicinal Products for Human and Veterinary Use: Good Manufacturing Practice, chapter 3, Premises and Equipment:
Principle: Premises and equipment must be located, designed, constructed, adapted, and maintained to suit the operations to
be carried out. Their layout and design must aim to minimize the risk of errors and permit effective cleaning and maintenance
to avoid cross-contamination, build up of dust or dirt and, in general, any adverse effect on the quality of products.2
EudraLex, volume 4, Medicinal Products for Human and Veterinary Use: Good Manufacturing Practice, annex 15, Qualification and Validation:
Cleaning Validation: Cleaning validation should be performed in order to confirm the effectiveness of a cleaning procedure.
The rationale for selecting limits of carry over of product residues, cleaning agents, and microbial contamination should
be logically based on the materials involved. The limits should be achievable and verifiable.2
International Conference on Harmonization Q7, Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients
The ICH Q7 was developed jointly by the European Union, Japan, and the United States for active pharmaceutical ingredient
manufacturing.3 API is the drug substance before final formulation; section 12.7 contains cleaning validation requirements for APIs.
Other Guidance Documents
Additional guidance documents have been established by regulatory agencies and industry associations, such as the FDA, the
Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (PIC/S), the Canada Health Products,
and the World Health Organization .4–7
BIOPHARMACEUTICAL MANUFACTURING PROCESSES AT GENENTECH
Genentech manufactures biopharmaceutical products from E. coli and Chinese hamster ovary host cells using multiproduct, dedicated, and single-use equipment. Product manufacturing involves
cell culture and bacterial fermentation processes, with the associated recovery processes (harvesting, initial and final purification),
followed by formulation, aseptic filling or lyophilization, and capping.
Genentech's manufacturing processes include steps for manufacturing and purification of the API, and steps for manufacturing
and packaging of the finished drug product. Steps up to and including final purification of the drug substance are considered
API manufacturing; the formulation of the drug substance into finished product and the packaging of that product is considered
finished drug product manufacture. This is consistent with regulatory expectations for these different categories of manufacturing,
with cleaning validation requirements including predetermined acceptance criteria, which may differ for each type of manufacturing.
Two separate cleaning validation master plans have been created: one for the API and one for the finished drug product.
Cleaning is performed to remove materials introduced into equipment during the manufacturing process. These materials may
include media, buffers, storage solutions, cell debris, non-API-containing placebos, and any formulation or concentration
of a given drug product or API. Manufacturing and cleaning equipment must be designed for effective and consistent cleaning.
The cleaning of manufacturing equipment surfaces at Genentech uses automated, semi-automated, and manual cleaning processes.
For larger, enclosed equipment, an automatic or semi-automatic clean-in-place (CIP) process is typically used. Cleaning process
parameters include cleaning agent concentration, temperature, flow rates, volume, and time.
Equipment cleaning procedures use cleaning agents to aid removal of process soils. The cleaning agents may be categorized
as caustic, acidic, neutral, or oxidizing. Some equipment at Genentech is cleaned with water for injection only, using no
cleaning chemicals. A typical CIP process includes an initial water pre-rinse, a washing step with one or more cleaning agents,
and a final rinse. Before conducting residue removal testing in cleaning validation, installation qualification and operational
qualification are performed on the equipment to be cleaned and on the equipment used for the cleaning process. Manufacturing
equipment is exposed to cleaning solutions by fully submerging the component (i.e., clean-out-of-place washer or manual cleaning
methods); by fully flooding the product-contacting surfaces (i.e., transfer lines or manually cleaned tanks); or by directing
fluids by use of spray devices such as spray balls, spray wands, and washer nozzles.
For equipment containing a spray device, qualifications include identifying and documenting the device, noting its proper
orientation and alignment, and performing a spray coverage test to assure complete coverage. Spray device coverage verification
testing for vessels that are cleaned in place is conducted according to an approved procedure. This procedure involves the
use of a visual marker (e.g., riboflavin solution, which fluoresces under ultraviolet light) and spray devices. For glassware
that is cleaned in washers, verification of coverage may be conducted with process soils, rather than riboflavin, if process
soils are readily visible against translucent glass surfaces.