CLEANED EQUIPMENT STORAGE AND HOLD TIMES
The duration between the end of equipment cleaning and the start of subsequent operations (e.g., autoclave, sterilization-in-place
[SIP], or production usage) is called clean hold time. Following cleaning, equipment to be reused should be stored to protect
it from contamination. Storage instructions are specified in a document such as that delineating the cleaning procedure or
the storage procedure.
Equipment should be stored dry following cleaning. There should be no visible water pool in the equipment or line after draining
(including air blowing) when viewed under appropriate lighting conditions. An exception to the dry storage recommendation
occurs when equipment is stored in solution. If equipment undergoes autoclave (or SIP) or production usage after CIP within
a manufacturing shift (or for approximately eight hours), then a clean hold time need not be established, provided the circumstances
are justified and documented. Clean hold time validation is not required for indirect product-contacting equipment that undergoes
autoclave or SIP, when operational controls are in place to minimize bioburden, and when a documented risk assessment demonstrates
no risk to product quality from potential accumulation of bioburden and endotoxin as a result of prolonged storage.
A validation study is used to establish an expiry period. The study includes measuring bioburden and endotoxin levels in the
equipment after a predetermined storage time. One protocol study, comprising three individual runs, for validation of an expiry
period for a given equipment family may apply to all pieces of equipment in the family, to all products using that equipment,
and to all cleaning processes for that equipment, provided the final state of the cleaned equipment and the storage conditions
are consistent. The bioburden criteria for clean hold times takes into account the relevant microbial control procedures that
may occur subsequent to cleaning and storage condition. Therefore, clean hold time bioburden criteria may exceed the end-of-cleaning
(time-zero) bioburden criteria. The justification for the bioburden acceptance criteria should be documented. If the validated
clean hold time elapses, the equipment must be cleaned again before use.
CHANGE CONTROL AND REVALIDATION
Changes to a validated cleaning process, and changes to a manufacturing process or equipment that may affect a validated cleaning
process, must be made in accordance with approved change control procedures. Such a change may result in additional testing
to demonstrate that cleaning processes remain in a state of control. Revalidation of cleaning processes is performed following
any significant change to a cleaning process that may affect its validated state. A change evaluation process determines the
extent of validation required.
Periodic review and revalidation are methods by which the performance of a validated cleaning process is evaluated to ensure
that a state of control is maintained. At Genentech, a risk-based approach is used for setting periodic review and revalidation
frequencies. The rationale for the revalidation frequencies should be appropriately documented and justified. The revalidation
frequency for product-contact surfaces (e.g., bioreactor and pool tanks) and manual cleaning should be higher than for indirect
product-contact surfaces (e.g., media and buffer tanks).
A periodic review is performed on each combination of cleaning process and equipment (or equipment family) according to an
established frequency. Such a review includes an assessment of cleaning-process documentation, including changes implemented
under the change control program since prior revalidation to determine if processes are still in a state of control. The periodic
review should be documented.
In addition to a periodic document review, one successful cleaning validation run is conducted for each unique equipment or
system on an established frequency, provided that the equipment has been used to manufacture a product that year. Such a validation
run may include any product manufactured using the unique system. For each equipment family cleaned by the same or similar
cleaning procedures, one successful cleaning validation run is also conducted on an established frequency using one equipment
item from the applicable equipment family. This validation run may include any product manufactured using the equipment family.
Each major equipment item in each family is included in cleaning validation runs in a predetermined period. Major equipment
refers to product-contacting equipment that serves a significant purpose in the manufacture of product (i.e., the main equipment
used in process unit operation). Examples include fermentors, hold tanks, purification equipment, and lyophilizers.
Training regarding approved processes or protocols used for cleaning validation studies such as cleaning processes and sampling
processes, is performed and documented by approved training policies or procedures. Personnel who collect samples for cleaning
validation and who perform visual inspections must be trained before these collections and inspections. Operators are routinely
retrained for validated manual cleaning procedures, particularly when there has been a change in any validated cleaning procedure.