BASIC PRINCIPLES IN THE VALIDATION OF STERILE PRODUCTS Theoretical Approaches

Generally, five basic steps are necessary to validate any manufacturing process
[15].
1. Written documentation
2. Manufacturing parameters
3. Testing parameters
4. In-process controls
5. Final product testing
In sterile product manufacturing, five major steps are involved in approaching
the validation of a sterile process. These are outlined below using thermal sterilization
as the example process.
1. Select or define the desired attributes of the product. Example: The
product will be sterile.
2. Determine specifications for the desired attributes. Example: The
product will be sterilized by a sterilization process sufficient to produce
a probability of nonsterility of one out of 1 million containers
(10−6).
3. Select the appropriate processes and equipment. Example: Use microbial
kinetic equations such as Eq. (11) to determine the probability
of nonsterility. Select cleaning equipment and container component procedures designed and validated to reduce the product bioburden to
the lowest practical level. Select an autoclave that can be validated in
terms of correct operation of all mechanical controls. Use the appropriate
types of thermocouples, thermal sensing devices, biological indicators,
integrated chemical indicators, and culture media to conduct
the validation tests.
4. Develop and conduct tests that evaluate and monitor the processes,
equipment, and personnel.
Examples:
a. Determine microbial load counts prior to container filling.
b. Determine D and Z values of biological indicator organism.
c. Perform heat distribution studies of empty and loaded autoclave.
d. Perform heat penetration studies of product at various locations
in the batch.
5. Examine the test procedures themselves to ensure their accuracy and
reliability.
Examples:
a. Accuracy of thermocouples as a function of variances in time and
temperature.
b. Repeatability of the autoclave cycle in terms of temperature and
F value consistency.
c. A challenge of the sterilization cycle with varying levels of bioindicator
organisms.
d. Reliability of cleaning processes to produce consistent low-level
product bioburdens.
Each validation process should have a documented protocol of the steps
to follow and the data to collect during the experimentation. As an example,
App. I presents a protocol for the validation of a steam sterilization process.
Upon completion of the experimental phase of validation, the data are
compiled and evaluated by qualified scientific personnel. The results may be
summarized on a summary sheet, an example of which is shown in Table 2.
Once a process has been validated, it must be controlled to assure that the
process consistently produces a product within the specifications established by
the validation studies. As shown in Table 2, documentation should present original
validation records, a schedule of revalidation dates, and data from the revalidation
studies. The interval between validation studies strictly depends on the
judgment of the validation team based on the experience and history of the
consistency of the process.
Table 3 lists the sterilization methods used for sterile products. There are
five basic methods—heat, gas, radiation, light, and filtration. The first four
methods destroy microbial life, while filtration removes micro-organisms. Vali-dation approaches and procedures used for most of these methods will be addressed
in the remainder of this chapter. Gaseous validation and radiation validation
approaches will be focused on ethylene oxide and gamma radiation,
respectively. The other gaseous and radiation methods, however, generally will
follow the same principles as those discussed for ethylene oxide and gamma radiation. Some extra coverage will be given to vapor phase hydrogen peroxide
because of its increased application, particularly in the sterilization of barrier
isolators.