Page 258 - Assurance of Sterility for Sensitive Combination Products and Materials

Regulatory pathway for labeling combination products as sterile 235

a sterile product. Although aseptic processing is typically associated with
pharmaceutical and biological products, ISO 13408-7 addresses aseptic
manufacturing of combination products, products that might use both ter-
minal sterilization and aseptic processing, or similar products that are typi-
cally manufactured in small batches. The validation in these cases is limited
to performing process simulations that incorporate the largest batch size
manufactured. Hence it must be recognized that the assurance of sterility
provided by validation using these lesser batch numbers will not be the
same as that provided by traditional 1000 or 10,000 unit runs of the typical
pharmaceutical manufacturer.

9.5.6 EN 556-2
EN 556-2, Sterilization of medical devices—Requirements for medical de-
vices to be designated “STERILE”—Part 2: Requirements for aseptically
processed medical devices was published in 2003. This standard parallels
EN 556-1 in respect of sterile medical devices that are prepared by aseptic
processing. This standard was revised in 2015 to update the references to
the European adoption of the ISO 13408 series of standards for aseptic
processing.
EN 556-2 requires control of a number of factors in order designate
aseptically processed medical devices as sterile. These factors relate to con-
trols and/or records of:
• the manufacturing environment
• the sterilization of components
• the competence of personnel
• interventions in the process
• the performance of process simulations
• inspections and tests of finished product
The acceptance limits and actions for occurrence of non-sterile units in
process simulations in initial performance qualification and periodic requal-
ification are the same as those in ISO 13408-1.
Compliance with EN 556-2 is shown by providing documentation and
records of the validation and routine control of the aseptic process.

9.5.7 Evaluation of medicinal products
The draft revision of the EMA decision trees for the selection of steriliza-
tion methods, Guideline on the sterilization of the medicinal product, ac-
tive substance, excipient, and primary container (EMA/CHMP/CVMP/
QWP/BWP/850374/201), indicates that terminal sterilization is preferred