Page 54 - Assurance of Sterility for Sensitive Combination Products and Materials

42 Assurance of sterility for sensitive combination products and materials

regulated to control microbial and particulate contamination to acceptable
levels and the process for manufacturing sterile products by which micro-
biological contamination is eliminated from the product and product con-
tact surfaces protecting the product from sources of contamination [5, 6].
The US FDA and European EMA define asepsis, as the aseptic state, is
the state of control attained by using an aseptic work area and performing
activities in a manner that precludes microbiological contamination of the
exposed sterile product, with aseptic defined as something that is free from
contamination caused by harmful bacteria, viruses, or other microorgan-
isms [Internet] [3, 4].
Each of these definitions places an emphasis on prevention of micro-
bial exposure through the design and implementation of a microbiological
contamination control strategy. Whereas terminal sterilization establishes
sterility assurance levels (SAL) or probability of non-sterile units (PNSU)
surviving the sterilization process, aseptic processing establishes a level of
confidence or an assurance of sterility through the prevention and control
of contamination.
There are useful regulatory, health authority, and industry guidance doc-
uments that present expectations for aseptic processing control strategies,
including the US FDA Aseptic Processing Guidance (2004), The European
Union Annex 1 GMPs for Sterile Medicinal Product Manufacturing (2008
with draft revision 2017), and the Parenteral Drug Association (PDA)
Aseptic Processing Points to Consider Parts 1 and 2 [3, 4, 7]. Despite these
guidance documents, aseptic processing in practice can be one of the more
challenging methods for manufacturing sterile drug product.
There are several reasons for the difficulty in manufacturing sterile
products using aseptic processing. Prevention of contamination might be
more advantageous for a product than active processes such as sterilization,
but it is generally more difficult to accomplish and prove that it was done
successfully. The following are some of the reasons aseptic processing can be
challenging.
The metric for success is not well defined. In a moist heat termination ster-
ilization process, we are actively eliminating microorganisms through phys-
ical destruction of those microorganisms. To accomplish this, the amount
of energy needed to destroy the level of microbial contamination is de-
termined. The amount of heat and duration of heat exposure under pre-
determined conditions needed to destroy the microorganisms can be both
calculated and measured and confirmed experimentally thus providing am-
ple evidence that the microorganisms have all been destroyed. In the case