Page 52 - Assurance of Sterility for Sensitive Combination Products and Materials

40 Assurance of sterility for sensitive combination products and materials

4.1 Aseptic processing of sterile combination products
Combination products are therapeutic or diagnostic products that combine
drugs, devices, and/or biological products [1]. They are defined as two or
more separate products packaged together in a single package or as a unit and com-
prised of drug and device products, device and biological products, or biological and
drug products [2]. Sterile combination products have the additional require-
ment that the final product must be sterile. Sterile combination products are
a growing and important segment of health-care therapies.
There are the US and international regulatory documents associated
with the manufacture of combination products. The FDA has published
guidance on both combination products as well as aseptic processing. The
FDA 2004 Guidance on Aseptic Processing outlines the expectations for the
manufacture of sterile drug products using aseptic processing. The GMPS
for combination product is a merger of relevant sections of CFR Parts 210,
211, and 820 [3]. The European Union has recently revised its Annex 1 for
the manufacture of Sterile Medicinal Products including those using aseptic
processing [4].
Manufacturers of sterile combination products are required to com-
ply with all relevant regulations applicable to all parts of the combined
product. In general, Drug GMPs are more prescriptive than Device GMPs,
while Device GMPs are more system focused. For the most part, the same
GMPs and rules for aseptic processing apply to the sterile drug part of the
combination product as do for any sterile drug product. While regulatory
requirements and in some cases, terminology may be different, the expecta-
tions for aseptic processing are the same. Therefore, with respect to the re-
quirements and expectations of aseptic processing, if a company follows the
Drug GMPs and guidance, that manufacturer is probably covering what it
will need from an aseptic processing perceptive. If the manufacturer follows
the Device GMPs and guidance, additional requirements are likely needed
to document device design controls, supplier controls, CAPA, management
controls for devices, design history, control over the device and the drug in
a combination product, risk analysis for the entire product, and interaction
of the drug and device.

4.2 Drug product sterility

Drug product sterility can be achieved by terminal sterilization of a sealed/
packaged product, aseptic processing, or a combination of these two meth-
ods. A key difference between sterilization and aseptic processing is the