Page 58 - Assurance of Sterility for Sensitive Combination Products and Materials

46 Assurance of sterility for sensitive combination products and materials

cycles, design of sterilization circuit, container integrity inspection and
testing, and process monitoring.
5. The fifth step develops the means to test if the control measures are
effective in addressing process variability and risk. This might be consid-
ered where traditional installation/operational qualification and process
performance qualification studies occur. Once step five is complete, the
company will have the documented evidence that the process can de-
liver product that meets critical to quality attributes with reliability and
capability and be confident that it is ready to begin commercial man-
ufacturing. This might include design and installation qualification of
clean room, HVAC system, critical utilities, operational qualification of
filling lines, and aseptic process simulations.
6. The sixth step occurs during commercial manufacturing. It involves the
continued or ongoing acquisition and evaluation of a subset of informa-
tion obtained from performing the process during manufacturing. This
step is designed to monitor the process to assure that the process is main-
tained in a qualified state. This enables additional variables that have not
been previously uncovered or adequately controlled to be identified and
additional controls to be implemented to address these new variables
to improve the control of the process. This might include environmen-
tal monitoring, process performance metrics (e.g., process capability),
statistical process control charting, process failures, investigations, OOS
results, sterility failures, and audits [9].
Control strategies and process steps designed to mitigate one risk may
add additional risks to other product attributes. The interaction of process
steps could pose a risk to the quality of the product. These unintended con-
sequences should be considered during the process design. For example, the
use of a more aggressive disinfectant and sanitization program might be a
control strategy for reducing the risk of environmental contamination but
may also damage filling equipment or pose a risk of chemical contamina-
tion to product. In this case, it would be important not only to address the
intended benefit of the mitigation action but also to address the potential
unintended consequence of the action.

4.7 Defining aseptic process requirements
The manufacturing of sterile combination drug products will involve sev-
eral key steps. These steps will depend on the objectives of the manufac-
turing operation, as reflected in the desired outcome of the process or the