Implications of risk determination on validation
What are the implications of high-risk processes or activities on validation? When validating high-risk processes or activities,
there should be proportionately increased sampling, testing, or more rigorous acceptance criteria to provide greater assurance
of process acceptability. The 2008 FDA process validation draft guidance specifically incorporates the following risk management
- "Risk analysis tools can be used to screen potential variables for DOE studies to minimize the total number of experiments
conducted while maximizing knowledge gained.
- "Qualification of utilities and equipment can be covered under individual plans or as part of an overall project plan. The
plan should consider the requirements of use and can incorporate risk management to prioritize certain activities and to identify
a level of effort in both the performance and documentation of qualification activities" (6).
The European Union's Guide to Good Manufacturing Practice, "Annex 15," also refers to the use of risk management in validation and states, "Significant changes to the facilities,
the equipment, and the processes, which may affect the quality of the product, should be validated. A risk assessment approach
should be used to determine the scope and extent of validation" (7).
How is risk management incorporated into validation? Risk-assessment tools are used to determine the extent of validation
and frequency of validation. A few practical examples of how risk-management tools are used in validation may be helpful.
A chilled water system was used to cool a jacketed tank during formulation of a product prior to sterile filtration. This
system contacts the tank jacket only. The chilled water system was controlled by an off-the-shelf temperature control system
with a chart recorder. A 3-D risk assessment of the chilled water system gave the results shown in Table VI.
Table VI: 3-D risk assessment—low risk system.
Because the system is low risk, no qualification was necessary beyond engineering commissioning of the system. Once commissioned,
the system was placed under a standard PM program, and the chart recorder and temperature controller were calibrated on an
A bulk formulation tank was used to compound a parenteral product before sterile filtration. This tank was connected to a
distributed control system (DCS) that controls mixing speed and temperature according to setpoints entered by the operator
from a local panel in the compounding area. Ingredients other than WFI were added manually by the operators. WFI was added
from a WFI drop at the mixing tank, which was opened by the operator from the DCS local panel. A level transmitter connected
to the tank indicates the volume of WFI added to the tank. A 3-D risk assessment of the formulation tank gave the results
shown in Table VII.
Table VII: 3-D risk assessment—medium risk system.
Based on the risk score of 60, the system was designated as a medium-risk system. Construction and operation of the formulation
tank were verified under installation qualification (IQ) and operational qualification (OQ) protocols. The compounding process
itself was verified under a performance qualification (PQ) protocol. After completing IQ, OQ, and PQ, the formulation tank
was placed under change control. No periodic requalification was required, but periodic assessment of the system was required
to ensure it maintained its validated state of control.
An injectable protein therapeutic was not stable in liquid form and requires lyophilization. The lyophilizer was highly automated,
with automated CIP and SIP, automated moisture content and product temperature monitoring using pressure rise methodology,
and a supervisory control and data acquisition system containing the lyophilization recipes for each dosage form of the product.
Product was loaded into the lyophilizer by an autoloading system. A 3-D risk assessment of the lyophilizer gave the results
shown in Table VIII.
Table VIII: 3-D risk assessment—high-risk system.
Based on the risk score of 125, the lyophilizer was designated a high-risk system. Extensive validation efforts, including
computerized system validation (CSV), CIP, and SIP validation, IQ and OQ including shelf mapping, condenser capacity and sublimation
rate, and other tests were performed to characterize the performance of the lyophilizer. PQ of the lyophilizer included surrogate
lots with site-specific sampling for moisture content, cake appearance and reconstitution, followed by media fills and conformance
lots for the protein therapeutic. The lyophilizer was placed under change control with periodic requalification, including
shelf mapping and requalification of the CIP and SIP processes. Media fills were performed using the lyophilizer on a quarterly