Contains Nonbinding Recommendations
how trending and calculations are to be performed and should guard against overreaction to
individual events as well as against failure to detect unintended process variability. Production
data should be collected to evaluate process stability and capability. The quality unit should
review this information. If properly carried out, these efforts can identify variability in the
process and/or signal potential process improvements.
Good process design and development should anticipate significant sources of variability and
establish appropriate detection, control, and/or mitigation strategies, as well as appropriate alert
and action limits. However, a process is likely to encounter sources of variation that were not
previously detected or to which the process was not previously exposed. Many tools and
techniques, some statistical and others more qualitative, can be used to detect variation,
characterize it, and determine the root cause. We recommend that the manufacturer use
quantitative, statistical methods whenever appropriate and feasible. Scrutiny of intra-batch as
well as inter-batch variation is part of a comprehensive continued process verification program
under § 211.180(e).
We recommend continued monitoring and sampling of process parameters and quality attributes
at the level established during the process qualification stage until sufficient data are available to
generate significant variability estimates. These estimates can provide the basis for establishing
levels and frequency of routine sampling and monitoring for the particular product and process.
Monitoring can then be adjusted to a statistically appropriate and representative level. Process
variability should be periodically assessed and monitoring adjusted accordingly.
Variation can also be detected by the timely assessment of defect complaints, out-of-
specification findings, process deviation reports, process yield variations, batch records,
incoming raw material records, and adverse event reports. Production line operators and quality
unit staff should be encouraged to provide feedback on process performance. We recommend
that the quality unit meet periodically with production staff to evaluate data, discuss possible
trends or undesirable process variation, and coordinate any correction or follow-up actions by
production.
Data gathered during this stage might suggest ways to improve and/or optimize the process by
altering some aspect of the process or product, such as the operating conditions (ranges and set-
points), process controls, component, or in-process material characteristics. A description of the
planned change, a well-justified rationale for the change, an implementation plan, and quality
unit approval before implementation must be documented (§ 211.100). Depending on how the
proposed change might affect product quality, additional process design and process
qualification activities could be warranted.
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Maintenance of the facility, utilities, and equipment is another important aspect of ensuring that a
process remains in control. Once established, qualification status must be maintained through
routine monitoring, maintenance, and calibration procedures and schedules (21 CFR part 211,
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Certain manufacturing changes may call for formal notification to the Agency before implementation, as directed
by existing regulations (see, e.g., 21 CFR 314.70 and 601.12).
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