Guidance for Industry - Process Validation: General Principles and Practices

Foreword
This guidance represents the Food and Drug Administration’s (FDA’s) current thinking on this topic

Chapter I, "Introduction":
This guidance does not cover the following types of products:
...
Medical devices(*5)
...

(*5) Guidance on process validation for medical devices is provided in a separate document, Quality Management Systems – Process Validation, edition 2, See infra note 6.
[The link is broken, but it points to "http://www.ghtf.org/sg3/sg3-final.html" making me believe that it can only be referring to Quality Management Systems - Process Validation Guidance]

Chapter I, "Introduction":
The use of the word should in Agency guidances means that something is suggested or recommended, but not required.

Chapter II, "Background":
This revised guidance replaces the 1987 guidance.

Chapter II, Section B "Approach to Process Validation":

For purposes of this guidance, process validation is defined as the collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality product.

Chapter II, Section B "Approach to Process Validation":

Manufacturers should:
• Understand the sources of variation
• Detect the presence and degree of variation
• Understand the impact of variation on the process and ultimately on product attributes
• Control the variation in a manner commensurate with the risk it represents to the process and product

Each manufacturer should judge whether it has gained sufficient understanding to provide a high degree of assurance in its manufacturing process to justify commercial distribution of the product. Focusing exclusively on qualification efforts without also understanding the manufacturing process and associated variations may not lead to adequate assurance of quality. After establishing and confirming the process, manufacturers must maintain the process in a state of control over the life of the process, even as materials, equipment, production environment, personnel, and manufacturing procedures change.

Chapter IV, Section A "General Considerations for Process Validation":

All attributes and parameters should be evaluated in terms of their roles in the process and impact on the product or in-process material, and reevaluated as new information becomes available. The degree of control over those attributes or parameters should be commensurate with their risk to the process and process output.

Chapter IV, Section B "Stage 1 - Process Design":

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. The results of DOE studies can provide justification for establishing ranges of incoming component quality, equipment parameters, and in-process material quality attributes. FDA does not generally expect manufacturers to develop and test the process until it fails.

Chapter IV, Section B "Stage 1 - Process Design":

It is essential that activities and studies resulting in process understanding be documented. Documentation should reflect the basis for decisions made about the process.

Chapter IV, Section C "Stage 2 - Process Qualification":

This stage has two elements: (1) design of the facility and qualification of the equipment and utilities and (2) process performance qualification (PPQ). During Stage 2, CGMP-compliant procedures must be followed. Successful completion of Stage 2 is necessary before commercial distribution. Products manufactured during this stage, if acceptable, can be released for distribution.

Chapter IV, Section C, Paragraph 2 "Process Performance Qualification":

...it is not typically necessary to explore the entire operating range at commercial scale if assurance can be provided by process design data.

Chapter IV, Section C, Paragraph 3 "PPQ Protocol":

The number of samples should be adequate to provide sufficient statistical confidence of quality both within a batch and between batches. The confidence level selected can be based on risk analysis as it relates to the particular attribute under examination.

Chapter IV, Section C, Paragraph 3 "PPQ Protocol":

Data should not be excluded from further consideration in terms of PPQ without a documented, science-based justification.

Chapter IV, Section C, Paragraph 4 "PPQ Protocol Execution and Report":

Execution of the PPQ protocol should not begin until the protocol has been reviewed and approved by all appropriate departments, including the quality unit.

Chapter IV, Section C, Paragraph 4 "PPQ Protocol Execution and Report":

A report documenting and assessing adherence to the written PPQ protocol should be prepared in a timely manner after the completion of the protocol. This report should:
• Discuss and cross-reference all aspects of the protocol.
• Summarize data collected and analyze the data, as specified by the protocol.
• Evaluate any unexpected observations and additional data not specified in the protocol.
• Summarize and discuss all manufacturing nonconformances such as deviations, aberrant test results, or other information that has bearing on the validity of the process.
• Describe in sufficient detail any corrective actions or changes that should be made to existing procedures and controls.
• State a clear conclusion as to whether the data indicates the process met the conditions established in the protocol and whether the process is considered to be in a state of control. If not, the report should state what should be accomplished before such a conclusion can be reached. This conclusion should be based on a documented justification for the approval of the process, and release of lots produced by it to the market in consideration of the entire compilation of knowledge and information gained from the design stage through the process qualification stage.
• Include all appropriate department and quality unit review and approvals.

Chapter IV, Section D, "Stage 3 - Continued Process Verification":

An ongoing program to collect and analyze product and process data that relate to product quality must be established (§ 211.180(e))... ...The data should be statistically trended and reviewed by trained personnel...

We recommend that a statistician or person with adequate training in statistical process control techniques develop the data collection plan and statistical methods and procedures used in measuring and evaluating process stability and process capability.

Chapter IV, Section D, "Stage 3 - Continued Process Verification":

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.

Chapter IV, Section D, "Stage 3 - Continued Process Verification":

Process variability should be periodically assessed and monitoring adjusted accordingly.

Chapter V, "Concurrent Release of PPQ Batches":

FDA expects that concurrent release will be used rarely.

Chapter V, "Concurrent Release of PPQ Batches":

Even when process performance assessment based on the PPQ protocol is still outstanding, any lot released concurrently must comply with all CGMPs, regulatory approval requirements, and PPQ protocol lot release criteria.

Chapter VI, "Documentation":

We recommend that firms diagram the process flow for the full-scale process. Process flow diagrams should describe each unit operation, its placement in the overall process, monitoring and control points, and the component, as well as other processing material inputs (e.g., processing aids) and expected outputs (i.e., in-process materials and finished product).