Quality risk-management review
Sterile-filling equipment and product delivery systems support processes (e.g., CIP/SIP, sterile filtration) and are well
defined in industry. Use risk-assessment tools to review automation software, controls, alarms, and to define PAT needs using
a QbD approach. Table I includes instructions and a key for severity, occurrence, and detection for use in Table II. Table
II includes three examples to demonstrate the use of risk assessment as described below. (This methodology provides a number
[e.g., ≥50 fails], which makes a result a clear decision, requiring modifications either to the process or finding a PAT alternative.)
Table I: Sample risk-analysis evaluation.
Isolators on a filling line.
Risk assessment in this case can highlight and quantify benefits. Assessment involves product and personnel safety and requires
process modifications to be successful.
Table II: Sample risk-analysis worksheet.
Manual loading of filled vials into a freeze dryer as compared with automatic loading.
It is possible to eliminate the need for using trays if the design includes the capability to transfer the freeze-dried vial
after processing in the freeze drier directly to a capper.
Automation software used in conjunction with unit operations and equipment.
This risk assessment example involves a sterile filler designed for 10% check weighing and compares it with 100% check-weighing
capability (6). Risk assessment can help demonstrate the importance of good CQA choices to support management approvals.
Draft guidance questions and concerns
There are some remaining questions despite the thoroughness of the draft guidance. Below are a few key issues.
- What is required for final PQ approval? The final guidance should include clarification on what constitutes validation. This
clarification is critical because the common practice of using three batches to verify validation no longer applies (3).
- In the case of a PAT strategy, will the approach to process qualification be different from other process designs? The final
guidance needs to include more specifics with regard to what degree of PAT is required to positively impact validation and
approvals (3). This clarification is especially important because often, the more PAT involved, the more investment and validation
- Industry needs to have a sense of which statistical methods and levels of sampling FDA recommends. Reference to specific documents
and testing level(s) may suffice (3).
- The final guidance should discuss the impact of the new guidance on existing products and processes and how to integrate them
into the new approach (3).
- The final guidance should discuss potential impact on current and future new drug and abbreviated new drug applications (NDAs
and ANDAs) and their site of manufacture. For example, is there an expected date to have the new process validation requirements
implemented in applications? For NDAs, additional time may be needed and patents may be affected. For ANDAs, shouldn't companies
be required to demonstrate equivalency of control as the innovator process?
- Finally, there is a concern that product development information could become available though freedom of information, thus
revealing data that have significant confidential information about the process. How will this be handled?