Warning letter / DuPont Nutrition USA Inc. / MARCS-CMS 627211/ 627211/ DECEMBER 02, 2022/ Observation 4

Failure to have an adequate change management program to evaluate and approve changes that may impact the quality of the excipient.

Avicel process performance qualification studies conducted from 2001 through 2007 identified conductivity as a critical quality parameter. However, in approximately 2011 firm removed the conductivity meters without a documented change control.

Firms response stated that at the time of the change potential impact on the quality of Avicel was evaluated, but did not document this evaluation. Firm also state it will evaluate the impact of any other process changes implemented without adequate review on the quality of your excipient. Firm also committed to evaluate process changes for potential impact on other critical quality parameters listed in the most current validations (dated 2001, 2004, and 2007). However, a detailed plan or timeline for implementation of the revised change management program is not provided.

In response to the Warning letter, Firm to provide:

A comprehensive, independent assessment of change management system. This assessment should include, but not be limited to, procedure(s) to ensure changes are justified, reviewed, and approved by quality unit. Change management program should also include provisions for determining change effectiveness.

A remediation plan that better assures ongoing management oversight throughout the manufacturing lifecycle of all excipients. Provide a more data-driven and scientifically sound program that identifies sources of process variability and assures that manufacturing (including both production and packaging) operations meet appropriate parameters and quality standards. This includes, but is not limited to, evaluating suitability of equipment for its intended use, ensuring quality of input materials, determining the capability and reliability of each manufacturing process step and its controls, and vigilant ongoing monitoring of process performance and product quality.

As can be seen from the FDA warning letter manufacture of Excipients need to comply with applicable cGMPs as per 21 CFR 210&211 and other applicable regulations just as the drug product and drug substance manufacturers.. Companies should have comprehensive change management (change control) procedure addressing: 

• Documentation of change, detailing of change, reason and justification of change
• Evaluation of impact of change – impact on product quality, regulatory impact. Changes initiated should be reviewed by a cross functional team, identify potential impact, a risk assessment of the change need to be performed and documented. The change management documentation should also identify all actions that need to be taken to implement the change with timelines – for e.g (but not limited to) process validation, changes in documentation – batch records, specifications, methods, requirement for notification of change to regulatory agencies and customers, initiation of stability studies. Quality unit should review the change documentation and ensure that all requirements for change implementation are addressed and approve the change for implementation. Only approved changes shall be implemented. There should be post implementation review of the change to ensure all change actions identified are implemented; Effectiveness of the change for achieving stated objective should also be verified and documented.

• Engage competent independent cGMP expert consultant to review and assess the overall system for change management. Evaluate all the changes implemented in the manufacturing process and control of excipients for potential impact on product quality.
• Based on the assessment,  take remediation measures, revalidate the manufacturing process / test methods where necessary
• The change management procedure and documentation should be comprehensively reviewed and revamped (refer the discussion in above section – What companies should have…)
• Perform a risk assessment of each of the excipient covering all aspects of manufacturing lifecycle:
  • Manufacturing process – each process steps, packing, testing and release, storage and handling
  • Distribution, shelf life and stability
  • Quality and variability of input materials
  • Manufacturing facility, equipment
• The risk assessment shall look at what can go wrong, its impact and risk, risk acceptability, identification of remediation measures to reduce the risk, reassessment of the risk after implementing remediation measures.
• Establish  / enhance procedure for (annual) Product Quality review to monitor product and process performance and quality. The review should cover – number of batches manufactured during the year, deviations, out of specifications (OOS), complaints, changes, implementation status of CAPAs, product quality trends and statistical evaluation of the trends, stability trends. The product quality review should evaluate and conclude on the status of control of the manufacturing process and manufacturing lifecycle and identify actions to be taken for improving process and product performance.
• It will be worth considering implementing a Continuous Process Verification (CPV) programme for ongoing monitoring of process performance and product quality.  

Work out a detailed action plan with timelines for completing all the actions identified. Keep track of all above actions. Provide FDA a comprehensive response and periodic updates on the progress of actions.