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Addressing data integrity, quality culture, aging facilities, investigations/corrective actions and preventive actions, and risk management is key when conducting audits, says Susan J. Schniepp, executive vice-president of post-approval pharma and distinguished fellow, Regulatory Compliance Associates.
Q. I am preparing my site for an audit and have prepared and trained our employees on the usual topics (training program, standard operating procedures [SOPs], change control, etc.). I am concerned that this traditional approach may not be enough in the current regulatory environment. Can you offer some guidance into other issues I should focus on in preparing for the audit?
A. This is a great question and shows an insight into the changing regulatory landscape. I think it will be critical in the coming years to focus on addressing certain intangible topics during routing regulatory audits. These topics should be addressed as part of your company’s overall improvement plans and programs.
I would focus on the following topics as a part of preparing for any routine audit: data integrity, quality culture, aging facilities, investigations/corrective actions and preventive actions (CAPA) and risk management. I am of the opinion that these topics will become routine areas of focus for regulatory inspections regardless of the affiliation of the regulatory authority performing the audit. These topics are not new to the industry. There has been much discussion on their impact on drug shortages. It is my opinion that developing robust programs addressing these issues and incorporating them into everyday routine operations will improve the drug shortage situation, improve a company’s operating performance, and improve the outcome of regulatory inspections for the company.
FDA has been publishing guidance on these issues over the years, and now as the agency gets ready to finalize the New Inspection Protocols Project (NIPP), it is time to revisit some of these recommendations and implement some of the advice offered. The intent of the NIPP program (1) is to provide inspectional assessments to support tracking and improvement of performance across pharmaceutical manufacturers and products and enhance the production, utility, and consistency of the establishment inspection reports.
Every company should have a program to address data integrity issues that includes guidance on what data integrity is, how to recognize it, how to prevent violations, consequences for violating the company’s data integrity policy, etc. The program should also address the frequency and effectiveness of employee training on this topic. The program should demonstrate an understanding of regulatory expectations as well as an explanation of how those expectations are incorporated into the data integrity program. The program needs to go beyond the concepts of ALCOA (attributable, legible, contemporaneous, original, accurate) and include the four new attributes in ALCOA+ (complete, consistent, enduring, available) (2, 3).
The concept of quality culture came about with the introduction of quality metrics. FDA introduced the concept of collecting quality metrics in 2013 (4). Since that time, the industry and regulatory authorities worldwide have embraced the idea that in order to rely on the metrics collected, the company needs to have a culture that supports an open, transparent reporting of “deviations, errors, omissions and aberrant results at all levels of the organization, irrespective of hierarchy” (3). There has been work done by the Parenteral Drug Association and Uni-versity of St. Gallen suggesting the there is a correlation between mature quality attributes and quality culture behaviors. To address the issue of a quality culture during a regulatory inspection, the company should be able to demonstrate their quality system is functional and identifies gaps so the company can implement changes to ensure continuous improvement.
Aging facilities are of concern because they can lead to drug shortages. It is hard to achieve compliance to current regulatory expectation when manufacturing new and novel products on manufacturing lines that are more than 30 years old and the analytical results rely on outdated methodology (5). The age of the line usually indicates that the processes being run on those lines are non-automated and require human driven steps. In these situations, it is critical a company demonstrates it has a quality mindset because of the human/product interface. The best way to address this issue in an inspection is to demonstrate that the company has a plan to update its facility over time. The plan should indicate what needs to be updated and a timeline for implementation.
The need for a robust investigation/CAPA process is clearly defined in global regulations, but it seems the industry still struggles with conducting and documenting root cause when it comes to investigations based on FDA 483 observations (6). The purpose of an investigation is to identify the root cause of a deviation and take appropriate action to correct the issue across the manufacturing/product line. The best way to demonstrate proper control of this process during an investigation is to ensure you have a robust investigation process, which routinely identifies root cause and that once the correction is made, it does not recur (7). The ability to demonstrate this depends on the understanding and training of the people involved in the investigation process and data that shows the problem was addressed and solved (8, 9).
Every company should have a quality risk management plan (10). A well-written and well-implemented quality risk management plan is an integral and valuable element of an effective quality system. Quality risk management plans are important because they help improve a company’s ability to provide quality product to patients. They are contingency plans with identified actions that help to ensure a continuous supply of product to the market that meets the expectations of being safe, effective, and available. They are dynamic documents that require integration into and data inputs from all departments in order to be successfully implemented at a company (11). Having the plan available for discussion and demonstrating a knowledge of the plan, how it is incorporated into the culture, and making sure it is revised as needed to reflect current practices is critical to having a successful outcome should you be audited on this topic.
The bottom line is that the regulatory landscape is changing, and it is conceivable that companies will begin to be audited on programs and process that are more subjective than tangible. To be prepared for an audit that touches on the intangibles of a functioning quality management system, companies should begin to formulate programs and systems that address the aforementioned topics.
1. Office of Pharmaceutical Quality, FDA Pharmaceutical Quality Oversight, One Quality Voice, FDA whitepaper.
2. S. Schniepp, Pharmaceutical Technology 43 (10) 2019.
3. World Health Organization, Annex 5, Guidance on Good Data and Record Management Practices (WHO, June 2016).
4. S. Schniepp, Pharmaceutical Technology 42 (10) 2018.
5. S. Schniepp, Pharmaceutical Technology 40 (8) 2016.
6. S. J. Schniepp, Pharmaceutical Technology 43 (12) 2019.
7. S. Schniepp and A. Harrison, Pharmaceutical Technology 40 (2) 2016.
8. S. Schniepp and A. Harrison, Pharmaceutical Technology 39 (10) 2015.
9. S. Schniepp and A. Harrison, Pharmaceutical Technology 39 (8) 2015.
10. S. Schniepp, Pharmaceutical Technology 44 (2) 2020.
11. S. Schniepp, Pharmaceutical Technology 43 (8) 2019.
Vol. 33, No. 4
When referring to this article, please cite it as S. Schniepp, "Critical Knowledge for Preparing Audits," BioPharm International 33 (4) 2020.