FDA Audit Practices: the 10 Most Commonly Cited Drug GMP Deficiencies of 2012-2013

Does the word "audit" make you shake in your shoes?
If there is one word within the life science industries that causes concern and anguish it is “audit.” As with any evaluation process, the success of getting through a regulatory audit is a combination of preparedness with regards to what to expect, knowing the current regulations that apply to your product and knowing what tends to be the areas of deficiencies in audits  performed. All of these items can be researched on the web and the time and effort to review and provide training on them will serve companies well. 
Understanding audit approaches used by FDA auditors, which have changed over the years, helps set the first area to focus for preparedness. Today’s approach and one used for all audits is the quality systems approach that takes into consideration the six systems that make up a quality program.The six systems include quality; facilities and equipment; production; materials; laboratory controls; and packaging and labeling.The review of these systems is now the basis for all audits, whether in the U.S. or internationally.

The approach used is often referred to as QSIT, or the Quality System Inspection Technique, which was the basis for audits of the medical devices industries ¹. The audits can either be a “full” audit, where the quality system and three other systems would be selected for review, or an  abbreviated audit, where the quality system and two other systems are reviewed. Whatever type of audit is performed, the quality system must always be examined.

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This practice indicates the importance FDA places on corporate quality programs. Companies must define their quality programs within their procedures manuals and demonstrate they are followed and documented where applicable. The importance of always examining the quality system is to "evaluate whether management with executive responsibility ensures that an adequate and effective quality system has been established and maintained."¹ To this end, it is critical that procedures that deal with the quality system delineate how upper management is made aware of quality-related issues. This could include daily reviews, weekly summaries, monthly meetings, etc. Perhaps the most important aspect of QSIT is that it  holds management accountable for the weaknesses found during the inspection.

Audit Approaches

One thing that can be said about the audit approaches performed by inspectors today is that there is nothing that is routine. Many audits and the directions they take can be influenced by the first impressions of the facility, attitudes of the company at the opening meeting or certainly the history of compliance, where applicable, that the facility holds. While some audits may focus on several different audits, recent client audits have focused on just one area. If one were to summarize what the results might indicate, they could range from enforcement, to data integrity, or  laboratory controls to name a few. Those that have just gone through a regulatory audit would probably be able to add even more. Of all the FDA, European or third part audits I went through and had to defend validation practices, I could say that the topics that would be inspected seemed to stay the same but the approach used by inspectors never did. We need to remember that as each of our personalities are different so will be the approach and never assume one successful audit will guarantee future ones.

A common audit technique today is defined as “top down” where the inspection begins with review of top system-wide procedures and policies. As more information is needed, the investigator bores down further into the records, taking a top-down approach. Findings and objectionable practices  can often lead to a road map of other systems impacted by what is found in the quality system. An effective training aid to use for preparing for a regulatory audit is to review the most commonly cited GMP deficiencies (easily found on the web) and then use them as a template to evaluate one’s own practices. Internal audits results should also be used to see if the same findings were reported. If there is one common deficiency found in all of the six quality systems mentioned above, it is the lack of or failure to conduct investigations and resolve discrepancies, testing failures, or deviations. This one fact should put companies on notice that procedures on how to conduct investigations, along with CAPA, should be closely examined, verified to be accurate as performed and results trended to verify effectiveness. A second weakness of such investigations, when conducted, is that the extent of the investigation tends to be limited to the immediate lots impacted with little review of lots produced prior to or after the lots in question.

A second approach used during audits includes verification that past audit observations have been addressed and this may then lead to evaluation of other systems based on the corrective actions taken³. As mentioned before, an effective internal audit program should include a review and determination of a state of control for past cited observations. This will help minimize inspectors from finding the same issues which they dislike and will note in their final reports.

Common GM Drug Deficiencies

In review of the top 10 most commonly cited drug manufacturing deficiencies for 2012-2013, the following items were cited, along with the applicable CFR section.

Regulatory Reference

21 CFR 211.22(d)
(responsibilities of QC)
The responsibilities and procedures applicable to the quality control unit are not in writing or fully followed. 

21 CFR 211.192
(production rec. review)
There is a failure to thoroughly review any unexplained discrepancy.  The failure of a batch or any of its components to meet any of its specifications whether or not the batch has been already distributed. 

21 CFR 211.100(a)
(written procedures)
There are no written procedures for production and process controls.

21 CFR 211.160(b)
(general requirements)
Laboratory controls do not include the establishment of scientifically sound and appropriate specifications, standards, sampling plans or test procedures.

21 CFR 211.67(b)
(Equipment cleaning/maintenance)
Written procedures are not established or followed for the cleaning and maintenance of equipment, including utensils.

21 CFR 211.113(b)
(control of micro contamination)
Procedures designed to prevent microbiological contamination of drug products purporting to be sterile are not established, written, or followed. 

21 CFR 211.67(a)
(Equipment cleaning/maintenance)
Equipment and utensils are not cleaned, maintained, or sanitized at appropriate intervalsl

21 CFR 211.165(a)
(testing /release for distribution)
Testing and release of drug products for distribution do not include appropriate laboratory determination of satisfactory conformance to the final specifications.

21 CFR 211.110(a)
(sampling/testing of in-process materials.)
Control procedures are not established which monitor the output and validate the performance of those manufacturing processes that may be responsible for causing variability.

21 CFR 211.166(a)
(stability testing)
There is no written testing program designed to assess the stability characteristics of drug products.

Keep in mind that these findings will change each year, but they provide an excellent basis on where one’s focus should be placed in preparing for your next audit.


¹ QSIT: The New Quality System Inspection Technique….Posted by mddiadmin on October 1, 1999 (http://www.mddionline.com/article/qsit-new-quality-system-inspection-technique)

² 2014 9th Annual Global Conference on Pharmaceutical Microbiology Bethesda, MD October 20-22, 2014 (Sharon K. Thoma, PharmD)

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Kenneth Christie has more than 30 years of sterile manufacturing and regulatory GMP consulting experience in the areas of Quality Assurance and Validation Management in the pharmaceutical and biotechnology industries. Mr. Christie is currently the Chief Operating Officer for VTS Consultants, Inc located in Amherst, MA. Specifically, his responsibilities include quality system auditing, GMP training, and serving as a subject matter expert for aseptic manufacturing processes, medical devices, APIs and solid dosage processing equipment, utilities, and systems on a global basis. Mr. Christie also performs vendor audits, site pre-approval inspections and assists clients with addressing and correcting regulatory observations. He may be reached at 413-253-0077 or at ken_christie@vtsinc.net.