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CDER Will Focus on Part 11 Compliance in Upcoming Inspections

FDA’s Center for Drug Evaluation and Research (CDER) will be conducting a series of inspections of drug manufacturers that will evaluate the industry’s understanding of and compliance with the Part 11 regulations.  The inspection findings will be used to assess whether or not the agency’s related regulations and guidance need to be adjusted.

CDER announced that it will begin the inspections at manufacturing and clinical investigation sites both in the US and abroad in the near future.  The agency will not disclose how the sites will be selected for inspection nor provide advance notifications of inspection to those sites.

In a mid-July press release, CDER pointed out that concerns with the 1997 regulation were addressed in its August 2003 “Scope and Application” guidance, which limited the way Part 11 would be enforced during inspections and provided discretion in interpreting compliance.  The press release explains that CDER “intends to take appropriate action to enforce Part 11 requirements for issues raised during the inspections that do not fall under the enforcement discretion discussed in the guidance.”

In the wake of this announcement, ISPE held a webinar on the new inspection initiative.  Conformity Director Sion Wyn and CDER Office of Compliance (OC) Project Management Officer George Smith provided background and details on the upcoming effort.  Wyn is an advisor to FDA on Part 11; Smith is co-chair of the FDA Part 11 working group.

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Wyn began with an overview of the regulatory expectations regarding Part 11 and the Scope and Application guidance.  The overall expectation, he said, is that a manufacturing company or clinical investigator site have adequate controls in place to ensure that the regulated electronic records are trustworthy, reliable and generally equivalent to their written counterparts.

The electronic records must also preserve the content and meaning of the records “so that the regulated company could then consistently use those records to fulfill regulatory duty and that they would be available for inspection by the agency.”

Noting that computerized systems are becoming increasingly “fundamental” to all business and manufacturing processes, Wyn highlighted two potential and related problem areas in particular:  record lifecycle and system interfaces.

“A particular electronic record may have quite a complex lifecycle, being passed along between many various systems, all of which need to be in a state of control and in compliance,” he stressed.

The Part 11 expert predicted that there will be less focus on individual systems in inspections and more scrutiny of the interfaces between the various interconnected systems.  “How they effectively communicate with each other across the infrastructure will become more and more important,” he emphasized.

Building on the background provided by Wyn, CDER’s Smith discussed the current state of Part 11 compliance and the center’s upcoming plans for initiating inspections focusing on those regulations.

Since the Scope and Application guidance was published in 2003, FDA has been “in a reevaluation phase,” he explained.  The agency has been monitoring Part 11 compliance and is “looking to put in place whatever is needed to move forward and make sure that the Part 11 requirements are enforced.”

Smith emphasized that Part 11 “did not go away” and that FDA continues to enforce it, though much of the enforcement “is not obvious” as the citations are generally to the predicate rules and do not reference Part 11 directly.

CDER’s Office of Regulatory Affairs (ORA) will begin inspection assignments focused on Part 11 requirements as per the enforcement discretion described in the scope and application guidance “very soon,” Smith explained.  “We hope to implement and complete it within 2010.  However, it might be expanded or might be shortened. It all depends on what we find.”

The initial focus will be on human drug clinical investigators and manufacturers. The initiative will include both surveillance and for cause inspections with a particular focus on “areas of high risk to find out if the appropriate controls are or are not in place,” the OC official stressed.  “Where industry may not be compliant or understand the enforcement, we will enforce it as described” in the 2003 guidance.

CDER intends to use the inspections to determine the current level of compliance in the industry and to “gather information to help us determine the path forward with regards to Part 11 reevaluation,” Smith said.

Possible outcomes of the reevaluation, he explained, include:  ● no changes to existing guidance ● publishing additional guidance to clarify issues found in the inspections ● amending Part 11 or its preamble ● updating existing compliance policy manuals that “might contain outdated interpretations of Part 11,” and ● a complete rewrite of Part 11.

Global and Legacy Systems Among Issues Addressed in Q&A Session

The implications for global computer systems and legacy systems were among the issues addressed by Wyn and Smith in the Q&A that followed.

Wyn responded to a question regarding how to define a process owner for a system that traverses multiple countries.  He referred to ISPE’s current Good Automated Manufacturing Practice guide (GAMP 5) and the associated good practice guide on global information systems as references to help companies “think about their specific cases and come up with answers,” including which decisions should be made at global, regional and local levels.

“I do not think it is a case that there is one person or a handful of people who have to make all decisions,” Wyn commented.  “Based on risk assessment, different people will probably need to get involved in different decisions and it will probably be a cascade or hierarchy to a certain extent, with certain decisions being escalated.”  System owners, he noted, should generally be the process owners as opposed to technical or compliance personnel.

Legacy systems have been of particular concern at drug manufacturers, many of which have data in older systems.  “We are not going to enforce that [systems in place before 1997] be Part 11 compliant,” Smith emphasized.  Wyn added that “there is no reason why a system that has been in place and operating successfully for many years…should not have an acceptable level of record integrity.”

The length of the upcoming inspections, what to expect, and training of the investigators conducting them were other focuses in the Q&A.

Smith stressed that “there is no such thing as a Part 11 inspection.”  The inspections will be “normal” inspections, with requests to the investigators regarding which systems and controls CDER wants them to look at.  The investigators will not receive specific training on what to look for, but will be briefed “on what we want to look at for that particular inspection.”

Responding to a question regarding what the investigators will be looking for, the OC official indicated that the agency “will not be giving specifics with regard to what we will be looking for because that is going to change over time depending on what we find.”  He added that previous citations and warning letters covering Part 11 violations “might be one place we start, but we are not going to be boxed in with specifics on this.”

An important focus of Part 11 is record integrity, and the so-called “preserved record.”  Smith clarified the meaning of this term and Wyn commented on its import.

According to Smith, the FDA perspective is that a preserved record is one that is retained for the period of time specified in the regulation and is complete, containing the information required by the associated predicate rule.

“It is not so much about the meaning of the preserved record, as preserving the meaning of the record,” Wyn commented.  It is important to “understand what is the real practical value now and in the future of that record, and how you can preserve the meaning and the value of that record.”

Wyn will conduct an ISPE-sponsored two-day training session on Part 11 December 6 – 7 in Philadelphia.


CDER Part 11 Inspection Press Release

FDA 2003 Scope and Application Guidance

ISPE Part 11 training by Sion Wyn





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