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A successful outcome to an FDA inspection is the fruit of planning, preparing, and training. Cultivate confident employees who are appropriately coached and clear about their responsibilities.
Perhaps it is time to change the common paradigm that uses "war room" nomenclature to describe the document preparation activities during compliance inspections from regulatory agencies. "War" implies conflict - and ultimate winners and losers. In truth, the real loser in this situation can only be the sponsor. Rather than winners and losers, consider that inspections provide the opportunity for the sponsor to demonstrate a high level of competence and proficiency to regulators - regulators who are primary customers who exercise control over when and how a product will be marketed.
Previous articles (1–3) have described the preparation for inspections and the activities during inspections. This article describes the scope and depth of the responsibilities of coordinators, liaisons escorting inspectors, and those who prepare documentation, and assemble staff or technical subject experts to meet with inspectors.
Accurate, timely document retrieval, data presentation, and staff preparation are essential to a successful inspection outcome. The activities associated with the document preparation area and the coaching of presenters should be coordinated by a single individual. This person - the coordinator - ensures the right people are in the right location at the right time. The coordinator also fills in and performs whatever activity is rate-limiting at a given time.
Roles and responsibilities for each individual need to be developed and communicated before the actual inspection. All participants: liaison escorts, document preparers, subject matter experts, coaches, and "runners," should meet so the coordinator can explain how areas will function and interact. This meeting is important so that everyone can see how his or her activities fit into the overall process. If the inspection begins in the early afternoon, it is a good idea to briefly review responsibilities on the morning of the inspection and address any last-minute questions or concerns. Document and personnel flow can be diagrammed on flip-chart paper and prominently displayed on the walls of the document preparation area. This serves as a constant reminder of the process and will be referred to more than once when activities peak.
Company representatives - liaisons - who accompany the regulatory inspectors are responsible for:
Liaison skills. An ideal ratio is to have one liaison for each agency inspector. Liaisons should have sufficient technical knowledge to work with the inspector to refine and document information requests, but they are not expected to respond to detailed technical questions. For example, when a request for "all validation protocols and data for the purification area" arrives in the document preparation room, it is not clear whether the inspector is interested in equipment installation qualification (IQ) and operational qualification (OQ), process validation, cleaning validation, or any of a variety of other possibilities. Returning the request for further clarification takes time and is disruptive to both the liaison and the inspector. Liaisons orchestrate the flow of documents and personnel to inspectors. When liaisons provide a smooth flow of data, documents, and staff to and from the inspectors, they eliminate the down time that frustrates inspectors.
Limiting participation. Some companies use three different individuals performing liaison tasks: one to accompany the inspectors, another to write requests, and a third to record discussions among different individuals. Companies may use "runners" to carry requests and documents between the liaison and the document preparation room. In selecting the approach to use, keep in mind the logistical difficulties that a large group can cause in a manufacturing suite or a conference room. Limit immediate participation to those who are essential to achieving the goal of a successful inspection.
Document room staff perform a variety of activities, including:
When operations in the document room function effectively, few people notice. But when there are difficulties in the document room, everyone notices, and the first to notice are the inspectors.
Skills needed. Behind-the-scenes activities are labor intensive and require a skilled group of individuals who work well together. The document room during an inspection is not the time or place for prima donnas or for staff who feel they have turf to claim or protect. Document area staffing should not be an afterthought. Staff working in the document area should be experienced and organized.
Documentation requests. Document preparation activities are labor intensive. For example, five recent preapproval inspections averaged five days each, excluding introductory meetings, facility tours, and the time inspectors spent writing and delivering the 483 observations. An average of 240 requests were made at each company, with a range of 154 to 364 requests (one inspection was likely an anomaly in the number of requests). Each inspector made approximately 12 requests per day with the peak number of requests during the last half of the inspection. Each request is not, however, addressed by providing a single document. For example, in an inspection during which 285 requests were made, 100 one-inch binders, almost 60 three-inch binders, and other material such as SOPs and batch records were retrieved, reviewed, presented, and stored.
Inspectors frequently request copies of documents or sections of documents. The volume of documents copied for regulatory inspectors to take with them can fill more than one cardboard box that holds standard-size file folders. The document preparation staff should retain copies of all materials provided to inspectors.
Limiting disruption. The document preparation room should be off limits except to necessary staff and should not be considered a social gathering area. Limiting access to this area minimizes the chance that important original documents get misplaced. Management, however, often likes to visit this room. Document room activities can seem chaotic, so it is useful to help management understand that this is actually a well-orchestrated activity. Before the inspection, brief management on the data collection, review, and storage activities that support the inspection.
An effective way to minimize disruption by management visits during the inspection is to post abbreviated versions of inspector requests on flip charts and hang the charts on the walls around the room. This way, management can ensure they understand the information being requested without disturbing the flow of activities. Management visits are also minimized or shortened by providing frequent lists of all inspector requests.
Requests for document or information should be recorded on a standard form that has been prepared for use during inspections. Request forms can be already numbered, or numbers can be assigned at the time the form is given to the document control group. Numbered requests serve as unique identifiers for tracking purposes, but do not establish request priority. When multiple documents are required to fulfill a single request, the identifier number should be placed on each of the documents. Frequently, the conference room table where inspectors work has dozens of documents spread out in various stages of review. Knowing which request each document supports is invaluable in keeping order in what might otherwise be a disjointed jumble of paper.
Multiple documents from a single request. As stated, a single request can require collection of multiple documents. Moreover, follow-up requests may be made. It is important to decide - before the inspection - how such situations will be handled. Are initial and follow-up requests given different identifiers? Listing the initial inspector request on a single form, then using another form for each follow-up request can be efficient.
Effectively documenting and tracking requests during an inspection permit staff to identify the status of all inquiries at any time. This is important because multiple inspectors frequently make almost identical requests, or the same inspector wishes to review a document evaluated earlier in the inspection. Documentation can be effectively managed using a paper-based system if only one or two inspectors are present. Inspections with more than two inspectors can overwhelm a paper-based system and slow the document retrieval process. A company can use one of several adequate commercially available computerized programs (such as FileMaker Pro or Access). At a minimum, the database should record the specific request, the time and date that it was recorded, which inspector made the inquiry, the company liaison associated with that inspector, and the staff member providing the documentation. It is also valuable to identify and link follow-up inquiries with the original request.
Computerized databases allow staff to rapidly determine the number and status of outstanding requests at any time. Reports, sorted by requesting inspector, can be provided to the respective company liaison several times during the day. This assists liaisons in supplying a smooth flow of documents for the inspector's review. Reports can also be provided to management so that they are aware of the current status of the requests.
Documents provided should address the inspector's question and not provoke tangential queries that might negatively affect the outcome of the inspection. Tedious as it is, every page of all the documents provided to FDA should be reviewed to ensure that miscellaneous email messages - and those ubiquitous little yellow sticky notes - don't make their way to the inspectors. At times, a dozen staff members may be devoted exclusively to document review. This is not to suggest that the staff reviewing the documents should remove or correct unflattering or problematic information if that material is key to the request from the inspector. The review, however, serves to identify problematic items so that the presenter is prepared for the discussion and is not taken by surprise when the inspector "discovers" them.
The company should establish a means of rapid communication between the document preparation room and the presenters. Several phones should be installed in the document preparation room, and it is useful to reserve one of the phones for outgoing calls only. Subject matter experts can be provided pagers or cell phones to be used specifically for this activity. If pagers or cell phones are leased, it is prudent to perform a 100% check to make sure they all function properly rather than discovering a glitch during the inspection. Phone codes can be established. For example, a page reading "999" could indicate that the recipient should go immediately to the document preparation room.
Companies should identify the individuals who will be subject matter experts, able to address technical topics. Be sure to do this early in your planning process, so that you allow the experts sufficient time to prepare for this exercise. Interestingly, the appropriate individual for addressing a specific topic is
always the scientist with the most expertise on the subject. Subject matter experts represent the company to FDA, so they need to be knowledgeable, but they also need to be able to communicate clearly and succinctly. Subject matter experts should not view their task as a "heroic" position in which they will "save" the company.
Subject matter experts should understand what their role is during the inspection and should practice responding to difficult questions that inspectors may ask. Every company has vulnerable points in product development and validation schemes. Company experts who are able to deliver a confident, consistent response can mitigate the effect of a technical deficiency. It's far better to be prepared for the hard questions than to just hope that the regulatory agency doesn't uncover a weakness.
Experienced quality assurance or quality control staff members are often effective in coaching subject matter experts immediately before their meetings with inspectors. An experienced coach can calm a nervous presenter and impart a last-minute dose of confidence.
Coaches should ensure that subject matter experts who will address specific topics to inspectors are familiar with the data, the conclusions, the associated deviations or investigations, and any potential weaknesses in the documents they will be providing and discussing. Subject matter experts and the document review staff are jointly responsible for identifying any weaknesses to avoid being taken by surprise when an inspector raises an issue. Effective coaching ensures that subject matter experts presenting information understand the relationship between the documents requested and the commitments made in product registration applications. Equally important, the subject matter expert should understand the context in which this documentation request was made.
Participating in inspections is challenging and stressful under the best circumstances, but it can also be a rewarding experience. The company should acknowledge the important contributions made by those participating behind the scenes during the inspection. That can mean, for instance, providing food and refreshments during the day. Rotating the lunch supplier ensures that staff is not eating the same turkey sandwich every day. Providing a variety of basic meals, coffee, tea, soft drinks, and cookies is a simple gesture that means a lot to the recipients.
Successful inspections are the sum of successfully executed components, many of which go on behind the scenes. Activities that have a critical effect on the outcome of an inspection are seldom highly visible. The responsibilities of the company liaisons and the document preparation staff and the interaction between the two are key features of a successful inspection outcome. Neither document preparation nor liaison activities are stress-free. Planning and coordination, however, can substantially minimize the stress and also increase the effectiveness of the staff involved in an inspection. Timely tracking and staging of documents result in efficient use of inspectors' time (and may even decrease the duration of the inspection), an efficiency that should certainly affect inspectors positively. Procedures for document control minimize the possibility that irreplaceable original documents are lost or misplaced, a serious consideration for contract manufacturers that have many regulatory inspections and client audits each year.
(1) Unger, B.W., "Using a Model and Tools to Standardize the Preparation for a Preapproval Inspection,"
, 15(2) , 14–18 (February 2002).
(2) Lavian, M. and Allen, P.W., "Survival Guide to FDA Inspections, Part 1: To Prepare or Not to Prepare, There Is NO Question," BioPharm 15(8), 20–26,49 (August 2002).
(3) Lavian, M. and Allen, P.W., "Survival Guide to FDA Inspections, Part 2: Conducting the Audit - Ready or Not, Here They Come," BioPharm, 15(10), 30–35 (October 2002).BPI