Compliance Focused Preapproval Preparation Program. By Mike Ronningen, RAC

Transcription

1 Compliance Focused Preapproval Preparation Program By Mike Ronningen, RAC 14 July 2011

2 Submitting a Premarket Approval Application (PMA) for a Class III medical device to the US Food and Drug Administration (FDA) initiates a cascade of activities that requires the company to be operating at peak performance. Once the PMA is submitted, it is logged and issued to the Division of Bioresearch Monitoring (DBM) for assignment of initial review to determine whether it is fileable. Once the determination is made that the submission contains appropriate information and data, assignments are issued for complete review and inspections for clinical activities under Bioresearch and Monitoring (BIMO) and the PMA manufacturing site. The PMA manufacturing site will be inspected for Quality System and Good Manufacturing Practice controls (QS/ GMP) related to the submitted product. This inspection will potentially bring into focus existing commercially distributed products controlled by the Quality System at the site and possibly across your entire company. Imagine sitting with your leadership team after a successful preapproval inspection under BIMO, with a well-run clinical trial demonstrating safety, effectiveness and true clinical benefit. The glow of success is short-lived, as you run into an issue during the QS/GMP preapproval inspection that could unravel the design integrity due to a process validation reference that lacked traceability. It is possible to work for years and spend millions of dollars designing, testing and manufacturing a new product, only to have a compliance issue derail a successful approval. This is similar to a 2-cent washer failing, preventing a high-performance race car from returning to the track after a pit stop. A PMA s success can suffer a similar fate due to a compliance failure in development, clinical studies or manufacturing. The possibility such a failure can be reduced or eliminated with a program that prepares for the PMA inspections well before the submission. When the PMA is submitted, you should be ready for an inspection of clinical trials, product design and manufacturing. In theory, you should always be ready for an inspection. Commonplace statements are likely to leave you unaware of existing risks, as issues similar to the 2-cent washer example may be not visible. Human interaction keeps a business running, where hand-offs between functions and groups occur. The human element may lead to failure to recognize the risks being created in the business s routine daily transactions. Each transaction adds or multiplies these risks, which can grow so slowly that the increase in noncompliance goes unnoticed. A Compliance Focused Preapproval Preparation Program (CF- 3P) can create understanding, awareness and alignment at the top and bottom of the organization and save significant frustration and unanticipated costs arising from a challenging preapproval inspection. You might ask why this is different than an internal audit. Audits are events that are visible for short periods of time. They occur with focused intensity and the company then falls back into the routine of addressing the observations through Quality System transactions. A CF-3P engages the entire organization and creates sustained visibility along with the product s development. This engagement is through the organizational focus on the anticipated new product launch to fulfill the company s strategic vision and goals. CF-3P transforms the organization connecting compliance to the business driver of product development. It becomes part of moving the company forward, unlike an audit, which frequently becomes something to endure and an activity to complete. To leverage this connection of product development and compliance, companies should initiate a preapproval inspection preparation program before PMA submission. An even better time is at the onset of product development. CF-3P is broken down into its major blocks in Table 1, where each program activity is described in general with that stage s goal. The first CF-3P activity is focused on program awareness and organizational alignment, the most important element in preparing for a PMA inspection. This establishes recognition of the compliance s importance to the organization. This recognition demonstrates that compliance has as key role to play in the success of the product and the company, as does the new and innovative product itself. No amount of great technology, clinical benefit or operational efficiency can overcome a lack of compliance when getting a new product approved. It is imperative that the recognition of compliance as an integral part of the success of designing and launching a new product be built into the fabric of the organization. Executive and senior managers, operational and project leaders and, most critically, scientists and engineers need to focus on being compliant to the procedures established to meet regulatory requirements. This is a significant challenge for employees who receive many signals that interfere with remaining compliant in the daily demands of keeping the project and business running. There are the demands for keeping the project on schedule, completing experiments, presenting progress reports and reducing costs. Each of these, when viewed singularly, is important, but looked at in isolation, can be a source of noncompliance. Couple these demands with complex procedures and interactions within the Quality System, and noncompliance risks are likely to occur. An illustration of this singular view would be when a purchasing department sources the polypropylene resin used for both existing products and your PMA product through a different supplier than the one you used during product design and clinical studies. The supplier change Regulatory Focus 15

3 Table 1. CF-3P Modules Activity Program Module Description 1. Program awareness and organizational alignment 2. Compliance analysis of product design controls and supporting quality systems. 3. Mapping of the interface of processes with a focus on identifying interrelationships between the product and the quality system. 4. Inspection readiness monitoring and communication to organization Creation of the needs for the CF-3P s through assessment of internal and external audits and interviews with key stakeholders and leaders. Communication of the compliance program as part of the readiness of the organization to successfully receive approval and launch the new Class III product that fulfills the strategy of the company. Analyzes the compliance to design control requirements established in procedures and protocols and identifies any gaps. Determines the state of compliance for existing quality system infrastructure that defines the design control process and support of products after commercialization. Creates the roadmaps for how the PMA product interfaces with the quality system procedures and helps guide employees through control points that have impact on the product design control. Communication of the progress from the compliance program and the readiness of the product and site for a pre-approval inspection. Creates the visibility of the importance of compliance activities as a key part of the business to achieving its goal of launching a new product. may not be visible to the development team, as the qualification and validation activities are focused on existing products. During the inspection, the resin part number in the PMA product s clinical study devices is not traceable to the supplier on the approved supplier list used in your products final Device Master Record. Validation documents do not address this change. The noble goal of reducing costs has become one that creates compliance risk for your multi-year and multimillion-dollar project. This lack of traceability of a part number to a supplier could be perceived as lack of control and may end up affecting the PMA submission s approval. CF-3P would provide visibility and awareness of the PMA inspection and activities to ready the company for product approval. The program should be communicated broadly and deeply to ensure the entire organization understands the program s importance to the company s new PMA product launch. The awareness and alignment alone will not prevent the purchasing example above from occurring, but other elements of CF-3P would identify these types of issues. Other module activities described below, in conjunction with the awareness and alignment, will address these potential problem sources. Now that your PMA is considered fileable, you are likely on the schedule for a preapproval inspection. The inspection will focus on the procedures and protocols you established to develop, verify, validate, manufacture and support your product. Each of these procedures and protocols contains process control elements that can be identified in a way that allows compliance to be achieved and confirmed. Unfortunately, all of these procedures and protocols and their resultant quality records become a web of complex interactions. Fortunately, each procedure and protocol can be broken down into basic compliance elements that can be achieved and confirmed. Each procedure or protocol contains discrete elements for compliance as listed below: 1. action or activity step 2. documentation or quality record creation step 3. evaluation of adequacy, approval or signature step 4. quality record filing step For many, these elements may seem redundant with the procedure creation and training employees receive. If you apply this element breakdown method to procedures, you will find some surprises in procedures, where a step is sometimes missed. A review of internal and external audit observations will likely provide examples where a procedure was not followed because an action or documentation step was not completed. This breakdown method will clearly separate the elements of the procedure from the words used to define responsibilities, educate, clarify, describe and instruct the user to meet procedural requirements. Additionally, you will likely discover that the requirements for actions, activities and approvals are repeated several times in the same procedure. Often, each repetition of the 16 July 2011

4 requirement is phrased differently and may not have the clarity needed by the user. This element breakdown can be demonstrated by an excerpt from FDA s Medical Device Quality Systems Manual. This excerpt is from the Document and Change Control section s exhibit of an Engineering Change Policy/Procedure, section 7.1 (Figure 1). 1 The element breakdown of the procedure shows several things. First, it outlines what steps require the creation of documents and the actions or activities to be taken by the employees involved in the document control process. Second, this breakdown shows how many requirements are embedded in a paragraph. Step has eight documentation requirements in a single paragraph. It is likely that an employee could easily forget one of the documentation creation requirements in this step of the procedure. Note in Step the evaluation of the where-used considerations, which would have prevented the resin issue from occurring as described earlier in the purchasing example. CF-3P would conduct a procedural control analysis and make these situations visible so they could be addressed before the PMA submission and inspection. The visibility of these issues allows for proper analysis of any nonconformity, implementation of corrections and corrective actions and understanding of risks when you are not in the heat of the moment in an inspection with an investigator across the table. This CF-3P module, focusing on the compliance analysis of product design controls and supporting quality systems, will require the most work and diligence by the organization. This is a step-wise and brick-by-brick analysis of each procedure and record created during the product design process. Covering the breadth and depth of the product and the transfer into manufacturing operations will require adequate resources and time to complete. This step could protect against delays affecting years of investment and millions of dollars. The side benefit of this compliance analysis output is that it allows improved clarity of procedures and will reduce audit observations as execution improves. The next module of CF-3P creates the maps that show how the product interfaces with the current Quality System. Creating these maps will identify where enterprise control points exist that affect the PMA product. This module connects with the previous module by linking the framework of procedural controls to physical systems for the PMA product. This module is best illustrated by a description (Figure 2) and example. The node diagram in Figure 2 shows the PMA product and associated software used for product design, and to verify and validate design, manufacture and support the product. A myriad of software tools are used in product design and manufacture and all that software Figure 1. Procedure for Design and Process Changes Regulatory Focus 17

5 Figure 2. Production and Process Control needs to be managed through a controlled process. As illustrated in Figure 2, the Software Control Process (SCP) is a control point for software used at the PMA manufacturing site. Not only does the SCP affect the software for product design, it also controls the software used for manufacturing the PMA product. This node diagram shows that the SCP needs to be thoroughly evaluated before the PMA inspection, as in this small view, the SCP affects three of the seven quality subsystems FDA inspects. The figure lists 10 software examples, but that is only a small subset of software used in an enterprise that should be under control. There could be dozens or hundreds of electronic spreadsheets, depending upon the company. Without this mapping and diagramming perspective, it would be easy to forget to ensure all software is validated and controlled to maintain the validated state. Also, the diagramming highlights the input systems to the SCP that need to be evaluated as part of CF-3P. If your IT infrastructure does not have control, all of the validations performed through the SCP may no longer be valid. This same model can be applied to other critical systems within the PMA site. A similar diagram could be done for a distilled water system, where the water is used for manufacture of multiple products, cleaning and quality control testing. This diagram would show the distilled water system affecting multiple products. If the water system were inspected during the PMA inspection, could it withstand the investigators scrutiny of the validation, maintenance, monitoring, testing and even the supplier control areas? CF-3P would find that forgotten electronic spreadsheet someone created to simplify calculations or that new statistical software application someone downloaded because it had certain graphing features. This is noble intent by individuals, but noncompliant to regulations and company procedures. The focus of confirming the compliance status of all things touching the PMA product will ensure you are in a state of full control. Selling CF-3P to management is not easy. The first time an organization engages in a CF-3P, it faces a lot of work getting ready for a PMA inspection. You are preparing 100% for an inspection that will cover far less 20% to 60% of the enterprise operations. You just do not know exactly which 20% to 60% will be inspected. Some leaders may look at the CF-3P as added work and cost. In reality, it can replace existing efforts if it is managed correctly. First, some of the work can be used to fulfill internal audit requirements for quality systems. Second, 18 July 2011

6 CF-3P activities can address a number of existing corrections and corrective actions that likely exist from internal and external audits. Third, it will have a transforming effect on how employees interact with the Quality System and procedures and reduce transactional noncompliance events. Each of those events requires documented response and management through your site s CAPA processes. Lastly, you are increasing the probability your PMA product will get to market faster. You will gain weeks from not having to respond to multiple Form FDA-483 observations, and months from not having to demonstrate the product data has integrity and performing additional submissions to address deficiencies. Each week lost means lost revenue and profit. CF-3P will improve the probability that your PMA QS/GMP inspection will go more smoothly and you will be able to defend your robust and comprehensive Quality System. An obstacle is removed once you successfully demonstrate the compliant Quality System used to design and manufacture the PMA product. Now your product s premarket approval relies on the safety and effectiveness demonstrated through design verification, validation and the clinical studies. That is a subject for a different article. You may also be interested in the following resources: Prosecuting and Defending Health Care Fraud Cases Foreign Corrupt Practices Act (FCPA) Assessing Risk and Maintaining Compliance (on-demand webcast) Visit RAPS.org/store References 1. US Department of Health & Human Services. Medical Device quality Systems Manual: A Small Entity Compliance Guide > 9. Document and Change Control. US Food and Drug Administration. gov/medicaldevices/deviceregulationandguidance/ PostmarketRequirements/QualitySystemsRegulations/ MedicalDeviceQualitySystemsManual/ucm htm. Accessed 16 June Author Mike Ronningen, RAC, has more than 28 years of experience in the medical device and pharmaceutical industries. He has worked for Fortune 100 and Fortune 500 companies and an international conglomerate. He has held a number of roles in regulatory, quality, technical product support and senior management. He holds a RAC for the US and EU. Regulatory Focus 19