De Novo Application: The beginning of a new device product class

This article explains the FDA’s De Novo application process for regulatory clearance of medical devices that do not meet the requirements of a 510k submission.

De Novo Pathway 300x169 De Novo Application: The beginning of a new device product class
De Novo Application:
The beginning of a new device product class

The best regulatory experts plan regulatory submissions months before the performance testing is completed, and often the strategic regulatory pathway is determined before the design of the device even begins. If your design team is developing an innovative technology, you may have difficulty finding a predicate device that is substantially equivalent to your device. If you have not completed a De Novo application before, where do you start?

History of the De Novo Application

Historically, a De Novo application required that your device be submitted through the 510k process first. If the FDA determined that your device was not substantially equivalent to the predicate you chose, then you received a “Not Substantially Equivalent” (NSE) letter from the FDA. Once you receive an NSE letter, you have three options: 1) select a different predicate and re-submit, 2) re-submit the device through the Pre-Market Approval (PMA) process, or 3) submit the device through the De Novo application process. You were not allowed to submit a De Novo application until you received an NSE letter.

The De Novo application process was revised on July 9, 2012 to allow manufacturers to submit a De Novo application without a preceding 510k submission. This was done because there are many products that are technologically equivalent to a predicate device, but the indications for use are quite different. For example, many in vitro diagnostic (IVD) products are indicated for diagnosis of new viruses, but the device uses technology equivalent to another IVD product the manufacturer already makes. For this reason, most of the first 100+ De Novo application approvals were for IVD products.

De Novo Application Draft Guidance Document

The De Novo application process does not have an approved final guidance document. For now, there is only a draft guidance document.

Pre-Sub Meetings Prior to a De Novo Application

Pre-sub meetings are generally recommended by the FDA for manufacturers that intend to submit a De Novo application without a prior 510k submission and subsequent NSE letter. If the device is a Class II, a  pre-sub meeting allows the manufacturer to request input from the FDA,  regarding performance testing and special controls. The draft De Novo guidance document specifically recommends following the existing content guidelines for a pre-sub meeting request, but the guidance also recommends including the following elements in the pre-sub meeting request:

  • Proposed product classification (i.e., Class I, Class II exempt, or Class II)
  • Details of efforts previously taken in order to identify a predicate
  • Risks and Risk/Benefit Analysis
  • Proposed Performance Testing and/or Special Controls

De Novo Applications for Class I and Class II Exempt Devices

Most manufacturers mistakenly assume that De Novo applications are only for devices that are Class II and will require a 510k submission for future product submissions in the same classification. However, the regulations require that the application cover letter include both a “Classification Summary” and a “Classification Recommendation.” The recommendation for a classification may be for Class I, Class II exempt or Class II non-exempt. If you recommend that the FDA classify the device as Class II exempt, then the recommendation must include a justification for why premarket notification is not required.

Regardless of which classification is recommended, the justification for classification needs to be based upon a risk/benefit analysis. Class I and Class II exempt classifications are likely to be recommended more in the future for many of the standalone software products that are being developed by manufacturers, because those software devices generally have a low risk. Existing product classifications may be used, but if the indications for use are not substantially equivalent to a predicate the manufacturers will submit a 510k and receive NSE letters. For the companies that are claiming substantial equivalence to products that already have a product classification that is exempt from premarket notification, manufacturers will continue to register and list products under existing classification codes until the FDA intervenes–even if the indications for use are not equivalent.

How to Modify Your 510k Templates

Twenty sections comprise a 510k submission, but regulatory experts typically use templates for each section in order to streamline the process of preparing a new device submission. For a De Novo application, a large percentage of the sections required for a 510k submission are the same. The draft guidance identifies one unique section to a De Novo application: the cover letter (i.e., Attachment II in the De Novo guidance). However, there are three sections of a 510k submission that also need to be eliminated for a De Novo application:

  1. Section 1: User Fee Cover Sheet, because De Novo applications do not require a user fee
  2. Section 5: 510k Summary or 510k Statement is not required, because this is not a 510k submission
  3. Section 12: Substantial Equivalence Comparison, because De Novo applications do not claim equivalence to a predicate

New De Novo Application Webinar

Companies developing devices with truly innovative technologies frequently have difficulty identifying suitable predicate devices. The best regulatory experts plan in advance for these regulatory submissions by honing their knowledge of the De Novo application process. On Thursday, January 28th I’m sharing my own tips and templates for De Novo applications. Click here to learn more about the webinar.

Posted in: 510(k)

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Three (3) important technical file and 510k submission differences

This article summarizes the three (3) important technical file and 510k submission differences: 1) the risk management file, 2) the clinical evaluation report, and 3) the post-market clinical follow-up report.

3 different apples Three (3) important technical file and 510k submission differences

3 important technical file and 510k submission differences

ISO 14971 requires a risk management file whether you are selling a medical device in the EU or the USA, but the US FDA doesn’t require that you submit a risk management file as part of the 510k submission. If you design and develop a medical device with software, you must submit a risk analysis if the software has a moderate level of concern or higher. However, the risk analysis is only a small portion of a risk management file.

Only 10-15% of 510k submissions require clinical studies, but 100% of medical devices with CE Marking require a clinical evaluation report (CER) as an essential requirement in the technical file. The clinical evaluation report (CER) is essential requirement (ER) 6a in Annex I of the Medical Device Directive (MDD). Even class 1 devices that are non-sterile and have no measuring function require a clinical evaluation report (CER). Yes, even adhesive tape with a CE Mark requires a clinical evaluation report in the technical file.

Annex X, 1.1c of the Medical Device Directive (MDD) requires that medical device manufacturers perform a post-market clinical follow-up (PMCF) study or provide a justification for not conducting a post-market clinical follow-up (PMCF) study. In the past, companies attempted to claim that their device is equivalent to other medical devices and therefore a post-market clinical follow-up (PMCF) study is not required. However, in January 2012 a guidance document (MEDDEV 2.12/2) was published to provide guidance regarding when a PMCF study needs to be conducted. This guidance makes it clear that PMCF studies are required for many devices–regardless of equivalence to other devices already on the market.

Risk management file for technical file and 510k submission

The FDA only requires documentation of risk management in a 510k submission if the product contains software and the risk is at least a “moderate concern.” Even though you are required to perform risk analysis, a knee implant would not require submission of the risk analysis with the 510k. If a product is already 510k cleared, you may be surprised to receive audit nonconformities related to your risk management documentation for CE Marking. The most common deficiencies with a risk management file are:

  1. compliant with ISO 14971:2007 instead of EN ISO 14971:2012
  2. reduction of risks as low as reasonably practicable (ALARP) instead of reducing risks as far as possible (AFAP)
  3. reducing risks by notifying users and patients of residual risks in the IFU
  4. only addressing unacceptable risks with risk controls instead of all risks–including negligible risks

If you are looking for a risk management procedure, please click here. You might also be interested in my previous blog about preparing a risk management file.

Clinical evaluation report (CER) for technical file and 510k submission

The FDA does not require a clinical evaluation report (CER), and up until 2010 only some CE Marked products were required to provide a clinical evaluation report (CER). In 2010 the Medical Device Directive (MDD) was revised and now a clinical evaluation report (CER) is a general requirement for all medical devices (i.e., Essential Requirement 6a). This requirement can be met by performing a clinical study or by performing a literature review. Since 510k devices only require a clinical study 10-15% of the time, it is unusual for European Class 1, Class IIa and Class IIb devices to have clinical studies. This also means that very few clinical studies are identified in literature reviews of these low and medium risk devices.

The most common problem with the clinical evaluation reports (CERs) is that the manufacturer did not use a pre-approved protocol for the literature search. Other common problems include an absence of documented qualifications for the person performing the clinical evaluation and failure to include a copy of the articles reviewed in the clinical evaluation report (CER). These requirements are outlined in MEDDEV 2.7/1, but the amount of work required to perform a clinical evaluation that meets these requirements can take 80 hours to complete.

If you are looking for a procedure and literature search protocol for preparing a clinical evaluation report (CER), please click here. You might also be interested in my previous blog about preparing a clinical evaluation report (CER).

Post-Market Surveillance (PMS) & Post-Market Clinical Follow-up (PMCF) Studies for technical file and 510k submission

Post-market clinical follow-up (PMCF) is only required for the highest risk devices by the FDA. For CE Marking, however, all product families are required to have evidence of post-market clinical follow-up (PMCF) studies or a justification for why post-market clinical follow-up (PMCF) is not required. The biggest mistake I see is that manufacturers refer to their post-market surveillance (PMS) procedure as the post-market surveillance (PMS) plan for their product family, and they say that they do not need to perform post-market clinical follow-up (PMCF) study because the device is substantially equivalent to several other devices on the market.

Manufacturers need to have a post-market surveillance (PMS) plan that is specific to a product or family of products. The post-market surveillance (PMS) procedure needs to be updated to identify the frequency and product-specific nature of post-market surveillance (PMS) for each product family or a separate document needs to be created for each product family. For devices that are high-risk, implantable or devices that have innovative characteristics the manufacturer will need to perform some post-market clinical follow-up (PMCF) studies. Even products with clinical studies might require post-market clinical follow-up (PMCF), because changes to the device, accessories and range of sizes may not be covered by the clinical studies. MEDDEV 2.12/2 provides guidance on the requirements for post-market clinical follow-up (PMCF) studies, but most companies manufacturing moderate risk devices do not have experience obtaining patient consent to access medical records in order to collect post-market clinical follow-up (PMCF) data–such as postoperative imaging.

Procedures & Webinars

If you are looking for a procedure for post-market surveillance (PMS), please click here. If you are interested in learning more about post-market surveillance and post-market clinical follow-up (PMCF) studies, we also have a webinar on this topic.

Posted in: 510(k), CE Marking

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Regulatory pathway document creation–a case study

This regulatory pathway case study is provided by Medical Device Academy for 510k submission, CE Marking application and Canadian Medical Device License application.

Regulatory Pathway 1 Regulatory pathway document creation  a case study

How do you select the right regulatory pathway for your device?

Manufacturers considering global expansion need to master the process of creating a regulatory pathway analysis. That analysis must be product-specific. I used to create long documents that were tedious to read, but in the past month I found a better way. I now use webinar recordings to help clients analyze the regulatory pathway for their products. I create a slides for each market that my client is considering for expansion. At the end of the 20-30 minute presentation, my client asks clarification questions and we discuss the possible next steps toward regulatory approval.

A Typical Regulatory Pathway Analysis

A typical regulatory pathway analysis involves 3 major markets for a new product: 1) USA, 2) Europe, and 3) Canada. There will be one slide per market identifying the classification rationale for each market, and if there are exceptions this will be explained. Exceptions often arise for specific indications for use, duration of contact and for unique components such as:

nanomaterials (Class III in European new regulations)
– antibiotics (Class III as per Rule 13 or combination product)

Recommended Regulatory Pathway Document Content

There will be a slide per market identifying the regulatory approval process. For devices without predicates, this will be a De Novo application or a PMA submission in the USA. For Canada, you might need an Establishment License or a Medical Device Distribution License.

There will be a slide per market identifying QMS requirements customized to reflect the QMS my client already has. If you already have ISO 13485 certification you only need 2-3 new procedures to launch in Canada, while there are typically more procedures required for launching a product in the USA due to differences between ISO 13485 and 21 CFR 820. Even in Europe, a Japanese company will need: 1) a vigilance reporting procedure, changes to their Advisory Notice Procedure, and 3) a procedure for creating a technical file.

Finally, most clients need help identifying the testing requirements for safety and efficacy. If the FDA has a recent special controls guidance this is much easier. If guidance is non-existent or outdated, then you need experts like Leo to help navigate international and European National (EN) Standards that might be applicable for safety and efficacy testing.

Regulatory pathway case study

In 2015 I published a series of three blogs explaining how to identify the regulatory pathway for different markets:

  1. CE Marking Approval of a Medical Device (Case Study)
  2. 510k Submission to the FDA (Case Study – Part 1)
  3. Obtaining a Health Canada Medical Device License (Case Study)

The blogs were specific to a hypothetical product–a tissue adhesive for topical approximation of skin. Therefore, I decided to use the same hypothetical product for this case study regulatory pathway. If you are interested in watching a recording of this regulatory pathway, click here to download the case study recording.

Are you planning a submission in 2016?

Please visit our regulatory pathway webpage if you are interested in purchasing this service.

Posted in: CE Marking

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Management review revisions for ISO 13485:2016

The article explains management review revisions required for ISO 13485:2016 compliance. The article tells a story about a recent re-certification audit nonconformity and how the revised ISO 13485:2016 Standard will help prevent this type of quality issue in the future. The article includes links to information about new and revised regulatory requirements, how to write a procedure and there is a link for downloading a free management review webinar.

Management Review 20161 Management review revisions for ISO 13485:2016

One of my clients recently had a re-certification audit in December with their Notified Body and they received a nonconformity in the first couple of hours of the 4 day audit. Here’s what happened.

First, they had an opening meeting with the auditor from 8:30am – 9:05am. Next they took the auditor on a tour of the facility to show her some of the areas of the facility that had been renovated since last year’s surveillance audit. The management representative and the auditor returned to the conference room at 9:40am and the auditor began with a review of the management review revisions to the procedure. The procedure had not changed since the previous year so the auditor asked to see the most recent management review. The company conducted a management review on Tuesday, December 8, 2015. The audit reviewed all the required inputs since the previous management review–which was conducted on Tuesday, December 9, 2014.

When the auditor reviewed data analysis of complaints, she noticed a spike in complaints related to shipping errors that occurred in the months of February through May. When she asked for an explanation, the management representative explained that the renovations caused some misplacement of inventory that resulted in shipping delays and a few mistakes. The auditor asked when the trend was first observed. The management representative indicated that the trend was observed in April, and corrections were made by the warehouse manager in May. The trend was confirmed to have reversed in the data from the third quarter.

The auditor asked if a formal corrective action was implemented. The management representative said that no formal CAPA was initiated, because the problem did not appear to be a systemic problem due to the small volume of complaints relative to the large volume of shipments. The auditor asked if shipping complaints were a quality objective. The management representative confidently indicated that they were. The auditor then asked when top management was notified of the negative trend and reviewed the spike in the performance of the quality objective. The management representative said that the quality objective performance is reviewed by top management during the management reviews and since the corrections appeared to be effective no further action was warranted.

The auditor responded that she would be issuing a minor nonconformity against the management review process. The reason the auditor provided was that top management and the management representative did not maintain effectiveness of the quality management system during a major renovation, because they did not monitor quality objectives on a sufficient frequency to react to quality issues in a timely manner. Furthermore, they failed to modify there planned interval for management reviews to take into account major changes in the facility that could negatively impact quality.

At the closing meeting, top management asked what should have been done to avoid this finding. The auditor was hesitant to provide advice, but she indicated that management could have been more proactive and taken measures to prevent the shipping complaints in the first place. A quality plan for the renovation could have included increased management oversight and more frequent review of quality objectives related to the areas being renovated. Instead of reviewing quality metrics quarterly, a monthly schedule might have been used during the renovations. Instead of scheduling the management review for December, top management might have scheduled a management review during or immediately after the renovations to address any quality issues with corrective actions or action items in the management review outputs. Another possible, and less proactive, approach would have been for the warehouse manager to initiate a formal corrective action as soon as the negative trend was observed. Then top management would have been aware of the quality issue through the CAPA process. Unfortunately, none of these actions were taken.

The auditor indicated that she could have written the finding against a number of different clauses (e.g., CAPA, monitoring and measurement of processes, quality system planning). She chose to reference the management review process in the finding, because the company will need to make management review revisions in 2016 to document the justification for management review intervals. There are also management review revisions required to address new and revised regulatory requirements in the meeting outputs. Therefore, the company’s corrective action plan might also address the requirements of the revised ISO 13485:2016 Standard.

Management review revisions to frequency of planned intervals

Most companies satisfy the requirement for conducting a management review (i.e., 21 CFR 820.20 and ISO 13485, Clause 5.6) in one of the following ways:

  1. conducting one meeting each year
  2. conducting one meeting each quarter

If your company is conducting only annual reviews, your reviews will be far more useful if you switch to a quarterly schedule. In the case of my client, top management would have discussed the negative trend in shipping complaints in April 2015 instead of December 2015–8 months earlier. Reviewing data from 9-10 months ago is too late to take action.

Management Review Revisions Medical Device Academy Made

You can download the management review procedure from this website that was just updated for compliance with ISO 13485:2016. If you have your own procedure, you might want to read my blog about improving your own management review procedure. The key to writing a procedure is link the procedure to template that will be used as a starting point for each management review. The template should include each of the 8 required inputs (i.e., Clause 5.6.2), the 3 required outputs (i.e., Clause 5.6.3) and a slide for covering both the Quality Policy and the overall effectiveness of the Quality Management System. The procedure should be short and the bullets should match the requirements verbatim.

Training Top Management

The biggest reason why management reviews are ineffective is that there is little engagement by most of the people in the room. Everyone in the room should be familiar with the requirements and contribute to the preparation for a management review and management review revisions. The best management representatives anticipate the needs of top management and give them tools that explain exactly what they need to do to prepare for a management review and their responsibilities during the meeting.

Additional Management Review Resources

If you are looking for more information on this topic, here are some resources:

  1. How to Improve Your Medical Device Management Review Procedure
  2. Management Review Procedure Case Study
  3. Management Review Webinar: Making your meetings more effective
  4. Medical Device Management Review Meetings: 3 Compliance Issues

Posted in: ISO 13485:201x, ISO Certification

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Post-market surveillance plans: How to write one for CE Marking.

This article explains how to write a post-market surveillance plan for CE Marking and how to determine if a post-market clinical follow-up (PMCF) study is required.

Screenshot 2015 12 15 at 6.18.57 AM Post market surveillance plans: How to write one for CE Marking.

A post-market surveillance (PMS) plan is only required for the highest risk devices by the FDA (i.e., typically devices that require a PMA or premarket approval). For CE Marking, however, all product families are required to have evidence of post-market clinical follow-up (PMCF) studies or a justification for why PMCF is not required.

Why is a post-market surveillance plan a “hot button” with auditors recently?

Post-Market Surveillance is an area of emerging concern around the world. Not just a procedure for PMS, but an actual product-specific plan for gathering post-production data about your product or product family. Product registries, the anticipated launch of Eudamed and the implementation of UDI regulations are part of this industry-wide movement. The FDA has articulated the US plan for strengthening PMS in a guidance document, while the European PMS efforts are being debated as a central part of the new European Medical Device Regulations.

The biggest mistake I see 

The biggest mistake I see is that manufacturers refer to their PMS procedure as the PMS plan for their product family, and they say that they do not need to perform a PMCF study because the device is similar to several other devices on the market. Manufacturers need to have a PMS plan that is specific to a product or family of products.

How often is post-market surveillance data collected?

Your post-market surveillance procedure needs to be updated to identify the frequency and product-specific nature of post-market surveillance for each product family or a separate document needs to be created for each product family. For devices that are high-risk, implantable or devices that have innovative characteristics the manufacturer will need to perform some PMCF studies. Even products with clinical studies might require PMCF, because changes to the device, accessories and range of sizes may not be covered by the clinical studies. MEDDEV 2.12/2 provides guidance on the requirements for PMCF studies, but most companies manufacturing moderate risk devices do not have experience obtaining patient consent to access medical records in order to collect PMCF data–such as postoperative follow-up data.

Additional Resources

Medical Device Academy has created a post-market surveillance plan template that you can download for free. If you are looking for a procedure for post-market surveillance, please click here. If you are interested in learning more about PMS and PMCF studies, we also have a webinar on this topic.

Posted in: Clinical Studies & Post-Market Surveillance

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Define medical device software verification and validation (V&V)

This article defines software verification and validation (V&V) for medical devices. The article also provides an overview of the CE Marking application and 510k submission requirements for medical devices containing software. Finally, we provide a link to our free download of a webinar on 510k software documentation.

Software Validation and Verification 1 Define medical device software verification and validation (V&V)

Software verification and validation is an essential tool for ensuring medical device software is safe. Software is not a piece of metal that can be put into a strain gauge to see if the code is strong enough not to break. That’s because software is intangible. You can’t see if it is in the process of failing until it fails. The FDA is concerned about software safety since many medical devices now include software. Software failure can result in serious injury, or even death to a patient. This places significant liability on the device manufacturer to ensure their software is safe. One way to ensure software safety is to perform software verification and validation (V&V).

What is software verification and validation (V&V)?

Definitions of software verification and validation confuse most people. Which tasks are software verification? and which tasks are software validation? Sometimes the terms are used interchangeably. Even the FDA does not clearly define the meaning of these two terms for software. For example, in the FDA’s design control guidance document the following definitions are used:

“Verification means confirmation by examination and provision of objective evidence that specified requirements have been fulfilled.”

“Validation means confirmation by examination and provision of objective evidence that the particular requirements for a specific intended use can be consistently fulfilled.”

Specific intended use requirement…specified requirements…what is the difference? To understand the difference between the two terms, the key is understanding “Intended Use.” It is asking the question: “What is the software’s intended use?”

“Intended Use” is not just about a bunch of engineers sitting around a table coming up with really cool ideas. “Intended Use” refers specifically to the patient/customer of the software and how it fulfills their needs (i.e., “User Needs”). Systematic identification of user needs is required, and the user needs must be addressed by the software. Identification of user needs is done through customer focus groups, rigorous usability studies and consultation with subject matter experts such as doctors and clinicians providing expert insight.

“Intended Use” also ensures safety of the process through the process of “Hazard Analysis” whereby any hazard that could potentially cause harm to the patient/customer is identified. For each identified hazard, software requirements, software design and other risk controls are used to make sure the hazard does not result in harm, or if it does, the severity of the harm is reduced as far as possible.

So if “Validation” ensures user needs are met, what is “Verification” and how does it apply to the software development process. “Verification” ensures that the software is built correctly based on the software requirements (i.e., design inputs), with regard to each task the software must perform (i.e., unit testing), during communication between software modules (i.e., integration testing) and within the overall system architecture (i.e., system level testing). This is accomplished by rigorous and thorough software testing using prospectively approved software verification protocols.

CE Marking requirements for software verification and validation (V&V)

European CE Marking applications include submission of a technical file that summarizes the technical documentation for the medical device. In order to be approved for CE Marking by a Notified Body, the device must meet the essential requirements defined in the applicable EU directive. The technical file must also include performance testing of the medical device in accordance with the “State of the Art.” For software, IEC/EN 62304:2006, medical device software – software life cycle processes, is considered “State of the Art” for development and maintenance of software for medical devices. This standard applies to stand-alone software and embedded software alike. The standard also identifies specific areas of concern, such as software of unknown pedigree (SOUP). As with most medical device standards, the standard provides a risk-based approach for evaluation of SOUP acceptability and defines testing requirements for SOUP.

FDA requirements for software verification and validation (V&V)

For 510k submissions to the US FDA, section 16 of the 510k submission describes the software verification and validation (V&V) activities that have been conducted to ensure the software is safe and effective. There are 11 documents that are typically included in this section of the submission for software with a moderate level of concern:

  1. Level of Concern
  2. Software Description
  3. Device Hazard Analysis
  4. Software Requirement Specification (SRS)
  5. Architecture Design Chart
  6. Software Design Specification (SDS)
  7. Traceability Analysis
  8. Software Development Environment Description
  9. Verification and Validation Documentation
  10. Revision Level History
  11. Unresolved Anomalies (Bugs or Defects)

The FDA does not require compliance with IEC 62304 as the European Regulations do, but IEC 62304 is a recognized standard and manufacturers must comply with all applicable parts of IEC 62304 if they claim to follow IEC 62304. The FDA also provides a guidance document for the general principles of software validation.

Additional Resources

If you are interested in learning more about the documentation requirements for a 510k submission of a software medical device, please click here to download a free recording of our 510k software documentation webinar.

Medical Device Academy also has a new live webinar scheduled for Tuesday, January 5, 2016 @ Noon (EST). The topic is “Planning Your 2016 Annual Audit Schedule”. We are also offering this live webinar as a bundle with our auditor toolkit.

About the Author

Nancy Knettell is the newest member of Medical Device Academy’s consulting team and this is her first blog contribution to our website. Nancy is an IEC 62304 subject matter expert. To learn more about Nancy, please click here. If you have suggestions for future blogs or webinars on the topic of medical device software, please submit your requests to our updated suggestion box.

Posted in: Software Verification and Validation

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How to handle FDA inspector with incompetencies and ego

Handle FDA inspector egos and incompetencies during an audit of your facility–including requests for exempt quality system records.

p31653 p v7 aa e1449491882329 298x300 How to handle FDA inspector with incompetencies and ego

This is not how to handle FDA inspector or auditor!

This topic was submitted to my suggestion box from a colleague in Australia. Originally I posted this as an announcement for my LinkedIn Group, but the post was limited to ISO certification body auditors and excluded FDA inspectors. The basic approach is the same, but there are some important nuances regarding how to handle FDA inspector incompetencies and ego that I am including in this article.

Handle FDA Inspector Distrust

In general anyone that works for the FDA is genuinely concerned about public health and welfare. They also have a very low tolerance for unethical behavior. This has not always been the case at the FDA and the agency has fought hard over the past twenty years to eliminate anyone from their ranks that is not ethical. Therefore, if an FDA inspector thinks that you have something to hide the best approach to handle FDA inspector concerns is to give them anything they ask for–and quickly.

Unlike ISO auditors, FDA inspectors are not allowed to review three types of records:

  1. Management Review Meeting Minutes
  2. Internal Audit Reports
  3. Supplier Audit Reports

The FDA can learn almost everything they want to know by reviewing CAPAs that resulted from Management Reviews, internal audits and supplier audits. However, some FDA inspectors will still ask to see records that are part of the quality system record exceptions (i.e., 21 CFR 820.180c). Some quality system managers design cover sheets for these three records to specifically show FDA inspectors only the information that they are entitled to. If I am faced with this situation, I handle FDA inspector requests for restricted quality system records in the following way.

“Here is a copy of the quality system record you requested. This is one of the records that is exempt from the requirements in 21 CFR 820.180. However, we have nothing to hide. Therefore, you can take as many notes as you like about the content of this record, but you may not take a copy of the record with you.”

The above approach is intended to convince an FDA inspector that you have nothing to hide, but it also requires that you review and edit your records prior to approval and archiving to make sure that statements made in the records are appropriate–regardless of the audience reading the record.

Handle FDA Inspector and auditor personality

100% of auditors are a little weird (yep, takes one to know one). You travel for a living and tell people what’s wrong with their quality system. If you don’t start out drinking scotch, you probably will eventually. However, a little patience, understanding and over communication helps. For example, provide directions (that are accurate). Recommend a hotel (middle of the road, not the Ritz or a flea bag). Tell them about the corporate discount. Ask them in advance if they have food allergies (I’m gluten-free, and not by choice), and then try to remember not to serve only the things they are allergic to (yes, Panera Bread is a crappy choice but a gluten-free pizza is heaven). If Uber makes sense recommend it, because nobody wants to negotiate with Payless Rent-A-Car at 11:59pm.

FDA inspectors are in the same situation as auditors with regard to being travel weary. However, FDA inspectors will probably not take your recommendation for a hotel. Instead they will follow FDA guidelines and stay at a hotel chain where they prefer to accumulate membership points and they can get a government employee discount. In addition, FDA inspectors will not eat at your facility. It seems as though a few companies entertained FDA inspectors at clubs and fancy restaurants in the past. In order to eliminate any possible perception of unethical behavior, FDA inspectors are now instructed to leave your facility for lunch and return to complete the day. They probably won’t even accept a cup of coffee unless you place a carafe on the table for everyone to drink. You can also count on the FDA inspectors driving a rental car if they do not live locally.

Handle FDA Inspector and Auditor Ego

Everyone has an ego. Auditors typically have a big one, and a few FDA inspectors do too. I’m not shy, I’m smart and I love a good debate. If I’m you’re auditor, you’re lucky because I’ll admit when I’m wrong or make a mistake. Most auditors will not admit mistakes. In fact, the stronger they argue a point the more likely that they are insecure on the topic or that they have a personal preference that is a result of a bad experience. Unfortunately, FDA inspectors seem to be even more likely to argue a point when they know very little experience.

Don’t ask FDA inspectors and auditors to prove something is in the regulations or the standard. Instead, try reading Habit 5 by Covey (7 Habits of Highly Effective People). You need to be an empathic listener. The FDA inspector or auditor doesn’t hate you. They might even be trying to help you. They also might be wrong, but try restating what the person is saying in your own words and try explaining why it’s important. This shows them that you were listening, you understand what they said and you understand how they feel about the issue. Pause. Then tell them how you were trying to address this issue.

One of the areas where the above approach is especially important is when and FDA inspector is reviewing complaint records and medical device reports (MDRs). You want to convince the FDA inspector that you are doing everything you can do to investigate the complaint or adverse event and you want to prevent recurrence. Remember that someone was hurt by your device or misuse of your device, and FDA inspectors take public safety very seriously. You will not be able to handle an FDA inspector that believes you are doing less than you could be.

Handle FDA Inspector and Auditor Incompetencies

FDA inspectors rarely have industry experience, but they know the regulations. Therefore, arguing the regulations with an FDA inspector is a huge mistake. The only frame of reference for “industry best practice” is what the FDA inspector has seen at other device manufacturers they audit. Therefore, it is very import to know how experienced your FDA inspector is. If they don’t have a lot of experience they will be defensive and you might need to “educate” them.

During ISO audits you have less time to retrain your auditor. Don’t even try. I do this for a living and we’re a stubborn bunch of orifices. Instead, try the empathic listening first. 99% of the time one or both of you is not communicating clearly. Either they can’t find what they are looking for, or they misunderstood what you were telling them. It could be a difference of interpretation, but it’s probably not. If it is, then say “We were interpreting that requirement as…”. Say this once. If they argue, let it drop for now.

Resolution of 483 Observations and Audit Findings

You shouldn’t just take incorrect findings lying down. Do your homework. Send me an email. Get help. If you’re right, then contest it at the closing meeting in a factual and persuasive way. If the auditor holds their ground, ask what the policy is for resolving disputes. This is supposed to be covered as part of the closing meeting of every audit. If your auditor is just lazy, sloppy and incompetent–request a new auditor. You might even disagree in writing, address the finding anyway and then request the new auditor. That shows the management of the certification body that you’re not lazy, sloppy or incompetent.

FDA inspection 483 observations are a little different. If you and the inspector disagree you should state this in the closing meeting when they give you the 483 observation, and you should be clear that you disagree prior to end of the inspection when they start preparing FDA Form 483. Once a 483 observation is issued, however, your only recourse is to persuade the district office that the 483 observation is undeserved. The FDA district office will have copies of all your procedures and records and a copy of the FDA inspector’s notes. Be careful with complaints to the district office though. FDA inspectors are far more likely to retaliate than ISO auditors.


If you make a habit of disputing everything, your auditor or FDA inspector will come prepared for war. You also will have little credibility with the managers at the certification body or the FDA district office. Dispute only things that are justified and provide a written, factual justification that is devoid of all emotion.

Responding to FDA 483 Observations

If you do receive FDA 483 observations, it is important that you respond with well-conceived corrective action plans. If you need help with responding to an FDA 483 inspection observation, you might be interested in my webinar on this topic.

Posted in: FDA

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How to write a quality system plan template (free download)

This article explains how to write a quality system plan template to revise and update your quality system for compliance with ISO 13485:2016 when it is released early next year. The end of the article includes a form to complete if you want to download a free quality system plan template.

Screenshot 2015 11 19 at 5.52.44 PM How to write a quality system plan template (free download)

Templates are the key to writing a quality system plan

Plan, do, check and act (PDCA) is the mantra of the Deming disciples, but does anyone know what should be in your quality system plan template. Everyone focuses on the steps–the “What’s.” Unfortunately, people forget to include the other important pieces of an all inclusive quality system plan template. Why? When? Who? and How much?

The table in the template is an example of “What?” steps to perform, but it is specific to my procedures. You will need to revise the table to reference your own procedures and the changes you make will be specific to your quality system plan. The other sections of the template tell you what needs to be included in that section, but I did not provide examples for those sections.

Why to write a quality system plan template

The purpose section of the quality system plan template answers the question of “Why?” You need to specify if the purpose of your quality system plan is compliance with new and revised regulatory requirements, preventing recurrence of quality issues or maybe a faster development cycle. The purpose section of the plan also provides guidance with regard to the monitoring and measurement section of your quality system plan template.

When to write a quality system plan template

Most changes have deadlines. In the case of ISO 13485:2016, there will be a 3-year transition period, but most companies establish internal goals for early implementation by the end of the fiscal year or the end of a financial quarter. Some of the changes can be made in parallel, while other changes need to be sequential. Therefore, there may be specific milestones within the quality system plan template that must be complete by specific dates. These dates define “When?” the steps in the quality system plan must be implemented.

Who should write your quality system plan template

As my quality system plan template indicates, I recommend defining both individual process owners and teams of process owners where processes can be grouped together. For example, I typically group the following four processes together as part of “Good Documentation Practices (GDPs)”: 1) control of documents (SYS-001), 2) control of records (SYS-002), 3) training (SYS-004), and 4) change control (SYS-006). In fact, I cover all four processes in a webinar called “GDP 101.”

It is important to have one person that is accountable and has the authority to implement changes for each process, but only one person should be in control of each process. If you have four related procedures, then the team of four people will need to coordinate their efforts so that changes are implemented swiftly and accurately. For the overall quality system plan template, I recommend assigning a team leader for the team of four process owners described above. One of those people should be responsible for team leadership and writing the quality system plan template.

Monitoring implementation of your quality system plan template

Monitoring the progress of your plan ensures successful implementation of the plan. Sometimes things don’t work as planned and corrections need to be made. Additional resources might be needed. The plan may have been too optimistic with regard to the implementation time required. I recommend assigning one person the task of retrieving team status reports from each of the teams and consolidating the team reports into an overall progress report.

Free download of ISO 13485:2016 quality system plan template

The sign-up form below will allow you to receive an email with the ISO 13485:2016 quality system plan template attached. This is a two-step process that will require you to confirm the sign-up.

Posted in: ISO Certification

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How to implement a new ISO 13485 quality system plan in 2016

This article is a case study that explains how to implement a new ISO 13485 quality system plan at an accelerated schedule of just four months. The quality system will also be compliant with 21 CFR 820.


QMS Implementation Plan How to implement a new ISO 13485 quality system plan in 2016

Typically, I recommend implementing a new ISO 13485 quality system plan over a period of 6 months. The reason for this is that people can only read procedures and complete training at a certain pace. Since there are approximately 30 procedures required for a full quality system, an implementation pace of one procedure per week allows a company to complete 90% of the reading and training in six months.

In October a new client asked me for a proposal to implement a new ISO 13485 quality system plan. The proposed quality system plan indicated that the project would start in October and finish in March. The client accepted my proposal, but they asked me help them implement the quality system plan in four months as indicated in the table above. We just started implementation of the quality system plan last week, and I have discovered some secrets that dramatically simplify the process.  This blog shares some of the lessons learned that help implement the quality system plan at this faster pace.

Outsourcing ISO 13485 quality system development

Not everyone has the skill and experience to write a quality system procedure, but if you have a good template, you understand quality systems–then you can write quality system procedures. Depending upon the length of the procedure, it may take four to eight hours of writing for each procedure. Therefore, an in-house quality manager needs to allocate one day per week if they plan to write all the procedures for their quality system in six months. For a four-month implementation of an ISO 13485 quality system plan, you need to allocate two days per week to writing.

Alternatively, you can outsource the writing of your quality system. However, someone must be responsible for “customizing” generic procedures to fit your company or the procedures need to be written from scratch. A third and final option is to have a hybrid of in-house procedures and outsourced procedures. If your quality manager has limited time resources, then you can supplement the managers time with procedures that are purchased and customized to fit your template. If there are certain procedures that the quality manager needs help with, such as risk management, then you can also purchase just those procedures.

ISO 13485 quality system plan

One of the basic principles of quality management systems is “continuous improvement.” The continuous improvement cycle is also known as the “Deming Cycle.” There are four parts to the cycle:

  1. Plan
  2. Do
  3. Check
  4. Act

When you are developing an ISO 13485 quality system, the first step is to develop the quality system plan. I recommend the following guidelines for a quality system plan. First, plan to implement the quality system at a steady pace. Second, organize the implementation into small groups of related procedures.

In this case study, I have 29 procedures that we are implementing and there are 11 recorded training webinars. During each of the four months approximately the same number of procedures are implemented. Then I organized the small groups of procedures around the scheduled webinar trainings. For example, the month of November will have a total of 24 documents (i.e., 8 procedures and 16 associated forms and lists) implemented and there are four webinar trainings scheduled. Therefore, four procedures associated with “Good Documentation Practices 101 will be implemented as a group under document change notice (DCN) 15-001. Two procedures associated with “Are your Suppliers Qualified? Prove it! will be implemented as a group under DCN 15-002. The remaining two procedures, design controls and risk management, will be implemented as a group under DCN 15-003 with two related webinars on design controls and ISO 14971.

Document Change Notice (DCN)

The next step in the Deming Cycle is to “Do.” For implementation of an ISO 13485 quality system plan, “doing” involves creation of procedures, forms and lists; but “doing” also involves the review and approval of these documents. The form we use to review and approve procedures is called a document change notice or DCN.

It’s been almost 20 years since I completed my first DCN. For anyone that is unfamiliar with the review and approval of new and revised documents, most quality systems document the review and approval of procedures and forms on a separate form. The reason for this is that when you make one change it often affects several other documents and forms. Therefore, it is more efficient to list all the documents and forms that are affected by the change on one form. This results in fewer signatures for reviewers and approvers. Several of the companies that I have helped to implement an ISO 13485 quality system plan for fail to review and approve the documents and forms in a timely manner. I think there are two reasons for this:

  1. they haven’t been responsible for document control before, and
  2. they don’t want to have to create and maintain quality system records any sooner than required.

The first reason can be addressed easily with training. The second reason, however, is flawed. It is important to implement the procedures as soon as possible in order to begin creating quality system records that can be audited by an ISO 13485 certification auditor or FDA inspectors. I have struggled with this hesitation in the past, but for this project I am completing DCNs for the initial release of all the procedures and forms. This ensures that all the procedures and forms will be reviewed and approved shortly after the webinar training is completed. In addition, this gives my client multiple examples of DCNs to follow as the make revisions to the procedures and forms over time.

Quality Objectives & Data analysis

The third step in the Deming Cycle is to “check.” I recommend using quantitative metrics to track progress toward your goal of completing the quality system implementation. For example, if you have 50 documents to review and approve you can track the % complete by just multiplying each document that is approved by 2%. You can also track the implementation of documents separately by type. Every DCN you route for approval will take a certain number of days to complete. You might consider tracking the duration of DCN approval. As a benchmark, an efficient

paper-based DCN process should average about 4 days from initiation to completion. I have seen average durations measured in months, but hopefully your average duration of DCN approval will be measured in days. Another metric to consider is the % of required training that has been completed for the company, for each department and for each employee. Regardless of which metrics you choose to evaluate your quality system implementation, you should pick some of these metrics as quality objectives (i.e., a requirement of ISO 13485, Clause 5.4.1). You should also analyze this data for positive and negative trends as required by ISO 13485, Clause 8.4.

Your first CAPAs

The fourth and final step in the Deming Cycle is to “act.” Acting involves taking corrective action(s) when your data analysis identifies processes that are not functioning as well as they should be. In order to achieve ISO 13485 certification, you will need some examples of corrective and preventive actions (CAPAs) that you have implemented. The actions you take in response to observed trends during data analysis are all potential CAPAs.

Download an ISO 13485 quality system plan

Later this week I will be posting a follow-up blog that explains how to write an ISO 13485 quality system plan for establishing a new quality system. There will also be a link for downloading a free ISO 13485 quality system plan. To receive an email notification of when this blog is posted, please subscribe to my blog. I will be writing additional blogs about lessons learned from this accelerated implementation project.

Posted in: ISO Certification

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Case Study Part 2: Packaging CAPA Preventive Action and Corrective Action

This article explains details of implementing a CAPA preventive action and corrective action for packaging issues. Specifically, containment measures, corrections, corrective actions and preventive actions to address the root cause identified in part 1 of this case study.

Screenshot 2015 11 08 at 12.34.46 PM 1024x504 Case Study Part 2: Packaging CAPA Preventive Action and Corrective Action

Comparing Incoming Inspection Results as a CAPA Preventive Action

CAPA Step 1: Containment of Product with Defective Packaging

When you learn of a packaging complaint related to a specific lot, you also need to determine if other product associated with the lot is safe to ship to customers. You should not attempt a correction and removal of product unless you have a reasonably high level of confidence that there is a packaging issue with the lot or a portion of a lot, but you might consider placing product from the same lot in your inventory on hold until your investigation is completed. If you confirm that you have an issue with a specific lot, lots or portion of a lot; then you should initiate correction and removal of product to prevent potentially, non-sterile product from being used. This type of problem could result in a Class 1 recall (i.e., the most severe of the three categories). Therefore, you need to act quickly and according to established procedures for corrections and removals.

CAPA Step 2: Correction(s) of Defective Packaging

If you find a problem there is little you can do to fix the existing, defective packaging other than to repackage the product. If the product has only been sterilized once, and you have revalidated the product for resterilization, then you can repackage, relabel and resterilize. In order to ensure traceability to the lot that has been reworked, you may need to revise the labeling (e.g., add an “R” to the lot number). If you have not revalidated the resterilization of product, you may want to use this lot for validation of resterilization instead of throwing it out. However, sometimes your best option is to scrap the product.

Additional corrections may involve correcting the calibration of a testing device or performing repair to sealing equipment. You might modifying a specification on a drawing. You might correct a work instruction that did not have the correct validated sealing parameters. All of these could be corrections.

CAPA Step 4: Corrective Action(s) for Packaging Issues

Investigation of root cause (CAPA Step 3) occurs in parallel with containment (CAPA Step 1) and correction (CAPA Step 2). Corrective actions (CAPA Step 4) prevent the packaging issues from recurring, and they occur after the first three steps, because you can only implement corrective actions once you understand the root cause of the quality issue. The best tool for evaluating your current process controls and evaluating the implementation of new corrective actions is a process risk control plan. In order to do this you need a process flow diagram and a process risk analysis. Each step of the process from raw material fabrication of film to the released product needs to have potential hazards identified, risks evaluated and risk controls implemented. You should use your process validation to verify the effectiveness of process risk controls quantitatively. If the process capability is greater than 95% for each parameter and you have addressed every possible source of problems, then you probably won’t gain much from additional risk controls. However, many companies reduce their sampling or rely on certificates of conformity to ensure that the process is controlled adequately.

CAPA Step 5: CAPA Preventive Action for Packaging Issues

You already had a packaging issue with one lot of product, but you could have another issue with a different product or lot for the same reason or a different reason. If the product is the same, and the reason is the same, then actions taken are corrective actions. If you take action to prevent occurrence of this issue with a different product, or you prevent other potential causes of packaging issues by initiating more robust monitoring and process controls, then your actions are preventive actions. Often you will want to implement both types of actions.

In the box plot example provided in this article, Lot D was detected at incoming inspection as having peel test results that were outside the alert limit but acceptable when compared to the specification limit for peel testing. The alert limit was established during validation of the pouches and comparison of lots A, B, C and D demonstrate that Lot D is slightly lower in peel strength. The manufacturer may choose to use the lot, but the sampling plan for in-process peel testing may be altered or the manufacturer may choose to place the new lot in quarantine while an investigation is performed. This is a CAPA preventive action.

Below I have listed six additional potential CAPA preventive actions to consider for your packaging process:

  1. Perform peel testing and/or bubble leak testing of packaging raw materials as part of the receiving inspection process and perform data analysis of the incoming inspection samples to determine if lower or higher alert and action limits should be established for the new lot of raw materials. The limits should be based upon the manufacturer’s seals as well as your own seal.
  2. Retain remnants of in-process peel testing, include the remnants with the sterilization load, and then store the remnants for real-time aging.
  3. Consider implementing visual inspection tools that are able to detect sealing imperfections non-destructively.
  4. Increase the number of samples you test (e.g., 1 to 3 or 3 to 5) for each lot of product sealed to increase your confidence that the seals will be within specifications.
  5. Perform statistical analysis of in-process data for seal peel strength in order to identify potential lots with packaging issues prior to release.
  6. Evaluate the performance of the packaging at temperature and humidity extremes that may be higher or lower than the conservative estimates for ambient conditions (e.g., 30C vs. 25C).

Additional Resources

In addition to the previous article that was part 1 of this case study, I have posted 10 other blogs specifically on the topic of CAPA. There is also a CAPA procedure you can download from this website.

Risk-based CAPA Webinar

If you are interested in learning more about a risk-based approach to CAPAs, then please click here.

Posted in: CAPA

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