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Biocompatibility for 510k Submissions vs CE Marking

asr 1 Biocompatibility for 510k Submissions vs CE Marking
Titanium is not biocompatible?!

This article compares the different documentation requirements of biocompatibility for 510k submissions with a technical file submission for CE Marking.

A couple of my clients recently received requests for additional information as part of their technical file submission for CE Marking. Both clients had titanium implants, and they submitted exactly the same justification of biocompatibility for 510k submissions as they were now submitting for their technical file. They were providing a one paragraph description of materials used and referencing the ASTM specification for implant-grade titanium. Both clients already had CE Marking for similar devices, and the wording of the justification for not conducting biocompatibility testing on the full device was identical to the previous submissions.

“Justifications are no longer permitted”

One of my clients questioned whether there was a new EN standard for implant-grade titanium that they might need to comply with. The other client was told by their auditor that the Notified Body would no longer accept justifications for not conducting biocompatibility testing.

On behalf of my clients I scheduled a meeting with their Notified Body to obtain clarification and to make sure that the policies for documentation of biocompatibility had not changed. The Notified Body had three important points to make:

  1. Justifications are PERMITTED as it states in EN ISO 10993-1:2009
  2. Competent Authorities noticed that some of the justifications accepted in the past were not sufficient
  3. What the FDA accepts for biocompatibility for 510k submissions is not sufficient for a technical file

FDA requirements of biocompatibility for 510k submissions

In 1995, the FDA published a biocompatibility guidance document. That guidance document includes a decision tree that asks a series of questions related to biocompatibility for 510k submissions that is intended to help manufacturers determine which biocompatiblity testing may be required for 510k submission of their new or modified device. The following questions are the critical items covered in that decision tree: 

  • Is the material the same as a marketed device?
  • Same manufacturing process?
  • Same chemical composition?
  • Same body contact?
  • Same sterilization method?
  • Is the material metal, metal alloy or ceramic?
  • Does it contain any toxic substances (e.g., Pb, Ni, Cd, Zr)?
  • Master file has acceptable toxicology data?

In the past, I recommended that clients with titanium implants prepare section 15 of their 510k submissions by answering each of the questions above. 99% of the time, the predicate device is substantially equivalent to the 510k submission device with regard to the first five questions. Except in the case of coated implants, their was seldom a Device Master File to reference and the metal was compliant with the ASTM standard for titanium implants–including the concentrations of heavy metals.

For other medical devices that were not made of just titanium or some other implant-grade metal, the manufacturer was forced into to conducting biocompatiblity testing. In these cases, I directed the clients to follow the biocompatibility testing matrix published by the FDA.

New Draft Biocompatibility Guidance from the FDA

In 2013, the FDA published a FDA 2013 draft guidance document for biocompatibility with additional requirements for biocompatibility documentation and testing. The newer draft guidance appears to be the current expectation of the agency for 510k submissions, but the draft guidance has not been finalized yet.

The new 2013 draft guidance document from the FDA indicates that biocompatiblity testing reports must be provided with 510k submissions instead of merely summarizing the testing performed. The FDA clarifies in the draft that materials will not be evaluated alone, and the full device must be evaluated for biocompatibility instead. The FDA also specifies that the device evaluation must be for a sterilized device if the device is intended to be delivered in a sterile state to users/patients. This draft incorporates new ideas regarding toxic chemicals, such as colorants. The FDA also suggests that manufacturers discuss their testing plans with the FDA before starting the biocompatibility testing.

Despite the changes proposed in the 2013 draft guidance, there are no changes to the requirements of biocompatibility for 510k submissions if the device is a metallic implant that is substantially equivalent to a predicate device.

Technical File Differences for Bioiocompatibility

In theory, there should be very few differences between biocompatibility for 510k submissions and technical file requirements for CE Marking, because the FDA recognizes ISO 10993-1:2009, and the content of the standard is nearly identical to the European national version of the standard. For European CE Marking, the expectation is for the technical file to include documentation of conformity with the current state of the art for biocompatibility (i.e., EN ISO 10993-1:2009). Summary Technical Documentation (STED) is preferred by Notified Bodies in order to reduce time and costs associated with the review of the technical documentation.

A STED that explains how your biocompatibility evaluation conforms to a harmonized European Standard is quite different from a justification based upon substantial equivalence. Notified Bodies expect you to review each of elements of the harmonized standard and explain how you address it in the STED. In Clause 7 of EN ISO 10993-1:2009, there are seven elements recommended for a biological safety assessment:

  1. the strategy and program content for the biological evaluation of the medical device;
  2. the criteria for determining the acceptability of the material for the intended purpose, in line with the risk management plan;
  3. the adequacy of the material characterization;
  4. the rationale for selection and/or waiving of tests;
  5. the interpretation of existing data and results of testing;
  6. the need for any additional data to complete the biological evaluation; and
  7. overall biological safety conclusions for the medical device.

The fourth element of the biological safety assessment will certainly include a reference to the implant-grade titanium that you are using. However, you also must address additional questions that are posed in Figure 1 of the standard. Questions that should be addressed in your biological safety assessment include:

  1. Are there any additives, contaminants and residues remaining on the device?
  2. Are there any substances leachable from the device? 
  3. Are there any degradation components of the device?
  4. Are there other components and how might they interact with final product?
  5. What are the properties and characteristics of the final product?

 If you conducted a cleaning validation, you need to reference that process validation report. If you conducted testing of EO residuals, you need to reference the ISO 10993-7 test report.

The message the Notified Bodies are sending you is that they agree that implant-grade titanium is biocompatible, but you need to systematically write a justification for not conducting the testing in accordance with the EN standard and you have to cross-reference to your objective evidence throughout the STED. 

Posted in: 510(k), CE Marking

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Risk Management File Compliance for 510k and CE Marking

This article compares risk management file FDA requirements for CE Marking and 510k submission requirements.

Risk Management File Risk Management File Compliance for 510k and CE Marking

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 then, the 510k submission only requires submission of a design risk analysis. Knee implants do not require submission of a risk analysis, even though manufacturers are required to perform risk analysis in accordance with ISO 14971, because knee implants do not contain software. Therefore, it is not uncommon for a product that is already 510k cleared to receive audit nonconformities related to the risk management documentation during a technical file review by a Notified Body.

The FDA recognizes ISO 14971:2007 as the standard for risk management of medical devices. CE Marking also requires compliance with ISO 14971, but specifically the European national version of the standard (i.e., EN ISO 14971:2012). The most common technical file deficiencies related to risk management during a CE Marking application include the following:

  1. compliance 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

Each of these deficiencies is also explained in Annex ZA, ZB and ZC of EN ISO 14971:2012.

7 Deviations

Notified Body auditors are supposed to be reviewing your risk management process and sampling your risk management files to verify that you conform with the requirements for risk management as defined in EN ISO 14971:2012 and in the applicable European directive. Most manufacturers with CE Certificates have updated their procedures for compliance with the European National version, but the updates are not always complete or done correctly. Therefore, auditors need to be systematic in their review for compliance. I recommend creating a three column table in your audit notes for each of the 7 deviations. The first column would state the requirement from the applicable annex of EN ISO 14971:2012. The second column is used to document where in the risk management procedure each of the seven requirements is addressed. If you can’t find it quickly during your review–as the person you are auditing to find it for you. The third column is used to document which risk management file you sampled and where in the risk management file the auditor was able to find compliance with one of the deviations. If the auditor can’t find an example of compliance in the procedure or the risk management file, then there is a minor nonconformity that needs to be corrected and recurrence needs to be prevented.

Note: Remember that auditing is about verifying compliance–not scouring 100% of the records for nonconformity.

Procedure Review

The first step in responding to correcting deficiencies in your risk management process is to update your procedure. The following basic elements need to be included in the procedure:

  • risk management plan
  • hazard identification
  • risk analysis
  • risk control option analysis
  • verification of risk control effectiveness
  • risk / benefit analysis
  • risk management report

Many of the procedures I review focus on the risk analysis process, and the most common tool for risk analysis is a failure modes and effects analysis. This is an excellent tool for process risk analysis, but it is only one of many possible tools and it is not ideally suited for design risk analysis. In addition, your procedure is not adequate as a risk management plan. You need risk management plans that are product-specific or specific to a product family. Your risk management plan must also change and adapt as products progress from the design and development process to post-market surveillance. Finally, many of the procedures only require a risk / benefit analysis to be performed when risks are not acceptable, while the European MDD requires that all CE Marked products include a risk / benefit analysis for each risk identified in the risk analysis and the overall risk of the product or product family.

Risk Management Plans

Risk management is required throughout product realization, but the activities are quite different during the pre-market and post-market phases. Therefore, I recommend including a risk management plan as part of the design and development plan to address pre-market needs for risk management. Once a product development project reaches the design transfer phase, then a post-market risk management plan needs to be written. I incorporate this plan into the post-market surveillance plan for the product or product family. This approach ensures that the the risk analysis will be linked directly with post-market surveillance after the product is released.

Hazard Identification

Many companies do create a specific document that identifies all the hazards associated with a product. This is an important step that should occur early in the design and development process before design inputs are finalized. During the development process these hazards may need to be updated as materials and production processes are developed. Some companies may choose to identify hazards at a different time or in a different way, but the proposed European Medical Device Regulations (EMDR) requires that the hazards are identified as one of the essential requirements. The ISO 14971:2007 standard suggests that design teams should identify as many hazards as possible, estimate the risks and then implement risk controls for any risks that are unacceptable. The EN ISO 14971:2012 standard requires that risk controls be implemented for hazards–regardless of acceptability. For this reason, I recommend companies restrict their identification of hazards to the most likely product malfunctions and hazards of high severity. This list should include any hazards already identified in the FDA’s MAUDE database.

Risk / Benefit Analysis & Risk Traceability Matrix

In order to perform a risk / benefit analysis you have to know the likelihood of potential hazards resulting in harm and the clinical benefits of a product. Unfortunately, reduced cost cannot be used to justify the acceptability of a device. Risk / benefit analysis must be performed for each risk and the overall residual risks. Therefore, it is important to identify clinical benefits that outweigh each of the risks. I recommend using a risk traceability matrix in order to document each risk / benefit analysis. This can be a separate risk management document or it can be incorporated into a design requirements matrix. It is also important to identify any warnings, precautions or contraindications that should be documented in information provided to patients and users when risks cannot be completely eliminated. This may be the last column of your risk traceability matrix.

Risk Management Report

The risk management report should be a summary technical document (i.e., STED). The STED should reference the procedure that was used and indicate all the risk management activities that were performed specific to the product or product family defined in the scope of the risk management report. The dates of activities, changes made and cross-references to any controlled documents should be included in the risk management report. I recommend maintaining the risk management report as a controlled document and revising the document to reference additional risk management activities when they occur. The bulk of details should be contained in the referenced risk management documents within the report.

Procedures & Templates

If you are looking for a procedure (SOP) for risk management please click here.

Posted in: Risk Management

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What is a Master Validation Plan and Do You Need One?

This article explains what a master validation plan is and explains when it is appropriate to have a master validation plan and when a master validation plan is unneeded.

Process Validation Protocol What is a Master Validation Plan and Do You Need One?In the United States, there are two applicable regulations for medical device manufacturing process validation:

  1. 21 CFR 820.75
  2. ISO 13485, Clause 7.5.2

Neither the QSR regulation, nor the ISO Standard, include any mention of a master validation plan. There is a requirement for product realization planning, and a master validation plan could be an important part of that planning. However, master validation plans are not mentioned anywhere.

MDD – Master Validation Plan?

For companies that manufacture CE Marked products, the term validation appears in the MDD (93/42/EEC as modified by 2007/47/EC) a total of two times. Only one of those references are specific to process validation, but there is no mention of a master validation plan. The single mention of validation appears in Annex VII, and the reference is specific to the requirement for including a copy of the sterilization validation report in a product technical file.

CMDR – Master Validation Plan?

For companies that hold one or more Canadian Medical Device Licenses, “validation” appears in the Canadian Medical Devices Regulations (CMDR) a total of eight times (four times as part of the French translation). The first four references are part of the definition of validation where the CMDR is referring to design validation. The remaining four references specifically mention the requirement for inclusion of process validation and software validation in a medical device license application for Class IV devices. None of those references mention of a master validation plan.

 

IQ/OQ/PQ Requirements?

Not only is there no mention of a requirement for master validation plans in any of the medical device regulations, there is no mention of installation qualification (IQ), operational qualification (OQ) or performance qualification (PQ). The only mention of validation protocol or report appears in 21 CFR 820.70 as it refers to using validation protocols for validation of software controlling automated equipment.

21 CFR 210 or 21 CFR 211 requirements?

The requirements for medical devices historically are derived from the pharmaceutical regulations–which included the requirement for process validation. However, neither 21 CFR 210 nor 21 CFR 211 mention master validation plans (need to verify). They also don’t mention IQ/OQ/PQ requirements.

Where did the Idea for Master Validation Plans Come From?

GHTF/SG3/N99-10:2004 is the guidance document that was created by the Global Harmonization Task Force’s Study Group 3 for the guidance on process validation. The guidance even includes templates for a master validation plan, IQ, OQ and PQ. The guidance indicates that the purpose of a master validation plan is to plan validation and revalidation activities. There are other planning documents that could be used instead. For example, design plans include the process validation as part of the design transfer activities when a new product is being developed. Quality plans are used to facility expansions and construction of new facilities. Some companies even include validation and revalidation plans in their process validation procedure and/or the sterilization validation procedure.

For companies that have equipment that requires validation, I like to use an equipment register that identifies calibration, preventive maintenance, validation and revalidation requirements as part of the equipment register. This allows me to use one single document to manage all the planning of calibration, preventive maintenance and validation. If there are no validation requirements, then the appropriate column of the equipment register will indicate “n/a.”

What is a Master Validation Plan?

A master validation plan (MVP) is simply a plan for your equipment and process validation activities. All the equipment, processes and software requiring validation should be included in the MVP. The plan should reference the applicable protocol and report for each item in the plan. If there are re-validation requirements, the plan should indicate when the last validation was performed and what the frequency of re-validation should be. Ideally, similar equipment will use the same validation protocols that are controlled documents and pre-approved. Over time the number of reports referenced will increase, but the plan should only reference the most recent approved protocol(s).

Some companies include the rationale or triggers for a revalidation in the plan–just as you would for a record retention table. However, other companies will include this detail in the validation protocol and/or in the process validation procedure. The rationale for revalidation only needs to be in one of three places, and duplication of the information just encourages errors and audit nonconformities.

Procedures & Templates

If you are looking for a procedure (SOP) for process validation please click here.

Posted in: Process Validation

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Strategic planning of a mock FDA inspection

This article shows you how to think strategically when you plan a mock FDA inspection to ensure that you successfully prevent an unpleasant FDA inspection.

strategic planning Strategic planning of a mock FDA inspection

For the past couple of years several, clients have asked me to conduct mock FDA inspections in order to prepare them for a potential FDA inspection. In fact, I am writing from Shanghai, China where I am conducting a mock FDA inspection for a medical device client with another auditor from the company’s business unit in the USA.

The mock FDA inspections I conduct are actually internal audits and technically not an inspection, because inspectors are looking for nonconformities and I am looking for conformity with the FDA regulations (i.e., 21 CFR 820, 21 CFR 803 and 21 CFR 806). Inspections are conducted by FDA investigators that are conducting an inspection in accordance with the FDA QSIT manual (http://www.fda.gov/ICECI/Inspections/InspectionGuides/ucm074883.htm). I use the process approach to conduct audits of the 4 major quality systems that FDA inspectors focus on during an FDA inspection, but as an auditor I have several advantages that an inspector doesn’t.

  1. I can evaluate auditees and coach them on how to respond to an FDA inspector more effectively.
  2. I can teach my client’s internal auditors and management team how to use internal audits and Notified Body audits as practice for their next FDA inspection.
  3. I can avoid any area that my client wants me to and focus on areas of concern.
  4. I can help my client identify the most likely product or product family to be targeted by the FDA.
  5. I can give my client advice and help them implement corrective actions.
  6. I can teach my client how to respond to potential FDA Form 483s in order to avoid a Warning Letter.

Opening meeting for a mock FDA inspection

FDA inspections are not planned, but it is important to make sure that the right people are available and present during a mock FDA inspection or your “inspector(s)” may not be able to review the records or interview the most important people. Therefore, I provide an agenda ahead of time indicating which processes I will be auditing on which days. My agenda of a mock FDA inspection begins with an opening meeting, but the purpose of this opening meeting is primarily training. I take advantage of having all the senior managers in one room as an opportunity to explain how they can benefit most from the audit, and to remind them of what to expect during a real FDA inspection.

CAPA Sources

After the opening meeting, I take a brief tour—unless I already know the facility well. Before I leave for the tour, I ask my client to be prepared for me to begin auditing nonconformities, complaint handling, MDRs and recalls when I return to the conference room. I select these areas, because the FDA always starts with the CAPA process, but they look closely at the sources of CAPAs at the same time. I believe that inspectors rarely take “random samples.” Instead, most inspectors use the sources of CAPAs to help them bias there sampling of CAPAs.

Production and Process Controls

The next major process in my agenda after CAPAs and sources of CAPAs is production and process controls. The sequence of my process for auditing this area is always the same: 1) request the Device Master Record (DMR) for the target product or product family, 2) request two or more recent Device Master Records (DHRs) that were associated with a complaint record or MDR (remember samples are never random), and 3) I then go to the production areas identified in the DHR and I try to interview the people that actually produced the lot identified in the DHR—rather than the people the department manager feels are the most experienced. This process of working backward from complaint records and MDRs to the activities on the production floor often allows me to help companies identify a root cause that they missed when the complaint or MDR was originally investigated.

Design Controls

Auditing a Design History File (DHF) is about as exciting as watching paint dry for most auditors, but I am always fascinated with how things work so I am more engaging with the design team members I interview during a mock FDA inspection. I also like to focus on aspects of the design that have proven to be less than perfect—by reviewing nonconformities, complaints, MDRs, recalls and CAPAs first. For example, if I see several complaints related to primary packaging failures, I am going to spend more time reviewing the shipping validation and shelf-life testing than I might normally allocate.

Management Processes

The FDA is somewhat limited in this area, because in accordance with 21 CFR 820.180(e) the records of internal audits, supplier evaluations and management reviews are exempt from FDA inspections. During a mock FDA inspection, I do not have this constraint. Therefore, I will often look more closely at these three areas than an FDA inspector to make sure my client has effective management processes. While procedures and schedules are the focus of and FDA inspector, I will make sure that the problems I observed in nonconformities, complaints, MDRs and recalls are being addressed by management. As a quality manager this is not always easy to do, but as an independent consultant I have the luxury of being blunt when a senior manager needs to hear from someone other than the typical “yes men.” I also am able to use this part of mock FDA inspections to benchmark best practices I have learned from the hundreds of companies against what my client is currently doing to manage their quality system.

When to schedule a mock FDA inspection

Scheduling a mock FDA inspection immediately after an FDA inspection is pointless, but there is an optimal time for scheduling your mock FDA inspection. The FDA target is to conduct inspections once every two years for Class II device manufacturers. However, some district offices do better or worse than this target. Therefore, it’s important to keep track of the typical frequency in your district and the date of your last inspection. If the FDA is on a two-year cycle, you want to conduct your mock FDA inspection approximately 6-9 months prior to the next FDA inspection in order to ensure that you have time to implement corrective actions before the FDA inspector arrives.

Additional Resources

If you are interested in learning more about this topic, I highly recommend watching and listening to my free webinar on how to prepare for an FDA inspection:

http://robertpackard.wpengine.com/how-to-prepare-for-an-fda-medical-device-inspection/

In addition to preparing for an actual inspection, it is critical that every company knows how to respond effectively to an FDA 483 inspection observation:

http://robertpackard.wpengine.com/7-steps-respond-fda-483-inspection-observation/

In addition to my blog, I also have recorded a webinar on this topic:

http://robertpackard.wpengine.com/7-steps-respond-fda-483-inspection-observation-webinar/

Finally, every manager needs to be reminded that FDA 483s are just another opportunity to write a CAPA and improve their quality system. Therefore, do yourself a favor and watch my new webinar on creating a risk-based CAPA process:

http://robertpackard.wpengine.com/create-a-risk-based-capa-process/.

Posted in: FDA

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21 CFR 820.180 – Exceptions to the US FDA’s Record Requirements

21 CFR 820.180 Exceptions to the US FDA’s Record Requirements 21 CFR 820.180   Exceptions to the US FDA’s Record RequirementsThis article provides practical advice for how to deal with records the FDA is not allowed to request during an inspection and FDA inspector tactics specific to 21 CFR 820.180 – exceptions. When I meet with a new consulting client, the phrase I dread hearing is “the FDA can’t see that.” It is true that the FDA is not supposed to review the content of internal audit reports, supplier audit reports and management reviews in order to encourage companies to use these tools to address quality problems without having to worry about the FDA beating them with their own reports. This policy is officially stated in subsection C of 21 CFR 820.180–exceptions:

21 CFR 820.180 – Exceptions

“[21 CFR 820.180 – exceptions] does not apply to the reports required by 820.20(c) Management review, 820.22 Quality audits, and supplier audit reports used to meet the requirements of 820.50(a) Evaluation of suppliers, contractors, and consultants, but does apply to procedures established under these provisions. Upon request of a designated employee of FDA, an employee in management with executive responsibility shall certify in writing that the management reviews and quality audits required under this part, and supplier audits where applicable, have been performed and documented, the dates on which they were performed, and that any required corrective action has been undertaken.”

The Problem with Hiding Records

The problem with the mentality of hiding things from the FDA is that it fails every time. The FDA can get to issues in your management reviews and your internal audits by asking, “Can I please see all the CAPAs resulting from audits and management reviews.” One client I spoke with said that they purposely don’t open any CAPAs from audits or management reviews for that reason. I was in complete shock, but I managed to keep my poker face and asked the client, “So what do you think the FDA will do when you say that you don’t have any CAPAs resulting from audits or management reviews?” Management responsibility is a frequent FDA inspection target. Most companies are subjected to a Level 2, QSIT inspection on a biannual basis. During these comprehensive inspections the inspector reviews the four major subsystems: 1) management controls, 2) design controls, 3) CAPA, and 4) production and process controls. The FDA will ask open-ended questions to determine the effectiveness of the QMS. If the inspector is not going to look at the actual meeting minutes from the management review, you can expect them to look at the following obvious targets:

  1. “May I see your procedure for Management Reviews?”
  2. “May I please have a copy of your organization chart?”
  3. “Could I see the agenda and attendees list from your last management review?”

The inspector could also ask for copies of inputs that are identified in the Management Review procedure, such as: “Could I have a copy of the most recent scrap trend analysis for production?” or “What is your threshold for taking corrective actions for rejects found in receiving inspection?” One Quality Manager told me a fascinating story about his local inspector. During a previous inspection, the inspector requested a copy of the management review. The Quality Manager showed him the cover page that indicated the agenda and the attendees. The Quality Manager refused to let the inspector see the rest of the meeting minutes. The inspector then proceeded to conduct a brutal 3-day inspection where a myriad of 483’s were written. Twelve months later the inspector returned to perform a “Compliance Follow-up.” This time when the inspector asked to see the management review, the Quality Manager agreed to let the inspector see the entire meeting minutes. From that point onward, each time the inspector got close to identifying a new 483’s the inspector would stop following the audit trail at the last moment before the nonconformity was identified. The Quality Manager said it was almost like the inspector was showing him that he could find all kind of problems to write-up if he wanted to, but he was taking it easy on the company because the Quality Manager was being cooperative. My personal philosophy is to create a QMS that is open for review by any customer, auditor and even the FDA. No matter what they find, it’s just another opportunity to improve. This has worked well for me, but you need to follow a few basic rules when writing audit reports and management review meeting minutes.

Rules for Writing Audit Reports & Management Reviews

  1. DO NOT write anything inflammatory or opinionated in your documents. My motto is, “Stick to the facts Jack (or Jill).”
  2. I ask other people in the management team to read and review the meeting minutes before they are finalized. The variety of perspectives in top management helps to make sure that the final document is well written and clear—especially to FDA inspectors.
  3. I structure the documents as per a standard template that is a controlled document. This ensures that each report or management review was conducted as per the procedure. In fact, I typically reference the applicable clauses and sub-clauses throughout the document. For example, I will reference ISO 13485:2003, Section 5.6.2h) for the slide titled “New and Revised Regulatory Requirements.” I put the reference next to the slide title just to make it clear what requirement this slide is addressing.
  4. If there is an area that I covered, but there was nothing to discuss, I write “There was no further discussion on this topic.”
  5. If there is an area that I did not cover, I make sure I do the following:
  6. write a justification for not covering the area,
  7. indicate the last time the area was covered (and the result at that time), and
  8. document when the area will be covered in future.

You can continue to listen to the advice of consultants that think of creative ways to hide things from the FDA or you can follow the above advice. If you follow my advice, then you can spend the rest of your time working on the CAPAs for each area where you identified a weakness—instead of spending your time trying to hide your problems. If you need help preparing for an FDA inspection or responding to FDA 483 inspection observations or warning letters, please email Rob Packard. We have two people on our team that used to work for the agency.

Posted in: FDA

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Selecting and Changing the European Authorized Representative

This article explains the roles and responsibilities of a European Authorized Representative for CE Marking of medical devices. The article also provides advice on selecting and changing the European Authorized Representative.

How to Select or Change Your European Authorized Representative Selecting and Changing the European Authorized Representative

European Authorized Representatives are the legal representative of non-European manufacturers for medical devices sold in Europe. If a company already has offices located in Europe, an Authorized Representative is not needed. However, if you don’t have offices in Europe, you must have a legal agreement with an Authorized Representative that is physically located in Europe to be your primary contact for receipt of customer complaints. The Authorized Representative can also act as your liaison between the Competent Authority in Europe and your company.

Why your distributor is not a good choice

Many manufacturers located outside of Europe choose their distributor as an Authorized Representative. Distributors often want to do this, because then their name is required to appear by law on the labeling and the IFU. Unfortunately, your distributor has a conflict of interest. The distributor does not want adverse event reporting, recalls or even complaints. Therefore, can you be sure that the distributor will notify you immediately of all potential complaints?

In January 2012, the European Commission released a guidance document explaining the roles and responsibilities of European Authorized Representatives: MEDDEV 2.5/10. Distributors rarely have the regulatory expertise to act as Authorized Representative.

Competent Authorities occasionally audit Authoritized Represenatives to ensure that the legal requirements are being met. When this happens, clients often ask me to recommend a European Authorized Representative to switch to.

Primary Responsibilities

The EU Authorized Representative has two primary responsibilities:

  1. Complaint handling
  2. Registration of CE Marked devices

The complaint handling function is the reason why the name and address of the European Authorized Representative must appear on the product labeling and IFU. Your distributor may still become aware of potential complaints, and therefore, distributors should still be trained on the importance of forwarding any potential complaints to your company immediately. The registration function is critical for Class I devices that are non-sterile and do not have a measuring function, because those devices do not have a Notified Body involved. It is often valuable to have an Authorized Representative located in one of the Member States where you intend to sell a larger percentage of product, because the labeling will include a physical address in that Member State.

Other ways an Authorized Representative Can Help

Some manufacturers complain that they are paying $3,000-$5,000 each year for a competent authority to do very little. However, Authorized Representatives are required to review your procedures prior to CE Marking and anytime you notify them of an update. This additional review of procedures is equivalent to hiring a consultant to review your procedures.

European Authorized Representatives can be helpful at other times too. For example, if your company and your Notified Body do not agree on the classification of a device the Authorized Representative may be able to assist you in the same way that an experienced regulatory consultant can. If you receive communication from a Competent Authority, the Authorized Representative can act as your liaison. Most important of all, the Authorized Representative can help you determine when complaints require vigilance reporting and provide support if a recall or advisory notice must be initiated.

How to Select an Authorized Representative

I recommend a three step approach to selecting your Authorized Representative. First, visit the EAARMED website. One of the 15 members of this association should be your starting point, because these are the most experienced Authorized Representatives. Next, you should determine which of the 15 members is located in a country that matches the country you intend to sell in. For example, if 100% of your sales is through a distributor located in Italy, Donawa would be a better choice than a German Authorized Representative. Finally, you should obtain quotes and interview more than one Authorized Representative. You want to make sure that the Authorized Representative is responsive and easy to communicate with. It’s surprising how much learn about responsiveness and communication during the quoting process.

If you need any additional help preparing for CE Marking product in Europe, please email Rob Packard.

Posted in: CE Marking

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5 Alternatives When You Can’t Find a Predicate Device

This article summarizes five alternatives that medical device manufacturers have for regulatory approval in the US when a 510k submission predicate device cannot be identified.

success and failure choices 5 Alternatives When You Can’t Find a Predicate Device

Choosing the best 510k submission predicate device is critical to success or failure.

The premise behind the FDA 510k regulation is that your new device is substantially equivalent to another device (i.e., predicate device) that is already on the market. Therefore, you only need to submit a premarket notification to the FDA instead of a premarket approval (PMA) submission. Most 510k submissions reference a similar device manufactured by a competitor, but what do you do when you can’t find a predicate device?

Your 5 Options

  1. Conduct a Clinical Study and Prepare a PMA Submission = $$$ + 2 years min.
  2. Prepare a DeNovo Submission = 120 days instead of 90 days
  3. Submit a 510k with Your Best, Poor Choice & Expect One of Two Responses: Refusal to Accept (RTA) or Not Substantially Equivalent (NSE)
  4. Request a Pre-Sub Meeting with the FDA = 60-day Delay at Front of Project
  5. Submit a 513(g) Request to the FDA = $ + 60-day Delay at Front of Project

Option 1 – Conduct a Clinical Study & Prepare a PMA

If you cannot identify a predicate device, you may need to conduct a clinical study to demonstrate that your new device is safe and efficacious. Some devices even require an investigational device exemption (IDE) approval from the FDA if the risks of the device are significant. If your device presents significant risks, it is likely that the De Novo process (Option #2 below) will not be an option and the device will be considered a Class III device by the FDA. In this case, the fastest pathway to regulatory approval is a modular PMA submission. The minimum timeline for this type of submission is typically two years, and the FDA user fee for a PMA submission is very high–unless you are a start-up company and this is your first product. The following FDA webpage summarizes the process for a modular PMA:

http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm089767.pdf

Option 2 – Prepare a De Novo Submission

Originally the De Novo process was created with IVD products in mind where the technological characteristics are nearly identical between two devices, but the intended use is different (i.e., device is used to diagnose a different disease). The problem with the original process is that you had to submit a 510k and have it rejected before you were allowed to submit a De Novo application. Now the De Novo process allows two pathways. A company can submit a 510k, have it rejected with a “not substantially equivalent” (NSE) letter and then submit a De Novo application. The new option allows a company to skip the initial 510k submission and submit a De Novo application first. This extends the decision time from 90 days to 120 days, but the previous option took even longer.
The following FDA webpage has the De Novo draft guidance document that was released last year:

http://www.fda.gov/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm273902.htm

The following FDA webpage summarizes all the De Novo applications that have been reviewed and approved recently:

http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDRH/CDRHTransparency/ucm232269.htm

Option 3 – Submit a 510k Anyway

This is probably not your best approach, but sometimes it’s worth a shot to see what the FDA will say instead of waiting to schedule a pre-submission meeting and this approach doesn’t eliminate option #2. There are two likely outcomes from this approach. First, the reviewer screening your 510k submission during the 15-day, refusal to accept (RTA) process will determine that you have not selected a suitable predicate device and you will receive an RTA letter. In this case you have an answer in just 15 days. You should never accept your first RTA letter. You should make the requested changes the reviewer indicates and re-submit. The FDA’s goal is to have all submissions make it through the RTA process on the second try. Therefore, you might have more success on the second try with another predicate or just by fixing other problems the reviewer identified.

The other possible outcome of this approach is that you will make it through the RTA process, but your submission will be determined to be NSE. In this case, you will received an NSE letter from the FDA and it will suggest options–typically a PMA or a De Novo submission. If a De Novo submission is a good option it will be stated in the letter.

Option 4 – Request a Pre-Submission Meeting

If you are not able to identify a suitable predicate you might consider preparing a classification rationale and select a potential predicate. Then this information can be summarized in a pre-submission meeting request to the FDA. The FDA will respond within 75-90 days from your submission. If you are still developing your device and you have not started any performance testing, then this option may be your best approach. I recently recorded a live webinar on the topic of pre-submission meetings for 510k submissions:

http://robertpackard.wpengine.com/live-webinar-on-510k-submissions-fda-pre-sub-meetings/

The webinar includes specific dos and don’ts for for pre-submission meetings. There is also a final guidance for the pre-submission program that was released last year on February 18, 2014:

http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance//guidancedocuments/ucm311176.pdf.

Option 5 – Submit a 513(g) Application

When a company has difficulty identifying a 510k submission predicate device, the FDA recommendation is to submit a 513(g) application. As I indicated in a past blog (http://robertpackard.wpengine.com/fda-device-classification/), the 513(g) process may not be your best choice for two reasons. First, the 513(g) process takes 60 days before the FDA provides a response. Second, the 513(g) process has a user fee that is higher than hiring a consultant to do the same research. Since the FDA 513(g) response is “non-binding”, the FDA’s opinion doesn’t necessarily hold any more weight than an experienced consultant. Therefore, paying a consultant to do the research and then requesting a pre-sub meeting is probably a better approach, but the timeline for a 513(g) submission is slightly shorter.

Do You Still Have Questions?

I will be recording a live webinar overview of the 510k submission process next Thursday, June 4 at Noon Eastern, but we have already sold-out 1,000 registration spots. Therefore, we are now offering a second webinar earlier in the day on this topic:

http://robertpackard.wpengine.com/510k-submission-predicate-device/

This second webinar starts at 9am Eastern, and it might be a better time for European companies that have questions specific to 510k submissions.

Posted in: 510(k)

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Combining a 510k Submission with CE Marking: 9 Sections that are Duplicated

This article explains how to reduce your workload by at least 35% if you integrate your two project plans for a 510k submission and CE Marking into one comprehensive regulatory plan.

510k submission and CE Marking Combining a 510k Submission with CE Marking: 9 Sections that are Duplicated

My first medical device regulatory submission was for CE Marking, while my second regulatory submission was for a 510k submission of the same product. This is a very common path for medical device regulatory submissions, but it is also an inefficient path. If you know that you will be submitting both types of documents, then you should plan for this from the start and reduce your workload by at least 35%.

The reason why you can easily reduce your workload is that there are nine key sections in both submissions that are very similar. Therefore, you can write the content for those nine sections in such as way that the content can be used for your 510k submission and CE Marking.

9 Sections are Duplicates

Here are the nine key sections that the two types of regulatory submissions have in common:

  1. Device Description
  2. Labeling
  3. Sterilization & Shelf-Life
  4. Biocompatibility
  5. Software
  6. EMC/Electrical Safety
  7. Bench Testing
  8. Animal Testing
  9. Clinical Testing

There are 20 sections required by the FDA for a Traditional 510k submission, but often some of the sections are boilerplating and other sections are not applicable to the device being submitted. A few sections are unique to a 510k submission, such as:

  • Substantial Equivalence
  • 510(k) Summary
  • User Fee Cover Sheet Form 3601 & Submission Cover Sheet Form 3514
  • Declarations of Conformity on Form 3654
  • Table of Contents

Technical Files for CE Marking also have a few unique sections, such as:

  • Essential Requirements Checklist
  • Classification Rationale
  • CE Marking Application to Notified Body
  • Declaration of Conformity
  • Table of Contents

How to Construct Your Plan

In one of my previous blogs I explained how I use the 510k Table of Contents as a project management tool for a 510k submission. You can do the same when you are constructing a combined plan for a 510k submission and CE Marking. The first step is to create the same kind of project management tool I use for a 510k submission (i.e., a Table of Contents) to manage your CE Marking Technical File. I recommend preparing your Technical File in accordance with the GHTF guidance document released by study group 1: N011:2008. This guidance mirrors the format that will be required in Annex III of the new European Medical Device Regulations that should be released next spring. I do not recommend using the NB-MED 2.5.1/rec 5 guidance document. Even though the content is similar to the GHTF guidance, the format is quite different. After I have two separate project plans organized in accordance with the Table of Contents, then I merge the two plans on a spreadsheet and consolidate the duplicate sections.

Scheduling Tasks & Project Management

If you are going to outsource sections of either submission, these 9 sections should be written and reviewed by someone that is familiar with both types of submissions. The headers and footers will be unique to the type of submission, but I write the text in Google Docs without formating for ease of sharing and so I can use my Chromebook.

If you have an in-house team that prepares your 510k submissions and Technical Files, you might consider training the people responsible for each section on the requirements for each type of submission. This eliminates rewriting and reformatting later. I like to assign who is writing each section in a separate column of my Table of Contents planning tool. Then I will sort the sections by expected date of completion. All the safety and performance testing, and any sections requiring validation, will typically be finished at the end of the project. Therefore, it is important to dedicate unique resources to those sections rather than asking one person to write several of those sections. You also will want to make sure any supporting documentation they need is completed early so that the project’s critical path doesn’t change. I typically use a Chromebook spreadsheet for all of this, because 20+ sections is just too few tasks to warrant the use of Microsoft Project or some other Gantt Chart planning tool. If you keep it simple, more of your team will read it and update it frequently.

RA Consulting Tip

I have several PCs (laptops and desktops of various vintages), but nothing is faster for writing plain text than a Chromebook. Then I export documents to Word format and work on tables and formatting of the information as needed. I can also jump on any computer with an internet connection and work on my documents. This enables me to travel very light when I need to. If you are a tablet user, there are some other solutions I prefer–such as Evernote.

Additional 510k Training

The new 510k book, “How to Prepare Your 510k in 100 Days,” ships on Monday, February 6th 2017. There is also an on-line 510k course series consisting of 24 webinars. Please visit my webinar page to purchase individual webinars. We also have live 510k workshops.

 

 

 

 

 

Posted in: 510(k)

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Status of the European Medical Device Regulations?

This article describes the status of the new European Medical Device Regulations, and it provides some advice for what you should be doing to prepare for the changes.

MudI 600x334 Status of the European Medical Device Regulations?

The picture above is not a picture of people on their way to the local maple sugar shack, trying to get a car unstuck during mud season in Vermont. It’s actually a photo of paid actors reenacting the European negotiations for a new medical device regulation. The European Parliament is in the overcoat on the left, the four men on the right represent the various presidents–Greek, Italian, Latvian and Luxembourg. The Dutch President is driving the horse team in the front in the hopes of getting unstuck in time for next Spring.

Yes, in a word the negotiations are “stuck”!

My friend Erik Vollebregt did a wonderful job of summarizing the status of negotiations on April 30, in his own blog posting. The best guess anyone has is that we might have a final version released next year in Spring 2016. It’s only 2 years later than I was expecting. I guess they encountered more mud than expected.

There are a number of issues that the member states appear to be stuck on:

  • Ingested products
  • Non-medical devices
  • Companion diagnostics
  • Non-viable human tissues and cells
  • Viable biologic substances
  • Reprocessing single-use devices
  • Genetic testing
  • Implant cards
  • Eudamed & UDI
  • Summary of safety & performance
  • Notified Bodies
  • Pre-market approval
  • Clinical investigations
  • Post-market surveillance
  • Market surveillance & vigilance
  • Reference laboratories
  • Hazardous chemicals
  • Classification rules
  • Governance & oversight

I’m not quite sure whether the remaining list of issues the member states agree upon is shorter than this or longer, but this list includes a number fundamental principles that could dramatically change the nature of medical device regulation in Europe. Our expectation is that many of these issues will be resolved with a compromise of some sort, but I suspect every medical device manufacturer with a CE Mark will be extremely busy from 2016-2019 revising their procedures, technical documentation and training personnel on the new European Medical Device Regulations.

 What Should You Be Doing to Prepare?

  1. Update Your Quality System to ISO 13485:2015 Early – The second Draft International Standard (DIS2) for ISO 13485 was released in February, and the final version is expected to be published this Fall. The changes to ISO 13485 are minor, but audits by your Notified Body will be far less complicated if you upgrade your quality system to the new revision before you attempt to address the new European Medical Device Regulations.
  2. Strengthen Your Internal Auditing & CAPA Processes – Companies with strong internal audit programs and CAPA processes have fewer findings resulting from Notified Bodies. When you have multiple findings from a previous audit to close, your annual surveillance audits and recertification audits  become longer and more complex. These findings must also be closed before a manufacturer may transfer a quality system or CE Certificate from one Notified Body to another. Therefore, strengthening your internal audit and CAPA processes will result in a shorter Notified Body audit and you will find it much easier to transfer from one Notified Body to another–if your current Notified Body is no longer able to issue a CE Certificate for one or more of your products.
  3. Update Your Technical Files – Companies that have a Design Dossier are required to submit all changes to their Design Dossier for approval prior to implementation, but companies with a Technical File for a lower risk device have their technical documentation sampled periodically. Sampling of technical documentation allows companies to fall behind in their documentation of changes. Re-issue of new CE Certificates will require a more thorough review of these Technical Files that may not have been sampled in several years. Therefore, I recommend that companies allocate resources to updating technical documentation now so that there is less work to update the technical documentation for the new European Medical Device Regulations.
  4. Review Your Product Portfolio and Prune It – The more mature product lines become the more likely it is that you have products you are maintaining that just aren’t selling. The cost of maintaining your technical documentation and updating everything for compliance with the new European Medical Device Regulations will be expensive. Therefore, you can save some money now and a larger amount of money later by eliminating any products from your CE Certificate that are not selling well. If you have customers that are still buying an older version of the product, now is the time to persuade them to transition to the current version of your product. You don’t want to maintain your Technical File for two versions of the same product.

Regardless of what compromises are made, the new European Medical Device Regulations are guaranteed to be the most substantial change in regulatory requirements that the medical device industry has endured since 2003–much more dramatic than the 2007/47/EC amendment to the Medical Device Directive (MDD).  

Will someone please buy the negotiators a pair of Bogs and a Subaru Crosstrek?

Subaru XTrek 300x199 Status of the European Medical Device Regulations?

Bogs Status of the European Medical Device Regulations?

Posted in: CE Marking

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Comparing HUD, HDE and 510k Submissions

This article compares the differences between the regulatory pathways for an HDE and 510k submission. The article also explains how the Humanitarian Use Device (HUD) designation  and Humanitarian Device Exemption (HDE) compare.

HUD Designation 300x229 Comparing HUD, HDE and 510k Submissions

Last year the FDA released a draft guidance document explaining the regulatory process for applying for an HDE:
http://www.fda.gov/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm389154.htm

HUD designation is for product that affect less than 4,000 patients per year in the United States. There are three steps required before a HUD may be used at a user facility:

  1. HUD Designation Request to Office of Orphan Products Development (OOPD)
  2. HDE Application to Center for Devices and Radiological Health (CDRH)
  3. Investigational Review Board (IRB) approval of using the HUD

Note: The above regulatory pathway may not apply to combination products. In the case of combination products, you should contact the Office of Combination Products (OCP).

Major Differences

  • Unlike the 510k process, HDE approval is device approval rather than “clearance” for marketing and distribution.
  • If another equivalent (actual term used is “comparable”) device is already being legally marketed, then the FDA may not approve an HDE application. In contrast, the first requirement for determination of substantial equivalence of a subject device for a 510k submission is that the predicate device must be a legally marketed device that is equivalent.
  • There are no user fees for an HDE application, while 510k submissions generally are subject to user fees; pediatric-only products are an exception to the requirement for 510k user fees.
  • There is no requirement to demonstrate effectiveness of devices in an HDE application. Instead, devices approved for HDE must provide an acceptable risk/benefit analysis.
  • HDE approved devices are not generally eligible to make a profit. In fact, any device that a manufacturer intends to sell for more than $250 requires a report issued by an independent public accountant.
  • IRB approval for use of a HUD approved for marketing is required, but the IRB approval is not for a clinical study and IRB approval is not required in the case of an emergency.

The FDA guidance document also explains how HDE approval is different from a pre-market approval (PMA).

 

Posted in: 510(k)

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