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Re-validation of EO Sterilization – When is re-validation required?

This article reviews some of the factors to consider when you are evaluating the need for EO sterilization re-validation.

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EO Sterilization Cycle Re validation of EO Sterilization   When is re validation required?

ISO 11135-1:2014 is the international standard for sterilization validation for Ethylene Oxide (EO or EtO) sterilizers. The standard describes multiple methods of sterilization validation: 1) overkill approach, 2) single lot release, and 3) parametric release. The overkill approach is the most common method for validation of your EO sterilization process. If you are using a contract sterilizer, the sterilizer will already have completed an Installation Qualification (IQ) and an Operational Qualification (OQ). You will need to complete a Performance Qualification (PQ) for your product. A typical PQ for initial process validation consists of the following:

  1. Process Challenge Device (PCD) validation
  2. Bioburden measurement
  3. EO residual measurement (as per ISO 10993-7:2008/R2012)
  4. Fractional Cycle (at least one)
  5. 3 Half Cycles
  6. 3 Full Cycles (or 1 Full Cycle, if performed in parallel with the three half-cycles)

Most contract sterilizers already have one or more Process Challenge Devices (PCDs) that they have developed, and they may evaluate multiple PCDs in your fractional cycle to determine which PCDs are more challenging to kill than an internal biological indicator (BI). In addition to the above “typical” PQ, you might also choose to validate partial loads and/or re-sterilization of product in the case of rework.

In the ISO 11135 standard, #4 and #5 are referred to as the microbial performance qualification (MPQ), while #6 is referred to as the physical performance qualification (PPQ). For a successful MPQ, at least some of the PCDs must be non-sterile after a fractional cycle to demonstrate the ability to recover the BI challenge organism. After a half-cycle, however, all biological indicators should be sterile.

Ethylene oxide sterilization is typically outsourced to a contract sterilizer due to the environmental and safety requirements of working with EO. Usually, the contract sterilizer will provide a standard validation protocol for full validation that is compliant with ISO 11135-1. However, the ISO 11135-1 standard requires that manufacturers perform annual process reviews to evaluate the need for re-validation of the sterilization process. Assuming there have been no problems, and no changes to the product or process, then re-validation is not required at the end of the first year. However, companies are expected to re-validate the process after two years–even if there have been no changes. So why do some companies perform re-validation after three years or more?

Longer Re-Validation Cycles

If there have been no changes to the sterilization process, the product, or the biological indicators, then the manufacturer can use this as a justification for waiting until two years have elapsed before re-validating the ethylene oxide sterilization process. Also, there should be no evidence of sterilization failures or other problems with the validated process. However, that alone is not necessarily enough to justify extending the duration between validations beyond two years. Companies that can justify intervals of three or more years have multiple products that are using the same sterilization process.

In this case, the manufacturer may alternate annually between three, four, or even five different product families that are using the same sterilization process. In this case, one of the product families is being re-validated each year or every two years, but the interval between validations for any one product family is longer. If the products are made of similar materials and using the same sterilization process, then this approach is valid. If you only have one product, then you need to re-validate the sterilization process once every two years to verify the process remains active.

Minimum Re-Validation Requirements

When you determine that it is time to re-validate your ethylene oxide sterilization process, you need to perform the following tests to meet the minimum requirements of ISO 11135-1:

  1. Re-validation of PCD
  2. Bioburden measurement
  3. EO residual measurement
  4. 1 Half Cycle
  5. 1 Full cycle (to verify the EO residuals are acceptable)

The purpose of #1 is to verify that the resistance of internal BIs used in the half-cycle is more resistant than the product bioburden. The purpose of #2 is to verify that bioburden levels have not changed, and the type of organisms has not changed. In practice, most companies monitor bioburden quarterly, and therefore this step should be routine. Step 3, EO residual measurement, should be performed to verify that there have not been minor changes to the product or process that would increase the concentration of EO, Ethylene Chlorohydrin (ECH), or Ethylene Glycol (EG) beyond the Tolerable Contact Limit (TCL). The purpose of this third test is to prevent localized irritation caused by residual chemicals from the ethylene oxide sterilization process.

Step 4 of the re-validation is intended to verify that a full injection of EO is more than required to kill the bioburden present for the number of injections required for a half-cycle.

The final step is to perform a full cycle. The product from the full cycle is typically used for EO residual testing. Any product from the full cycle that is not used for testing can be sold after sterility testing is complete.

Partial Loads & Rework

If you occasionally sterilize loads that are less than “full loads,” then you need to ensure that you have validated a minimum load or a specific partial load (e.g., half-pallet, instead of a full pallet). In the case of a partial or minimum load, you may identify different locations in your load that is considered “worst-case.” These are the locations that had PCDs that were not sterile in a fractional cycle.

Most companies do not have concerns about the cost of the actual sterilization runs during re-validation, and biological indicators are typically less expensive than boxes of product. The primary cost concern for re-validation is any product that must be scrapped. Therefore, many companies will accumulate dunnage (i.e., empty packaging or scrap product) over time to fill a sterilizer. This dunnage may be used to ensure that every load is a full load, or it may only be used for re-validation.

Another alternative to using dunnage for re-validation is to validate a rework process. Any product that is exposed to a fractional cycle or half-cycle can be resterilized in a full cycle. To justify the commercial use of that product, a company needs to validate that the product will not be damaged by exposure to two full cycles. One of the key acceptance criteria for rework is the EO residual levels in the product. However, the manufacturer also needs to determine if there has been any deterioration of the product by a second exposure to EO that would affect performance.

Other Considerations

Many companies do a poor job of reviewing the potential impact of changes to a product, packaging, and biological indicators. Ideally, initial validation involves different lots of product, packaging, and biological indicators to assess lot-to-lot variability. However, many times, the packaging and biological indicators consist of only one lot during validation. Minor changes to the tolerances may reduce the amount of ethylene oxide that is absorbed by the product or change the resistance o the biological indicator to the sterilization process. Therefore, these minor changes should trigger a re-validation.

Changes in suppliers with the same specification can also be difficult to evaluate. If a component is made of a material that absorbs EO, then it may be recommended to re-validate sterilization for any changes to suppliers of those components. Re-validation in these cases may consist of only a fractional cycle, half cycle, or a full-cycle to evaluate risks associated with the change.

Who Should Be Making Evaluations

The evaluation of the need for re-validation should include the input of three types: 1) microbiological, 2) materials, and 3) performance. To make these assessments, typically, a cross-functional team is needed. Someone with responsibility for design and development can assess the performance impact of changes. A materials engineer is generally needed for assessment of the interaction between components and EO. Finally, a microbiologist is needed to confirm that there is no impact related to biological indicators or bioburden.

Purchase the EO Sterilization Validation Procedure (SYS-031) – $299

EO Sterilization Cycle 1 150x150 Re validation of EO Sterilization   When is re validation required?
SYS-031 EO Sterilization Validation Procedure

This new procedure defines the requirements for ethylene oxide (EO) sterilization validation and revalidation which has been outsourced to a contract sterilizer.

Price: $299.00

Bioburden Failure Analysis Webinar Re validation of EO Sterilization   When is re validation required?Medical Device Academy also released a new webinar recording on the topic of Bioburden Failure Analysis last week – Read More…

If you need assistance with sterilization validation or bioburden failure analysis, please contact me by email at rob@13485cert.com or call me at +1.802.281.4381.

 

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510k Submission, Section 14-Sterilization Validation and Shelf-life

This article explains the process for preparing the sterilization validation and shelf-life section of a 510k submission.

sterilization validation 510k Submission, Section 14 Sterilization Validation and Shelf lifeSterilization validation and shelf-life, Section 14, is typically one of the last sections of a 510k submission to be completed. However, most of the work in preparing this section of your 510k submission should be completed more than a month before actually completing the associated testing. The reason why you can write this section, before receiving the results, is that your results are 99% predictable. If you are unlucky enough to be part of the 1% that have surprising results during sterilization validation, then you will need to make changes and repeat your testing.

Design Planning Aspects Related to Sterilization Validation

During your design and development process, sterilization validation testing is part of design verification testing—not design validation. This testing is verification, rather than validation because you are testing in accordance with recognized standards (i.e., design inputs) to ensure that the sterilization process parameters are adequate to consistently meet the sterility specification (i.e., design output). In your design plan, it is critical to understand which of the following three categories your sterilization process falls under:

  1. Traditional Sterilization (e.g., ethylene oxide)
  2. Non-traditional Sterilization (e.g., Hydrogen Peroxide)
  3. Novel, Non-traditional Sterilization (e.g., Chlorine Dioxide)

You must identify which category your sterilization process falls into because the review process used by the FDA for each category of the sterilization process is different. Traditional sterilization processes have recognized standards that a reviewer can easily compare your validation methods with.

Non-traditional sterilization methods are becoming more popular for products that are sensitive to degradation caused by high temperature, or exposure to radiation or ethylene oxide. However, the FDA has identified non-traditional sterilization processes as being a priority for inspection. Therefore, after your product receives 510k clearance, you can expect an FDA inspection sooner than products that use traditional sterilization methods (i.e., 6-12 months instead of 12-24 months). 

The novel, Non-Traditional Sterilization

The novel, non-traditional sterilization methods require a different 510k clearance process, because the FDA requires an internal consultation from the Infection Control Devices Branch (INCB) before issuing 510k clearance. A consultation is needed for evaluation of the sterilization process because reviewers lack sufficient expertise in the field of microbiology and Sterilization to evaluate novel sterilization processes. The INCB can also provide a consult for non-traditional sterilization processes, but this is not typically needed if the process is following established ISO Standards for sterilization validation. 

For the novel, non-traditional sterilization processes, and INCB consult is required, and it is recommended to consult with the FDA early regarding the use of this type of sterilization process. Part of the reason for this early consultation is that a pre-clearance priority inspection is required before issuing the 510k. The FDA published draft guidance on this topic in 2008 that can be found on the following webpage – Click Here.

The image below shows where the INCB is located within the hierarchy of the FDA’s organization.

incb 510k Submission, Section 14 Sterilization Validation and Shelf life

Creating Summary Technical Documentation (STED)

The sterilization validation and shelf-life section of a 510k submission may be copied from the summary technical documentation (STED) that you prepare for CE Marking applications or a Canadian Medical Device License Application. Instead of including all of the protocols and testing reports from your validations, the regulators only require a summary of the validation activities and results. If the STED is thorough and well-organized, the reviewer should not request validation reports. However, if the STED is incomplete, then the reviewer is likely to request a copy of the validation reports.

Any STED should include the following elements:

  1. Identification of the validation dates
  2. Identification of the organization(s) that performed the validation
  3. Reference to the ISO standard or other recognized standard that was used
  4. Identification of any deviations from the referenced standard
  5. Number of lots and samples per lot tested
  6. Description of the testing performed—including testing parameters
  7. Identification of the document control numbers and revisions for protocols and reports
  8. Acceptance criteria for the validation
  9. Summary of the results

For your STED specific to sterilization validation and shelf-life, you will also need to ensure you include a description of the packaging used to maintain the device’s sterility (primary packaging) and a description of the packaging used to protect the primary packaging (i.e., secondary packaging).

For a 510k submission, you will only need to make a few modifications to the STED that you use for European CE Marking and Canadian licensing. First, you need to ensure you are referencing standards recognized by the FDA. If you followed a different method, the differences need to be documented in Section 9 of your submission on FDA Form 3654 for each Standard.

Second, you will need to include a reference to Ethylene Oxide (EO) residual testing summarized in Section 15 for biocompatibility (not applicable to non-EO methods of Sterilization). EO residual testing must be performed in accordance with ISO 10993-7. You should also include an outline of the validation methods that were used in your comparison of substantial equivalence in Section 12 of your submission. Finally, you should reference the methods used briefly in your executive summary (i.e., Section 10) and the 510k summary (i.e., Section 5)—assuming that you did not use a 510k statement.

If you are writing your first STED for sterilization validation and shelf-life, I recommend reviewing the RTA checklist in advance.

You may want to organize your STED with headlines that address each of the questions outlined in the RTA checklist.

You should also be aware that although the FDA references the 2002 guidance document K90-1 for the format and content of the sterilization validation section, there is a 2008 draft guidance the represents the FDA’s current thinking on the topic of sterilization validation. That draft guidance document is also identified as a priority for the FDA to release as a final guidance in FY 2015 (i.e., before October 1, 2015).

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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Setting and Validating Bioburden Limits

Rob Packard of Medical Device Academy provides an example for setting and validating bioburden limits. 

Last week, I was in Europe reviewing product specifications with a potential contract manufacturer for a medical device implant. Due to the raw materials that the contract manufacturer currently is using for a similar product, bioburden levels are higher than we can accept. The company is using an ISO Class 7 cleanroom for assembly and packaging, which is clean enough for these implants, but the molded components used for the assembly are not clean enough.

Validating Bioburden Limits Setting and Validating Bioburden Limits

The average bioburden is 220 CFU/device (i.e., colony-forming units/device), and the maximum observed bioburden exceeded 500 CFU/device. We want to use a lower dose range of gamma radiation to prevent deterioration of bioabsorbable plastics, but a lower dose range requires that the average bioburden never exceed 100 CFU/device.

There are quite a few Clauses in ISO 13485 that are different from ISO 9001. One example is Clause 6.4–Work Environment. Subsection 6.4(b) states, “If work environment conditions can have an adverse effect on product quality, the organization shall establish documented requirements for the work environment conditions and documented procedures or work instructions to monitor and control these work environment conditions.” This is the applicable clause of ISO 13485 related to setting bioburden limits. Unfortunately, this vague requirement does not explain how to establish or validate bioburden limits.

Rules of Thumb

One of my microbiologist friends recommends using the following “rule of thumb”: +2 sigma for alert limits, and +3 sigma for action limits. This rule of thumb assumes that you are performing data analysis of bioburden, and you have calculated a “sigma” value for the standard deviation. There are a few problems with the “rule of thumb” approach.

First, this method assumes a normal distribution and a controlled process–which bioburden seldom is. Second, the cleanliness you need for your product and the cleanliness your controlled environment is capable of are not always appropriately matched. In my example, we need the finished device to have a bioburden of <100 CFU/device before gamma sterilization. Molded parts are essentially bioburden free due to the hot temperatures of the parts ejected from the mold. Unfortunately, molded components attract dust like a magnet. Therefore, how you handle and store molded parts is important to the bioburden of the molded parts.

What Affects Bioburden?

For this example, we have three aspects that are critical to the final bioburden limit of the finished medical devices.

  1. How are the molded parts handled and stored?
  2. Are molded parts cleaned before assembly?
  3. What is the cleanliness of the work environment where the device is assembled?

The cleanliness of the molding environment matters, but parts can fall into a container that keeps the parts clean. It also matters how molding machine operators handle the parts. Gloves should be used, and typically the container the parts are in will be placed in an outer bag for storage. It is possible to clean molded parts with ultrasonic cleaning before assembly, but if the parts are kept clean after molding, this is unnecessary.

For your assembly operation, you need an environment with suitable cleanliness. Sometimes a controlled environment is sufficient. Other times a certified cleanroom is more appropriate. In either case, it is important to control the bioburden in the assembly area to a level that meets the needs of the most critical product assembled in that area. Cleanroom procedures, design of the cleanroom, and your cleaning/sterilization processes should match the needs of the product. Fortunately, cleanroom procedures and bioburden limits for cleanrooms are well established in ISO 14644-1 (e.g., for an ISO Class 7 cleanroom, particles ≥ 0.5 microns must be fewer than 352,000). If you have devices of different types in the same manufacturing area, then you need to plan according to the most critical needs.

Validating Bioburden Limits

After you have established your bioburden limits, you need to validate these limits. Once again, cleanroom validation has established ISO Standards to follow. The more challenging validation is a validation of the bioburden of parts and the final assembly. It’s important to validate the component levels first to reduce the variability of inputs to the final assembly process. Typically the first step is to perform data analysis of other molded parts produced in the same molding area by the same operators. If this data meets your needs for cleanliness, then further measures for controlling bioburden may not be needed. However, if you need to reduce bioburden, you might consider measuring parts at critical control points. The goal is to identify where the bioburden is being introduced. This analysis is typical of the type of root cause investigation that is performed when bioburden increases for unexplained reasons as well.

Once the sources of bioburden are identified and quantified, then process controls should be implemented to reduce bioburden. Gloves, double-bagging of product, and keeping containers covered during the molding operation are typical risk controls that may be implemented. To validate the effectiveness of these measures, you should write a bioburden validation protocol that evaluates each of the following aspects:

  1. lot variability of component bioburden
  2. operator variability for assembly
  3. variability in the cleanliness of the assembly area
  4. number of operators in the assembly area
  5. duration of the manufacturing lots

After you have validated the bioburden limits for the component parts, then the same process should be conducted for the final assembly of the product. A sampling of bioburden after transfer to the assembly area, and before assembly begins, should be done. This is important because often improper storage of components and/or failure to remove and clean outer packaging will contaminate the component parts and your assembly area.

process validation webinar Setting and Validating Bioburden LimitsIf you are interested in learning more about process validation in general, please visit my website to download a new webinar on the topic: CLICK HERE

I will also be publishing a blog soon on the topic of documenting sterilization validation for 510k submissions.

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Performance Testing for a 510k Submission-Case Study-Part 2

Performance Testing for a 510k Submission-Case Study-Part 2 explains the performance testing for a 510k submission to obtain clearance from the US FDA for marketing a new medical device. Performance testing is an essential part of new product development and is usually the last section that you can complete before your submission.  510k part 2 Performance Testing for a 510k Submission Case Study Part 2 In my previous 510(k) case study article (http://www.MedicalDeviceAcademy.com/510k-submission-fda-case-study), I showed you how to research the FDA classification database to determine if there is a special controls guidance document to follow in the preparation of your 510k submission. The example I used was for topical adhesives (i.e., MPN). Topical adhesives do not have any Recognized Consensus Standards listed. Instead, all the performance testing requirements are specified in the special controls guidance document.

In this case study article, I selected a different product code that has Recognized Consensus Standards, but it does not have a special controls guidance document. After identifying the device classification and product code, if there is no Special Controls Guidance, you need to plan your performance testing based upon other sources of information. If there is no Special Controls Guidance document, I use three methods for determining what performance testing is needed:

  1. Look for any device-specific standards
  2. Review other 510k summaries
  3. Order previous 510k submissions via FOIA requests

For this case study, the product code selected was a bone fixation screw (i.e., HWC). The number of predicate 510k submissions to choose from for this product code is extensive. There are 29 from Arthrex alone. Some of these 510k submissions include a 510k statement, while others include a 510k summary. A statement is not directly helpful in identifying any of the performance testing that was used for the clearance of the potential predicate device. However, 21 CFR 807.93 requires that the company that submitted the 510k shall provide a redacted copy of the 510k submission within 30 days of the request. If this is requested early in your 510k project, you should have a copy of the submission in time to plan your performance testing for verification and validation of the subject device. You can also order predicate 510k submissions through the Freedom of Information Act (FOIA) request process:

(http://www.fda.gov/regulatoryinformation/foi/howtomakeafoiarequest/default.htm).

In the case of a 510k summary, the summary indicates what performance testing was performed to demonstrate substantial equivalence. In the case of K103705, the section titled “Substantial Equivalence Summary” states that mechanical testing data for torque and pull-out testing was submitted for the subject device and the predicate device. Other 510k summaries may provide additional data or a more descriptive list of testing that was performed. In the case of this 510k example, there is a second product code listed: HRS, bone fixation plate. The HWC bone fixation screw product code indicates that there are 5 Recognized Consensus Standards:

Only three of the above standards are included in the list of eight Recognized Consensus Standards related to the HWS product code. One of those eight standards should probably be covered under the HWC product code, as well:

Now you have a total of six different device-specific standards that can be used for planning the performance testing of your bone screw. This is significantly more helpful than a 510k summary that says torque and pull-out testing was performed. After you have ordered and reviewed each of the standards, you then create a list of performance tests that apply to your screw and create an overall verification and validation plan.

It is essential to perform this review each time, because there may be new or revised testing methods established as the Recognized Consensus Standards are updated. If you outsource testing, then you will need to obtain a quotation from a testing lab for each of the applicable tests.

Once you have created a comprehensive testing list, and you have quotations for all the testing required, you need to schedule the testing and ship samples to the testing lab. Once testing has begun, this is the best time to start the preparation of your 510k submission. Performance testing often takes several months to complete. If you start preparing the 510k before you have ordered the testing, then you are starting too early, and you may have to change your performance testing summary multiple times.

If you start your 510k preparation after you order your testing, then you can create the entire performance testing summary. The only information that you will be missing is the final report number for each test being performed. For the most part, you do not need the specific results of the testing, because the tests are designed to show that the subject device is “equivalent” or “not worse” in performance. Quantitative comparisons between your subject device and the predicate device are not allowed by the FDA for a 510k submission. Your subject device must be “equivalent” or “not worse than” the predicate device concerning safety and efficacy.

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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510k Submission to the FDA (Case Study – Part 1)

This article is the first part of a two-part case study providing an overview of the premarket notification process (i.e., 510k submission) to obtain clearance from the US FDA for marketing a new medical device. This first part of the series focuses on the initial steps of a 510k submission project: 1) identifying product classification, 2) identifying any applicable international standards and special controls guidance documents, and 3) selecting a primary predicate device.

case study 510K 510k Submission to the FDA (Case Study   Part 1)

For this case study, I chose the maker of Krazy Glue® as a hypothetical new client. The company wants to start selling cyanoacrylate as a topical adhesive in the U.S. market. As with the Canadian and European markets, the US FDA considers cyanoacrylate a medical device when it is used as a topical adhesive. The first step toward obtaining FDA clearance for marketing the new product is to determine the device’s classification.

Device Classification

My client was considering asking the FDA to identify the classification of topical adhesives using the 513(g) submission process. Still, I provided the following reasons why the client should not use the 513(g) process:

  1. the 513(g) process takes 60 days to get a response from the FDA, while a qualified consultant can make the same determination in less than a day
  2. hiring a consultant typically costs less than the 513(g) fee (i.e., $3,387 for large companies and $1,694 for small businesses)
  3. the FDA’s classification determination is non-binding, and the accuracy of the FDA’s response is highly dependent upon the quality of the information provided by the company

In this case, I was able to answer the client’s question about device classification over the phone without any charge. The client indicated that they wanted to launch a product similar to Surgiseal. I was able to use the US FDA Registration and Listing Database to identify the product classification by merely typing “Surgiseal” in the field for “Proprietary Name.” Adhezion Biomedical LLC is registered as the manufacturer of Surgiseal. The three-letter product code “MPN,” and the device is a Class II device requiring premarket notification via a 510k submission.

This product classification also gives my client additional options that are not available to all companies that are trying to achieve 510(k) clearance for the first time. Most new products can only achieve initial 510(k) clearance from the US FDA by submitting a “traditional” 510(k). This process is supposed to take 90 days—assuming there are no significant questions about the submission, and the reviewer has a manageable workload to review. The average time for determination of 510k clearance is currently between 120 and 180 calendar days.

Applicable International Standards & Special Controls Guidance

For some products, there are recognized consensus standards (i.e., ISO Standards) that define the performance requirements for a medical device or a Special Controls document published by the FDA that identifies which performance Standards the FDA requires for specific product classification. In the case of topical adhesives, the FDA has issued a Special Controls document. When there is a Special Controls guidance document available (http://bit.ly/FDA-topical-adhesive), the company may submit an Abbreviated 510k instead of a Traditional 510k submission.

An Abbreviated 510k submission contains summaries of all the testing results required in the Special Controls document or an ISO Standard recognized by the US FDA. Since all the testing of performance needed to be presented in an Abbreviated 510k submission is in accordance with a previously accepted standard, the FDA reviewer only has to verify that the performance testing identified in the Special Controls document or the ISO Standard has been completed and acceptance criteria have been met. Therefore, the reviewer needs less time, and the FDA’s performance target for making a clearance decision is 60 days—instead of 90 days.

In addition to Special Controls documents, the FDA also has guidance documents related to 510k submissions, such as: “Format for Traditional and Abbreviated 510(k)s.” By following this document verbatim, my client can avoid a lot of time-consuming questions from a reviewer that is having trouble finding the information they are looking for. If a section of the suggested format is not applicable, I still include this section. However, I indicate the reason why this section is not applicable in a brief paragraph (i.e., a one-page section).

As I read through the Special Controls Guidance document, I realized that a specific format for an Abbreviated 510k is described for topical adhesives. Therefore, I need to modify my normal template to match the FDA format for a topical adhesive Abbreviated 510k submission. As I read further, I realized that there would be some additional testing required that my client may not have anticipated.

In the Special Controls document, there are several risks and recommended mitigation measures identified:

fig.1 510k 510k Submission to the FDA (Case Study   Part 1)

The risks of adverse tissue reaction, chemical burns, and infection have all been addressed by biocompatibility testing and sterility testing. My client also performed animal testing to identify any problems in a simulated use environment. However, the client did not perform any testing to address unintentional bonding specifically, wound dehiscence, applicator malfunction or delayed polymerization. The client needs verification protocols and test reports to address these specific risks.

Selection of a Primary Predicate

Another unique requirement from the US FDA for a 510k submission is the concept of a predicate device. A predicate device is a similar product that currently has a valid 510k. In July 2014, the US FDA released a guidance document that clarifies that companies submitting a 510k should identify only one primary predicate–rather than identifying multiple predicates. Ideally, a recent 510k submission should be selected because “old” technology may no longer be considered acceptable from a safety standpoint. In the case of topical adhesives, the applicator is one of the primary differences between legacy products and more recent 510k submissions. The most recent version of Surgiseal™ is an example of a new applicator for a monomeric, 2-octyl cyanoacrylate.

My client has a similar applicator design, and therefore Surgiseal is selected as the primary predicate device for this 510k submission. For all the testing protocols that need to be created for this 510k submission, comparative testing is performed with a sample of Surgiseal and a sample of products made by my client. In each of these protocols, the acceptance criteria are performance “not worse than Surgiseal.” 

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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Updates on Electrical Safety Standards for Medical Devices-IEC 60601

This blog summarizes updates on electrical safety standards for medical devices-IEC 60601.

electrical saftey 1 Updates on Electrical Safety Standards for Medical Devices IEC 60601

OSHA finally approved some Nationally Recognized Test Laboratories (NRTL) to AAMI ES 60601-1 (equivalent to IEC 60601-1 edition 3.1 or 3rd ed + A1). Leo Eisner posted a blog summarizing this change (http://bit.ly/OHSA-NRTL-Approval-Update) on January 7, 2015. The blog identifies which labs can issue NRTL Marks and which test labs have OSHA approval in progress. UL 60601-1 is still an approved standard that an approved NRTL can issue an NRTL test mark to, but a few of the NRTLs are now authorized to issue an NRTL Mark to AAMI ES 60601-1 3rd edition + Amendment 1.

The best place to confirm if a Safety Test Lab is an approved NRTL for your medical device is by confirming the notifications published in the U.S. Federal Register. You can also visit the OSHA NRTL website (http://bit.ly/OSHA-NRTL), but the OSHA website is updated less frequently. Eventually, UL will formally announce the withdrawal of UL 60601-1, and OSHA will take steps to withdraw that Standard from their list of Approved Standards.

On January 14, 2015, Leo Eisner posted a second blog (http://bit.ly/IEC-60601-2-52-amd1-ed1) on the topic of IEC 60601-2-52 Medical beds as a pre-release. He discusses the actual changes between the 1st edition and 1st edition + A1. This version is the pre-release before the updated Standard is issued as an International Standard (IS), and it is currently available as a Final Draft International Standard (FDIS). IEC website (http://bit.ly/buy-IEC60601-2-52-amd1-ed1) states: “By purchasing this FDIS now, you will automatically receive, also, the final publication.” The voting period ended on February 13, 2015, and the FDIS should be published shortly after (forecasted to be published on March 27, 2015).

Leo’s blog summarizes each of the changes to the Standard. Among the changes, there is a specific requirement to include hazards related to patients taller than 185 cm (like me). These hazards should be included in the risk management file. The new symbols required to identify the requirements for an “adult” are below: 

electrical Saftey 2 Updates on Electrical Safety Standards for Medical Devices IEC 60601

I find this new symbology particularly interesting because there are many medical devices where users frequently select the incorrect size for the patient. Consistent internationally recognized symbology for weight and height would be helpful for these devices, and bariatric specialty devices could benefit from the use of the last symbol.

If you need additional support for any of the IEC 60601 series of standards, please contact Rob Packard by email or phone (+1.802.281.4381) to discuss your specific needs.

Posted in: IEC 60601

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Good Documentation Practices (GDP 101) Webinar

good documetnation practice GDP101 300x261 Good Documentation Practices (GDP 101) Webinar

No White Out!

Medical Device Academy released a new webinar this week for training companies on good documentation practices.

Have you ever wondered where the FDA regulation is that says, “…shall not use white-out to correct quality system records.”

Don’t bother looking, because you won’t find it. You also won’t find any regulations against the use of red pens, highlighters, pencils, or markers. You can’t even find a guidance document that tells you not to put a single line through mistakes, initial and date it.

The applicable regulation is 21 CFR 820.180, but the regulation doesn’t specifically say these things. Instead, the regulation states: “Records shall be legible and shall be stored to minimize deterioration and to prevent loss.” The ISO 13485 Standard is not much different. It states that you must establish a procedure that will “Define the controls needed for the identification, storage, protection, retrieval, retention time and disposition of records.”

Over time medical device companies have developed some standard approaches to meet the requirements for Document Control, Control of Records, and Training. These are the three core processes that I call “good documentation practices.” If you need training or you need tools for training employees, click on the link below to purchase our new webinar on good documentation practices.

http://robertpackard.wpengine.com/good-documentation-practices-webinar/

The webpage also includes an exam for training people on good documentation practices. The exam serves as a useful check for the training, but we recommend that process owners monitor these processes–especially if the process is manual. For example, QC inspectors will complete inspection records and file the record as a quality system record. The QC supervisor, or process owner, should periodically review these records for completeness and accuracy. If the supervisor notices an error, the supervisor should notify the inspector and have them correct the mistake. The supervisor should also track how many times each error is made and specifically where errors are occurring. The collection of this data gives the supervisor trend data to help them identify which forms need to be updated to prevent mistakes and which employees require retraining. This data also provides evidence of competency for each employee concerning good documentation practices.

After you have completed the training, you might also be interested in downloading our procedures for Document Control, Control of Records and Training:

http://robertpackard.wpengine.com/standard-operating-procedures-medical-device-academy/

Posted in: ISO Certification

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Our 510k Project Management Tool – An Inside Look at Our Process

This article explains our 510k project management tool, the 510k Table of Contents, and we provide a form to request a free template.

Table of Contents Screen Capture Our 510k Project Management Tool   An Inside Look at Our Process

Despite all the perceived changes to the FDA’s pre-market notification process (i.e., 510k process), the format and content requirements have not changed much. The most significant change to the 510k process was the introduction of the Refusal to Accept Policy (now updated for 2019) in 2012. The RTA process did not, however, change requirements for format and content. The RTA process simply provides a checklist for reviewers to screen submissions to ensure the submission is complete and follows the required format. Actual content requirements can be found in a 2005 guidance document titled, Guidance for Industry and FDA Staff: Format for Traditional and Abbreviated 510(k)s”. To ensure that you don’t deviate from this required format, use a standardized template for the Table of Contents.

Overview of our 510k project management tool

There are 20 sections to a 510k submission. For each section, Medical Device Academy’s consulting team created a template for the documents to be included in that section. Each section is assigned a volume number (i.e., 1-20), and typically there is an overview document for the section that is identified by Vol x Doc 1. We also use a consistent header and footer for every document to identify the subject device of the submission, the name of the section, and the volume/document numbers. In addition to the templates our consulting team created, several FDA forms must be used for specific sections. These forms are a mixture of MS Word® documents and PDF documents that must be edited in Adobe Acrobat®.

Table of Contents Used as our 510k Project Management Tool

When one of our consultants is starting a new 510k project, we use a spreadsheet version of the Table of Contents. This allows us to perform a gap analysis of the existing documentation available from the client. If the client owns the 510k for the predicate device, then the client may only need to update documents to reflect changes. If the client has a Technical File, then most of the information is available. Still, the consultant must revise the format and organization of the content to fit our 510k document templates. In one of the columns of the spreadsheet, the consultant performing the gap analysis makes comments about what is available and what needs to be done to complete the 510k submission.

Status of Documents

To communicate the status of documents in the gap analysis, and throughout the 510k project, the consultant will color code the sections of the table of contents:

  • green = ready for submission
  • blue = ready for the client’s review and approval
  • yellow = document requires revision and/or reformatting of content
  • red = the information does not appear to be available

Our consulting team also uses this same color coding approach when we create a Technical File or a Design Dossier for CE Marking. We will include cross-references to document and report numbers if controlled documents are available. We also add two columns to track our estimated and actual consulting time for the project. Estimated hours required to complete each section are provided, and then as the project progresses, we update the spreadsheet to include the actual time spent on each section.

Using Dropbox

We share the planning spreadsheet and the documents created for each section of the 510k submission with our clients using http://www.dropbox.com/. In each client’s Dropbox folder, we have sub-folders for the 20 sections of the 510k Table of Contents. As we finalize each document, the documents are reviewed and approved by the client. After final approval of the documents, each document is saved as a PDF–as required for eCopy submissions (updated in 2020). Periodic updates are provided to the client via conference calls. Still, the client can view progress on the overall 510k submission project in almost real-time by reviewing the 510k Table of Contents in spreadsheet form.

Team coordination using our 510k project management tool

We also use our 510k Table of Contents to help identify who is responsible for each section of a 510k submission. Not every consultant is an expert in electrical safety (section 17), biocompatibility (section 15), and pre-clinical animal studies (section 19). Most of Medical Device Academy’s consultants are specialists in a narrow discipline. Therefore, it is common for us to assign different sections to different consultants. By using the same templates and process for each submission, a team can work efficiently from 3 or 4 countries simultaneously on the same 510k submission.

Prioritizing Section Completion

Each section of the 510k submission must be completed, but the order of completing the sections is important. For example, we find that the first section to complete is in section 4–the Indications for Use. This section is essential because the Indications for Use should match the predicate device we are claiming substantial equivalence to in section 12.

Another section we like to work on very early in the project is section 13 for Proposed Labeling. The labeling includes the Instructions for Use (IFU), and the IFU must consist of a statement of the Indications for Use. The sections we prioritize last are the sections that summarize verification and validation testing that has been done. These sections are done last because we find we are almost always waiting for a test report at the end of the project. We also find that testing sometimes needs to be repeated.

Please fill in the form at the bottom of this page if you would like to receive Medical Device Academy’s template for the 510k Table of Contents. We updated our Table of Contents in 2021 again and you can receive a copy via email if you complete the AWeber form below and confirm your desire to receive email updates.

Additional 510k Training

The new 510k book, “How to Prepare Your 510k in 100 Days,” was completed in 2017 but the book is only available as part of our on-line 510k course series consisting of 24+ webinars. Please visit the webinar page to purchase individual webinars.

Posted in: 510(k)

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Auditing the Nonconforming Material Process-21 CFR 820.90-Part III

This blog, “Auditing the Nonconforming Material Process-21 CFR 820.90,” identifies process interactions with the nonconforming material process. 

auditing for compliance 21CFR 829.90 Auditing the Nonconforming Material Process 21 CFR 820.90 Part III

Nonconforming material is not a “bad” thing in and of itself. Having no nonconformities is conspicuous. There are three critical aspects to verify when you are auditing nonconforming materials:

  1. nonconforming materials are identified and segregated
  2. disposition of nonconforming materials is appropriate
  3. feedback from the nonconforming material process interacts with other processes

This article focuses on the third aspect–process interactions. The most efficient method for auditing process interactions is to use turtle diagrams because turtle diagrams provide a systematic framework for identifying process linkages (http://bit.ly/Process-Approach).

Turtle Diagram Step 1

The first step of completing a turtle diagram involves identifying the process owner and obtaining a brief description of the process. This typically will not lead directly to the identification of process interactions–unless the person being interviewed describes the process using a process flow diagram.

Turtle Diagram Step 2

The second step of completing a turtle diagram is where the auditor identifies inputs of raw materials and information to the process. For nonconforming materials, the key is to review the incoming inspection record and the trend of nonconformities from the supplier. In a thorough investigation of the root cause for nonconforming raw materials, an investigator may recalculate the process capability for each dimension to determine if the process capability has shifted since the original process validation by the supplier.

Turtle Diagram Step 3

In the third step of completing a turtle diagram, the auditor documents the flow of product and information when the process is done. The transfer from one process to another will often involve an in-process inspection and updating of the product status. The best practice is to identify these in-process inspection steps in a risk control plan as part of the overall process risk controls for product realization. Although risk control plans are not required in most companies, they will become more prevalent as companies update their quality systems to a risk-based process for compliance with the 2015 version of ISO 9001.

Turtle Diagram Step 4

The fourth step of the turtle diagram identifies calibration, maintenance, and validation that applies to the process of being audited. It is common for nonconformities to occur when measurement devices are out-of-calibration, or equipment is not adequately maintained. Therefore, auditors should always ask what device was used to measure a nonconformity, and what equipment was used to manufacture the product. Auditors should also review calibration and maintenance records for evidence that corrections are being made frequently.

Whenever frequent corrections are needed, the probability of devices being out-of-calibration and/or equipment malfunctioning increases. Auditors should also verify that the process parameters in use match the validated process parameters. Ideally, validation of process parameters is also directly linked to process risk analysis, and in-process inspections are performed whenever process capability is inadequate to ensure conforming parts. If an auditor observes a high frequency of nonconformities, then an in-process inspection should be implemented for containment, and the validation report should be compared to current process performance.

Turtle Diagram Step 5

The fifth step of completing a turtle diagram involves the identification of personnel and sampling training records. The procedure for control of nonconforming material should be required training for anyone responsible for initiating, investigating, or completing a nonconforming product record (i.e., NCR). Critical interactions to verify for effectiveness are related to process changes. If a procedure changes, training may need to be updated. An auditor should verify that there is a mechanism for tracking which revision of the procedure each person is trained to. In addition, training records should verify that training requirements are documented, training is effective, and that the person can demonstrate competency by correctly completing the sections of an NCR form. The auditor can review completed records to verify competency, but the auditor can also interview personnel and ask hypothetical questions.

Turtle Diagram Step 6

The sixth step of completing a turtle diagram involves the identification of all applicable controlled documents, such as procedures, work instructions, and forms. The auditor should also verify that the process for control of external standards is effective. In the case of controlling nonconforming product, there are seldom any applicable external standards. However, it is critical to verify that the current forms and NCR identification methods are being used for control of nonconforming product.

Turtle Diagram Step 7

The seventh and final step of the turtle diagram is data analysis of metrics and quality objectives for a process. For control of nonconforming product, there should be evidence of statistical analysis of the nonconforming product to identify the need for corrective actions. This is a requirement of 21 CFR 820.250. This data analysis should then be used to quantify process risks that may be used for decision-making and to explain those decisions during regulatory audits.

The above process interactions are just examples, and auditors may identify other essential process interactions during an audit. Each process interaction that touches a record of nonconforming product is a potential audit trail that could lead to value-added findings to prevent future nonconformities.

If you need help improving your process for controlling nonconforming product, or with auditing in general, please email Rob Packard.

Posted in: ISO Auditing

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Management Review Procedure Case Study Example

This article, “Management Review Procedure Case Study” describes an error-proof method for review and approval of procedures.

Redlined Management Review Procedure Management Review Procedure Case Study Example

The first time I was ever formally trained on how to conduct a document review was during a lead auditor course. I thought the topic seemed out of place, but as I audited more companies, I realized that missing a regulatory requirement in a procedure was quite common. Regardless of who reviews a procedure, or how many times it is reviewed, something is always missed. Unfortunately, a desktop audit of procedures is not an effective corrective action or verification method. Auditing procedures is an ineffective method for reviewing procedures because audits are limited by sampling.

Instead of random sampling, a systematic review of 100% of regulatory requirements is needed to ensure that none of the regulatory requirements are accidentally omitted. Systematically reviewing the requirements for each country your company is selling in is tedious at best. You need a tool to make the reviewing process error-proof and straightforward. You also need each reviewer of the procedure to have a defined function to eliminate the duplication of work.

Procedure Reviewer Roles

Typically, there are 3-5 reviewers of procedures in most companies. Some companies make the mistake of having as many as 8-10 reviewers of procedures, but more is not better in this case. There are four primary roles for review and approval of procedures:

  1. process owner
  2. quality management
  3. regulatory
  4. independent

The process owner may be the author of a procedure, but I don’t recommend it. Editing someone else’s work is much more useful than editing your own work. Therefore, I recommend that department managers delegate the responsibility for writing a draft of a procedure to a subordinate that needs to perform the procedure. Then the department manager, who should also be the process owner, is responsible for reviewing and approving the initial draft.

The quality management person should be responsible for reviewing the procedure for accuracy and interactions with other processes. For example, the management review process has eight required inputs (i.e., ISO 13485, Clause 5.6.2a-h). Each of those inputs comes from another process and procedure. It is essential to ensure that if you are reviewing the complaint handling procedure, somewhere in that procedure, it should state that the monitoring and measuring of complaint trends should be input into the management review process.

The regulatory person is responsible for verifying that the procedure meets 100% of the regulatory requirements. This person should verify that the scope of the procedure identifies the relevant markets. If there are references to documents of external origin, the regulatory person should verify that these references are accurate. It is recommended to eliminate references to revisions of documents of external origin and internal procedure revisions because the inclusion of revisions will increase the frequency of minor revisions to procedures that add no value.

Finally, the independent reviewer is looking for two things:

  1. Does the procedure make sense–to someone that performs the procedure (if that person was not the author); and to an external auditor, such as a certification body (internal auditors can fill this role)?
  2. Are there typos, spelling, or grammar mistakes?

The independent reviewer does not need to be a manager. It needs to be someone that writes well. Copy editing is tedious, but apparent mistakes in spelling or grammar prompt auditors to review procedures more carefully. I recommend asking an internal auditor to be the independent reviewer.

Reviewing Regulatory Requirements

The two most common reasons for audit findings are:

  1. the procedure is not being followed, and
  2. a regulatory requirement is not being met.

The first problem should be addressed by having processing owners review and write procedures instead of asking quality assurance to provide a procedure. If you are purchasing a procedure, it’s important for the person that will be performing the procedure to carefully review the procedure to ensure it matches how they intend to perform that process. If it’s a manufacturing procedure, I like to conduct the training of personnel with a draft procedure and hand out red pens. That also dramatically reduces complaints from the people that do the work.

For regulatory requirements, your regulatory reviewer needs to create a checklist that includes 100% of the requirements for that procedure. The model I like to follow is the Essential Requirements or Essential Principles Checklist used for technical documentation (i.e., for CE Marking). There are 13 Essential Requirements, and most of the requirements have multiple subparts. The regulatory person that completes an Essential Requirements Checklist must indicate the following information next to the applicable requirement in the checklist table:

  • yes, the requirement applicable or justification if it’s not applicable
  • a reference to any applicable standards
  • a cross-reference to the record where evidence of meeting the requirement can be found (e.g., the risk management file)

Regulatory personnel can revise this approach slightly by doing the following for a review of procedures:

  • yes, the requirement applicable or justification if it’s not applicable
  • a reference to the applicable specific sub-clause in a Standard or a regulation
  • a cross-reference to the subsection of the procedure where evidence of meeting the requirement can be found (e.g., section 5.1 of the SYS-003)

Case Study of SYS-003, Management Review Procedure

In the Medical Device Academy Management Review Procedure, Section 8 is the “procedure section.” Sub-section 8.3 of the procedure lists all the required inputs to a Management Review meeting. Next to each input, I have included a cross-reference to the sub-clause in ISO 13485:2003 for the Management Review input. There is also a requirement in 21 CFR 820.20 for conducting Management Reviews at scheduled intervals. This requirement is met by sub-section 8.1 of the Management Review procedure.

Teaching Auditors to Review Regulatory Requirements

Now, when I teach my version of the Lead Auditor Course, I ask attendees to split into small groups and review one of their procedures. In the last company I did this, each of the four teams found a regulatory requirement missing in the procedure they were reviewing. All four procedures the teams selected were reviewed, approved, and currently in use.

Management Review Webinar & Procedure – Free Download

Posted in: ISO Certification

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