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Bioburden Failure Analysis: How auditors can investigate spikes in environmental monitoring

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This webinar explains how auditors can investigate unexpected increases in bioburden as part of a bioburden failure analysis that will be used to implement containment, corrections, and corrective actions.

Every medical device company with a controlled environment and sterilized products is required to monitor bioburden and to implement process controls to ensure that bioburden remains within the validated limits. Unfortunately, there are so many possible sources of bioburden it is easy to have a sudden increase (i.e., spike) in the bioburden of raw materials, finished devices, or the controlled environment. Human error is usually blamed, but retraining people is not an effective corrective action. You need to design solutions that eliminate the need for human perfection. When a spike occurs, what do you do?

This webinar will help you pinpoint the actual cause of your bioburden problems. Identifying the actual cause of quality issues is critical to developing effective corrective actions. If you do not narrow the potential causes down to the actual cause or causes, then you will waste time and money implementing solutions you didn’t need. If miss the actual cause of exceeding your validated bioburden limits, then your corrective actions will not be effective and you will need to re-open your CAPA or initiate a new CAPA. You may also be forced to recall non-conforming products.

In this presentation, our speaker explains how to use the process approach to auditing in order to identify the root cause for excursions above established bioburden limits for 1) raw materials, 2) finished devices, and 3) controlled environments. It’s easy to think of ways your process controls could have failed, but you will save time and money if you can identify how your process controls actually failed.

Join us for this webinar as our speaker teaches you how to use your auditing skills to investigate the cause of exceeding validated bioburden limits.

This webinar covers:

  • Important environmental monitoring data to collect and analyze
  • Most common reasons for exceeding validated bioburden limits
  • Containment and Corrections
  • Corrective Actions & Preventive Actions
  • Training & Quality Objectives

Who should watch?

  • Internal Auditors and Supplier Auditors
  • Anyone Responsible for Controlled Environments
  • Anyone Responsible for Investigation of Bioburden Failure Analysis

Please Note: Purchase of the webinar includes the Native PowerPoint slide deck and the recording of the webinar. You will have the ability to share this content with anyone in your company—as many times as they wish.

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This webinar recording is only $129 (AND INCLUDES – SLIDE POWERPOINT PRESENTATION):

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This webinar explains the process for auditing the environmental monitoring process and controlled environments. The recording will be sent in a separate email and this product includes a copy of the native PowerPoint slide deck.
Price: $129.00

Exam and Training Certificate available for $49.00:

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This is a 10 question quiz with multiple choice and fill in the blank questions. The completed quiz is to be submitted by email to Rob Packard as an MS Word document. Rob will provide a corrected exam with explanations for incorrect answers and a training effectiveness certificate for grades of 70% or higher.
Price: $49.00
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About Your Instructor

Home page video cropped 150x150 Bioburden Failure Analysis: How auditors can investigate spikes in environmental monitoringRob Packard is a regulatory consultant with ~25 years of experience in the medical device, pharmaceutical, and biotechnology industries. He is a graduate of UConn in Chemical Engineering. Rob was a senior manager at several medical device companies—including the President/CEO of a laparoscopic imaging company. His Quality Management System expertise covers all aspects of developing, training, implementing, and maintaining ISO 13485 and ISO 14971 certifications. 2009-2012, he was a lead auditor and instructor for one of the largest Notified Bodies. Rob’s specialty is regulatory submissions for high-risk medical devices, such as implants and drug/device combination products for CE marking applications, Canadian medical device applications, and 510(k) submissions. The most favorite part of his job is training others. He can be reached via phone at 802.281.4381 or by email. You can also follow him on YouTube, LinkedIn or Twitter.

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Validating Bioburden Limits

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This article explains the process for setting and validating bioburden limits, and you will learn when investigations are needed. 

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 uses 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 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 the 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 differ 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.

Rule of Thumb for Setting Limits

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 that 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.

Which factors affect bioburden?

For this example, we have three aspects 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, the 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, you must plan according to the most critical needs.

Validating Bioburden Limits

After establishing 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 (i.e., bioburden failure), 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 performed when bioburden increases for unexplained reasons.

Once the sources of bioburden are identified and quantified, 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 components, 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 parts and your assembly area.

process validation webinar Validating Bioburden LimitsIf you are interested in learning more about process validation, please download the process validation webinar. We also published a blog on sterilization and shelf-life validation for 510k submissions.

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

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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.

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Complaint Investigation Case Study (21 CFR 820.198): Part 2

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This article is part 2 of a two-part series specific to complaint investigation requirements as specified in 21 CFR 820.198 (http://bit.ly/21CFR820198) of FDA QSR. This second part explains how to perform a complaint investigation and provides a complaint investigation case study.

complaint part 2 Complaint Investigation Case Study (21 CFR 820.198): Part 2

 

Last week’s blog  reviewed the requirements for a complaint investigation, while this blog includes the following information on how to conduct an investigation:h

  1. How thorough should your investigation be?
  2. Investigation Methods
  3. Verification of the Cause
  4. Documenting Your Investigation
  5. Complaint Investigation Case Study

How thorough should your investigation be?

The depth of investigation should be appropriate to the importance of the complaint. If a previous complaint of similar nature has already been investigated, the investigation may only gather enough information to verify that complaint has the same root cause. However, if a complaint involves an adverse event (i.e., is reportable under 21 CFR 803), then additional information needs to be recorded in the complaint record as per 21 CFR 820.198d:

  1. Does the device fail to meet specifications?
  2. Was the device used for treatment or diagnosis?
  3. What was the relationship, if any, between the device and the reported event?

If the person gathering information from the complainant cannot immediately identify a cause code, or the incident involves a severe injury or death, then it is essential to collect as much information as possible. Typically, the complainant will be asked to return the device to determine if the device malfunctioned.

Investigation Methods

A complaint investigation is not any different from any investigation you perform for a CAPA. The most critical first step is to determine the cause of the complaint. To determine the cause, you need to sample additional records and inspect the device if it is available. If the device is not available, you might also look at other product from the same lot that remains in inventory. The following article I wrote suggests seven ways to investigate a complaint when a device is not returned: http://bit.ly/DeviceNotReturned.

One of the methods described in the article above is an Ishikawa Diagram or “Fishbone Diagram.” This is one of the five root cause analysis tools that I teach in my CAPA webinar (http://bit.ly/enKapCAPAwebinar). Ishikawa Diagrams are an ideal tool for root cause analysis if you have no idea what the cause of the complaint is because this tool provides a systematic process for narrowing down the potential causes, to the narrow few that are most likely. You are not required to use this tool, but you should describe in your complaint record what type of root cause analysis was performed.

Verification of Cause

Once you have identified the root cause, or at least narrowed your list to the most likely causes, you should then verify that the cause will result in the observed malfunction by recreating the scenario if possible. Ideally, you should be able to simulate the event that resulted in the complaint and demonstrate that you can reproduce the problem. This is important because if you cannot verify the cause of a device malfunction, then you will have difficulty verifying the effectiveness of corrective actions for an infrequent complaint.

Documenting Your Investigation

There is no specific format for the way a complaint investigation is documented. Still, most complaint records have a small section on the complaint form that allows them to write a short paragraph summarizing the investigation and the results. Unfortunately, most of the spaces provided on forms are completely inadequate for the amount of information that should be recorded. Therefore, the best approach is often to write, “See attached complaint investigation.” This is especially true if the complaint is reportable (i.e., requires MDR under 21 CFR 803). Good documentation is quantitative and specific. You need to identify which records were sampled as part of the investigation. You should demonstrate that you have expanded your initial search to determine if the problem exists in multiple production lots of the same product code, multiple product codes within the same product family and any other product families that may use similar raw materials, design features, equipment, testing methods or procedures.

Complaint Investigation Case Study

If your company manufactures cast orthopedic implants for the knee and you receive a complaint about an implant that has a small imperfection in the bearing surface of the femoral implant, you may need to perform an investigation–especially if this has not occurred previously. You should request a return of the implant for inspection to verify that the imperfection is nonconforming and not just a cosmetic defect.

Your investigation should include a review of the lot history record for an entire lot of implants–as well as any other parts that they may have been cast at the same time. All the process conditions identified throughout the manufacturing process should be compared to the validated process parameters. Special attention should be given to the inspection results that were recorded for the castings (i.e., radiographic inspection, fluorescent penetrant inspection, and metallurgical inspection). Ideally, these inspection methods should be repeated for 100% of the production lot to ensure that the inspection results meet the acceptance criteria. Documentation of the investigation should include copies of all records that were reviewed and photos if visual inspections were repeated.

If you are interested in learning more about complaint handling, you might be interested in downloading the webinar that Medical Device Academy recorded last year for complaint handling and vigilance reporting (http://bit.ly/Complaint-Webinar-Landing). We can also help you one-on-one with a current complaint investigation you are conducting. Please don’t hesitate to contact me. Mobile: 802.281.4381 or rob@13485cert.com.

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FDA Inspections-Complaint Investigation Requirements-Part I

1 Comment / Complaint Handling / By / , , ,

“FDA Inspections-Complaint Investigation Requirements-Part I” is a two-part series that provides an overview of 21 CFR 820.198 requirements. 

complaint part 1 FDA Inspections Complaint Investigation Requirements Part I

Last week, I received a message from someone asking for advice on how to perform a complaint investigation. She has a complaint handling procedure that explains how to determine if complaints are reportable (http://bit.ly/Medical-Device-Reporting), and she is the complaint coordinator. Her procedure includes a list of pre-determined cause codes for the most common complaints the company has received in previous years. Her system does not require a complaint investigation if an existing cause code is identified. She would like to know how to perform an investigation if she receives a complaint that does not fit one of the existing cause codes.

Is It a Complaint?

Most discussions about complaint handling begin with the definition of a complaint [i.e., 21 CFR 820.3(b); http://bit.ly/21CFR820-3]. However, if a complaint is received during an investigation of a device rather than the use of the device, the FDA will still consider this as being “after releasing for distribution.” The reason is that release for distribution occurs at final inspection. If the device breaks during installation, the device was still distributed.

One last question. Is it correct to consider a complaint only when the device is live and not during the settings and installation process of the device? (The definition states “after it is released for distribution,” what do they mean by this?).

What is Required?

The FDA QSR section specific to complaint handling is 21 CFR 820.198 (http://bit.ly/820-198). There are seven subsections (i.e., “A” through “H”) that comprise the regulation.

  1. Manufacturers shall maintain complaint files and establish procedures for complaint handling.
  2. Manufacturers must review and evaluate if an investigation is needed.
  3. Manufacturers must perform an investigation automatically for any complaint involving a device malfunction–unless an investigation has already been performed for a similar complaint.
  4. Separate files shall be maintained for complaints that involve adverse events that are reportable under 21 CFR 803 (http://bit.ly/21-CFR-803).
  5. The content of a complaint investigation record is specified in this subsection.
  6. When the complaint handling unit is located at another facility, the records of investigations shall be reasonably accessible to the manufacturing establishment.
  7. When the complaint handling unit is located outside the USA, then the records must be reasonably accessible at a U.S. manufacturer or the location of an initial distributor.

What Does the FDA Expect to See?

FDA inspectors are guaranteed to sample complaint records and CAPA records during every routine inspection. The complaint records sampled will typically be limited to a specific product family that has been selected as the focus of the investigation. Most companies have an electronic log of the complaints, and the investigator may request a sorted list that only includes complaints specific to that one product family. The investigator will already be aware of all of your reported adverse events associated with the product family, and there may be one or two records they specifically want to investigate. The investigator will also review the complaint log to see if there are any complaints with a description that sounds like it might be reportable–even though the complaint was not reported.

The investigator will verify that each complaint record includes the content specified in subsection “E”:

  1. name of the device;
  2. the date the complaint was received;
  3. any device identification(s) and control number(s) used;
  4. the name, address and phone number of the complainant;
  5. the nature and details of the complaint;
  6. the dates and results of the investigation;
  7. any corrective action is taken; and
  8. any reply to the complainant.

In my response to the question that I received, I also included advice on how to conduct an investigation. In general, the investigation is no different than an investigation for any CAPA. The first step is to perform a root cause analysis. The second part of this article will explain the investigation process in more detail.

Register to receive email notification of new blog postings (http://bit.ly/MDA-Blog), so you can read the second part of this article next week. If you are interested in learning more about complaint handling, you might be interested in downloading the webinar that Medical Device Academy recorded last year for complaint handling and vigilance reporting (http://bit.ly/Complaint-Webinar-Landing). We can also help you one-on-one with a current complaint investigation you are conducting. Please don’t hesitate to contact me and ask for help: Mobile: 802.281.4381 or rob@13485cert.com.

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11 Steps to Obtaining CMDCAS Certification-Part 2

2 Comments / Health Canada / By / , ,

11 steps CMDCAS part2 11 Steps to Obtaining CMDCAS Certification Part 2

“11 Steps to Obtaining CMDCAS Certification-Part 2” focuses on the process of updating the quality system and preparing for your certification audit. The first three steps focus on classification and selecting a registrar. 

Steps 4: Writing a Licensing Procedure

Nowhere in the Canadian Medical Devices Regulations (CMDR), or ISO 13485, does it require that you have a procedure for licensing or writing your technical documentation. However, most of the registrar auditors I have observed expect to see a procedure for this. You can reference Health Canada’s guidance documents (http://bit.ly/CanadianGuidance) and the CMDR (http://bit.ly/CanadianMDR), but that’s not enough. Typical audit questions I see on regulatory checklists include:

  • Is the company required to notify Health Canada of changes to the certificate within 30 days?
  • Is the classification rationale documented?
  • What is the procedure for maintaining technical documentation for Health Canada?
  • Is there a procedure for identifying significant changes that require notification of Health Canada (http://bit.ly/Canada-Significant-Change)?

Step 5: Mandatory Problem Reporting (MPR)

Some companies choose to have one procedure for adverse event reporting that covers all the countries that they distribute the product(s) in. However, I recommend having a separate procedure for each country that is shorter and will require updates less often. It’s a personal preference, but I find people are intimidated by a longer, combined procedure. The following are the key elements for the MPR procedure:

  • decision tree for when to report
  • timescale for reporting deadlines
  • form references
  • address for reporting
  • reminder to report the event to the US FDA if the product is also sold in the USA

Step 6: Recall Procedure

Unlike the MPR procedure, I recommend having only one recall/advisory notice procedure to comply with Health Canada’s requirements and the rest of the worlds’ regulatory requirements. I typically choose this approach, because the recall/advisory notice procedure is less complex than the adverse event reporting procedures. The key element I look for in this procedure is the address for notifying Health Canada of a recall because there is a different address in each region of Canada.

Step 7: Finding a Distributor

A Canadian Medical Device License is a license to distribute medical devices. Only Class I devices require an establishment license. Therefore, your company will be able to sell directly to physicians prescribing your device if you have a Class II, III, or IV Medical Device License. If you choose to use a distributor in Canada, the distributor must meet the requirements for record-keeping, and demonstrate the ability to conduct a recall, if necessary. Often, this is done by having a quality agreement in place, which stipulates the retention of distribution records. Also, your company should conduct a mock recall once distribution has begun. This will ensure that the distributor is compliant with the requirements for maintaining distribution records. The instructions for conducting a mock recall will be included in the revisions to the recall/advisory notice procedure described in Step 6.

Step 8: Training

The most common root cause of audit findings related to the CMDR is a lack of understanding with regard to the regulatory requirements. A better procedure can help, but there is no substitution for training on the CMDR. The CMDR is relatively easy to understand when compared to European Regulations, and the CMDR is shorter in length than US FDA regulations. However, most people have a lot of difficultly understanding the jargon of medical device regulations unless they are a regulatory expert. Therefore, it is essential to develop training that summarizes the CMDR for anyone in your company that will be involved with complaint handling, adverse event reporting, recalls and regulatory submissions–including design changes.

Medical Device Academy has a recorded webinar designed explicitly for company-wide training when companies are preparing for CMDCAS certification: http://bit.ly/CMDCAS-webinar. The cost of the webinar is $129, and there is a 10-question exam to verify the effectiveness of training. The exam costs $49 to grade, correct answers are explained for each question, and a certificate is issued for a passing grade of 70% or more.

Step 9: Internal Auditing

Your registrar will verify that you conducted an internal audit of the quality system for compliance with applicable sections of the CMDR. This can be performed by one of your internal auditors or a consultant. The audit can be completed on-site, but sometimes a remote desktop audit will suffice. Since there will be no records of distribution, licensing, complaints, or recalls before the CMDCAS certification–there is little value in conducting an on-site audit before certification. The duration of the internal audit should not exceed a day. It typically can be completed in four hours by an experienced auditor–plus a couple of hours of audit report writing.

Step 10: Conducting the CMDCAS Certification Audit

Your registrar conducts this step. Any audit findings will require a corrective action plan that is accepted by the auditor before the new certificate can be issued. The new CMDCAS certificate will look very similar to the existing certificate, but there is typically an additional logo indicating compliance with CMDCAS. This is not the same as the SCC logo indicating accreditation by the Standards Council of Canada. Once the initial extension to the scope is completed, the continued certification is evaluated as part of the normal surveillance audits and re-certification audits.

Step 11: License Application Submission

For a Class 2 device license application, you need to complete a form, send a check, and include a copy of your new ISO 13485 Certificate with CMDCAS. The response from Health Canada is typically within 15 days or less–depending upon the current workload. Class III and IV device license applications are more complex and require technical documentation–including a clinical evaluation.

The timelines for approval of a Class III or IV device license is closer to the timeline for a 510(k) clearance letter from the US FDA. Health Canada’s Device Licensing Division is quite responsive to email inquiries, and they will respond to voicemail messages. Once a license is issued, it is typically faxed to the company, and a hardcopy is mailed. I recommend a dedicated fax number for your regulatory affairs department.

Medical Device Academy, Inc. has a complete set of generic quality system procedures–including Canadian Medical Device Licensing and Mandatory Problem Reporting. Since the requirements for reporting adverse events is quite different in each country, it is not recommended to combine these procedures with other procedures. The cost of purchasing generic procedures from Medical Device Academy in a native MS Word Format is $300/procedure. Purchase grants your company a non-exclusive license to the content of the procedure for internal use. Please email Rob Packard if you are interested.

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Nonconforming Materials Disposition

4 Comments / ISO Certification / By / , , , , ,

Nonconforming materials disposition can be simplified into four categories: scrap, return to supplier, rework, and use as is.

Sorting Disposition of Scrap Nonconforming Materials Disposition

Nonconforming materials disposition

In our previous blog, we focused on requirements to identify and segregate non-conforming materials. Once nonconformities are labeled and locked in your quarantine cage, what do you do next? The next step in the process of determining nonconforming materials disposition. The most common dispositions are:

  • Scrap
  • Return to Supplier (RTS)
  • Rework
  • Use As Is (UAI)

Some companies also have dispositions of sort and repair. The sort is not a disposition and often creates confusion for anyone auditing records of nonconforming materials. Sorting is the process that you must perform when a lot of material fails to meet acceptance criteria. Still, some of the individual units within the lot meet the acceptance criteria. In this scenario, the following sequence of events is recommended.

Sorting nonconforming materials

First, the lot is segregated from a conforming product, and an NCR number is assigned. Next, the lot is 100% inspected for the defect, and the results of the inspection are recorded on the inspection record. It is important to record the specific number of non-conforming units on the NCR record–not the total amount inspected. The final step is to release a conforming product back into the production process or warehouse, and the Material Review Board (MRB) will disposition the units identified as non-conforming.

If identifying a non-conforming product requires an inspection method that is not typically performed, then the inspection plan needs to be corrected, or a corrective action plan is needed. New and unforeseen defects may indicate a process change, a change in the raw materials, or inadequate training of personnel at your company or your supplier. An investigation of the root cause is needed, and it is recommended to consider documenting this investigation as an internal CAPA or a Supplier Corrective Action Request (SCAR).

Material Review Board (MRB) determines the nonconforming materials disposition

Most companies have a “Material Review Board” (MRB) that is responsible for making the decision related to the disposition of non-conforming material. Typically, the MRB will be scheduled once per week to review the most recent nonconformities. The board usually consists of a cross-functional team, such as:

  • Quality Assurance
  • Research & Development
  • Manufacturing
  • Supply Chain
  • Regulatory

The reason for a cross-functional team is to review the potential adverse effects of rework and potential risks associated with a UAI disposition. If rework is required, the cross-functional team will typically have the necessary expertise to create a rework instruction and to review and approve that rework instruction–including any additional inspections that may be required beyond the standard inspection work instructions.

Scrap

If the material is going to be scrapped, there is no risk to patients or users. Therefore, the entire MRB team should not be required to scrap products. Because there may be a cost associated with a scrap of non-conforming products, it is recommended that someone from accounting and a quality assurance representative approve scrap dispositions. Other departments should be notified of scrap, but a trend analysis of all non-conforming products should be reviewed by each department and by top management during management reviews. Auditors and FDA inspectors, specifically, will be looking for evidence of statistical analysis of non-conforming material trends and the implementation of appropriate corrective actions.

Return to Supplier (RTS)

Returning non-conforming material to the supplier that produced it is the most common disposition, but the trend of RTS should continuously be improving. If the trend of RTS is not improving, your supplier qualification process or your supplier control may be inadequate. The best way to ensure that the trend is improving is to initiate a SCAR. Some companies automatically wait until they have a trend of non-conforming material before initiating a SCAR. However, if you wait until a defect occurs twice, you are doubling the number of nonconformities for that root cause. If you wait until a defect occurs three times, you are tripling the non-conformities. For this disposition, there also does not need to be approval from the entire MRB. Typically, only someone from the supply chain management and quality assurance are needed to return non-conforming products to a supplier.

Note: You should not always wait until there is a “trend” to request supplier corrective action.

Rework

Almost every auditor looks for a specific phrase in the procedure for Control of Nonconforming Material: “The MRB will review and document the potential adverse effects of rework.” Most companies are doing this, but the procedures often do not specifically state this requirement, and rework instructions are often missing any specific inspection instructions that have been added to reduce risks associated with the rework process. Repeating the normal inspection criteria is seldom adequate for reworked product because the rework process typically results in different defects.

Another phrase that auditors and inspectors are looking for is the requirement to document the rework instructions and to have the instructions reviewed and approved by the same functions that reviewed and approved the normal production process. This requirement is often not specifically stated in the procedure, and FDA 483 inspection observations are commonly issued for this oversight.

Use As Is (UAI)

The UAI disposition should be rare. When I see a large number of NCRs with a disposition of UAI, I expect one of two reasons for this situation. First, the NCRs are for cosmetic defects where the acceptance criteria are too subjective and inspectors need clear guidelines regarding acceptable blemishes and unacceptable nonconformities. The visual inspection guides used during solder joint inspection for printed circuit boards are an excellent example of best practices for clearly defining visual inspection criteria. Personally, I prefer to use a digital camera to take pictures of representative “good” and “bad” parts. Then I create a visual inspection chart with a green, smiley face for “good” and a red, frowny face for “bad.” The best inspection charts identify the proper inspection equipment and quantitative acceptance criteria with pictures and symbols instead of words.

The second reason for a larger percentage of UAI dispositions is that the product specifications exceed the design inputs. For example, if a threaded rod needs to be at least 1” long, but 1.25” long is acceptable, then you should not approve a drawing with a specification of 1.00” +/- 0.05”. Often, the legend of drawings will define a default tolerance that is unnecessary. A more appropriate specification would be 1.13” +/- 0.12”. No matter how much work it is to specifically define tolerances for each dimension on a drawing, the work required to do this at the time of initial drawing approval is much less than the work required to justify a UAI disposition. FDA inspectors will consider a UAI disposition as a potentially adulterated or misbranded product, and a formal Health Hazard Evaluation (HHE) may be required to justify the reason why the product is not recalled.

Regardless of the disposition of the product, the decision for disposition should be a streamlined process that is not delayed unnecessarily. In order to ensure that your non-conforming material dispositions are effective and processed in a timely manner, our next blog in the series about control of non-conforming materials will focus on process interactions, monitoring and measuring of non-conforming product and when to initiate a CAPA or SCAR to prevent more NCRs.

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7 Steps to Respond to an FDA 483 Inspection Observation Webinar

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Rob Packard of Medical Device Academy provides 7 proven steps to effectively respond to an FDA 483. Included are examples, recommendations and tips; for implementing the 7 steps including:

  1. Respond within 15 business days
  2. Use your CAPA form
  3. How to document a root cause investigation
  4. Don’t forget correction and containment
  5. Corrective action plans
  6. Show you have already taken action
  7. Follow up before the FDA

Other topics reviewed include: 

  • 8 D Process-“8 Disciplines” to be utilized as a model for an effective CAPA process
  • Recalls
  • Documentation
  • Effectiveness checks (examples)
  • Trend analysis

7 steps 7 Steps to Respond to an FDA 483 Inspection Observation Webinar

This webinar recording is only $129 (AND INCLUDES NATIVE SLIDE POWERPOINT PRESENTATION FILES):

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SOPS 7 Steps to Respond to an FDA 483 Inspection Observation Webinar

About Your Instructor

Medical Device Academy Robert Packard 7 Steps to Respond to an FDA 483 Inspection Observation WebinarRobert Packard is a regulatory consultant with 20 years experience in the medical device, pharmaceutical and biotechnology industries. He is a graduate of UConn in Chemical Engineering. Robert was a senior manager at several medical device companies—including President/CEO of a laparoscopic imaging company. His Quality Management System expertise covers all aspects of developing, training, implementing, and maintaining ISO 13485 and ISO 14971 certification. From 2009-2012, he was a lead auditor and instructor for one of the largest Notified Bodies. Robert’s specialty is regulatory submissions for high-risk medical devices, such as implants and drug/device combination products for CE marking applications, Canadian medical device applications and 510(k) submissions. The most favorite part of his job is training others. Specialties: CE Marking, Canadian Medical Device Applications, Post-Marketing Activities, Supplier Quality, CAPA, Risk Management, Auditing, Sterilization Validation, Lean Manufacturing, Silicone Chemistry, Extrusion, Bioprocess Engineering, and Strategy. He can be reached via phone 802.258.1881 or email. You can also follow him on Google+, LinkedIn or Twitter.

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7 Steps to writing an FDA 483 response

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Responding in 15 business days is one of 7 steps on how to write an FDA 483 response, but do you know what should be in your response?7 steps fda 483 blog 7 Steps to writing an FDA 483 responseWhen an FDA investigator has an inspection observation, the investigator issues an FDA 483. “Form 483” is the FDA form number. If your company receives an FDA 483, it is critical to understand how to write your FDA 483 response in order to avoid a Warning Letter. In the words of a former FDA investigator, “Many, many times I have seen an [Official Action Indicated (OAI)] classified inspection that had been recommended for a Warning Letter by the compliance branch be set aside based upon the response of the firm.”

The best way for your company to write a FDA 483 response is to provide a brief cover letter and to use your CAPA process. Every 483 inspection observation needs to be addressed in the FDA 483 response as a separate CAPA. Make sure that your response includes the following seven steps below:

  1. respond within 15 business days (earlier is better)
  2. use your CAPA form and a cover letter–instead of a memo
  3. document the investigation that was conducted with a concisely stated root cause
  4. identify containment measures and corrections to address each specific observation by the FDA inspector
  5. identify corrective actions planned and the date(s) you expect to complete implementation
  6. Include documentation of containment, corrections and corrective actions that are completed at the time you submit the response
  7. follow-up with a memo confirming that all the corrective actions are complete and include all related documentation–including training for any new procedures or any new corrective actions that warranted training

Your FDA 483 response is required in less than 15 business days

The FDA has always involuntarily required a medical device firm, or any firm under FDA jurisdiction that received an FDA 483, to provide a written FDA 483 response to the District Office within 15 business days. As of two years ago (http://www.gpo.gov/fdsys/pkg/FR-2009-08-11/pdf/E9-19107.pdf), it became mandatory that the Agency must receive a FDA 483 response within 15 business days, or an automatic Warning Letter is issued. You need to respond aggressively to FDA 483s with corrective actions, and submit your response early. The FDA has also modified the format of the response to require email responses.

Use your CAPA forms instead of a memo.

I have asked several former FDA investigators whether they would prefer to see firms submit responses in memo format, or by using their CAPA forms and a cover letter. Some told me that they prefer to see firms use their CAPA forms, while others don’t seem to have a preference. Nobody from the FDA has ever indicated a preference for a memo. I see no point in doubling your work and risking transcription errors. If you have an electronic system that does not have an easy-to-follow output format, go ahead and copy-and-paste the information from your electronic database to your memo. If the CAPA system output is easy to follow, just use a cover letter and copies of the forms.

Document the investigation and root cause

This is definitely my pet-peeve, but a one-sentence “root cause” is not enough for an FDA 483 response. Regardless of whether I am doing a mock-FDA inspection, an internal audit, or a supplier audit–I expect you to document how you determined the root cause (http://robertpackard.wpengine.com/five-tools-for-conducting-root-cause-analysis/). If it’s trivial and obvious, then it must have been something important, or I would not have written a nonconformity. Therefore, you should be looking beyond the immediate scope of the FDA 483 to ensure that a similar problem cannot occur elsewhere. In the language of the FDA, this is a preventive action, because you are preventing occurrence with another process or product. Most ISO certification auditors are purists, and they won’t accept this as a preventive action. You will have to show the purists something special–maybe from your data analysis.

Don’t forget containment and correction

For every 483 observation, including the subparts, you need to identify if immediate containment is necessary and how you can correct the problem. Whenever possible, you should attempt to implement the containment and corrections during your FDA inspection. It would be fantastic to give the FDA inspector a copy of the new CAPA you initiated during the audit. The new CAPA would identify containment and corrections that have been or will be implemented–including any nonconformity(s) you initiated to quarantine product. You may still get an FDA 483 inspection observation, but you are likely to convert a possible Official Action Indicated (OAI) into a Voluntary Action Indicated (VAI). You can also modify the CAPA wording later in your FDA 483 response to include a cross-reference to the FDA 483 and quote the exact wording the inspector uses.

Explain the corrective action plans and timelines

Clarity, brevity, and realistic plans are critical in this section of your response. I prefer a table that looks like the example shown below.

7 steps 483 chart 7 Steps to writing an FDA 483 response

Show the FDA you have already taken action in your FDA 483 response

Whenever possible, you want to show the FDA that you are taking action without delay. If you revised the SOP for MDRs and scheduled a group training for July 15, then you should provide the FDA a copy of the revised procedure and a copy of the agenda for your planned training session. The only caution is to only commit to actions you are certain you will implement. You can always do more, but it will be much harder to explain why you did not implement an action you submitted in your FDA 483 response.

Follow-up with a second FDA 483 response before the FDA asks for it

The FDA’s compliance office will be looking for a response when an FDA 483 is issued, and they will review your response. The investigator will get a copy of the FDA 483 response, and the investigator will comment on the response. The compliance office and the investigator enter their comments into a CDRH database. Still, the comments are only general, as to whether the response is adequate or inadequate and will require additional review.

If you do not hear back from the FDA, do not assume that the compliance office or the investigator was satisfied. You should also follow-up several months later (earlier if possible) with a letter that includes evidence of the completed corrective actions, and your verification of effectiveness. If the verification is compelling and received in less than six months of the inspection, you may convince the compliance office to hold off a planned Warning Letter.

If you are interested in root cause analysis and improving your CAPA process, we have two related webinars:

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Stage 2 Audit – How to Prepare (Part 1 of 2)

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This blog teaches you how to prepare for a stage 2 audit on your pathway to ISO 13485 certification, and this blog is part 1 of 2.last prep Stage 2 Audit How to Prepare (Part 1 of 2)

Stage 2 Audit

If you are not sure what ISO 13485 is, please consider our 2-part training webinar on the topic. Health Canada requires ISO 13485 certification as a requirement for all Medical Device License Applications, and most companies choose ISO 13485 certification as their method for demonstrating conformity to the requirements of the European Medical Device Regulations (MDR)–instead of a special MDD audit.

To achieve ISO 13485 certification, you must successfully complete a Stage 1 and Stage 2 certification audit with your chosen certification body. If you are interested in an overview of this certification process, you can download Medical Device Academy’s white paper on this topic, or you can watch a webinar we recorded recently on 6 steps to ISO 13485 Certification.

Management Processes are covered during the Stage 1 and Stage 2 audit

The Stage 1 audit is typically a one-day audit where the auditor is evaluating your readiness for the Stage 2 audit. The auditor will review your Quality Manual, and your procedures (19 are required) to ensure compliance with ISO 13485. Also, the auditor will sample records from critical processes to assess your readiness for the Stage 2 audit. Typically, these processes will be:

  1. Management Review
  2. CAPA
  3. Internal Auditing

After you complete the Stage 1 audit, you may have a few nonconformities identified by the auditor. Responding to these nonconformities is the first step in preparing for your Stage 2 certification audit. You need to initiate a CAPA for each of the auditor’s findings and begin implementation before the Stage 2 audit. Typically, you will have about six weeks to implement these actions. This is not usually enough time to complete your CAPAs because you need more time before you can verify the effectiveness of corrective actions.

Preparing CAPA Records is critical for your Stage 2 audit

In preparation for your Stage 2 audit, prepare for the auditor to review any CAPAs that you completed since the Stage 1 audit–especially if you have evidence of completing an effectiveness check. You may think this is unnecessary because the auditor previously reviewed CAPAs during Stage 1. However, you probably received a nonconformity related to your CAPA process (almost everyone does), and you should expect auditors to review your CAPA process during every audit.

CAPA Effectiveness Graph 300x218 Stage 2 Audit How to Prepare (Part 1 of 2)Each CAPA record you present should be provided in a separate folder as a paper, hardcopy. The paper, hardcopy makes it easier for the auditor to review. The folder should include documentation of the investigation, a concise statement of the root cause, and copies of records for all corrections and corrective actions implemented. Corrective actions include procedure revisions and training records. If there is a quantitative measurement of effectiveness, include a graph of current progress with the record. Ideally, the graph will be one of your quality objectives. The graph to the right is an example.

Production Process Controls will get the auditor out of the conference room 

Every company has at least some production and process controls implemented before the Stage 2 certification audit. Most auditors and inspectors spend too much time in conference rooms reviewing paperwork and too little time interviewing people that are performing work. However, many companies also outsource production activities. Therefore, unless you have a software product, you can expect your auditor to review incoming inspection activities. The auditor is also likely to review the finished device inspection, storage, and distribution. If the auditor is thorough, they will also follow the trail from inspection activities to calibration activities, nonconforming materials, and data analysis.

Design Controls

If your company is a contract manufacturer, then you probably are excluding design controls (ISO 13485, Section 7.3) from the scope of your Quality System. However, if you are a manufacturer that performs design and development, then it is an element of the quality system that warrants special attention. During the Stage 1 certification audit, the auditor reviewed only your Design Control procedure. During Stage 2, the auditor will look for evidence of implementing design controls. Therefore, even if your company has not completed your first design project, the auditor will still want to see some evidence of implementation. The auditor will expect at least one design plan to be written, and at least one design review should be completed.

If you are familiar with the FDA Quality System Inspection Technique (QSIT) process for inspection, you might have noticed that this blog is divided into the same subsections identified in the QSIT Manual.

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