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Performance Qualification (PQ) for EO Sterilization Validation

Article explains requirements for a performance qualification (PQ) of EO sterilization validation and how it is different from other PQ process validations.

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Mind your ps and qs 1024x291 Performance Qualification (PQ) for EO Sterilization Validation

Performance Qualification (PQ) – What is the difference between an IQ, OQ and PQ?

When you are performing a process validation, the acronyms IQ, OQ and PQ sometimes cause confusion. IQ is the installation qualification of the equipment used in your validated process. The purpose of the installation qualification is to make sure that your equipment was installed correctly–this includes calibration and connection to utilities. OQ is the operational qualification. The purpose of the operational qualification is to make sure that the equipment you are using is capable of operating over the range of parameters that you specify in order to make your product. The PQ is a performance qualification. The purpose of the performance qualification is to ensure that you can consistently make product within specifications (i.e., repeatable).

Different Definitions for Operational Qualification (OQ)

The GHTF guidance document for process validation provides the following definition for an OQ: “Establishing by objective evidence process control limits and action levels which result in product that meets all predetermined requirements.” ISO 11135-1:2014, the international standard for ethylene oxide (EO) sterilization validation, provides a slightly different definition for an OQ: “process of obtaining and documenting evidence that installed equipment operates within predetermined limits when used in accordance with its operational procedures.” The difference in these two definitions is important, because the OQ is typically performed by contract sterilizers and does not need to be repeated unless there is a significant change or maintenance to the sterilizer that requires repeating the OQ. In contrast, when you perform an OQ for packaging, the OQ is specific to the packaging materials you are going to be sealing and therefore a new OQ is required whenever new packaging materials are developed. For EO sterilization, the analogous step of the validation process is called a microbial performance qualification (MPQ).

Performance Qualification (PQ) = MPQ + PPQ

A performance qualification (PQ) for ethylene oxide sterilization validation consists of two parts: 1) microbial performance qualification (MPQ), and 2) physical performance qualification (PPQ). The microbial performance qualification is intended to determine the minimum process parameters for the EO sterilizer sufficient to ensure product bioburden is killed. These parameters are referred to as the half-cycle, because the full production cycle will be twice as long in duration. For example, a half-cycle consisting of 3 injections will correspond to a full cycle of 6 injections.

What are fractional cycles?

Fractional cycles are typically shorter in duration than the duration of a half-cycle. The purpose of a fractional cycle is to demonstrate that external biological indicators (BIs) located outside of your product, but inside the sterilization load, are more difficult to kill than internal BIs. Fractional cycles are also be used to demonstrate that the product bioburden is less resistant than the internal BIs. To achieve both of these objectives, it is typical to perform two fractional cycles at different conditions to achieve 100% kill of internal BIs and partial external BI kill in one fractional cycle, and 100% kill of product bioburden but only partial kill of internal BIs in the other fractional cycle. When your goal is partial kill, you should also target more than one positive BI, because this reduces the likelihood that poor technique resulted in a BI positive from growth.

Microbial Performance Qualification (MPQ)

The microbial performance qualification (MPQ) typically consists of three half cycles and one or more fractional cycles. 100% kill of external BIs is not required for the MPQ during a half cycle–only the internal BIs must be 100% killed, but the external BIs are only useful if 100% kill of the external BIs is achieved in the full cycles. If you are re-validating the sterilization process, you are only required to complete one half cycle and one fractional cycle. For re-validation, the fractional cycle is intended to achieve 100% kill of product bioburden but only partial kill of internal BIs in order to verify that the product bioburden remains less resistant to sterilization than the internal BIs. You are also required to perform bioburden measurements of non-sterile product for the initial MPQ and re-validation to demonstrate that bioburden can be adequately recovered from the product and measured.

Physical Performance Qualification (PPQ)

The physical performance qualification (PPQ) typically consists of three full cycles and measurement of EO residuals in accordance with ISO 10993-7:2008. If PPQ is performed during the MPQ, then it is only necessary to complete one full cycle–assuming the MPQ consists of at least three half cycles. If you are performing a re-validation of the sterilization process, then you are required to perform three full cycles and measurement of EO residuals.

Repeatability, Reproducibility, Product Variability and Environmental Factors

Typically a performance qualification (PQ) is intended to verify that the same person can repeat the process multiple times, other people can reproduce the first person’s results and any variation product from lot to lot will not prevent the process from producing acceptable product. In addition, any variation in environmental factors should be assessed during a PQ. In sterilization processes, however, the equipment is typically automated. Therefore, variation between operators is typically a non-issue. In addition, sterilization lots also typically consist of a large volume of product where multiple samples are tested for sterility. Therefore, performing three runs sufficiently challenges the repeatability and reproducibility of the sterilization process–including any product variability. The issue of environmental variations in heat and humidity are addressed by designing preconditioning cycles into the sterilization process. Sensors are included in each validation load to verify that the process specifications were achieved and maintained for temperature and humidity, but the sensors also help to identify the worst-case locations in a load to use for sampling and placement of BIs.

If you are interested in learning more about sterilization validation, please read our blog from last year on evaluation of the need to re-validate your sterilization process or you can watch our webinar on sterilization and shelf-life testing. You can also purchase our procedure for EO sterilization validation by clicking on the link below.

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

%name Performance Qualification (PQ) for EO Sterilization Validation
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

 

Posted in: Process Validation, Validation

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IFU Validation and Post-Market Surveillance – A risk-based approach

This article describes how to perform IFU validation prior to commercialization and how to conduct post-market surveillance to ensure that your IFU continues to be suitable as your user population and patient population expand.

IFU Validation and PMS IFU Validation and Post Market Surveillance   A risk based approach

Most companies create an IFU for a new product by plagiarism. They merely copy a competitor’s IFU and change the name. If the IFU is created by a regulatory expert, the IFU will be nearly identical to the competitor IFU. However, if the IFU is created by a marketing person, the IFU will explain how your product is total different from the competitor product. Neither approach is effective.

Creating a risk-based IFU

EN ISO 14971:2012 identifies deviations between the ISO 14971:2007 international standard and the three EU Directives. However, deviation #7 is specific to labeling and instructions for use. Even if your product is not CE marked, you should be developing a risk-based approach to IFUs. The first priority of risk controls is to eliminate and reduce risks by design, manufacture and selection of materials. The second priority is to implement protective measures such as alarms to warn users of risks. The last priority for risk controls is to inform users of residual risks. The best practice is to utilize a risk traceability matrix to document each of the risk controls you implemented to eliminate and reduce risks of hazards identified.

The EN version of ISO 14971 will not allow you to reduce risks quantitatively in your risk assessment for information provided to users about risks, because this type of risk control is not completely effective. However, you are required to verify that each residual risk is disclosed to users in your IFU and you must validate that your warnings, precautions and contraindications are adequately identified such that users understand the residual risks. You are also required to determine any user training needed to ensure specified performance and safe use of your medical device in accordance with ISO 13485:2016, Clause 7.2.1d. Clause 7.2.2d) requires that your company ensure that user training is made available. Any user training you provide should also be validated for effectiveness.

When to perform IFU validation

Some companies ask physicians that helped them with product development review draft IFUs. However, these physicians are already familiar with your product, your company and they are highly skilled in the specific procedures your device will be used for. After your own experts have make their final edits to your draft IFU, you now need a “fresh set of eyes.”  The best approach is to validate the effectiveness of your IFU with potential users that don’t know you or your company. If your product requires animal performance testing or human clinical studies, you could use these studies to validate your IFU. However, I recommend conducting a simulated use study prior to conducting animal or human studies. Conducting a simulated use study prior to animal and human studies can prevent deviations from your documented protocols that were caused by inadequate review of the IFUs.

Methods of IFU validation

The best method for validating your IFU is to perform a simulated use study or human factors study. The FDA published a human factors guidance document that can help you assess the risk of human factors and ergonomics. The FDA guidance requires that you identify your intended user population(s). For each individual population of users, you are required to have a minimum of 15 users for your study. If your product is not for specific indications, you may be able to randomly select 15 users at a few sites. However, if your device is intended for two different specialties, then you need to 30 users–15 for each specialty.  I recommend recording a video of simulated use studies too. Videos identify small details that you might miss, and clips from the videos are useful in creating training videos for future users.

Gathering Post-Market Surveillance

Post-market surveillance is not just asking customers if they are satisfied. You need to continue to monitoring adverse event databases, your own complaint database and any service records to determine if there are any new risks and to verify that the risks you identified were accurately estimated with regard to severity and probability of occurrence of harm. In fact, clinical studies and PMS are the only way you can gather data regarding probability of occurrence of harm. When you design your post-market surveillance questions, make sure you include questions specifically targeting the residual risks you identify in your IFU. You should also ask, “What indications do you use this device for. Specifically, please identify the intended diagnosis, treatment and patient populations.” This wording is more effective than asking if a physician is using your product “off label.”

Revalidation of IFU after labeling changes

Changes to labeling and IFUs should always be considered design changes and may require revalidation. If the change is in response to a complaint or CAPA, then it is crucial that you revalidate the IFU and labeling to verify effectiveness of your corrective action. Any validation should be documented, reviewed and approved prior to implementation and acceptance criteria should be determined ahead of time. Your acceptance criteria should be quantitative so you can objectively determine if the change is effective or not. You might be able to copy your previous IFU validation protocol or simulated use protocol and simply repeat the validation exactly as you did before with new users. However, sometimes the reason why the IFU was not 100% effective in the past is that the risk you are addressing in the revised IFU was not evaluated adequately in the original simulated use protocol.

New webinar for risk-based IFU validation and PMS

If you want to learn more about using a risk-based approach to developing IFUs, validating IFUs and performing post-market surveillance to monitor the effectiveness of your IFU, then please click on the webinar link below.

IFU Validation Webinar Button 300x62 IFU Validation and Post Market Surveillance   A risk based approach

 

Posted in: Clinical Studies & Post-Market Surveillance, Validation

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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

In fact, 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 prior to 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 prior to 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 prior to 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 validation of the bioburden of component parts and the final assembly. It’s important to validate the component levels first in order to reduce 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. In order 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 product. 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 in the near future on the topic of documenting sterilization validation for 510k submissions.

Posted in: Validation

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Medical Device Validation Document Resources

This blog provides a list of medical device validation resources and explains how to create your own resource list.

medical device academy valdiation resources Medical Device Validation Document Resources

The first step to understanding how to conduct successful validations are always to read and re-read the requirements of the documents below:

  • 21 CFR 820.30(g)
  • 21 CFR 820.75
  • ISO 13485, Clause 7.3
  • ISO 13485, Clause 7.5.2

Unfortunately, we sometimes need to consult a reference guide that explains aspects of the requirements.

Max Sherman (http://bit.ly/MaxSherman) is finishing a new handbook on design and process validation that will be published through RAPS. The following is a list of resources for process and design validation that I am submitting for publication in the book. Many of these resources are free, and these are the resources I personally use to learn and teach principles of validation.

  1. GHTF/SG3/N99-10:2004 – Process Validation Guidance (http://bit.ly/N99-10)
  2. ISO 14969 – ISO Guidance document for ISO 13485 (http://bit.ly/iso14969)
  3. 13485 Plus – CSA Guidance document for ISO 13485 (http://bit.ly/13485Plus)
  4. AAMI The Quality System Compendium: Bundled Set of Textbook & CD (http://bit.ly/AAMI-Store)
  5. Preamble to the QSR (http://bit.ly/QSR-preamble)
  6. ICH Q2: Validation of Analytical Procedures: Text and Methodology (http://bit.ly/Q2-Analytical-Validation)
  7. FDA Guidance for Part 11: Electronic Records (http://bit.ly/Part11Guidance)
  8. FDA Guidance for Software Validation (http://bit.ly/FDA-Software-Validation)
  9. FAQs about Implementation of IEC 62304:2006 (http://bit.ly/Team-NB-IEC62304)

In addition to these resources, you may also need additional resources for design validation. Here are some examples of design validation resources I use in my design controls training “tool kit:”

  1. http://bit.ly/do-it-by-design
  2. http://bit.ly/DesignControlGuidance

As a regulatory affairs professional, it is critical to maintain a list of the most current standards and an organized list of links to those standards. I used to keep a list of favorites in my web browser for this purpose, but my database now exceeds the utility of “favorites.” Now, I use my own webpage for this purpose. You can do this yourself by creating a free WordPress blog, and having one of the webpages to the blog be specifically for the purpose of maintaining a list of Standards that are applicable. Here’s a link to my own webpage that I share: http://bit.ly/RA-Resources

 

 

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