Selection and Qualification of Biomaterials: Biological Risk Assessment ISO 10993
ISO 10993-1 biocompatibility standard is only one of many considerations for biomaterials qualification. Simply picking out and running tests is not enough. We work with you to develop your Biological Risk Assessment. This required analysis establishes potential hazards associated with materials in your medical product relative to its intended use. Your biocompatibility program must be consistent with other aspects of the overall device qualification, such as manufacturing, cleaning and sterilization.
First, Paladin Medical guides you in the pre-selection of biomaterials with high potential for suitability in your medical device design. There are no “FDA-approved” biomaterials, however, materials can be selected with a higher potential for successful application in medical device design. Even when a material supplier provides an FDA Master File (MAF) , the information must be presented as part of the comprehensive analysis within your Biological Risk Assessment. Read more below
ISO 10993 has many interrelated parts and FDA has its own interpretative guidance for this standard. Understanding this qualification plays a major factor in the cost of the testing and whether your test results will be accepted by the regulatory authorities. Following a check-box approach or just paying for expensive tests the laboratory salesperson suggests does not guarantee success.
We can help you interact with the laboratories who conduct the testing to ensure you are only doing the right tests on the right test articles to reach the best conclusion. We do more than just coordinate testing. We help you to present the biocompatibility assessment program for your product in the best way in your regulatory submission. As part of your change control we also help you manage the inevitable process or supplier changes to select the best confirmatory evaluation.
Device Master File (MAF)
Companies that sell materials, components or manufacturing services should consider the benefits of a DEVICE MASTER FILE (MAF) with the Center for Devices and Radiological Health (CDRH).
A Master File is a separate filing to FDA (no fee for filing) which holds proprietary processing and qualification information held by the material or process producer which remains “outside” of the premarket submission. Originally conceived as a means for submitting data in support of a PreMarket Approval Application (PMAA), Master Files now serve to support Investigational Device Applications, 510(k) applications and deNovo submissions. The Device Master File owner controls the content and access by FDA to the file by way of a letter to the customer. The access letter is provided by the customer to FDA as part of their submission.
Paladin Medical can help you get started and can work with you to create this valuable asset from your existing documentation. It is important to craft the access letter so that the FDA has access to the specific information necessary to support the premarket submission at hand, and not a blanket access. The value of this access by FDA to the proprietary information about your material, quality systems and prior testing can greatly speed the approval of the device and reduce the additional testing by the customer. We can also support the continual updating of the Master File and support the communication between the holder of the Master File and the customer.
Due Diligence for Mergers & Acquisitions
Companies considering investment in or merger with a medical device firm benefit from expert Due Diligence for assets subject to FDA regulation. Paladin Medical can conduct regulatory and development due diligence audits. Assessment of the regulatory and quality practices of a target medical device can offer insight into investment risks. Corporate mergers require an understanding of the impact of potential deficiencies on valuation. We can provide comprehensive due diligence assessments of regulatory, design and development and technical documentation. We can determine whether new medical device firms have sound regulatory and development documentation, meet minimum regulatory requirements, and if there are significant deficiencies that might encumber future plans or could devalue an acquisition. Because due diligence activities are often limited by time and access to internal personnel, we can help you determine where the greatest compliance risks may be and determine a plan of action to quickly evaluate these risk sources. Typical areas where a target company may have deficiencies can include improper product classifications and device listing, inadequate quality system compliance, open corrective actions and audit findings, adverse event reporting and complaint management deficiencies, open recalls, under supported marketing claims, import compliance, and clinical trial management deficiencies, just to name a few. Identifying regulatory and documentation deficiencies can help you assess the proper value of the assets.
Good Laboratory Practice 21 CFR Part 58
For many years, functional animal studies of medical devices have been informally allowed to skim GLP regulations, but future studies may be in peril if the sponsor does not realize the risks involved in failure to demonstrate GLP compliance. 21 CFR Part 58 is NOT a suggestion! According to the GLP preamble, safety studies must follow GLPs, but “functionality studies” are considered excluded. This has been the source of confusion since device manufacturers have often argued that testing an animal-version of a medical device constitutes a “functional” evaluation and is thus exempt. Unfortunately, the draft guidance of August 28, 2013 does nothing to clarify obligations. When device manufacturers evaluate a medical device for biocompatibility, bone in-growth or potential wear; particularly when histopathology is an outcome measure, FDA typically views these studies as first and foremost: safety. You could be in for a shock if preclinical studies are submitted to FDA without a statement of compliance to Good Laboratory Practices.
Paladin Medical will assist you in developing scientifically sound preclinical protocols for your functional animal studies that result in data to support your submission. But if you have conducted a study where GLP compliance cannot be ascertained, we will help you with methods to augment GLP-compliance deficiencies. We employ an itemized checklist and demonstrate section by section how the study quality and facility control systems were maintained. Post-study systems auditing can be useful to demonstrate the data should be considered valid.
Conducting ISO 10993 required studies are most often conducted under GLPs because these are considered “safety” studies. But there may be occasions when GLP-compliant testing is not required. Although the “GLP fee” is modest, screening studies or studies to investigate alternative materials might not require the fee and the additional time.
Consider Paladin Medical services if you need an adjunct Quality Assurance Unit to augment large animal facility quality program before you begin, and any time you need to conduct a supplier audit for GLP compliance.
Hazard Analysis/Risk Assessment and Risk Management
The backbone of medical device development and quality compliance is analyzing potential hazards, assessing potential risks and implementing mitigation to assure an on-going safe and effective product. ISO 14971 has become the international currency of risk analysis and mitigation. FDA expects a medical device manufacturer to integrate risk management effectively throughout the lifecycle of the product. The risk management culture of a company shows through in all aspects of product and marketing management, but it starts at the development phase.
Paladin Medical can guide your team through the early work of design level risk analysis and qualification planning. Integration of risk analysis into a solid Design Control and Review program is necessary for efficient and effective risk controls. Starting with a well-defined inputs requirement document based on customer’s needs and recognized standards and guidance documents, we help your team begin the regimen of analyzing for potential hazards if the product were to fail to meet those requirements. The analysis should factor in the potential causes and effects of such failures, the potential to detect the failure and the severity of any harm should the risk occur. From this analysis the proper level of risk mitigation can be established and this in turn leads to qualification planning, customer information and quality controls.
Process level hazard analysis and risk mitigation is a valuable tool to determine which elements of medical device manufacturing and production may introduce risks to the user, the patient, or the quality of the device. Software and hardware risk analysis can help to isolate within the integrated requirements where risk mitigation is necessary. With complicated systems it is often necessary to assure the user can effectively perform their required role. SEE HUMAN FACTORS and USABILITY STUDIES
But risk management only begins within the development of the product. Continual product performance monitoring through complaint monitoring and analysis systems, medical device adverse effect monitoring, and change control management are at the core of reducing risks in order to assure patient benefit. Paladin Medical can provide expert services that train and enable your personnel to integrate these principles into product quality programs.
Human Factors and Usability Studies
USER ERRORS can undermine the performance of a medical device and introduce risks. Part of the qualification of certain new medical devices, and changes as well, can require assessment of the user’s ability to properly employ the device as intended. It is not uncommon for a design level risk analysis to reveal intrinsic hazards associated with the use of the device, such as radiation hazards, which can be mitigated by design. But it is also true that the environment of use can contribute to risks or the interface between the device and user can be a factor. Both the design consideration for factors related to human use and the potential that a user’s education or condition can affect the safety and performance of the device may need evaluation in order to assure safety and performance. Our experience with these aspects of human factor design, assessment and evaluation can contribute to the work your team may undertake to assure device safety and performance in its environment.
Deciding when to submit a 510(k) to a device with an existing 510(k)
Changes to a medical device are inevitable for safety and performance reasons, to stay abreast of competitors and simply to maintain production when a supplier is no longer suitable or available. Quality systems require that a company document changes with approvals and in some circumstances, it is necessary to review, evaluate and revalidate these changes. So, at what point might a change to a device trigger the need to make a new 510(k) application? FDA has provided ample guidance. In like token, other regulatory schemes stipulate with a new authorization may be necessary. Paladin Medical can help your company work through these guiding principles and make the best determination. Making the determination is one task, but proper documentation of the justifications is equally important. Your team may understand these requirements full well; but, may simply need a third-party review of the determination and documentation in order to feel more comfortable with the decision. Often it is not merely one change to a device, but several that may accumulate or may be suddenly triggered by events such as a change in supplier or a recall of the product. With our expertise and experience we can aid your team in making the best choices and establishing sound decisions.
Global Regulatory Strategy
Paladin Medical will help you think globally. If your company intends to market internationally, you need to know how your product will be regulated in these markets in order to optimize your resources. Compliance with FDA export and import regulations ensures smoother international access.
Paladin Medical assists in strategic regulatory planning and quality development planning. Knowing the global regulatory requirements and applicable conformance standards is the starting point for medical device input requirements. We can help with:
• Global product requirements
• Exporting to regulated nations
• Import requirements for devices made outside the USA
• Applications to Competent Authority for Class I products
• Technical Construction Files and Design Dossiers
• European product requirements for foreign compliance
• Canadian, European, Australian, Latin American, and Japanese submissions
• Integration of the ISO 13485 quality standard with US 21 CFR 820 Quality Systems
We guide you in the preparation of your submissions to regulatory agencies outside USA and work with your Notified Body if you are seeking the CE Mark. Although there are common elements for most submissions each jurisdiction can have different requirements and interpretations of how standards are applied.
For the EU, Class I self-declaration requires preparation of the Technical File and labeling for presentation to the competent authority. We can author these documents and prepare your submission and work with your Foreign Representative to prepare what you need. The rules can be confusing for a US-based company preparing their first Technical Construction File in anticipation of a European market introduction. Paladin Medical helps you integrate your Design History File with the Design Dossier and your product Device Master Record with the Technical Construction File contents.
Companies based outside the USA will find Paladin Medical can optimize your current documentation into an FDA submission. We serve as the US Agent for clients and help with compliance with regulations such as MDR reporting, recalls, and quality systems (CFR 820).
Companies based outside the USA will find Paladin Medical can often optimize current regulatory documentation into an FDA submission. We serve as the US Agent for clients and help with compliance with regulations such as MDR reporting, recalls, and quality systems (CFR 820). Paladin Medical can also troubleshoot if your import is held in Customs! Read more in US Agent for Medical Device.
As medical devices become more complex your may find your product may prove to be determined to be a COMBINATION PRODUCT, even without your intent. The basis for the determination of the whether a device may be a drug, a device or a combination product centers around some basic principles generally known as “mode of action”. A combination product may include a device and drug, a device and biologic or other “combinations”. This greatly depends upon whether the new product includes or constitutes a drug, a device, a biologic, and it is not as straight forward as it may seem. FDA provides definitions of each of these categories, but it is possible a single constituent in a device can trigger concern by FDA that the device has more than one mode of action. The Office of Combination Products (OCP) develops cross-cutting FDA guidance for product classification, jurisdiction and criteria for determining if a device could be a COMBINATION PRODUCT. Finding out after a submission has been made that FDA considers your new product to be a COMBINATION can set back your track to market immeasurably. With our experience and expertise, we can help you to present your argument to FDA for the determination of jurisdiction and whether or not the device has some elements which might require review as a combination product.
Customized Medical Device Training
Paladin Medical will produce and deliver customized medical device training at a level suitable for your medical device and regulatory complexity. Start-ups often require training to new quality system procedures in order to ensure uniform understanding among the various new employees. Established firms may need training as the company moves into new areas of product control. Standards are always changing, and personnel move to new responsibilities. We help you keep up with these needs at appropriate times and scale that you need.
U.S Agent for Medical Device
Paladin Medical, Inc. may serve as the U.S. Agent for clients with foreign establishments engaged in the manufacture of a medical device imported into the United States. As a U.S. Agent we provide the required services:
- assisting FDA in communications with the foreign establishment
- responding to questions concerning the foreign establishment’s devices that are
imported or offered for import into the United States
- assisting FDA in scheduling inspections of the foreign establishment
- if FDA is unable to contact the foreign establishment directly or expeditiously
FDA may provide information or documents to the U.S. agent, and such an action shall be considered to be equivalent to providing the same information or documents to the foreign establishment.
Although the FDA does not require the U.S. agent to be responsible for Medical Device Reporting regulation (21 CFR Part 803), we can provide advice, including template in-house procedures and guidance to help assure compliance with these requirements.
We also serve as liaison should there be a need for recall or corrective actions. We stay on the look-out for any new guidance documents or regulations that may affect your products. These services are provided for a modest fee on an annual basis.