A Good Paper on Comparison of Approaches to Regulation of Different Countries

The paper titled "Ensuring Medical Device Effectiveness and Safety: A Cross-National Comparison of Approaches to Regulation" by Kramer et al. provided a systematic and in-depth comparisons of regulation of the US, EU, Japan, and China. The comparisons are based on six key features of device regulation:

1. Regulatory Authority
2. Pre-Market Evaluation
3. Adverse Event Reporting
4. Quality System Regulation
5. Post-Approval Studies
6. Post-Market Regulation Actions

Emerging strategies of post-approval surveillance were also discussed such as unique device identifier (UDI) system.

New Final Guidance of 510(K) by the FDA

On July 28, 2014, FDA issued the newest "Final Guidance of The 510(k) Program: Evaluating Substantial Equivalence in Premarket Notifications [510(k)]" after revised draft guidance issued in Dec 28, 2011. The final guidance gives more examples than the 2011 draft guidance to better illustrate the decision-making process during a 510(k) review. It also includes a sample 510(k) summary which is more much detailed than most 510(k) summary documents found on the FDA website. Special and Abbreviated 510(k) sections were removed. FDA intends to finalize these sections separately. Although FDA states that this guidance is "not intended to implement significant policy changes," the guidance clarifies and addresses many key issues in the 510(k) program.

The US FDA requires that the manufacturers demonstrate safety and efficacy of the product, unless the devicecan be shown to be substantially equivalent (SE) to a predicate product that is legally marketed in the United States (via the 510(k)). For most new products, those without predicates, and certain high-risk products (typically Class III), a PMA is required. Certain Class I and exempted Class II medical devices are permitted to be marketed without the FDA’s prior authorization, although manufacturing(Quality System Regulations) and/or documentation controls may still apply. Some important points are summaried below:

Predicate Device

Predicate device is a the legally marketed device a legally marketed device, which is a device that (i) was legally marketed prior to May 28, 1976 (preamendments device) and for which a PMA is not required; or (ii) has been reclassified from Class III to Class II or I; or (iii) has been found SE through the 510(k) process. Although a manufacturer can identify multiple predicate devices, FDA recommends identifying a primary predicate in the submission.

Study Clinical Trials of Medical Device by FDA Bioresearch Monitoring (“BIMO”) program

FDA Bioresearch Monitoring (“BIMO”) program are to protect the rights, safety, and welfare of human research subjects and to assure the quality, reliability, and integrity of data collected. It is a good source to learn good clinical practice, responsibilities of sponsors, clinical investigators, contract research organizations, monitors, institutional review boards in clinical trials of medical devices and preparing for FDA inspections. 

FDA Launches Online National Medical Device Curriculum

FDA has launched a new learning tool for academic institutions and science and technology innovators called the National Medical Device Curriculum, to advance their understanding of FDA's medical device regulatory processes. The curriculum offers students FDA-endorsed knowledge about navigating the regulatory process, including how to design, test, and clinically evaluate devices; identify the root causes of adverse events and device malfunctions; and develop iterative device designs. The curriculum includes a series of four fictional case studies based on real-world medical device scenarios in a format similar to Harvard Business School Case Studies. 

By understanding FDA's regulatory process, innovators can accelerate the delivery of innovative medical products to patients.

FDA guidance to nanotechnology products

Nanotechnology is an emerging area which can create many new materials for medical devices, medicine, electronics and energy industries. On the other hand, more and more concerns about nanotechnology are raised about the toxicity and environmental impact of nanomaterials. 

Today, FDA issues three final guidances and one draft guidance to support the responsible development of nanotechnology products (the link).

In guidances, FDA has not established regulatory definitions of “nanotechnology,” “nanomaterial,” “nanoscale,” or other related terms. It aims to help industry when they should consider potential implications for regulatory status, safety, effectiveness, or public health impact that may arise with the application of nanotechnology in FDA-regulated products. FDA advises industry to consult with FDA early in the development process to facilitate a mutual understanding of the specific scientific and regulatory issues for their nanotechnology products.

In "Guidance for Industry Considering Whether an FDA-Regulated Product Involves the Application of Nanotechnology", FDA identifies two Points to Consider that should be used to evaluate whether FDA-regulated products involve the application of nanotechnology.

1. Whether a material or end product is engineered to have at least one external dimension, or an internal or surface structure, in the nanoscale range (approximately 1 nm to 100 nm);
2. Whether a material or end product is engineered to exhibit properties or phenomena, including physical or chemical properties or biological effects, that are attributable to its dimension(s), even if these dimensions fall outside the nanoscale range, up to one micrometer (1,000 nm).

Different Needs that Guide the Design and Development of Medical Devices

The customers of medical devices are involved patient, doctor, nurse and purchasing agent who has different preference. The book Combination Products: Regulatory Challenges and Successful Product Development" (page 39) gives a summary of typical voices of customers for using combination products, which is a good reference for medical devices as well:

• Patient: Needs to be safe, should be covered by insurance, result in minimum pain with no side effects, etc. 

• Doctor: Needs to be easy to use/intuitive, have less morbidity/mortality and excellent and proven clinical benefits. Easy to place during procedure, excellent support from sales rep, overwhelming clinical superiority.

• Nurse: Easy to use, store, unwrap, dispose, clean and sterilize; minimal nurse supervision of the patient. clear instructions with plenty of pictures, ergonomic and intuitive.

• Purchasing agent: Cost-effective, reimbursable, excellent product-related service, clear codes that can easily be entered in system.

新修订的中国《医疗器械监督管理条例》Revised Version of “The Regulations for the Supervision and Administration of Medical Devices”

昨天中国发布了修订的《医疗器械监督管理条例》。条例分为8章80条（相比2000年的条例为4章48条）。

和2000年4月施行的条例（以下称旧条例）比较，一些个人感觉重要的修改总结如下： 

1. 总则

新条例第一条去掉了“为了加强对医疗器械的监督管理”。可能是为了突出“为了保证医疗器械的安全、有效”的医疗器械监督管理原则和目的。

新条例将医疗器械的定义放在了附则部分。将旧条例中医疗器械所指的“单独或者组合使用于人体的仪器、设备、器具、材料或者其他物品”改为“直接或者间接用于人体的仪器、设备、器具、体外诊断试剂及校准物、材料以及其他类似或者相关的物品”。明确了间接用于人体的体外诊断（in vitro diagnostics）试剂和医疗器械等作为医疗器械的一部分。医疗器械使用目的中相应加入了“通过对来自人体的样本进行检查，为医疗或者诊断目的提供信息”。

新条例增加了国务院和县级以上地方人民政府有关部门在各自的职责范围内负责与医疗器械有关的监督管理工作的内容。明确了有关部门如工商、卫生、质监、海关、公安等参与到医疗器械的生产、经营和使用的监督管理工作。

Pass FDA 's Tests

FDA websites, specially Center for Devices and Radiological Health (CDRH) is certain to the first study source for medical device industry and research. After study carefully of 21 CFR part medical device, cosmetics and drug, CDRH learn materials, I have passed serveral important tests.

Factors to consider before a innovative idea to real market success in medical device.

It is easy to find ideas that appear to have promising business potential, but ultimately very few have the potential for real market success. Many factors need considered before we determine if a idea will have real impact. Serveral considerations which may increase the chances of success in medical device development are listed:

1. A new medical device must solve a real clinical problem or substantially lowers the cost of treatment and decreases mortality or serious morbidity relative to the standard of care.
2. Understand how large the potential market (size and growth) for the new product is, and how ready the clinical users will be to adopt it.
3. Learn intellectual property. Obtain protection of own patent and avoid infrigement of other's patents.
4. Conduct clinical trials as early as possible if necessary.
5. Plan the regulatory strategy early. The better you understand the regulatory framework, the greater your chance of success.
6. Understand the reimbursement landscape.
   
   

Online Medical Devices Registration: Licensale.com

Medical device industry is highly regulated. Regulatory affairs of medical devices are complex and time-consuming procedures. Just find a unique, cloud-based, global regulatory system LICENSALE.COM from Arazy Group that simplifies international regulatory affairs.

Smith&Nephew Global Wound Academy

Smith&Nephew is a top company in wound management and surgery materials. They have a very good online study source of wound knowledge: Global Wounda Academy.

Regulations of Medical Devices in Asia

Handbook of Medical Device Regulatory Affairs in Asia is an excellent starting book to learn medcial device regulation in Asia. The handbook is the first to cover medical device regulatory affairs in Asia.

Third Parties of Biological Evaluation and Biocompatibility Testing of Medical Devices

The biocompability of medical device is the basic requirement to ensure safety of medical devices. Biocompatibility testing shall be conducted in compliance with Principles of Good Laboratory Practice (GLP) and/or ISO/IEC 17025. Before any test, check related administration if test results of the third-party is accepted.

Some third parties which can carry out biocompatibility testing according to ISO 10993 are listed as below:

• TUV-SUD.
• UL.
• Toxikon.
• Pacific Biolabs.
• Nelson Labs.
• American Preclinical Services.
• Cytox.
• NAMSA
• Medical Engineering Technologies Ltd.
• Shanghai Biomaterial Research and Test Center, cerificated by CFDA.
• WuXi Apptec, cerificated by CFDA.
• GLR Labs.
• RCC Labs.
• PWG.

International Standards on Sterilization of Medical Devices

Both the Association for the Advancement of Medical Instrumentation (AAMI) and the International Organization for Standardization (ISO) have developed standards and viable validation guidelines for sterilization of medical devices. These standards often prepared in response to regulatory requirements related to good manufacturing practices and quality assurance.

Except ISO 10993-7 Biological Evaluation of Medical Devices-Ethylene Oxide Sterilization Residuals, other main standards on sterilization of medical devices can be learned in the ISO website. FDA also issued a guidance document.

Validation of Medical Device Sterilization

Prior to beginning routine sterilization, a product with a sterile claim needs to complete a validation process to ensure the Sterility Assurance Level claimed is met. Normally, A 10^-6 SAL, or greater (i.e. 10^-6, 10^-7, etc.) is used for:

• Products intended to come into contact with breached skin or compromised tissue
• Invasive products that enter normally sterile tissue
• Products with claims of sterile fluid pathways
• Surgically implanted devices
• Components used in aseptic processing

A 10^-3 SAL, or greater (i.e. 10^-4, 10^-5, etc.) is used for:

• Products not intended to come into contact with breached skin or compromised tissue
• Topical products that contact intact skin or mucous membranes
• Products that cannot withstand a 10^-6 SAL process

Sterilization validation studies must document that the product attains the re- quired SAL after exposure to the proposed process. In the industry, sterilization validation is generally evaluated by, first, determining the qualitative and quan- titative bioburden (the type and number of viable microorganisms present on the device just prior to sterilization) after the manufacturing process, then, studying the rate of killing using fractional-run sterilization studies and, finally, deducing the time required to achieve a 10^-6 SAL. Validation studies must be done on product samples prepared under actual manufacturing conditions and exposed to the sterilization process under its final packaging configuration. 

Two methods are used in validation:

Bioburden method:

Bioburden: Population of viable microorganisms on a product. In the context of irradiation sterilization, bioburden is determined immediately prior to sterilization. The unit of measurement is CFU: Colony Forming Unit.

Broadly speaking, and validation consists of three steps: Installation Qualification (IQ), Operational Qualification (OQ) and Performance Qualification (PQ). The IQ and OQ portions are often performed ahead of time by the contract facility and provided in the form of a commissioning package to the customer. The performance qualification demonstrates that the sterilization equipment consistently operates in accordance with predetermined criteria and that the process produces product that is sterile.

Over-Kill Method:

The overkill method is the most commonly used method for gas/vapor phase sterilization modalities. This method uses a biological indicator with a population of 10⁶ of the most resistant organism (MRO).  A fractional (Sub-lethal) cycle(s) is run to determine the D-Value of the product in a given sterilization process. The D-Value determines the amount of time needed to kill one log of the MRO.  The half cycle is determined my multiplying the D-Value determined in the fractional cycle by six, plus a safety factor. The calculated half cycle is then tested to verify that a six log reduction is achieved in all locations within the load. A full cycle is double the time/injection of a half cycle. This provides you with a SAL of 10^-6 or 12 log reduction. 

Material and Packaging Compatibility in Medical Device Sterilization

When designing medical device products, sterilization should be considered as early in the development as possible to ensure the material challenges of the sterilization process on the product and packaging. AAMI TIR 17:2008 titled "Compatibility of materials subject to sterilization" is a very important reference.

EO is highly compatible with polymer-based, single-use medical devices, procedure kits and surgical trays. PVA, PGA, and PLA is not compatible with EO sterilization.

The Gamma irradiation process can modify polymers, add an ozone odor to the package contents, or cause some discoloring and embrittlement. Gamma irradiation also has undesirable consequences due to the potential production of toxic degradation products such as 4,4’-methylenedianiline (MDA) that can be produced when a high-molecular-weight polyurethane material decomposes as a consequence of irradiation. Polypropylene, PTFE, and polyacetals is not compatible with radiation sterilization.

A good summary of materials which can be used in Gamma ray irradiation is from Steris Company and Nordion.

Sterilization Methods of Medical Device

Sterilization of medical devices plays an important role in the product development although it is not heavily invovled or nealy not involved in academic research in universities. It need to be considered in the earlier stage of prototype development, which can avoid the complex or even failure in the later stage.

Sterilization is defined as a “validated process used to render product free from viable microorganisms.” Terminal sterilization is defined as the “process whereby product is sterilized within its sterile barrier system.” The terminal sterilization process is considered a manufacturing process step itself and usually takes place at, or near, the end of the manufacturing process.

The presence of microorganisms is expressed as a probability. While the probability can be reduced to a very low number, it can never with certainty be reduced to zero. This is why we use the term Sterility Assurance Level (SAL) to express a sterile claim. SAL is the probability of a viable microorganism being present on a product after sterilization. Normally expressed as 10^-n. 10^-3 or a 10^-6 value being used most frequently for sterilization. Common SAL for medical devices is 10^-6.

Sterilization is accomplished principally by radiation, chemical sterilants, steam under pressure, dry heat, and filtration or combinations thereof. General application and method of sterilization can be learned in Wiki. A more detailed Guideline for Disinfection and Sterilization in Healthcare Facilities can be found in Centers for Disease Control and Prevention (CDC)

It is important to distinguish sterilization from disinfection, which does not ensure the same security level and does not necessarily inactivate all forms of microorgan- isms – bacterial spores, for instance. 

A sterile medical device is one that is free of viable microorganisms. For a sterile medical device this can be achieved through:

• A terminal sterilization process
• Sterilization of components, followed by sterile filtration and aseptic filling into a sterilized container
• A combination of chemical/physical sterilization and aseptic processing
 

The choice of the sterilization method for medical devices depends on a number of factors including the type of material used in medical devices, the type of packaging materials (product packaging and final packaging), the number and type of microorganisms involved, and the classification of the item.

Medical Device Exhibitions

Although company website, online searching, and FDA database can provide a lot of information on the medical device company, exhibitions are still traditional and rich sources to learn medical device industry. Main exhibitions of medical devices are:

• Medica and Compamed
• FIME 
• Medtec
• China International Medical Equipment Fair
• Arab Health

More exhibition information can be found: http://10times.com/top100/medical-pharma

Summary on Format of 510(k) Premarket Notification Submission

After reading the FDA guidance for Industry and FDA staff: Format for Traditional and Abbreviated 510(k)s, a good summary on the format of an original 510(k) submission including sections and related regualtions, guidance documents, internet links which can be found in Chapter III of the guidance.

510(k) is a type of premarket submission that is intended to demonstrate that the device to be marketed is at least as safe and effective as a legally marketed device that does not require PMA. A legally marketed device is a device that was legally marketed prior to May 28, 1976, for which a PMA is not required, or a device which has been reclassified from class III to class II or I, or a device which has been found substantially equivalent through the 510(k) process. A legally marketed device is commonly known as the "predicate" device in 510(k).

FDA recommends that 510(k) submission includes the 21 sections preferaly in the sequence below:

1. Medical Device User Fee Cover Sheet (Form FDA 3601)
2. CDRH Premarket Review Submission Cover Sheet 
3. 510(k) Cover Letter
   
4. Indications for Use Statement
5. 510(k) Summary or 510(k) Statement
6. Truthful and Accuracy Statement
7. Class III Summary and Certification
8. Financial Certification or Disclosure Statement
9. Declarations of Conformity and Summary Reports
10. Executive Summary
11. Device Description
12. Substantial Equivalence Discussion
13. Proposed Labeling
14. Sterilization and Shelf Life
15. Biocompatibility
16. Software
17. Electromagnetic Compatibility and Electrical Safety
18. Performance Testing – Bench
19. Performance Testing – Animal
20. Performance Testing – Clinical
21. Othe

Multinational Companies for Contract Sterilization of Medical Devices

Terminal sterilization plays an important role in the development of medical devices. Medical device companies can access to the state-of-the-art sterilization facilities without investing in the equipment or labor required. Contract Sterilizers can be found in the database of FDA Establishment Registration & Device Listing. (Select contract sterilizer in establishment type).

The multinational companies that provide ethylene oxide, gamma ray or E-beam sterilization services in the different countries are:

• Synergy Health 
• Sterigenics
• IONISOS

Their websites have the rich resources to learn sterilization of medical device.