Clinical Handbook FINAL

UNITED STATES HQ Life Technologies Corporation 5791 Van Allen Way Carlsbad, CA 92008 USA Telephone 760.603.
7200 Fax 760.602.6500
Clinical Diagnostics Handbook

US & EU Edition 2010
2009 Life Technologies Corporation. All rights reserved. Trademarks of Life Technologies Corporation include: AIM V, AmnioMAX, DynaChip, DYNAL, GIBCO, Life Technologies, Life Technologies (logo), Molecular Probes, Prodigy, SPOT-Light, StemPro, Tropix. TaqMan is a registered trademark of Roche Molecular Systems, Inc. All other trademarks are the sole property of their respective owners. ID C-088255
03 05 Contents 07 15
Introductions
39 45 51 57
US FDA IVD Regulations
Clinical Diagnostics Dos and Donts
The European In Vitro Diagnostic Directive
Life Technologies Clinical Diagnostics Overview
Definitions
Frequently Asked Questions
Index
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Life Technologies portfolio of in vitro diagnostic (IVD) products is growing rapidly and, as such, many employees are now very active in supporting key processes that deliver IVD products to our customers. To that end, the Regulatory Affairs Team has assembled this handbook in order to help address the most common questions associated with IVD products and to clarify some of the regulated product terminology. This handbook prioritized the US and European IVD requirements. Additional sections addressing IVD requirements for China, Taiwan, Korea, Canada, Australia, etc. will be prioritized for distribution in early 2010.
The questions that are discussed in the handbook are real-life questions brought to us by the various customer-facing teams around the world. We can help you discuss these matters with customers directly to provide even more depth and guidance on the regulatory environment. The Regulatory Affairs team is here to enable and drive your business. Any questions, concerns or suggestions relating to this handbook or to the Life Technologies IVD products should be sent to the Regulatory Affairs global email address: !LIFE-Global Regulatory Affairs@lifetech.com.
John DAngelo Global Head of Regulatory Affairs and Compliance
john.dangelo@lifetech.com
Many employees have been wondering when Life Technologies will become a player in the clinical diagnostics market. We are already in that market. We already cover a whole continuum of products for clinical diagnostics.

We produce and commercialize FDA- and ISOregulated IVD products. We also provide OEM components to other diagnostics manufacturers, who put our components into their kits. We provide appropriate materials directly to commercial clinical laboratories, who develop and validate their own diagnostic tests.
understanding of human physiology and disease, leading to assays with diagnostic potential like detection of drug-metabolizing enzymes and biomarkers for heart disease and other conditions. The trend of research is moving steadily toward personalizing and improving medicine. We will leverage our capability to partner with customers from discovery to applied science to drive revenue in the clinical diagnostics market. As Head of Medical Marketing Ill be working with the Divisions to align clinical diagnostics strategies and activities, develop marketing plans, channels and overall go-to-market strategies. Feel free to direct questions or concerns you may have pertaining to our activities in the clinical diagnostics market segments to me.
Kim Caple Head of Medical Marketing
kimberlee.caple@lifetech.com
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Life Technologies Confidential Information. For internal use only.
In these latter two scenarios it is important to inform the end user that these products do not have a clinical utility. The end user should comply with applicable regulations before incorporating our materials in their IVD product, lab developed tests, etc. Weve supported research in the life sciences for many years through our Invitrogen and Applied Biosystems brands. Over time weve seen discoveries like sequencing of the human genome yield deeper
For Americas Regulatory Affairs: Kelli Tanzella 716-774-3122 kelli.tanzella@lifetech.com
For EMEA Regulatory Affairs: Mario Wijker +31 229 850 283 mario.wijker@lifetech.com
For AsiaPac Regulatory Affairs: Hongbo (Julie) Su +86 10 58 08 58 64 hongbo.su@lifetech.com
For full definitions of the abbreviations used in the Handbook, please refer to page 51, Definitions.
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Clinical Diagnostics Dos and Donts
CLIA Laboratories Do understand that it is the customers responsibility to fulfill the appropriate regulatory requirements if their application does not fall within the intended use of the marketed device. Do market diagnostic devices to CLIA laboratories but dont promote them for use in homebrew diagnostic assays or any other use for which the product is not specifically cleared. Do speak with Regulatory Affairs or Medical Marketing if the customer wants to use a Life Technologies product to develop a commercial IVD test or collaborate with Life Technologies on a diagnostic application. Dont help a customer validate a diagnostic or clinical protocol. Dont analyze patient data on behalf of the customer in order to provide a diagnostic result.
IVD Products Do promote Life Technologies IVD products for diagnostic applications only in accordance with the FDA-cleared or EU regulated intended use. Dont market the device beyond its FDA-cleared or EU regulated intended use statement or imply that the device has clinical utility beyond the intended use. Dont respond to tenders in clinical hospitals for diagnostic disease targets for which we do not have an IVD device.
Complaint Handling & Quality Assurance/ Regulatory Affairs Questions Do log all product complaints in the complaint handling system. Do report all safety incidents involving an IVD to Regulatory Affairs as soon as you become aware of them. Do follow this up by logging a complaint.
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Do provide the customer with ISO certificates as required and follow up with Quality Assurance on customer audit requests. Do send customer questionnaires to Technical Support or Quality Assurance for completion. Do contact Regulatory Affairs with any IVD-related questions or concerns. Dont delay in logging a product complaint in the complaint handling system.
Life Technologies Clinical Diagnostics Overview

Diagnostics Mission Statement Through its Applied Biosystems and Invitrogen brands, Life Technologies is dedicated to the success of its Clinical Diagnostics customers. We are a trusted supplier of instruments, reagents, software and other components. We are committed to meeting your scientific, technology, diagnostic, and regulatory compliance needs. We can assist you in your quality and regulatory compliance activities. We partner appropriately with our customers every step of the way, from target discovery and validation through to diagnostic test commercialization.
Accelerating translational research discovery Personalizing medicine
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Our Vision for the Future
Improving the human condition
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Life Technologies Is Dedicated to Providing Diagnostic Products Spanning the Value Chain OEM Components

Each Life Tech Division Provides Products Across the Diagnostics Value Chain Cell Systems Division
(examples)
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Molecular Biology Division
(examples)
Lab Developed Test Products

FDA IVD Products

Genetic Systems Division

(examples)
Quality Products Quality Systems Manufacturing Capability Reliable Supply
Breadth of Technologies Quality Components Global Field Service Global Technical Support Assay Partner Program Assay Partner Program
Variety of Products Compliant Quality Systems Global Field Service Global Technical Support Assay Partner Program
OEM Components

OEM Components
OEM Components
Dynal Beads Molecular Probes fluorescence products Tropix chemiluminescence substrates
BigDye Terminator v1.1 Cycle Sequencing Kit
Dye-labeled oligonucleotides
Variety of appropriate capillary electrophoresis instruments and reagents
Variety of appropriate rtPCR instruments and reagents
Marketed IVD Products
Variety of appropriate benchtop instruments and reagents

AB 7500 Fast Dx Real-Time PCR Instrument
AB 3500 Dx and 3500xl Dx Instruments Invitrogen DynaChip System

AmnioMAX-II Complete Medium Invitrogen SPOT-Light HER2 CISH Kit
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Life Technologies Is an OEM Provider to Many In Vitro Diagnostic Manufacturers

OEM Components Powered by Life Technologies Examples:

Life Technologies Provides Tools for Clinical Labs Who Develop and Validate Diagnostic Assays

Example of Molecular Dx Assay Development Partnership DiaGenic Announces Launch in India of First Breast Cancer Gene-Expression Blood Test* India chosen as first commercial market to demonstrate tests potential for rapid uptake
OSLO and FOSTER CITY, Calif. November 10, 2008
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Wide range of high-quality instrument and reagent components Multiple manufacturing sites and planning systems assure continuity of component supply Focus on lean manufacturing and utilization of Six Sigma process excellence methodologies Quality systems and manufacturing infrastructure suitable for variety of regulated product requirements Custom laboratory services and manufacturing capabilities
Dynal Beads Molecular Probes fluorescence products Dye-labeled oligonucleotides Tropix chemiluminescence substrates
Broad range of instruments and reagent technologies Variety of high-quality reagents and consumables Thousands of academic journal publications referencing Applied Biosystems and/or Invitrogen products http://www.invitrogen.com/site/us/en/home/ support.html http://www3.appliedbiosystems.com/AB_Home/ Support/index.htm
Global infrastructure of Field Service and Technical Support personnel Assay Partner Program
DiaGenic ASA (OSL:DIAG) and Applied Biosystems Inc. (NYSE: ABI) today announced the launch of BCtect, a blood-based test for early detection of breast cancer. The test searches for a unique gene expression signature identified by DiaGenic using a custom TaqMan Array manufactured for DiaGenic by Applied Biosystems. India was chosen as the first country for the introduction of BCtect after successful completion of a large study in the country.
* Not available for diagnostic purposes in the U.S.
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Life Technologies Develops, Manufactures, and Commercializes IVD Products
Marketed IVD Products Examples: AmnioMAX-II Complete Medium AB 7500 Fast Dx Real-Time PCR Instrument
Variety of IVD instruments and reagent technologies - Real-time PCR - Transplant diagnostics - Pathogen detection - Molecular pathology
rtPCR platform
Quality systems and manufacturing infrastructure compliant with ISO 13485:2003 and QSR Global infrastructure of Field Service and Technical Support personnel Assay Partner Program
Invitrogen SPOT-Light HER2 CISH Kit
Quantitative measure of HER2 gene expression in breast cancer tumors
Invitrogen DynaChip System
Detection and identification of Class I and II HLA antibodies
Frequently Asked Questions

The following Q&A guidelines are to help assure that Life Technologies fully complies with the applicable law in connection with the sale of its products by providing information on how to respond to questions from diagnostic customers. IVD Frequently Asked Questions & Answers 1. When do my customers need to use an IVD product vs. an RUO labeled product?
utility, and not represented as an effective in vitro diagnostic product. During this phase, the focus of research is typically to evaluate limitedscale performance and potential clinical or informational usefulness of the test. Clinical samples may be used, but no test information should be provided to a teaching physician or patient. 2. Who is our Authorized Representative? The Life Technologies Authorized Representative is John Marr and he is based in Inchinnan, Scotland. The Authorized Representative represents IVD products that are manufactured outside of the EU. 3. Where can I obtain copies of Declarations of Conformity? Declarations of Conformity can be obtained from the Authorized Representative. For products manufactured in the EU, the Declarations of Conformity are available from the Regulatory Affairs staff at the manufacturing site.
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If the customer wants to analyze human samples for the purpose of providing a diagnostic result, they must use an FDA-cleared or EU regulatory compliant instrument with an assay that is also cleared by the appropriate regulatory authority (FDA or EU) for use with that instrument. Life Technologies IVD products can be used as part of the customers diagnostic system. RUO labeled products are intended for the laboratory research phase of development to identify test kit methods, components, and analytes to be measuredthat is, either basic research or the initial search for potential clinical
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4. Where can I obtain copies of our ISO Certificates? Please contact the Quality Assurance group, who can provide this information. 5. Where can I obtain a copy of the Certificate of Free Sales? You can request a Certificate of Free Sales from the Authorized Representative or another member of the Regulatory Affairs group. 6. Whats the difference between products that are labeled RUO, IVD, or have a DMF or 510(k)?
An RUO labeled device, in contrast, is not subject to FDA regulations, so long as it is not used to diagnose clinical samples and report them to doctors or patients. An RUO labeled device, as its name implies, is limited to research use only. Thus, clinical samples may be analyzed but not for the purpose of diagnosing a patient. Rather, the RUO labeled devices are intended to be used in preclinical research. An IVD is an in vitro diagnostic device. In vitro means that the test occurs outside of the patients body. An IVD can be 510(k) cleared, in which case it can be used in clinical diagnosis consistent with its clearance or as an RUO directed to preclinical research. A DMF is a drug master file. A DMF is a file established at FDA that contains confidential information about a product. This information can be referenced by a drug manufacturer for use in seeking FDA approval. Life Technologies has established DMFs on its products so that information can be used by drug companies seeking New Drug Application (NDA) approval for a drug that will be used in conjunction with a Life Technologies IVD.
7. Where can I get a 510(k) or Premarket Approval summary? FDA 510(k) substantial equivalence determination summaries for Class II devices and FDA PMA summaries of safety and effectiveness for Class III devices are currently available on the CDRH OIVD webpage (http://www.accessdata.fda.gov/scripts/ cdrh/cfdocs/cfPMA/pma.cfm). Should you require help locating these, please contact Regulatory Affairs. 8. Under which Competent Authority is an IVD registered? In which European countries can the IVD be sold? The Authorized Representative can provide you with this information. In Europe, IVD products are usually registered in the country where the Authorized Representative is based. They are registered with the Competent Authority in that country and can be sold there after registration. The IVD product can be registered and sold in other EU countries where the local requirements have been met, for example local language translation. An IVD cannot be sold in a country where the local regulatory requirements have not
been met and the product is not registered. 9. Why are we not selling the diagnostic products in all European countries? In order to sell an IVD in an EU country, the specific requirements of that country must be met in addition to the requirements of the IVD Directive. The decision to sell in a particular country and therefore translate the IVD documentation is made by the Product Management team. 10. How is an IVD product categorized under the EU IVD Directive? Is it an Annex II product or is it CE marked by self declaration? The Authorized Representative or a member of the Regulatory Affairs group can answer this question for specific IVD products. In Europe, IVD products are categorized according to their risk. The Directive contains a specific target list of what is considered a high risk; this list is contained in Annex II of the Directive. If the IVD is associated with one of the tests listed in Annex II, then the product is high-risk and must be assessed by an
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A 510(k) clearance is an authorization by FDA to market an IVD in accordance with its FDAcleared intended use. A 510(k) device is subject to a variety of FDA regulations, including Good Manufacturing Practices (GMPs), adverse event reporting, recalls, and various enforcement remedies for violation of the regulations. A 510(k) cleared device may be used by CLIA laboratories to analyze clinical samples and report the results to physicians (assuming that the assay has been appropriately cleared for use with the instrument).
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external body. All other IVDs are considered low risk and can be CE marked by the manufacturer in a process known as Self Certification. 11. What do I do if I receive a complaint involving a diagnostic product? Complaints involving IVD products should be processed in the complaint handling system as per normal practice. For more details on the complaint handling process, please contact your local Technical Support or Quality Assurance representative. Complaints that involve serious injury or death must be reported to the authorities within a specific time frame. Please inform the Regulatory Affairs group as soon as you become aware of them. 12. What do I do if there is a safety incident involving a diagnostic product? Safety incidents involving a Life Technologies IVD must be reported to Quality Assurance and Regulatory Affairs immediately. The company has a legal obligation to report these incidents to the authorities within a specific time frame. In
addition, safety incidents involving IVD products should be entered into the complaint handling system. 13. In the US, how do I know if the order/complaint/ tender I have received concerns an IVD product? How do I identify IVD products?
symbols and have the following statement on the label: For in vitro diagnostic use.
15. How do I respond to customer questionnaires concerning IVD products/diagnostic applications? Customer questionnaires concerning IVD products or diagnostic applications should be processed in the same way as other customer questionnaires and sent to either Technical Support or Quality Assurance for completion. If you need to include statements specifically relating to IVDs, you should approach your local Regulatory Affairs representative for guidance. 16. Are there any specific internal procedures (e.g.,
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IVD
All IVD products are labeled with the IVD symbol and have the following statement on the label: For in vitro diagnostic use.
IVD
Any customer order, complaint, or tender in Europe that includes the terminology clinical, human diagnostics, or CE IVD relates to products or processes that are covered by the IVD Directive. If you have any concerns on how to address these customer requests, you should approach your local Regulatory Affairs representative for guidance.
This labeling allows the end user to use the finished product in his or her diagnostic applications after the user has qualified the product for its intended use and/or received approval from regulatory authorities for its intended use.
14. In the EU, how do I know if the order/complaint/ tender I have received concerns an IVD product? How do I identify IVD products?
All IVD products are labeled with the CE and IVD
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SOPs) that I need to be aware of, and if so, where can I find them? Every department should have procedures for the activities being performed. Additionally, all customer-facing employees should be aware of the complaint handling process for customer complaints, and how to respond to potential safety incidents (known as Vigilance or Medical Device Reporting cases). Please contact Quality Assurance, who can advise on the availability and location of IVD-related internal procedures. 17. How should I apply the intended use statement? Can I promote an IVD product beyond its intended use statement? The intended use statement is defined by the manufacturer and is a statement outlining the manufacturers intention on how the IVD should be used and under which purpose the IVD has been registered. You cannot promote an IVD for any use that is not covered by the intended use statement. For example, the intended use of the 3500 Dx instrument, which is currently marketed in the EU, is: The instrument is intended to be used by trained operators in the analysis of
human DNA or RNA, for the detection of genetic changes that may lead to disease presence or susceptibility. Therefore, we cannot promote the 3500 Dx for specific disease detection. 18. Can we train the customer on how to validate a protocol? You cannot train the customer on how to validate a clinical protocol. You can refer to particular ISO standards or guidelines that may apply: ISO 9001 (Quality management systems requirements), ISO 13485 (Medical devices quality management systems), ISO 17025 (General requirements for calibration and testing laboratories), and ISO 15189 (Medical laboratories. Requirements for quality and competence). 19. What is ISO 17025, and how can we help our customers with accreditation? ISO 17025 is an International Standard that specifies the general requirements for laboratory testing and calibrations. Laboratories gain accreditation to ISO 17025 as a way of demonstrating their competence to provide
testing or calibration services. Any questions on assisting customers with their accreditation efforts should be directed to Regulatory Affairs. 20. What is an audit? A quality audit is the process of examining a companys quality system to determine if it complies with a set of predetermined requirements. Audits can be conducted internally by Quality Assurance or Regulatory Affairs, or externally by compliance organizations and customers who wish to confirm that our facilities meet certain requirements. Quality audits conducted by external auditors or customers usually last one or two days and require planning and participation of all key personnel within the scope of the audit. 21. Can the customer audit our facilities? Customers who wish to visit our facilities and learn more about our processes to help ensure that we meet their needs may audit our facilities subject to prior advance notice and approval of Life Technologies. Various Life Technologies
facilities are in compliance with 21 CFR 820 and have ISO 13485 certification. Please contact Quality Assurance or Regulatory Affairs to discuss the customers audit request. Any approved customer audit is to be conducted during regular business hours, and the customer may be asked to comply with certain safety and confidentiality prerequisites relating to the audit. 22. What is an FDA inspection? FDAs inspection programs include two types of assignments: routine inspections and directed inspections (sometimes termed for cause). The routine assignments include inspections of clinical investigators, sponsors, Institutional Review Boards (IRBs), or nonclinical laboratories that are randomly selected for coverage under one of four compliance programs. These assignments are issued to monitor adherence to FDA regulations. A directed inspection is requested when some specific problem has been identified within one or all entities of the program. The problem may be observed during the review of sponsor submissions related to ongoing IDE investigations, or following evaluation
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of clinical data submitted in a PMA or 510(k) application. Verbal or written complaints from patients, physicians, or competitors may also result in a directed inspection. Inspections issued for PMA data audits also fall into this category. Once an inspection has been completed, an establishment inspection report (EIR) is prepared and submitted by the district office. This report is then reviewed and classified by the Division of Bioresearch Monitoring. Classifications assigned to inspections indicate whether or not the establishment is operating in compliance with the regulations. The classification scheme used by the FDA is as follows: NAI No Action Indicated VAI Voluntary Action Indicated OAI Official Action Indicated 23. What are FDA 483s and Warning Letters?
Warning letters are a written communication in letter form from the FDA to advise an individual or corporation that the FDA considers one or more products, practices, processes, or other activities to be in violation of the Federal Food, Drug and Cosmetic Act, or other acts. The letter states that failure of the responsible party to take appropriate and prompt action to correct and prevent any future violations may result in enforcement action.
Lab Developed Tests (LDTs) Frequently Asked Questions & Answers 1. If a clinical lab wants to order an RUO labeled product for research use, can we sell it to them? Yes. Many clinical labs perform research and require access to research platforms and reagents. We can sell our RUO labeled products to labs as long as the products are appropriately labeled as RUO and no claims around clinical validity or performance are made. We cannot promote RUO labeled products for clinical use, and it is important to inform the customer that these products do not have a clinical utility. Please contact Regulatory Affairs for more information. 2. Can we set up collaborations to develop application notes with hospital customers using our products in their LDTs? No. Life Technologies should not participate in the use of RUO products for use in an LDT. Please contact Regulatory Affairs or Medical Marketing for more information.
3. Can we support a hospital customer with developing its LDT protocols? No. Life Technologies should not be supporting results of RUO products in LDTs. Life Technologies provides support towards general product characteristics such as analytical specificity and analytical sensitivity. Please contact Regulatory Affairs or Medical Marketing for more information. 4. Can the customer provide a diagnostic result to a patient using RUO labeled product? No. RUO labeled products have no clinical diagnostics intended use. The customer is responsible for any validation and compliance with any regulatory requirements that pertain to the customers procedures and instrument use. 5. Can we market IVD products to CLIA labs? Yes, IVD labeled products can be marketed to CLIA labs, but they should not be promoted beyond their intended use. If a customer wishes to incorporate the IVD device into their homebrew workflow, it is the customers responsibility for
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When FDA investigators inspect a firm and find deviations from current GMPs, they are required to provide the firm with their observations using form FDA-483.
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any validation and compliance with any regulatory requirements that pertain to the customers procedures and instrument use. Working with Clinical Diagnostics Customers 1. Can the customer provide a diagnostic result to a patient using an IVD product?
3. Can we organize clinical seminars in hospitals? Yes, you can. Please ensure consistency in the presentation and avoid interchanging IVD and non-IVD products. Please also be aware that any materials presented or shared at such seminars must be reviewed and approved by Legal and Regulatory Affairs prior to being presented. 4. Can we respond to tenders in clinical hospitals on diagnostic targets? If the intended use of a Life Technologies product meets the requirements of the tender, then we can respond. We cannot respond to tenders towards specific diagnostic disease targets for which we do not have an FDA-cleared or EU regulated IVD device with that specific IVD use. If the tender requires particular regulatory labels and certifications we currently do not have, you cannot respond by saying we comply. Please check with local management and Regulatory Affairs on how best to respond.
5. Can we participate in a tender with another company, for instance, an assay provider, to address all the requirements in the tender? Not unless Life Technologies has a contract in place with this company that regulates partnering in IVD tenders. These contracts have to go through global Legal and Regulatory Affairs approval. 6. Can we suggest another companys IVD product to our customer? You can refer to publications that describe the workflow, products, and procedures that apply. You should never promote or market any IVD product that Life Technologies does not have control over. 7. Can we analyze patient data to help our customers resolve issues or improve their results? You can analyze anonymous data to assist a customer with their technical procedure. Anonymous data is data that cannot be traced to an individual person. You can review
the customers procedure and see where improvements can be gained from an analytical perspective. You should not make any statements pertaining to providing a clinical result (e.g., disease status, treatment response, etc.) These analyses must be consistent with the FDA-cleared or EU regulated intended use for the IVD. 8. Can we set up collaborations with hospital customers to develop application notes using our products? Absolutely, but only if consistent with the FDAcleared or EU regulated intended uses. Any publication or application note must be reviewed and approved by Legal and Regulatory Affairs. 9. Can we support a hospital customer with developing its protocols? You can help a customer develop a protocol on integrating Life Technologies products in accordance with the products instructions for use.
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Life Technologies IVD products can provide diagnostic results only in accordance with the intended use statement of that product. If a customer wants to run an IVD assay on an IVD instrument, they should confirm whether the regulatory requirements have been met for that system or if they need to conduct further validation.
2. What is the difference between clinical and diagnostic protocols? Typically there is no difference; however, some customers may define clinical as clinical research, and how the end result is used may be different. The clinical research segment does not fall under the IVD or diagnostic regulations.
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10. My customer is running a 510(k) assay. What Life Technologies instrument can they run this assay on? The customer would have to use whatever instrument is specified in the 510(k) for that assay, which may or may not be a Life Technologies instrument. If a customer uses an assay that has not received 510(k) clearance for use with the instrument, they will be operating in violation of the FDA regulations. 11. Can we publish papers with customers on clinical or diagnostic protocols? Not at this point, but please forward these to Application Support and Medical Marketing. 12. Can I help a customer license a new technology for clinical diagnostics purposes? You can support a customer with the technical procedure on Life Technologies products as you would do with any other customers. We cannot take part in clinical validation at this point. If you are asked by a customer to do so, please contact Regulatory Affairs or Medical Marketing, as this
request may turn out to be a future opportunity for collaboration. 13. Can we help the customer to validate a clinical/ diagnostic protocol? You can support a customer with the technical procedure on Life Technologies products as you would do with any other customers. We cannot take part in clinical validation at this point. If you are asked by a customer to do so, please contact Regulatory Affairs as this request may turn out to be a future opportunity for collaboration. 14. Can we train the customer on how to validate a protocol? You cannot train the customer on how to validate a clinical protocol. Customers in CLIA Labs must validate all assays using standards recognized by the Clinical Laboratory Standards Institute (CLSI). 15. Can we re-label an RUO labeled product for IVD use if requested by a customer? No, we cannot re-label Research Use Only products. These products have not been
developed, manufactured, or registered as IVDs and cannot be sold for diagnostic applications. 16. Can the customer use one of our instruments and/or reagents in developing a diagnostics kit? When promoting our instruments or reagents, you must stick to the intended use of that product. Customers may choose to use Life Technologies products in their own diagnostic kit development, but the regulatory requirements for the diagnostic kit are the customers responsibility. If you are approached by a customer who wishes to do this, please contact Regulatory Affairs or Medical Marketing, as this request may turn out to be a future opportunity for collaboration. 17. Can the customer buy TaqMan assays for diagnostics development? Life Technologies does not currently have a license to market TaqMan assays for diagnostic use. Please contact the Legal department. 18. Can we directly sell TaqMan/TLDA assays for diagnostic purposes?
You cannot promote or sell an RUO labeled product for diagnostic purposes. 19. Can I advise a customer who is developing a diagnostic test on the regulatory requirements? Can I answer questions from a customer on IVD regulations? You should not advise customers on regulatory requirements without confirming the response with a member of the Regulatory Affairs Team. 20. If a customer is interested in collaborating with us on the validation of a biomarker for clinical diagnostics, whom should I contact? Please forward any collaboration requests to the Head of Medical Marketing for appropriate triage.
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21. If a customer has a homebrew test they would like to license to us to manufacture and sell to other clinical labs as an IVD, what should I do? Please forward any development requests to the Head of Medical Marketing for appropriate triage. 22. Can we develop custom products for our IVD customers? Life Technologies can develop custom devices for IVD customers, but needs to be assured that development is consistent with all applicable FDA and European regulations. The customer will be responsible for interacting with regulatory authorities and receiving required market authorization. Please direct your inquiry to Business Development, Regulatory Affairs, and Legal. 23. My customer has set specifications for incoming quality for a Life Technologies product that are different from our products specification. The customer wants to return the material. What do I do?
You should log the customers request as a complaint, following the complaint handling process. The Quality Assurance department will advise on the response to the customer. 24. My customer has received a complaint regarding one of their Laboratory Developed Tests (LDTs) that utilizes a Life Technologies component. The customer wants us to investigate. What do I do/ whom do I contact?
IVD Instrument Frequently Asked Questions & Answers 1. Do we sell any applications with the IVD instrument? Yes, the customer can use the IVD instrument with RUO or IVD applications. Below are the various scenarios:
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You should log the complaint as per the complaint handling process. If it meets the definition of a complaint, then the problem with the Life Technologies product will be fully investigated. The LDT and other non-Life Technologies components will not be investigated by us and are the customers responsibility. Complaints that involve serious injury or death are high-priority and should be escalated to Regulatory Affairs as soon as you become aware of them. For more details on the complaint handling process, please contact your local Quality Assurance representative.
A customer can purchase appropriate RUO applications to run on an IVD instrument, assuming that the applications are compatible and the results are used for research purposes. The data produced will be suitable for research purposes only and cannot be used for diagnostic applications. It is the customers responsibility to ensure the integrity of the IVD instrument, including any re-validation after the RUO application has been removed. A customer can purchase an IVD application to run on an IVD instrument, assuming that the application and the instrument have both been approved for IVD use together. If this combination has not been cleared/approved as a diagnostic system by the regulatory authorities, then it is the
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customers responsibility to fulfill the appropriate regulatory requirements if they wish to use this system for clinical diagnostics. A customer can purchase an IVD system including instrument and application, which have both been cleared/approved by the regulatory authorities for use together as a diagnostic system.
to validate diagnostic applications. Having an IVD instrument removes some of the workload in the customers validation effort. 4. Can a customer use our IVD instrument for diagnostic applications? What diagnostic results can a customer get with our IVD instrument? Yes, customers can use our IVD instrument for diagnostic applications and they can produce diagnostic results in accordance with the FDA-cleared or EU regulated intended use of the instrument, so long as the regulatory requirements for the particular application have been met. 5. Can a customer use diagnostic applications from another supplier on our IVD instrument? Diagnostic applications from other suppliers may be used on our IVD instruments. However, you should not advise the customer on such use unless the other suppliers application is cleared for use with the Life Technologies instrument. Furthermore, if the customer wishes to provide a diagnostic result using this combined
system, then it is their responsibility to fulfill the regulatory requirements for that specific test. 6. Can a customer run IVD applications on an RUO instrument? IVD applications can be run on an RUO instrument but the customer is responsible for any validation and compliance with any regulatory requirements that pertain to the customers procedures and instrument use. You should advise the customer that the instrument is for research use only and not for diagnostic uses. You should not discuss any diagnostic uses with the customer. 7. Do service engineers need to have any specialized training to deal with IVD instruments? All Service Engineers have to go through a rigorous technical training program on each IVD product before they are allowed to service them unsupervised. IVD instruments have their own individual requirements that are covered within the specific instrument training course.
8. What differences are there in a service agreement for an IVD instrument compared with RUO labeled instruments? IVD instruments are required to have specific qualifications after a critical service intervention and planned maintenance. So the cost of a service contract for an IVD instrument would also include the cost of having the qualifications performed.
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2. Can we sell an IVD instrument in the US without selling any accompanying diagnostic applications? Yes, as long as the instrument has a clearance/ approval from the FDA. The instrument will ultimately be linked to an appropriate assay by the customer (e.g., 7500 Fast Dx and H5N1), but the instrument has a separate 510(k) enabling Life Technologies to sell it individually to customers. 3. Can we sell an IVD instrument in the EU without selling any accompanying diagnostic applications? Yes, by providing the customer with an IVD instrument, they have an instrument that has received regulatory clearance, which they can use
9. Can a customer service our IVD instrument themselves or use a third party? If the customer is using an entity that has been certified by Life Technologies the servicing will be valid. If the instrument is serviced by an unauthorized third party dealer or customer the accuracy of the instrument is no longer valid and we will not be able to support their system. If you become aware of such a case, please notify Service Management and Regulatory Affairs.
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10. Can we provide the customer with evidence that service engineers test tools have been calibrated? Yes, Service Engineers will carry calibration certificates with them for the tools they are using to validate an IVD instrument. These are available to customers on request.
IVD Chemistry Frequently Asked Questions & Answers 1. Do we have evidence of the compatibility with other products? Yes we do. Please contact Technical Support if you require additional information about a specific product. 2. Does the customer need to use reference materials? Where/how can they get these reference materials? If reference materials are required these materials will either be included with the kit or identified in the product insert for the customer. 3. Is it possible to give customers results from stability studies? Have Life Technologies performed open vials studies? We do not provide our stability testing results to customers but if required we can provide a summary indicating the shelf life of the product. Contact Technical Support if you require additional information about product stability.
Cellular Therapy Questions (taken from the Cell Systems Customer Handout) 1. What is ISO 13485 and how does this differ from GMP? A customer can buy a GMP growth factor from Cellgenix and Mitenyi, but only ISO 13485 growth factors from us. What is the difference? ISO 13485 is an International Standard, which represents the requirements for a comprehensive management system for the design and manufacture of medical devices. 21 CFR 820 are the medical device good manufacturing practices (GMPs) published by the US FDA in the code of federal regulations. The medical device GMPs must be followed by manufacturers who produce Class I, II, or III medical devices in the US. Although the ISO 13485 European quality system requirements are very similar to the US 21 CFR Part 820 quality system (GMP) requirements, they are not identical. However, they are both considered GMP standards. Life Technologies growth factors are manufactured at the Camarillo facility which currently meets US 21 CFR Part 820 quality system (GMP) and ISO 13485 requirements.
2. A customer operates (or contracts) a GMP facility for the manufacturing of clinical cell therapy productsand Life Technologies also has GMP facilities. Are these facilities operated to the same standard as the customers GMP cell therapy facilities? One would expect that if a site is registered with the FDA, then the site meets the minimum requirements of the standard. Life Technologies facilities that are registered with the FDA are designed to operate in compliance with the GMPs and meet US 21 CFR Part 820. These facilities are listed on the FDA website as device manufacturers and are inspected by the FDA for compliance with these regulations. Obviously there are different levels of implementation of the GMPs, and some facilities may employ additional controls based on customer requests and product configurations. At some facilities there are areas designated for manufacturing research products only to provide an extra level of segregation. Additionally, different product technologies will require different facility infrastructure to support their GMP compliance.
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3. Life Technologies may procure raw materials which are non-GMP but may market these same materials as GMPwhat kind of processing and qualification do we undertake on such materials to ensure they are qualified to a GMP level? Life Technologies does not procure non-GMP material and then market the same material as GMP. However, we do procure non-GMP raw materials and further process these materials into finished products at one of our GMP facilities registered with the FDA and compliant with US 21 CFR Part 820. Our facilities have validated processes and procedures in place to ensure that products meet our internal product specifications. The regulations do not require that all raw materials used in the finished product be manufactured under the GMPs but they do expect that the raw materials used meet USP/ EP compendia requirements or equivalent where available. If these grade raw materials are not available, additional testing may be required to show that the raw material is safe.
4. What use is implied in the following GMP marketing claims: KSR XF: By using KSR XF, researchers will benefit from the regulatory-friendly nature of a cGMP formulation containing only human and/ or recombinant proteins, defined human-origin, xeno-free serum replacement supplement StemPro MSC SFM: Batch-to-batch consistency with each lotproduced under cGMP and qualified using a hMSC performance assay The above marketing claims are not clearly stated.
Life Technologies facility. As part of the finished product release specifications, an hMSC performance assay is conducted on each batch of finished product to ensure that the media is not toxic to hMSC cells. 5. A customer would like to use Life Technologies cell preservation (e.g., Synth-a-Freeze) products for cells which will be used for clinical purposes do we support this application? We are currently making process improvements in order to support the use of these products in a clinical setting. These improvements will be completed in quarter three (Q3) 2009. However, manufacturing these products under GMPs is only part of the regulatory requirement. As the cell therapy manufacturer, the customer must have controls in place to ensure that the products provided to them are qualified for their intended
use. In addition, the customer must have the appropriate regulatory approval to carry out the clinical studies, i.e., IND, IDE. 6. Can a customer buy GMP PBS from us? Yes, a customer can purchase PBS manufactured under GMPs from Life Technologies. This product is manufactured under the GMPs and is labeled For in vitro diagnostic use. CAUTION: Not intended for human or animal therapeutic use. However, manufacturing these products under GMPs is only part of the regulatory requirement. As the cell therapy manufacturer, the customer must have controls in place to ensure that the products provided to them are qualified for their intended use. In addition, the customer must have the appropriate regulatory approval to carry out the clinical studies, i.e., IND, IDE. 7. Can testing materials into compliance be a substitute for GMP? Testing products into compliance is not a substitute for following the GMPs. GMP manufacturing facilities have processes and
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KSR XF Medium is manufactured under GMPs and is an animal origin free media formulation that contains human origin materials. The animal origin free status is beneficial when submitting an application to regulatory authorities as the use of animal origin components can raise additional questions from regulatory authorities. StemPro MSC SFM is manufactured under GMPs. Lot-to-lot consistency is obtained via process and product controls in place at each
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controls in place to ensure that the raw materials purchased meet internal specifications and that the product is produced in a way to ensure batchto-batch consistency via validation or verification processes. Life Technologies procures non-GMP raw materials and further processes these materials into finished products at one of our GMP facilities. 8. At what point during clinical trials will a customer have to have all their raw materials produced under GMPs? After completion of Phase I clinical trials, the FDA expects that all finished products will be manufactured following the GMPs. The regulations do not require that all raw materials used in the finished product be manufactured under the GMPs but they do expect that the raw materials used meet USP/EP compendia requirements or equivalent where available. If these grade raw materials are not available, additional testing may be required to show that the raw material is safe. When a marketing application is submitted to FDA, it is easier for them to approve products that contain
components that are GMP compliant. RUO labeled products create a challenge for FDA as performance standards or quality attributes may not be readily available or understood. 9. If a customer agrees to take on the risk of using one of Life Technologies materials as part of a final cell therapy formulation to be introduced into a patient with supportive toxicology data, should we allow it? Yes, Life Technologies will help to support the customer in their regulatory filings (i.e., IND, IDE) and work very closely with the customer by supplying the necessary documentation to support the integrity of the raw materials and finished products supplied to them with Certificates of Analysis and raw material specifications. Currently, we have many customers that have used our products in these types of applications and other product filings with regulatory bodies worldwide. 10. If GMP materials are available through a particular vendor, do regulatory authorities (FDA) require that our customers use these materials
for generating cell products for clinical use, or can they use non-GMP, but qualified reagents such as ISO 13485 produced reagents made by other vendors? Do the guidelines for this change if the customer is using these reagents in an academic setting vs. a corporate setting? Regulatory authorities do not require raw materials used to manufacture clinical product to be GMP; however, they do look favorably on compendia raw materials and products. RUO labeled raw materials and products are accepted but do create a challenge for regulatory authorities, depending on how they are to be used, as performance standards or quality attributes may not be readily available or understood. 11. Can a customer use cell characterization reagents, such as FACS antibodies, that are NOT IVD approved for characterizing their cell therapy products during their manufacture? If so, what specific process does the customer need to go through to validate them for this kind of use? Yes, a customer can use Life Technologies RUO FACS antibodies for in-process characterization of their cell therapy products during the
manufacture process (but not for in vitro diagnostic use or any other diagnostic purpose). However, like any analytical method, the customer will need to validate them for this use. We recommend that the customer work with the FDA and agree upon validation criteria that will meet the FDA requirements. 12. Can a 510(k) be issued for a product that has animal-derived components in it, such as HSA? Yes. Life Technologies currently has 510(k) clearance for our AIM V product that contains HSA.
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US FDA IVD Regulations

Abbreviations
510(k) ASR CBER CDER CDRH CFR CLIA FDA GMP GPR IDE IVD LDT MAF OIVD PMA RUO Premarket Notification Analyte Specific Reagent Center for Biologics Evaluation and Research Center for Drug Evaluation and Research Center for Devices and Radiological Health Code of Federal Regulations Clinical Laboratory Improvement Amendments Food and Drug Administration Good Manufacturing Practices General Purpose Reagent Investigational Device Exemption In Vitro Diagnostic Laboratory Developed Tests Master File Office of In Vitro Diagnostics Premarket Approval Research Use Only
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OIVD is the FDA division within CDRH that has regulatory responsibilities over IVD devices. The FDA has recognized three main classes of medical devices based on the level of control necessary to assure the safety and effectiveness of the device regulated. The FDA regulation of medical devices for commercialization is based on the categorization into these three classes. Class I: e.g., ASRs, Cell Culture Media, Reagents
Subject to 510(k) Premarket Notification, covered by 21 CFR 807, Subpart E, and adverse event reporting
What is the difference between a 510(k) and a PMA? A PMA demonstrates that the product is reasonably safe and effective, whereas a 510(k) claims that your device is substantially equivalent to a predicate device; that is, a device that is legally marketed in the US. Whether a device is reviewed under a 510(k) or a PMA is based on the risk-based regulatory classification of the device. Why are IVDs considered devices? In vitro diagnostics (IVDs) meet the definition of a device under the Federal Food, Drug, and Cosmetic Act (the Act). Section 201(h) of the Act defines a device as: an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including any component, part, or accessory, which is: 1. Intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals, or
Class III: e.g., SPOT-Light HER2 CISH Kit

High-risk device Subject to general controls and special controls Subject to Premarket Approval (PMA), covered by 21 CFR 814
2. Intended to affect the structure or any function of the body of man or other animals, and which does not achieve its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of its primary intended purposes. 21 U.S.C. 321(h). How do IVDs differ from other devices? Most other devices function on or in a patient. In contrast, IVDs include products used to collect, prepare, and examine specimens (e.g., blood, serum, urine, spinal fluid, tissue samples) after they are removed from the human body. Is there a regulation that specifically addresses labeling of IVD Products? Labeling for in vitro diagnostic products (21 CFR 809.10) specifies the information required on labeling and in package inserts of marketed products as well as products in development that are distributed for use in studies.
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Subject to the least regulatory control
Subject to general GMP controls, registration, listing, and adverse event reporting
What is an IVD? IVD products include reagents, instruments, and systems which are intended to be used in vitro for the diagnosis of disease or other conditions, including a determination of the state of health, in order to cure, mitigate, treat, or prevent disease or the condition resulting from a disease. IVD products are intended for use in the collection, preparation, and examination of specimens taken from the human body. An IVD can be a reagent, reagent product, calibrator, control material, kit, instrument, apparatus, equipment, interpretation software, or system, which is either used alone or in combination.
Most Class I devices are exempt from 510(k) clearance
Class II: e.g., 7500 Fast Dx Real-Time PCR Instrument, HLA Typing Kits, Cell Culture Media for ex vivo application

Moderate risk device Subject to special controls, which could include special labeling or performance standards
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What is Medical Device Reporting (MDR)? Medical Device Reporting (MDR), included in regulation 21 CFR, Part 803, is the mechanism for the Food and Drug Administration to receive significant medical device adverse events from manufacturers, importers and user facilities, so they can be detected and corrected quickly. How does Life Technologies report a problem with a Medical Device? It is every employees responsibility when they become aware of an adverse event to report this immediately to Regulatory Affairs. Device adverse events or product problems are submitted to the FDA by Regulatory Affairs via the MedWatch program either online, or by phone, fax, or mail. This process requires that all adverse events detected by Life Technologies staff are reported immediately to the Regulatory Affairs department.
What is a reportable event or device adverse event that needs to be reported? This is classified by the FDA as either a
Serious injury/(Serious illness) [803.3(aa)(1)] is an injury or illness that: - Is life threatening, results in permanent impairment of a body function or body structure; or - Necessitates medical or surgical intervention - Examples: Customer receives electrical shock, Customer injures himself using instrument
A malfunction [803.3(m)] is a failure of the device to meet its performance specifications or otherwise perform as intended. - Example: Instrument fails in delivering correct diagnostic or monitoring results that may lead to death or injury based on diagnostic decision.
The European In Vitro Diagnostic Directive

Abbreviations
AR EMCD EU IVD IVDD LVD TF Authorized Representative Electromagnetic Compatibility Directive European Union In Vitro Diagnostic In Vitro Diagnostic Directive Low Voltage Directive Technical File
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In Europe, Manufacturers must meet the requirements of the In Vitro Diagnostic Directive before they can market their IVD medical devices. This section explains what the IVD Directive is and clarifies some of the IVD-related terminology. What is a Directive? A Directive is a legislative act of the European Union that requires member states to achieve a particular result without dictating the means of achieving that result. Directives leave member states with a certain amount of leeway as to the exact rules to be adopted.
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What is the European In Vitro Diagnostic Directive (IVDD)? The full name of the IVDD is Directive 98/79/EC of the European Parliament and of the Council of 27 October 1998 on In Vitro Diagnostic Medical Devices. It is one of a set of Directives that controls how medical devices are managed in Europe. The objective of the IVDD is to allow free movement of IVD products within Europe and to ensure the safety and performance of IVDs and the health of patients and users. What is an IVD? In accordance with the IVDD, an IVD medical device is one which is intended by the manufacturer to be used in vitro for examining human samples for the purpose of providing information concerning a physiological or pathological state, or a congenital abnormality, or to determine the safety and compatibility with potential recipients, or to monitor therapeutic measures. An IVD can be a reagent, reagent product, calibrator, control material, kit, instrument, apparatus, equipment, or system, which is used either alone or in combination.
Who is the Manufacturer? The Manufacturer is the natural or legal person with responsibility for the design, manufacture, packaging and labeling of a device before it is placed on the market under his own name, regardless of whether these operations are carried out by that person himself or on his behalf by a third party. What do Manufacturers have to do to comply with the IVDD? The manufacturers of IVD products must comply with all the requirements of the IVDD before they market their IVDs in Europe. EU member states have transferred the IVDD into their national law, and manufacturers must check the legal requirements in the EU country where they wish to market their IVD to ensure that any additional country regulations have been met. This can include a range of technical, quality and other requirements and can also mean that the manufacturer has to translate the IVD labeling and instructions for use into the primary language of the country where they wish to sell the IVD.
What are the IVDD requirements? The manufacturer must have a quality system in place that meets the requirements of the IVDD; certification to ISO standard 13485 is often used as part of the evidence. The IVD has to be designed and manufactured in accordance with the requirements of the IVDD and specific documentation has to be available as evidence. All IVD devices must meet the applicable essential requirements on safety, performance, and labeling. Safety requirements are not restricted to patients but include users and, where applicable, other persons. The manufacturer is obliged to maintain a technical file for the respective device or device family and keep on file a Declaration of Conformity for the device. If the
manufacturer is not based in Europe, then they must have a representative in Europe who will communicate with the European Authorities on their behalf. This person is known as the Authorized Representative. Once the product is on the market, the manufacturer must ensure that post-market data are actively collected and analyzed. This data is used to assess the post-production phase of the device and can include customer complaints, field issues, and customer surveys. In addition, the manufacturer must ensure that any incidents involving the IVD are dealt with promptly and appropriately, in a process known as Vigilance Reporting. What does a manufacturer do when a Vigilance case occurs? Manufacturers are required to report safety related incidents to the Competent Authority. A reportable incident is a malfunction or deterioration of the IVD or inadequacy in the labeling, which either directly or indirectly has led to, or could have led to, a death or serious injury. The manufacturer must notify the Authorities of a serious public health threat within 2 days, of a death or serious health issue within 10 days, and of any other incident within 30 days.
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Complaint handling is an important input into the Vigilance monitoring system and all complaints must be handled as per the internal complaint handling procedures. For further information on the complaint handling or vigilance processes, please contact your local Quality representative. What are the different risk categories for IVDs? The IVDD has classified certain types of IVDs as highrisk. These IVDs are listed by name in Annex II of the IVDD and include reagents and reagent products for determining HIV, HTLV, hepatitis B, C, D, PSA tumor markers, CMV, etc. The registration process that a manufacturer must follow for high-risk IVDs involves an assessment by an external third party known as a Notified Body. IVDs that are not listed in Annex II and are not for self-testing are considered lower risk products and these can be registered by the manufacturer without an external assessment in a process known as Self Certification. What is the difference between list A and list B in Annex II? Annex II of the IVDD contains two lists of devices. List A includes what are considered the highest risk
devices such as reagents and reagent products for determining AOB blood groups, and for the detection of HIV, HTLV and Hepatitis B etc. The devices in List B are considered a medium risk and include, for example, reagents and reagent products for determining rubella, CMV, and PSA tumor markers. The registration route for both lists of devices is slightly different but all products in Annex II require a Notified Body assessment. What is CE Marking? The term CE Marking is often used to refer to the IVD registration process. Affixing the CE Mark to a product, however, actually demonstrates that the product complies with an EU Directive. CE Marks are used to show compliance to one or more of the Directives such as the Low Voltage Directive (LVD) and Electromagnetic Compatibility Directive (EMCD). For example, when placing an IVD instrument on the EU market, the device needs to comply with the IVD, LVD and the EMCD Directives. EU Directives are available for many consumer and industrial products like electronic devices, toys, eyewear, etc. For CE Marking to the IVDD, labeling includes the CE Mark plus the label for IVD.
Definitions
Dx/dx/DX Diagnostic Intended Use Statement a statement outlining what the manufacturer intends the IVD to achieve. All product labeling (vial, kit, product insert, instruction/ operation/maintenance manuals), promotional materials (including email promotions), PowerPoint presentations, press releases, website content and oral communications concerning the IVD device must be consistent with the intended use statement and cannot make claims that are not covered by the intended use. OEM Original Equipment Manufacturer. An OEM manufactures products or components which are purchased by Life Technologies and then marketed under the Life Technologies brand name. Post Market Surveillance the active collection, analysis and interpretation of data and information received from a variety of sources during the post-production phase of a marketed IVD product in order to monitor the products quality, safety, and performance, and, where needed, make
improvements to the product or associated processes. Product Labeling this extends to more than the label affixed to a product. In addition labeling covers any information that accompanies the IVD product such as User Guides or Instructions that relate to identification, technical description, or use of the IVD.
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Research Use Only (RUO) RUO labeled products are typically used in the laboratory research or feasibility phase of development and not for use in diagnostic procedures. The FDA does not require RUO labeled products to be manufactured under GMP conditions or registered with the FDA. US-Specific Definitions Analyte Specific Reagent (ASR) are antibodies, both polyclonal and monoclonal, specific receptor proteins, ligands, nucleic acid sequences, and similar reagents which, through specific binding or chemical reaction with substances in a specimen, are intended for use in a diagnostic application for identification and quantification of an individual chemical substance or ligand in biological specimens. The FDA requires ASRs to be manufactured under GMP
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conditions, as ASRs are typically used by CLIA labs and Pharmaceutical companies in their product development activities. Certificate to Foreign Government is a document prepared by FDA containing information about a products regulatory or marketing status. CLIA Clinical Laboratory Improvement Amendments of 1988 is Congressional legislation that promulgated quality assurance practices in clinical labs, and required them to measure performance at each step of the testing process from the beginning to the end-point of a response to a test result. CLIA Laboratory is any laboratory facility which performs laboratory testing on specimens derived from humans for the purpose of providing information for the diagnosis, prevention, treatment of disease, or impairment or assessment of health and which has met the requirements of the Clinical Laboratory Improvement Amendments (CLIA). Device Classification Medical devices are classified into Class I, II, and III. Regulatory control increases from Class I to Class III. The device classification
regulation defines the regulatory requirements for a general device type. Most Class I devices are exempt from Premarket Notification 510(k); most Class II devices require Premarket Notification 510(k); and most Class III devices require Premarket Approval. Drug Master File (DMF) a Drug Master File is a submission to the FDA that may be used to provide confidential detailed information about facilities, processes or articles used in the manufacturing, processing, packaging and storing of one or more human drugs. Law or FDA regulation does not require the submission of a DMF. A DMF is submitted solely at the discretion of the holder. The information contained in the DMF may be used to support an Investigational New Drug Application (IND), a New Drug Application (NDA), an Abbreviated New Drug Application (ANDA), another MAF, an Export Application, or amendments and supplements to any of these. There are five types of DMFs. Type I: Manufacturing Site, Facilities, Operating Procedures, and Personnel
Type II: Drug Substance, Drug Substance Intermediate, and Material Used in Their Preparation, or Drug Product Type III: Packaging Material Type IV: Excipient, Colorant, Flavor, Essence, or Material Used in Their Preparation Type V: FDA Accepted Reference Information Life Technologies Cell Systems Division submits a Type II DMF, and our customers submit their INDs, NDAs, etc., to both CDER and CDRH. Exempted Devices some medical devices are sufficiently well known and their safety and effectiveness are sufficiently well characterized and established that they require no premarket review by the FDA. They are still subject to general regulations that require proper labeling, manufacture, and investigation of adverse events. (Class I)
General Purpose Reagent (GPR) is a chemical reagent that has general laboratory application, that is used to collect, prepare, and examine specimens from the human body for diagnostic purposes, and that is not labeled or otherwise intended for a specific diagnostic application. The FDA does not require GPRs to be manufactured under GMP conditions. Good Manufacturing Practices (GMPs) followed by medical device, pharmaceutical and biotech firms so that the products produced meet specific requirements for identity, strength, quality, and purity. FDA regulates these industries to verify compliance. The Medical Device GMPs are included in 21 CFR, Part 820, and the Pharmaceutical & Biotech Industries follow the GMPs in 21 CFR, Part 210 & 211. Homebrew these are products that are brewed in the laboratory by combining components or reagents. These components and reagents are often sold in bulk for further manufacturing, and in some cases are modified for in-house clinical assays. If they are modified, they must be validated according to the laboratory quality regulations of the Clinical Laboratory Improvement Amendments of 1988 (CLIA)
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or otherwise properly approved. Investigational Device Exemption (IDE) application which, when approved, allows the Class III device to be shipped lawfully for the purpose of conducting clinical studies regarding the safety and effectiveness of the device, without complying with certain requirements of the Act. Laboratory Developed Test (LDT) these are assays developed by a clinical laboratory, which are for internal use and are not sold to outside entities. Master File (MAF) a Master File is a submission to the CDRH center of the FDA that may be used to provide confidential detailed information about facilities, processes or articles used in the manufacturing, processing, packaging and storing of one or more medical devices. Premarket Approval (PMA) is the FDAs process of scientific and regulatory review to evaluate the safety and effectiveness of higher risk medical devices. (Class III devices are those that support or sustain human life, are of substantial importance in preventing impairment of human health, or
which present a potential, unreasonable risk of illness or injury, or are new and present unknown safety or effectiveness issues or risks). PMA is the most stringent type of device marketing application required by the FDA. To gain approval, the manufacturer must present adequate scientific evidence to verify that the device is safe and effective for its intended use (FDA Approval). Premarket Notification also referred to as a 510(k), is a submission to FDA that contains information to demonstrate that a medical device is substantially equivalent (SE) to a legally marketed (predicate) device (FDA Clearance). Substantially Equivalent (SE) is a device that has the same intended use and characteristics as an earlier device that has already received FDA clearance. EU Specific Definitions Annex II an annex in the IVD Directive, which contains lists of the high-risk IVD devices (list A and list B). An IVD product associated with these tests cannot be self certified and must instead be evaluated by a Notified Body.
Authorized Representative a person based in the EU who is designated by a manufacturer located outside of Europe to represent the manufacturer with regard the obligations of the EU IVD Directive. The Authorized Representative registers the IVD, acts as the point of contact with the Competent Authorities, and is contactable for all post-sales queries related to the IVD product. Certificate of Free Sales a certificate that manufacturers can request from the Department of Health in the country where the product is registered. A Certificate of Free Sales certifies that the specified product is normally and freely sold in that countrys open markets and is approved for export. Non-EU countries may require this document in order to accept imported IVD products. Competent Authority is the organization within an EU country that has the responsibility for performing duties arising from the IVD Directive. Declaration of Conformity a statement made by Life Technologies to confirm that the requirements of the IVD and other Directives have been fulfilled and we are therefore placing the named product on the market.
Notified Body In the European Union, the Notified Body is an organization that has been accredited by a Member State to assess whether a product meets certain preordained standards. Assessment can include inspection and examination of a product, its design and manufacture. Self Certification The process by which a manufacturer ensures that an IVD product meets the legal requirements of the IVD Directive and can therefore be sold on the EU marketplace. Self Certification is only permitted for IVD products that are not listed in Annex II of the IVD Directive and are not for self-testing. Technical File Documentation that demonstrates how the IVD complies with essential requirements of the IVD Directive. Vigilance Reporting the process of documenting, reviewing, and reporting to the regulatory authorities all adverse events leading to a death or serious injury that involve an IVD device.
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Index
21 CFR part 820 .............................................................................34, 35 510(k) ....................................................17, 18, 23, 31, 38, 4042, 53, 55 Adverse Event...............................................................17, 41, 43, 54, 56 Analyte Specific Reagent (ASR) ........................................40, 41, 52, 53 Annex II ...............................................................................18, 49, 55, 56 Applications ........................................................6, 19, 20, 28, 3032, 37 Audit ............................................................................................6, 22, 23 Authorized Representative ..........................................1618, 46, 48, 56 CE Mark/CE Marking .........................................................18, 19, 49, 55 Center for Biologics Evaluation and Research (CBER) .................... 40 Center for Devices and Radiological Health (CDRH) ..........................................................................18, 40, 41, 54, 55 Center for Drug Evaluation and Research (CDER) ......................40, 54 Certificate of Free Sales ................................................................17, 56 Certificate to Foreign Government .................................................... 53 Class I .................................................................................34, 41, 53, 54 Class II ..........................................................................18, 34, 41, 53, 55 Class III .........................................................................18, 34, 41, 53, 55 Classification ............................................................................23, 42, 53 Clinical .................... 5, 6, 8, 16, 17, 2029, 31, 34, 36, 37, 38, 40, 5355 Clinical Laboratory Improvement Amendments (CLIA) ..........................................5, 17, 24, 27, 40, 53, 55 Code of Federal Regulations (CFR) ......................22, 34, 35, 4043, 54 Collaboration............................................................................24, 2628 Competent Authority ...............................................................18, 48, 56 Complaint ...........................................................6, 1921, 23, 29, 48, 49 Custom Products ................................................................................ 29 Declaration of Conformity .............................................................48, 56 Diagnostic.................................. 3, 5, 6, 8, 1620, 24, 25, 27, 28, 3032, 36, 38, 40, 42, 43, 46, 47, 52, 54 Directive ............................................................18, 20, 46, 47, 49, 55, 56 Drug Master File (DMF) ...........................................................17, 53, 54 Exempted Devices............................................................................... 54 Food and Drug Administration (FDA) ........6, 1618, 22, 23, 2527, 29, 31, 34, 35, 37, 38, 40, 41, 43, 5255 General Purpose Reagent (GPR) ..................................................40, 54 Good Manufacturing Practices (GMP) ......17, 23, 3438, 40, 41, 52, 54 Homebrew ............................................................................5, 24, 29, 54 In Vitro Diagnostic (IVD)..............................3, 5, 6, 1621, 2433, 36, 38 4042, 4649, 52, 55, 56 Inspection .................................................................................22, 23, 56 Intended Use .......................... 5, 6, 17, 19, 21, 2426, 28, 31, 36, 52, 55 Investigational Device Exemption (IDE) ......................23, 36, 37, 40, 55 ISO............................................................. 4, 6, 13, 17, 21, 22, 34, 38, 48 IVD Directive .................................................................18, 20, 46, 55, 56 Labeling ............................................................19, 41, 42, 4749, 52, 54 Laboratory Developed Tests (LDT) ....................................24, 29, 40, 55 Manufacturer ................. 4, 11, 17, 19, 21, 34, 36, 43, 4649, 52, 55, 56 Master File (MAF)...............................................................17, 40, 53, 55 Medical Device Reporting (MDR) ..................................................21, 43 Notified Body ............................................................................49, 55, 56 OEM ........................................................................................4, 911, 52 Office of In Vitro Diagnostics (OIVD) ........................................18, 40, 41 Patients...............................................................................17, 23, 47, 48 Post Market Surveillance ................................................................... 52 Premarket Approval (PMA) ...................................18, 23, 4042, 53, 55 Premarket Notification 510(k)........................................40, 41, 53, 55 Protocol ................................................................................5, 21, 2427 Questionnaire ...................................................................................6, 20 Reference Material ............................................................................. 33 Re-label ............................................................................................... 27 Reportable Event................................................................................. 43 Research Use Only (RUO)........ 16, 17, 24, 27, 28, 30, 32, 37, 38, 40, 52 Risk Categories ................................................................................... 49 Safety Incident............................................................................6, 19, 21 Self Certification ......................................................................19, 49, 56 Seminar ............................................................................................... 25 Service Agreement ............................................................................. 32 Service Engineer ............................................................................32, 33 Specifications .....................................................................29, 3537, 43 Stability Studies .................................................................................. 33 Standard Operating Procedures (SOPs) ............................................ 21 Substantially Equivalent (SE).........................................................42, 55 TaqMan .........................................................................................12, 28 Technical File ...........................................................................46, 48, 56 Tender .............................................................................6, 19, 20, 25, 26 Validate/Validation . 4, 5, 8, 12, 21, 24, 25, 27, 28, 3033, 35, 37, 38, 54 Vigilance .............................................................................21, 48, 49, 56
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UNITED STATES HQ Life Technologies Corporation 5791 Van Allen Way Carlsbad, CA 92008 USA Telephone 760.603.

7200 Fax 760.602.6500

Clinical Diagnostics Handbook

US FDA IVD Regulations

Clinical Diagnostics Dos and Donts

The European In Vitro Diagnostic Directive

Life Technologies Clinical Diagnostics Overview

Frequently Asked Questions

Life Technologies Confidential Information. For internal use only.

For Americas Regulatory Affairs: Kelli Tanzella 716-774-3122 kelli.tanzella@lifetech.com

For AsiaPac Regulatory Affairs: Hongbo (Julie) Su +86 10 58 08 58 64 hongbo.su@lifetech.com

Clinical Diagnostics Dos and Donts

Life Technologies Confidential Information. For internal use only.

Life Technologies Clinical Diagnostics Overview

Our Vision for the Future

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Improving the human condition

Lab Developed Test Products

FDA IVD Products

Genetic Systems Division

Quality Products Quality Systems Manufacturing Capability Reliable Supply

Dynal Beads Molecular Probes fluorescence products Tropix chemiluminescence substrates

BigDye Terminator v1.1 Cycle Sequencing Kit

Lab Developed Test Products

Lab Developed Test Products

Lab Developed Test Products

Variety of appropriate capillary electrophoresis instruments and reagents

Variety of appropriate rtPCR instruments and reagents

Marketed IVD Products

Variety of appropriate benchtop instruments and reagents

Marketed IVD Products

AB 7500 Fast Dx Real-Time PCR Instrument

AB 3500 Dx and 3500xl Dx Instruments Invitrogen DynaChip System

Marketed IVD Products

AmnioMAX-II Complete Medium Invitrogen SPOT-Light HER2 CISH Kit

Life Technologies Is an OEM Provider to Many In Vitro Diagnostic Manufacturers

OEM Components Powered by Life Technologies Examples:

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Life Technologies Develops, Manufactures, and Commercializes IVD Products

Invitrogen SPOT-Light HER2 CISH Kit

Quantitative measure of HER2 gene expression in breast cancer tumors

Invitrogen DynaChip System

Detection and identification of Class I and II HLA antibodies

Frequently Asked Questions

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Life Technologies Confidential Information. For internal use only.

Life Technologies Confidential Information. For internal use only.

All IVD products are labeled with the CE and IVD

Life Technologies Confidential Information. For internal use only.

Life Technologies Confidential Information. For internal use only.

Life Technologies Confidential Information. For internal use only.

Life Technologies Confidential Information. For internal use only.

Life Technologies Confidential Information. For internal use only.

Life Technologies Confidential Information. For internal use only.

Life Technologies Confidential Information. For internal use only.

Life Technologies Confidential Information. For internal use only.

Life Technologies Confidential Information. For internal use only.

US FDA IVD Regulations

Life Technologies Confidential Information. For internal use only.

Class III: e.g., SPOT-Light HER2 CISH Kit

Life Technologies Confidential Information. For internal use only.

Subject to the least regulatory control

Most Class I devices are exempt from 510(k) clearance