Originally Published MX January/February 2005

GOVERNMENTAL & LEGAL AFFAIRS

Medtech executives have a lot to consider when searching for liability defense counsel.

Jon LeSage

Sidebar: Medtech Product Liability Defense Firms

When it comes to dealing with product liability matters, there's just no replacement for the specialized expertise offered by firms with a full understanding of issues related to medical product design and manufacture. Leading candidates offering specialized services to medical device companies include a number of well-known law firms with offices throughout the country. Nevertheless, when seeking expert legal counsel, it's important for company leaders to weigh and balance the various strengths and specialties that such firms can bring to the table.

Medical device product liability cases can be highly complex, involving a multitude of jurisdictions, state and federal laws, and interpretation of regulatory requirements. McCarter & English (Newark, NJ) offers clients this type of perspective and experience.

Tony Brazil

Originally Published MDDI January 2005

Quality

Good Laboratory Notebook Practice

Laboratory notebooks can be an integral part of a company's controlled documentation but must be managed carefully to ensure quality.

John A. DeLucia

Manufacturers must consider many factors during a product's development to ensure proper end-use of the device.

Controlled documentation is a vital component of a quality system. Its benefits include information availability, knowledge preservation, and controlled review and approval of revisions and obsolete documents. Typically, controlled documents may include work instructions, procedures, policies, product drawings, and specifications. Laboratory notebooks are sometimes neglected; but their information can be used in the documentation required in FDA-regulated industries.

Laboratory notebooks can be a primary source for documenting raw data generation for the test engineer and laboratory technician. The notebooks also are used for recording patented inventions and concepts. Laboratory data not otherwise controlled by standard operating procedures or test forms also can be recorded in the notebooks. Such data include, but are not limited to, laboratory data resulting from product development, failure investigations, complaint investigations, product validations, or competitive product testing to support marketing claims. Any individual in a company who is required to gather data could use a laboratory notebook successfully. However, generally, individuals who use laboratory notebooks are from research and development, quality engineering, manufacturing engineering, and testing laboratories departments.

Good Laboratory Notebook Practice

Good laboratory notebook practice is just one way to comply with the much larger concept of good laboratory practice. FDA promulgated the good laboratory practice (GLP) regulations, 21 CFR Part 58, on December 22, 1978. The regulations became effective in June 1979 and established standards for the conduct and reporting of nonclinical laboratory studies. The regulations are intended to ensure the quality and integrity of safety data submitted to FDA.¹ GLP addresses the documentation of research. It provides a means of ensuring that all work is done according to agreed procedures and that the data are properly recorded. The recommendations in this article are designed to help companies develop procedures for good laboratory notebook practice. Moreover, these recommendations can be adapted to develop a procedure for a particular company.

Laboratory Notebook

A laboratory notebook is a permanently bound, rigidly constructed book that can protect its contents in a laboratory environment. Typically, notebooks are issued by the document control department and are tracked and controlled by a serial number. When issued to laboratory workers, the serial number is entered on the cover of each notebook along with the recipient's name and the date the notebook was issued. The serial number should also be noted in a log maintained by the document control department. Once issued, the user should write his or her name and the title of project or purpose of the notebook on the front page.

The notebook should also contain a table of contents that includes a listing, by page number, of all experiments or entries. A space should be provided where report titles or numbers can be entered. On each page, the user should state the report title and project number, laboratory notebook number, and page number. Each page should have a space for a “performed by” signature and date. If the page describes a potential patented product or process, the inventor should sign an “invented by” signature space. A “witnessed by” or “reviewed by” signature and date also should be required on each page. A witness is defined as a member of the organization who can objectively review the information, but who is neither a coinventor nor integrally involved in data collection. Notebooks are available that have a preprinted table of contents, report description, page entry, and signature lines.

Data Entry

Various data entries may be made in a laboratory notebook. The more prevalent practice uses the laboratory notebook to document an experiment and collect test data. So it is worthwhile to look at the proper documentation practices involved in this activity.

Before recording any data, a standardized format should be used to make entries. The list below outlines the information that should be included.

Purpose and Objectives. The purpose and objectives section should include a statement about or definition of the experiment. This section identifies anticipated outcomes and provides an action plan to achieve the outcomes.

Test Articles. A description of all test articles must be written in the laboratory notebook. It is important to provide the test-sample lot numbers and reference any documents that contain the complete history or traceability of the test articles. For instance, if the protocol assesses a newly designed component, minimum information would include the component specification number, revision level, supplier, lot or control number, purchase order number, supplier shop order record, and a copy of the certificate of compliance. All test samples should be retained until after the work has been witnessed in the notebook. If the test samples are to be archived, the archive location should be indicated in the laboratory notebook.

Test Preparation. The test preparation section is where the relevant test methods, equipment, and conditions must be described. All laboratory equipment must be identified by type, manufacturer, and model or tool number. It is important to verify that the calibration and preventive maintenance are current on all equipment.

All test methods and test specifications must be described in detail. This can be done by referencing previously approved and issued documents (including revision levels) or by referencing previous laboratory notebook entries by notebook number and page. Environmental conditions, which may be important and relevant to a test, should be noted. It is important to describe all conditions relevant during testing, such as room temperature, humidity, or sample conditioning. All monitoring equipment used to collect environmental data must be identified in the same way. Laboratory equipment used in the study must also be included.

Test Results. Minimum requirements for collecting test information include entering test results with units. All data transformations, calculations, or operations performed on the data need to be described. Statistical analysis of the data should be carried out according to the prospective protocol instructions and recorded in the notebook before performing the analyses on the data set. A summary of the test results with conclusions should be included in this section. If inconsistent results or unusual data points were encountered, then these must be identified and explained. Lastly, study initiation and completion dates also should be documented.

Maintenance of Data Integrity. Maintaining data integrity is critical to good laboratory notebook practice. It is important to write legibly and clearly and to use recognizable and accepted terms. If abbreviations, code names, trademarks, trade names, or numbers are used, they should be defined at least once, at first use, in every notebook. As with any quality record, errors should be deleted by drawing a single line through the error that does not render the deletion illegible. A notation stating the reason for the deletion should be added, initialed, and dated by the person who made the deletion. Pages should never be removed from a laboratory notebook.

All data must be entered directly into the notebook, rather than on separate papers for later copying into the notebook. When attaching forms, photographs, charts, statistical printouts, etc., using glue or tape ensures permanence. A mark or signature should be placed across any portion of the attachment and lab notebook page. There must be no document replacement after the witness signs. If there is blank space at the bottom of the page, lines drawn across the length and width prevent additional comments or results from being added after the page is witnessed. All transcribed data must be signed and dated by the individual performing the transcription. The location of the raw data should also be included if it is not in the notebook.

Control of Laboratory Notebooks

The document control department is responsible for the issuance, retrieval, and maintenance of laboratory notebooks. However, during use, the assigned individual assumes responsibility for the care and whereabouts of the book at all times. The control of laboratory notebooks should be no different from other controlled documents or quality records.

The laboratory notebook should be returned to the document control department when completed or upon termination of its use. Before a laboratory notebook is returned, appropriate personnel should review it to ensure that all items were entered in accordance with procedure. The document control department should note the return date in its log. All returned laboratory notebooks should be filed in a centralized holding area in the department and should not leave the area unless they are signed out. If a laboratory notebook is lost, the document control department should be notified in writing, detailing the circumstances surrounding the loss. This notice must be signed and dated by the employee and his or her immediate supervisor.

Lastly, laboratory notebooks should be retained like any other controlled document. Their retention should be specified in the company's records retention procedures.

Conclusion

Laboratory notebooks are an important component of a company's quality system and controlled documentation. The notebooks play an important role in preserving and transferring valuable information and knowledge within a company.

An employee's laboratory notebook is subject to inspection by colleagues, supervisors, or outside regulatory body auditors. Thus, it is imperative that GLP notebook practices are implemented and that a standardized procedure is in place for handling laboratory notebooks. Laboratory notebooks must contain all of the pertinent information required by the company. They must also be maintained in a controlled manner. Defining these requirements ensures that the contents of laboratory notebooks can withstand any challenges to their validity, accuracy, or legibility.

Reference

1. FDA Compliance Program Guidance Manual, Program 7348.808, Chapter 28, “Bioresearch Monitoring: Good Laboratory Practice (Nonclinical Laboratories),” February 21, 2001.

John A. DeLucia is vice president of regulatory affairs and quality assurance at Smiths Medical ASD Inc. (Keene, NH).

Copyright ©2005 Medical Device & Diagnostic Industry

Originally Published MDDI January 2005

EDITOR'S PAGE

Drip by drip, CDRH has been getting more aggressive about making device companies do postmarket studies. After Vioxx, expect that trickle to turn into a flood.

(click to enlarge)

When it comes to linical studies, the device industry is used to doing the minimum required for market approval, and little, if any, more.

That is changing, and firms must adapt.

The withdrawal of Merck's drug Vioxx from the market after postmarket studies showed it put patients at greater risk for heart attack and stroke, and allegations that the company may have suppressed that evidence, can only accelerate CDRH's desire for more clinical work from device companies. Expect CDRH to ramp up its demands for more and larger premarket studies, and to require more firms to conduct post-market studies as a condition of approval.

Why would a controversy over a drug affect the device regulatory landscape? There are several reasons.

First, with the advent of combination products, the drug and device worlds are converging. Figuring out whether a device is safe and effective takes a relatively short time. Doing so for a drug-device or biologic-device combination takes much longer. After the Vioxx incident, CDRH could very well require a higher burden of proof for combination products. Given the culture at FDA, that demand could creep across to standard devices as well.

Second, bad news for any part of FDA is bad for the whole agency. In 1989, when a few FDA reviewers were found to have taken payoffs from generic-drug companies, the fallout hit all agency review teams, not just those in the drug center. As a result, CDRH reviewers fell under intense scrutiny and became more cautious in their reviews. There's no reason to think it can't happen again.

And last, the lessons learned from the Vioxx incident correspond to some CDRH initiatives already in play. Since taking office, CDRH director Daniel Schultz has made it a priority to improve postmarket studies. The Vioxx incident should give momentum to his plans for requiring more device postmarketing studies and for making firms design and track them better.

At the Cleveland Clinic Medical Innovation Summit in October, executives seemed aware of this new landscape.

Michael A. Mussallem, chairman and CEO of Edwards Lifesciences, noted that because FDA reviewers are "charged with the health and safety of the U.S. public, they get punished for making a mistake. They rarely get rewarded for opening the door [to a new technology]. Therefore, if we punish them because of a Vioxx, they are likely to turn more cautious when the next innovation is developed."

Boston Scientific chairman and CEO James R. Tobin chronicled the extensive premarket and postmarket studies done for its drug-eluting stent, Taxus. These experiences, he said, might soon become commonplace for device makers.

"Device companies do just enough trials to get their products approved. But we didn't stop there," he said. "We went from the 'lay-up lesions' [studied in premarket trials] to [postmarket studies] with more of the tough clinical situations you see in the real world. We can understand how our product performs in real-world situations, as opposed to in carefully designed pivotal trials."

So, device companies can expect to have their premarket studies questioned more vigorously. Some may have to resort to more-expensive tactics such as larger patient populations and outcomes research to prove their case to the agency.

They can also expect more postmarket studies to be required. And as Melissa Walker, a vice president of Stereotaxis Inc., noted, they may see greater scrutiny of post-approval issues such as device tracking, complaint handling, and customer feedback. "This means you need a postmarket risk assessment plan," she said at the Regulatory Affairs Professionals Society annual conference in October. "You need to decide on how you will handle, recognize, and act upon issues. A good analysis is never done as long as the product is on the market."

The days when a device company did not need to verify safety and efficacy after FDA approval are fast dwindling. The Vioxx incident will only speed that process.

The Editors

Copyright ©2005 Medical Device & Diagnostic Industry

Originally Published MX January/February 2005

EDITOR'S PAGE

Last May, David J. Brailer, MD, was named the first occupant of the office of national coordinator for health information technology (ONCHIT).

Since then, Brailer has become an active and outspoken proponent of the goal of creating a national healthcare IT infrastructure, which was announced in April by then-secretary of the Department of Health and Human Services (HHS) Tommy Thompson, who resigned in December. But leadership requires a lot more than just personality—like funding.

Funding for ONCHIT projects was expected to be included in the omnibus federal appropriations bill for fiscal 2005. The legislation designated $50 million to support healthcare IT demonstration projects, the development of interoperability standards, and a program to certify the interoperability of IT-based healthcare products.

Originally Published MX January/February 2005

MILESTONES

Cytyc Corp., a medical device company that designs, develops, manufactures, and markets products focused on women's health, has relocated its corporate headquarters from Boxborough to Marlborough, MA. "Our new headquarters in Marlborough will expand our training, manufacturing, and research and development capabilities," said Patrick J. Sullivan, Cytyc chairman, president, and CEO. "In addition, the new location will provide an improved office environment for employees."

Originally Published MDDI January 2005

Quality

Good Laboratory Notebook Practice

Laboratory notebooks can be an integral part of a company's controlled documentation but must be managed carefully to ensure quality.

John A. DeLucia

Manufacturers must consider many factors during a product's development to ensure proper end-use of the device.

Controlled documentation is a vital component of a quality system. Its benefits include information availability, knowledge preservation, and controlled review and approval of revisions and obsolete documents. Typically, controlled documents may include work instructions, procedures, policies, product drawings, and specifications. Laboratory notebooks are sometimes neglected; but their information can be used in the documentation required in FDA-regulated industries.

Laboratory notebooks can be a primary source for documenting raw data generation for the test engineer and laboratory technician. The notebooks also are used for recording patented inventions and concepts. Laboratory data not otherwise controlled by standard operating procedures or test forms also can be recorded in the notebooks. Such data include, but are not limited to, laboratory data resulting from product development, failure investigations, complaint investigations, product validations, or competitive product testing to support marketing claims. Any individual in a company who is required to gather data could use a laboratory notebook successfully. However, generally, individuals who use laboratory notebooks are from research and development, quality engineering, manufacturing engineering, and testing laboratories departments.

Good Laboratory Notebook Practice

Good laboratory notebook practice is just one way to comply with the much larger concept of good laboratory practice. FDA promulgated the good laboratory practice (GLP) regulations, 21 CFR Part 58, on December 22, 1978. The regulations became effective in June 1979 and established standards for the conduct and reporting of nonclinical laboratory studies. The regulations are intended to ensure the quality and integrity of safety data submitted to FDA.¹ GLP addresses the documentation of research. It provides a means of ensuring that all work is done according to agreed procedures and that the data are properly recorded. The recommendations in this article are designed to help companies develop procedures for good laboratory notebook practice. Moreover, these recommendations can be adapted to develop a procedure for a particular company.

Laboratory Notebook

A laboratory notebook is a permanently bound, rigidly constructed book that can protect its contents in a laboratory environment. Typically, notebooks are issued by the document control department and are tracked and controlled by a serial number. When issued to laboratory workers, the serial number is entered on the cover of each notebook along with the recipient's name and the date the notebook was issued. The serial number should also be noted in a log maintained by the document control department. Once issued, the user should write his or her name and the title of project or purpose of the notebook on the front page.

The notebook should also contain a table of contents that includes a listing, by page number, of all experiments or entries. A space should be provided where report titles or numbers can be entered. On each page, the user should state the report title and project number, laboratory notebook number, and page number. Each page should have a space for a “performed by” signature and date. If the page describes a potential patented product or process, the inventor should sign an “invented by” signature space. A “witnessed by” or “reviewed by” signature and date also should be required on each page. A witness is defined as a member of the organization who can objectively review the information, but who is neither a coinventor nor integrally involved in data collection. Notebooks are available that have a preprinted table of contents, report description, page entry, and signature lines.

Data Entry

Various data entries may be made in a laboratory notebook. The more prevalent practice uses the laboratory notebook to document an experiment and collect test data. So it is worthwhile to look at the proper documentation practices involved in this activity.

Before recording any data, a standardized format should be used to make entries. The list below outlines the information that should be included.

Purpose and Objectives. The purpose and objectives section should include a statement about or definition of the experiment. This section identifies anticipated outcomes and provides an action plan to achieve the outcomes.

Test Articles. A description of all test articles must be written in the laboratory notebook. It is important to provide the test-sample lot numbers and reference any documents that contain the complete history or traceability of the test articles. For instance, if the protocol assesses a newly designed component, minimum information would include the component specification number, revision level, supplier, lot or control number, purchase order number, supplier shop order record, and a copy of the certificate of compliance. All test samples should be retained until after the work has been witnessed in the notebook. If the test samples are to be archived, the archive location should be indicated in the laboratory notebook.

Test Preparation. The test preparation section is where the relevant test methods, equipment, and conditions must be described. All laboratory equipment must be identified by type, manufacturer, and model or tool number. It is important to verify that the calibration and preventive maintenance are current on all equipment.

All test methods and test specifications must be described in detail. This can be done by referencing previously approved and issued documents (including revision levels) or by referencing previous laboratory notebook entries by notebook number and page. Environmental conditions, which may be important and relevant to a test, should be noted. It is important to describe all conditions relevant during testing, such as room temperature, humidity, or sample conditioning. All monitoring equipment used to collect environmental data must be identified in the same way. Laboratory equipment used in the study must also be included.

Test Results. Minimum requirements for collecting test information include entering test results with units. All data transformations, calculations, or operations performed on the data need to be described. Statistical analysis of the data should be carried out according to the prospective protocol instructions and recorded in the notebook before performing the analyses on the data set. A summary of the test results with conclusions should be included in this section. If inconsistent results or unusual data points were encountered, then these must be identified and explained. Lastly, study initiation and completion dates also should be documented.

Maintenance of Data Integrity. Maintaining data integrity is critical to good laboratory notebook practice. It is important to write legibly and clearly and to use recognizable and accepted terms. If abbreviations, code names, trademarks, trade names, or numbers are used, they should be defined at least once, at first use, in every notebook. As with any quality record, errors should be deleted by drawing a single line through the error that does not render the deletion illegible. A notation stating the reason for the deletion should be added, initialed, and dated by the person who made the deletion. Pages should never be removed from a laboratory notebook.

All data must be entered directly into the notebook, rather than on separate papers for later copying into the notebook. When attaching forms, photographs, charts, statistical printouts, etc., using glue or tape ensures permanence. A mark or signature should be placed across any portion of the attachment and lab notebook page. There must be no document replacement after the witness signs. If there is blank space at the bottom of the page, lines drawn across the length and width prevent additional comments or results from being added after the page is witnessed. All transcribed data must be signed and dated by the individual performing the transcription. The location of the raw data should also be included if it is not in the notebook.

Control of Laboratory Notebooks

The document control department is responsible for the issuance, retrieval, and maintenance of laboratory notebooks. However, during use, the assigned individual assumes responsibility for the care and whereabouts of the book at all times. The control of laboratory notebooks should be no different from other controlled documents or quality records.

The laboratory notebook should be returned to the document control department when completed or upon termination of its use. Before a laboratory notebook is returned, appropriate personnel should review it to ensure that all items were entered in accordance with procedure. The document control department should note the return date in its log. All returned laboratory notebooks should be filed in a centralized holding area in the department and should not leave the area unless they are signed out. If a laboratory notebook is lost, the document control department should be notified in writing, detailing the circumstances surrounding the loss. This notice must be signed and dated by the employee and his or her immediate supervisor.

Lastly, laboratory notebooks should be retained like any other controlled document. Their retention should be specified in the company's records retention procedures.

Conclusion

Laboratory notebooks are an important component of a company's quality system and controlled documentation. The notebooks play an important role in preserving and transferring valuable information and knowledge within a company.

An employee's laboratory notebook is subject to inspection by colleagues, supervisors, or outside regulatory body auditors. Thus, it is imperative that GLP notebook practices are implemented and that a standardized procedure is in place for handling laboratory notebooks. Laboratory notebooks must contain all of the pertinent information required by the company. They must also be maintained in a controlled manner. Defining these requirements ensures that the contents of laboratory notebooks can withstand any challenges to their validity, accuracy, or legibility.

Reference

1. FDA Compliance Program Guidance Manual, Program 7348.808, Chapter 28, “Bioresearch Monitoring: Good Laboratory Practice (Nonclinical Laboratories),” February 21, 2001.

John A. DeLucia is vice president of regulatory affairs and quality assurance at Smiths Medical ASD Inc. (Keene, NH).

Copyright ©2005 Medical Device & Diagnostic Industry

Originally Published MDDI January 2005

NEWSTRENDS

Maria Fontanazza

DePuy's Charité artificial spinal disk has generated enthusiasm in the orthopedics sector.

DePuy Spine Inc.'s (Raynham, MA) artificial spinal disk, which received long-awaited FDA approval in October, has been touted as a revolutionary alternative to spinal fusion. It is also part of the device industry's growing trend to develop minimally invasive technologies. If this device and its soon-to-arrive competitors live up to industry expectations, it could further validate many firms' strategies around products that restore quality of life to patients quickly.

The United States is the largest market for minimally invasive devices, from imaging equipment to handheld instruments and surgical tools. DePuy's Charité artificial disk is one of many emerging technologies that result in shorter hospitalization and recovery times, lower cost, and a reduced chance of complications associated with incisions. As such, it has gen- erated much enthusiasm in the orthopedics sector.

It will expand the spectrum of care to those who would never have considered spinal fusion. —Scott Blumenthal, MD

"We've seen patients who were waiting for this technology to be approved and would never have otherwise entered the fusion market," says Scott Blumenthal, MD, director of the Center for Spine Arthroplasty at the Texas Back Institute (Plano, TX). "Not only will it infringe upon the fusion segment, but it will expand the spectrum of care to those who would never have considered spinal fusion."

Anthony Viscogliosi, principal at Viscogliosi Bros. LLC (New York City), an equity and merchant banking firm in the musculoskeletal and orthopedics sector, predicts that the device will garner incredible patient demand. "I think that the effect for this technology will be the greatest effect that there has ever been for a new technology in spine surgery," he says. He estimates that the market for spine arthroplasty will reach $5 billion by 2010, and that 440,000 Americans per year will have undergone the procedure by then.

The device is only for use in patients who have degenerative disk disease at the lowest segments of the lumbar spine and have experienced no relief from at least six months of nonsurgical ther- apy. Degenerative disk disease causes pain from a worn spinal disk. More than 200,000 U.S. patients undergo spinal fusion each year. This could soon change.

"The demand from surgeons and patients is extremely large," says John J. Regan, MD, codirector of the Cedars-Sinai Institute for Spinal Disorders (Los Angeles). "There's a great deal of enthusiasm about this as a revolutionary technology." A Web site survey conducted last year by Spinehealth.com even found that nearly half of spinal fusion candidates were opting to hold out for the artificial disk procedure.

"We'll see a deeper penetration each year into the spinal fusion segment of the business," says Blumenthal, a lead investigator in the clinical trial. "In this circumstance, it will be unbelievably beneficial to be the first company to market the device."

Developed in Germany in the 1980s, the disk has been used in Europe for nearly two decades. According to Blumenthal, surgeons in the United States have the advantage of clinical trial data and evidence from the device's lasting results in Europe. "It's not like this is a brand-new technology. There will be fewer false starts than if it were, say, a five-year-old device."

Despite the long-term results already seen overseas, FDA still requires a postmarket study, which involves patient follow-up for at least two more years. DePuy's parent company, Johnson & Johnson, is providing a two-day training course that surgeons must attend prior to initiating the procedure in patients.

Doctors say artificial disks offer faster recovery times and an earlier return to a regular routine than a spinal fusion procedure. "Patients have experienced better pain relief, with earlier returns to normal activity," says Regan, also a principal investigator in the clinical trial. "They leave the hospital in one to two days and return to work in two to three weeks." He says 91% have returned to work within three months.

The disk is made of a plastic center between two metallic endplates. Once implanted, it imitates the spine's natural movement and helps to decrease the deterioration of adjacent spinal levels. "This is the first device that not only relieves back pain but also preserves motion," says Blumenthal. "This is a transformational technology. It helps patients. If you have severe and incapacitating back pain, you now have an option."

Other companies in the process of developing artificial spinal disks include Medtronic Sofamor Danek Inc. (Richmond, VA); SpineCore (Summit, NJ), recently acquired by Stryker Corp. (Kalamazoo, MI); and Synthes Inc. (Oberdorf, Switzerland).

Copyright ©2005 Medical Device & Diagnostic Industry

Originally Published MX January/February 2005

IT IN HEALTHCARE

FDA rules for electronic compliance documents are headed toward a major overhaul.

Christina Elston

Sidebars: Part 11, Departing? Industry Coalition on 21 CFR Part 11 Commercial Resources: Regulatory IT Providers

Once upon a time, medical device companies could expect to make their manufacturing processes more efficient by using the same real-time management systems used by other types of companies. "In the old world, medical product companies could use the same systems that were being used in other industries, as long as they paid close attention to the tracking and control of materials, to good manufacturing practices (GMPs), and to their ability to support recalls," says Bill Burke, president and CEO of Merit Solutions (Wheaton, IL).

But that was before FDA went electronic.

In 1997, FDA issued a new regulation designed to make it easier for manufacturers to use wholly electronic methods of maintaining and approving compliance-related records.¹ The new regulation, 21 CFR 11—commonly referred to as Part 11—was a good idea. But it soon became clear that FDA had no idea how to implement it.

Originally Published MX January/February 2005

BUSINESS NEWS

Weldon

Over the years they've talked before—but to no avail. But this time—pending antitrust scrutiny by the Securities and Exchange Commission (SEC)—the deal between Johnson & Johnson Inc. (New Brunswick, NJ) and Guidant Corp. (Indianapolis) looks like the real thing.

Under the terms of the deal, J&J will pay $23.9 billion to acquire Guidant. The deal represents the largest-ever acquisition by J&J, almost doubling the $13 billion the company paid for drug-delivery firm Alza in 2001.

In acquiring Guidant, J&J gains access to the company's cardiac rhythm management business, a medical device segment in which J&J currently has no products. Guidant's 2003 sales from implantable defibrillators and pacemakers were around $2.2 billion of its $3.7 billion total revenue for the year. Commenting on the acquisition, William C. Weldon, chairman and CEO of Johnson & Johnson, said, "The combination of these businesses will enable us to bring innovative new therapies to patients and their physicians in this very important and fast-growing therapeutic area."

Valeriani

Originally Published MDDI January 2005

Quality



Laboratory notebooks can be an integral part of a company's controlled documentation but must be managed carefully to ensure quality.

John A. DeLucia

Manufacturers must consider many factors during a product's development to ensure proper end-use of the device.

Controlled documentation is a vital component of a quality system. Its benefits include information availability, knowledge preservation, and controlled review and approval of revisions and obsolete documents. Typically, controlled documents may include work instructions, procedures, policies, product drawings, and specifications. Laboratory notebooks are sometimes neglected; but their information can be used in the documentation required in FDA-regulated industries.

Laboratory notebooks can be a primary source for documenting raw data generation for the test engineer and laboratory technician. The notebooks also are used for recording patented inventions and concepts. Laboratory data not otherwise controlled by standard operating procedures or test forms also can be recorded in the notebooks. Such data include, but are not limited to, laboratory data resulting from product development, failure investigations, complaint investigations, product validations, or competitive product testing to support marketing claims. Any individual in a company who is required to gather data could use a laboratory notebook successfully. However, generally, individuals who use laboratory notebooks are from research and development, quality engineering, manufacturing engineering, and testing laboratories departments.

Good laboratory notebook practice is just one way to comply with the much larger concept of good laboratory practice. FDA promulgated the good laboratory practice (GLP) regulations, 21 CFR Part 58, on December 22, 1978. The regulations became effective in June 1979 and established standards for the conduct and reporting of nonclinical laboratory studies. The regulations are intended to ensure the quality and integrity of safety data submitted to FDA.¹ GLP addresses the documentation of research. It provides a means of ensuring that all work is done according to agreed procedures and that the data are properly recorded. The recommendations in this article are designed to help companies develop procedures for good laboratory notebook practice. Moreover, these recommendations can be adapted to develop a procedure for a particular company.

Laboratory Notebook

A laboratory notebook is a permanently bound, rigidly constructed book that can protect its contents in a laboratory environment. Typically, notebooks are issued by the document control department and are tracked and controlled by a serial number. When issued to laboratory workers, the serial number is entered on the cover of each notebook along with the recipient's name and the date the notebook was issued. The serial number should also be noted in a log maintained by the document control department. Once issued, the user should write his or her name and the title of project or purpose of the notebook on the front page.

The notebook should also contain a table of contents that includes a listing, by page number, of all experiments or entries. A space should be provided where report titles or numbers can be entered. On each page, the user should state the report title and project number, laboratory notebook number, and page number. Each page should have a space for a “performed by” signature and date. If the page describes a potential patented product or process, the inventor should sign an “invented by” signature space. A “witnessed by” or “reviewed by” signature and date also should be required on each page. A witness is defined as a member of the organization who can objectively review the information, but who is neither a coinventor nor integrally involved in data collection. Notebooks are available that have a preprinted table of contents, report description, page entry, and signature lines.

Data Entry

Various data entries may be made in a laboratory notebook. The more prevalent practice uses the laboratory notebook to document an experiment and collect test data. So it is worthwhile to look at the proper documentation practices involved in this activity.

Before recording any data, a standardized format should be used to make entries. The list below outlines the information that should be included.

Purpose and Objectives. The purpose and objectives section should include a statement about or definition of the experiment. This section identifies anticipated outcomes and provides an action plan to achieve the outcomes.

Test Articles. A description of all test articles must be written in the laboratory notebook. It is important to provide the test-sample lot numbers and reference any documents that contain the complete history or traceability of the test articles. For instance, if the protocol assesses a newly designed component, minimum information would include the component specification number, revision level, supplier, lot or control number, purchase order number, supplier shop order record, and a copy of the certificate of compliance. All test samples should be retained until after the work has been witnessed in the notebook. If the test samples are to be archived, the archive location should be indicated in the laboratory notebook.

Test Preparation. The test preparation section is where the relevant test methods, equipment, and conditions must be described. All laboratory equipment must be identified by type, manufacturer, and model or tool number. It is important to verify that the calibration and preventive maintenance are current on all equipment.

All test methods and test specifications must be described in detail. This can be done by referencing previously approved and issued documents (including revision levels) or by referencing previous laboratory notebook entries by notebook number and page. Environmental conditions, which may be important and relevant to a test, should be noted. It is important to describe all conditions relevant during testing, such as room temperature, humidity, or sample conditioning. All monitoring equipment used to collect environmental data must be identified in the same way. Laboratory equipment used in the study must also be included.

Test Results. Minimum requirements for collecting test information include entering test results with units. All data transformations, calculations, or operations performed on the data need to be described. Statistical analysis of the data should be carried out according to the prospective protocol instructions and recorded in the notebook before performing the analyses on the data set. A summary of the test results with conclusions should be included in this section. If inconsistent results or unusual data points were encountered, then these must be identified and explained. Lastly, study initiation and completion dates also should be documented.

Maintenance of Data Integrity. Maintaining data integrity is critical to good laboratory notebook practice. It is important to write legibly and clearly and to use recognizable and accepted terms. If abbreviations, code names, trademarks, trade names, or numbers are used, they should be defined at least once, at first use, in every notebook. As with any quality record, errors should be deleted by drawing a single line through the error that does not render the deletion illegible. A notation stating the reason for the deletion should be added, initialed, and dated by the person who made the deletion. Pages should never be removed from a laboratory notebook.

All data must be entered directly into the notebook, rather than on separate papers for later copying into the notebook. When attaching forms, photographs, charts, statistical printouts, etc., using glue or tape ensures permanence. A mark or signature should be placed across any portion of the attachment and lab notebook page. There must be no document replacement after the witness signs. If there is blank space at the bottom of the page, lines drawn across the length and width prevent additional comments or results from being added after the page is witnessed. All transcribed data must be signed and dated by the individual performing the transcription. The location of the raw data should also be included if it is not in the notebook.

Control of Laboratory Notebooks

The document control department is responsible for the issuance, retrieval, and maintenance of laboratory notebooks. However, during use, the assigned individual assumes responsibility for the care and whereabouts of the book at all times. The control of laboratory notebooks should be no different from other controlled documents or quality records.

The laboratory notebook should be returned to the document control department when completed or upon termination of its use. Before a laboratory notebook is returned, appropriate personnel should review it to ensure that all items were entered in accordance with procedure. The document control department should note the return date in its log. All returned laboratory notebooks should be filed in a centralized holding area in the department and should not leave the area unless they are signed out. If a laboratory notebook is lost, the document control department should be notified in writing, detailing the circumstances surrounding the loss. This notice must be signed and dated by the employee and his or her immediate supervisor.

Lastly, laboratory notebooks should be retained like any other controlled document. Their retention should be specified in the company's records retention procedures.

Conclusion

Laboratory notebooks are an important component of a company's quality system and controlled documentation. The notebooks play an important role in preserving and transferring valuable information and knowledge within a company.

An employee's laboratory notebook is subject to inspection by colleagues, supervisors, or outside regulatory body auditors. Thus, it is imperative that GLP notebook practices are implemented and that a standardized procedure is in place for handling laboratory notebooks. Laboratory notebooks must contain all of the pertinent information required by the company. They must also be maintained in a controlled manner. Defining these requirements ensures that the contents of laboratory notebooks can withstand any challenges to their validity, accuracy, or legibility.

Reference

1. FDA Compliance Program Guidance Manual, Program 7348.808, Chapter 28, “Bioresearch Monitoring: Good Laboratory Practice (Nonclinical Laboratories),” February 21, 2001.

John A. DeLucia is vice president of regulatory affairs and quality assurance at Smiths Medical ASD Inc. (Keene, NH).

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