DATA ACQUISITION FOR CONTROLS ANDINSTRUMENTATION IN 21 CFR PART 11 APPLICATIONS

Ravi Jethra

Product ManagerEndress+Hauser Instruments

Greenwood, IN 46143 U.S.A.

KEYWORDS

21 CFR Part 11, Current Good Manufacturing Practice (CGMP), 21 CFR Part 210 and 211, U.S. Foodand Drug Administration (FDA), U.S. Department of Agriculture (USDA), Compliance Policy Guide(CPG), Pasteurized Milk Ordinance (PMO), High-Temperature Short-Time (HTST), pasteurization,Hazard Analysis and Critical Control Point (HACCP), Safety Thermal Limit Recorder (STLR), Clean InPlace (CIP), videographic paperless recorder, data acquisition system, electronic signature, biometric,nonbiometric (non-biometric)

ABSTRACT

Regulations pertaining to electronic records and signatures are incorporated into Title 21 of the Code ofFederal Regulations Part 11 (21 CFR Part 11)1. This paper explores the effects 21 CFR Part 11requirements can have for data recording within regulated applications in general and within sanitaryenvironments (pharmaceutical, biotechnology, and food & beverage) in particular. To provide a baselinefor discussion, the paper opens by reviewing the importance of instrumentation and controls (includingtraditional paper-based recorders) in regulated applications. Next, the discussion reviews some paperlessrecording methods in the regulated environment, describing some of the considerations and advantagesin transitioning to a paperless recording solution. The discussion concludes by reviewing the advantagesand benefits of a paperless recorder designed specifically for 21 CFR Part 11 applications and some ofthe challenges users may confront when converting from paper to paperless recording solutions.

INTRODUCTION

During recent years, several regulatory agencies-- especially departments of environmental protection atthe State and local levels-- have increasingly been willing to accept paperless records.2 In recent years,instrumentation and software suppliers have developed several software packages aimed towards

pharmaceutical users in support of Current Good Manufacturing Practice (CGMP) as outlined in thefederal regulations 21 CFR Parts 210 and 211.3 However, many producers in the sanitary regulatedmarkets have not converted or even planned for transitioning to advanced paperless solutions.According to recent polling, “13% of the food and beverage industry responders say they haven’t evenbegun planning,” and 27% of respondents from the pharmaceutical industry claim they have a plandeveloped but not funded.4 Traditional circular paper chart recorders still dominate many recordingactivities, even while several sources in recent years have highlighted the advantages of paperlessrecording solutions compared to paper chart recorders.5,6,7

In support of their responsibility to promote and protect the public health, the U.S. Food and DrugAdministration (FDA) and the U.S. Department of Agriculture (USDA) require pharmaceutical,biotechnology, and food and beverage producers to maintain process measurement and control records.Historically, these regulatory-mandated measurements have been in the form of paper records, and themost common method of recording these measured values has included the use of a circular paper chartrecorder.

During the past 10 years, several interested parties (including manufacturers, trade associations, andeven other Federal agencies) have engaged the FDA in discussions regarding the use of paperless recordsystems in FDA regulated environments.8 Responding to this interest, the FDA issued a ruling onelectronic records and electronic signatures, effective August 20, 1997. The regulation “21 CFR Part 11”(see Appendix 1) is a reference to Title 21 (Volume 1) of the Code of Federal Regulations, Part 11.1Often, this is abbreviated to 21 CFR Part 11. Or, when the context is understood, it is referenced simplyas “Part 11.”

Part 11 is the result of the FDA’s discussions with interested parties favoring paperless recordingsolutions. The regulation identifies broad requirements under which electronic records will beacceptable in lieu of paper records, and electronic signatures will be equivalent to handwritten signaturesor initials on documents and records. The regulation itself does not require users to maintain recordselectronically, but only describes the requirements if a user chooses to do so.9

On July 21, 1999, the FDA reinforced its position on Part 11 by issuing Compliance Policy Guide(CPG) section 160.850. This compliance guidance document (see Appendix 2) advises what is requiredto be fully compliant with Part 11 requirements. More than a background document, CPG 160.850provides regulatory action guidance for producers who are non-compliant with the requirements of 21CFR Part 11.9

After allowing producers several years to become familiar with Part 11 and to make preparations forimplementation, the FDA is increasing its rhetoric about compliance and enforcement of 21 CFR Part 11requirements. Users who do not begin to show progress towards implementation and compliance riskreceiving regulatory citations

PROCESS INSTRUMENTATION IN SOME REGULATED APPLICATIONS

INSTRUMENTATION AND CONTROLS

In pharmaceutical industries, instrumentation and controls perform necessary functions in the productionprocess (media preparation, fermentation, filtration, downstream processing) as well as in the laboratory.Figure 1 shows an example of some of the critical control points that might be found in a typicalfermenter process. Data collection and the maintenance of measured values are critical activitiesthroughout the pharmaceutical environment.

In food and beverage applications, and particularly in dairy pasteurization, the Pasteurized MilkOrdinance (PMO) outlines pasteurization procedures and equipment tests.10 These guidelines requiredairy producers to record measured values from specific instrumentation points within the pasteurizationprocess. The process and some of the applicable controls for a typical High-Temperature Short-Time(HTST) continuous flow pasteurization system are presented in Figure 2.

Also with respect to food and beverage producers, the United States Department of Agriculture (USDA)and the FDA in recent years have been adopting the Hazard Analysis and Critical Control Point(HACCP, pronounced hassip) food safety program. The HACCP system involves seven (7) principles(see Appendix 3), including the establishment and monitoring of critical control points and effectiverecord keeping. The final rule for seafood HACCP became effective in 1995, and most meat and poultryplants were required to start using HACCP in January 1999. During 2002, the FDA began implementingHACCP for juice producers and is also monitoring pilot plant testing in the dairy industry. The FDA isconsidering developing regulations that would establish HACCP as the food safety standard throughoutother areas of the food industry, including domestic and imported food products.11

As regulations and guidelines continue to evolve in the pharmaceutical, biotechnology, and food andbeverage industries, the instrumentation and legal record keeping will increase in importance and,consequently, in visibility. As one industry expert noted, “In FDA’s experience thus far, we have seen adirect correlation between the quality of records and the quality of the products produced.”6

TRADITIONAL PAPER-BASED RECORDERS

Many regulated applications use a traditional paper-based recorder for maintaining permanent recordsfor State and local legal requirements. The purpose of these records is to provide support for producersduring process inspections and to provide backup details in the event of a review or a recall. Instrumentmanufacturers offer several different recorder models that can be used to maintain the permanentrecords, including both standard versions and specialized versions. For example, STLR (Safety ThermalLimit Recorder) and pasteurization flow versions are specialized versions that have become popular inthe dairy industry. The commercially available models marketed towards regulated producers mayrecord one or more of the following measurements:

� Product variables (temperature, pH, level, flow rate, pressure, dissolved oxygen, turbidity)� Process variables (e.g. cooling water temperature)� Reference temperatures at secondary points in the process (e.g. divert valve)

� Trends or event marks to indicate process CIP (Clean In Place).

Some models include PID controller capabilities and analog output (retransmission) - although the useof retransmission is often dependent upon the ‘comfort level’ of local regulators who may be concernedabout the appropriate use of the retransmitted value. Other designs have indicators to visually signal theflow of product for continuous processes. Most recorder designs use a circular chart with a selectabletime base (e.g. 8 or 12 hours) for each chart. Circular chart recorders are used to satisfy the legalrecording requirements for most applications. In the dairy industry, the PMO guideline even listsspecific equipment and procedure requirements for paper chart recorders.10

Paper chart recorders offer some advantages when used in regulated applications. However, alternativepaperless recording methods offer advantages of their own. The FDA “acknowledges the potentialbenefits to be gained by electronic record/electronic signature systems” compared to traditional paperrecorders.2 Table 1 lists a comparison of some of the advantages and disadvantages of traditional paperbased recorders as compared to any other recording methods.

PAPERLESS RECORDING METHODS FOR REGULATED ENVIRONMENTS

TRANSITION FROM PAPER RECORDERS TO PAPERLESS RECORDING SOLUTIONS

Tradition (“That’s the way we’ve always done it…”) is a significant factor in the continuing use of paperchart recorders in many regulated applications. However, tradition is not the only reason why Part 11paperless recorders were slow to develop. Instrument manufacturers faced several challenges indeveloping paperless solutions for regulated environments.

In practice, an operator often makes handwritten notations onto the paper chart itself, documentingvarious details about the specific production run at the time of recording (see Figure 3). These notationsare often followed by the operator’s handwritten signature or initials and perhaps by a supervisor’ssignature or initials as well. These notations vary broadly – both within companies and between them –but nevertheless give the regulatory inspector confidence that the producer is closely monitoring theprocess and is in compliance with applicable regulations. One of the challenges for instrumentmanufacturers has been to develop a paperless recording format that allows a user to match electronic‘notations’ to recorded events without compromising the tamper proof integrity of the entire electronicrecord. The measured values themselves must remain secure from any manipulation, and event notationssimilarly must be secure once they are created.

Another challenge for manufacturers has been achieving the requirements for electronic signaturesidentified in Part 11. As one writer stated, a “…majority of vendors simply state that they are Part 11compliant without any knowledge of what that claim entails.”12 Many industrial instruments, includingcomputer-based and paperless recording instruments, offer a single level password or passcode option.This feature often consists of a single alphanumeric entry (or multiple entries in the case of a supplier’s“backdoor” passcode) usable by any and all users. However, Part 11 defines an electronic signature asbeing the legally binding equivalent of an individual’s handwritten signature. “Universal” passwords

and passcodes are not unique to a specific individual and thus do not satisfy Part 11’s definition for aunique signature.

The FDA does not mandate a specific method for electronic signatures, nor does the FDA expectelectronic signature systems to be guaranteed foolproof. However, the FDA reinforces its “intent thatelectronic signatures are the legally binding equivalent of traditional handwritten signatures.” 8 TheFDA does specify controls when electronic signature systems are used. A biometric-based electronicsignature, as defined by Part 11, is a method of verifying an individual’s identity based on measurementof the individual’s physical features or repeatable actions where those features and/or actions are uniqueto that individual and measurable.1 Whether biometric or nonbiometric based electronic signatures areused, companies will face a transition period as they convert to electronic signature-based instruments.

ALTERNATIVES TO TRADITIONAL PAPER-BASED RECORDERS

Electronic paperless solutions for regulated recording applications include data acquisition systems(computer plus data acquisition software) and paperless recorders (devices similar to paper recorders,except they record values to memory instead of to paper). A brief review of some of the potentialadvantages of paperless recording solutions includes the following:

1. Data can be formatted and evaluated electronically. Typically, data can be exported to othercommercially available applications such as MS-Excel® or other PC applications.

2. Most designs can recall several recording periods of data, rather than the prior 8 or 12 hours only.Users can observe trends that might otherwise be overlooked between several different charts.

3. Audit trails are informative and summarize important data using calculations such as minimum-maximum-average summaries, extended mathematical capabilities, and text messages. (See Figure 4for an example of a paperless audit trail, in contrast to handwritten notations on a paper chart.)

4. Since many paperless recorders are available with 6, 8, or more recording channels (compared to 3or 4 channels for most paper chart recorders), additional channels of information may be recorded.Users (working in cooperation with their regulatory officials) may even consider combininginstruments into a single paperless recording device, such as a temperature recorder combined with adifferential pressure switch or flow controller.

5. Users can reduce or even eliminate their paper handling and will not need to manage, store, ormaintain large numbers of paper records.

6. Paperless recorders are comparatively maintenance-free, with no pens, paper drives, or motormechanisms. (Users may want to maintain some spare inputs boards, power supply boards, and/orsecondary memory storage drives for emergency replacement, but these components are not movingparts and do not suffer wear, as do traditional chart recorders with moving pens and charts.)

7. Most paperless recorders allow several selectable display modes for viewing trends and data from avariety of perspectives, providing additional information and details.

8. Videographic display screens feature ‘drop down’ menu lists and ‘help’ screens, providing easierrecorder setup and operation for increased operator comprehension and understanding.

DATA ACQUISITION SYSTEMS

In 1988, the Milk Safety Branch of the U.S. FDA issued Memorandum M-I-88-11 that outlined therequirements for using computerized systems for Grade ‘A’ public health controls. The body of thisdocument subsequently was added to the PMO and now exists as Appendix H, Section V. The sectionidentifies criteria for “all computers or programmable controllers” when applied to specifiedpasteurization systems.10

More recently (July 1999), the FDA made available a new Compliance Policy Guide (CPG) section160.850 announcing the agency’s position on enforcement of Part 11 requirements.9 This update to theCompliance Policy Guides Manual (August 1996 ed.) increased the visibility of 21 CFR Part 11requirements and fueled much of the growth in the development, and subsequent availability, ofsoftware/paperless solutions for Part 11 compliance.

Several data acquisition software solutions are now available – primarily to pharmaceutical andbiotechnology users. These solutions offer advantages for “behind the scenes” users who must manageand maintain large databases of background information in a networked environment. However, the“data acquisition software” approach may not be suitable for all regulated or validated productionactivities. While computer performance has vastly improved in recent years, computers may evaluatetasks sequentially rather than in parallel. Some computer and software packages may not provide full-time monitoring, as do the traditional chart recorders. Further, there are concerns that control logic andprogramming may be susceptible to errors or user initiated alterations, while the recorded data must beproven tamper resistant.10 Additionally, operators in traditional recording applications may not beproperly trained for – or may even be intimidated by – computers and software applications, making thetransition from traditional recorders more difficult.

Test studies have demonstrated that paperless data acquisition systems can record accurately andreliably in place of traditional paper chart recorders.13 However, users should remain cautious. Acomputerized data acquisition system, even though it may be accurate and reliable, still may not complywith all the specifications for data recording.

VIDEOGRAPHIC PAPERLESS RECORDERS

A paperless (videographic) recorder is an instrument that resembles a traditional paper chart recorder.However, instead of recording a trace with pen and paper, a videographic paperless recorder displays thetrace and/or numeric value on a display screen and also records the measured values to memory. Likecomputers, paperless recorders have also made significant advancements in recent years. Typically, apaperless recorder can handle more inputs than a paper and pen (or printhead) recorder. Also, paperlessrecorders can create text event logs. Further, since paperless recorders store data to disk, a user can “dosomething” with the recorded data, such as sort, graph, and print the data for further evaluation.

Like traditional paper recorders, videographic recorders differ in the options and features available.Some paperless recorder solutions address Part 11 requirements directly at the recorder, some via therecorder’s accompanying personal computer (PC) application software, and some cover therequirements at both the recorder and the PC. Some may have indicator lights to signal flow direction,while others may only record events in the PC viewable data. Figure 5 shows a videographic recorder,along with some highlighted features.

Videographic recorders designed or customized specifically for regulated applications may provide aneasier transition from paper to paperless recording compared to an entirely PC- or network-basedsolution. Operators might have a higher comfort level in transitioning from one type of recorder (paper)to another (paperless), versus transitioning to a PC-based data acquisition system. The higher comfortlevel for operators may translate into less start-up training, fewer operational errors, and greater useracceptance.

CHALLENGES WHEN TRANSITIONING TO PAPERLESS RECORDING

Decision-makers should consider several factors when evaluating a change from a traditional paper-based recorder to a paperless solution. Among those considerations are the points listed below.

TRADITION

Certainly, tradition is important and requires careful consideration. Users are familiar with circular orstrip chart paper recorders, and they may be less familiar with computers and/or videographic recorders.Do the employees have the skill sets to adapt to a different way of getting the job done? If not, whatextra training needs to be offered to help them adapt? With respect to the recording devices, instrumentmanufacturers can ease the user’s transition by providing on-screen ‘Help’ descriptions and “dropdown” (multiple choice) menu selections wherever possible.

REGULATORY OFFICIALS

As stated previously, paper chart recorders have been the dominant method for maintaining legal recordsin regulated applications. Along with users and operators, regulatory officials and inspectors are mostcomfortable with the paper chart recorders. Users who want to transition to electronic paperlessrecording solutions will want to work closely with their regulatory inspectors. Clear communicationwith inspectors during the planning stages can help the user identify potential problems and difficultiesof the proposed installation.

ELECTRONIC SIGNATURES

The method by which a paperless solution meets the Part 11 criteria is one of its most importantoperating characteristics. Part 11 does not mandate any particular method for electronic signatures, but it

does list criteria for different electronic signatures. Part 11 differentiates between biometric andnonbiometric electronic signatures, and the Preamble8 makes further distinctions between “electronicsignatures that are executed repetitively during a single, continuous controlled period of time (logged onperiod),” and those that are not. Depending on a variety of factors, an operator using a nonbiometricelectronic signature might need to enter his/her personal password several times during a productionshift. Additionally, a supervisor may need to certify each record with his/her own electronic signature.Companies reviewing paperless solutions should give very careful consideration to the electronicsignature features for paperless devices since this parameter may be invoked repeatedly during a singleoperating session.

COMMENTS AND NOTATIONS

‘Ease of use’ is important for the successful implementation of any solution, but it is especiallyimportant in a food & beverage, pharmaceutical, and other regulated environments where users areaccustomed to making handwritten comments, notations, and data entries directly onto the paper recordsthemselves. The information recorded onto paper charts varies between users, but some examplesinclude product name, batch ID and production volume, indication of Start/Stop times, and notes aboutany unusual events or anomalies. Each organization has its own formats, batch identification systems,and data requirements for each process chart. The most successful paperless solutions will be the onesthat maximize flexibility and ‘ease of use’ for making electronic comments and notations.

DATA STORAGE

The paperless solutions eliminate the need for careful climate controlled storage of the paper chartsthemselves, but regulators typically require users to maintain the data measurements for some period oftime. This time can vary depending on the type of record, the State and local regulations, and thespecific company requirements. Typically, the maintenance time is a minimum of ninety (90) days forPMO applications; and “cradle to grave” for pharmaceutical products.6 For the pharmaceutical andbiotechnology industries, a record must be maintained -- even after it has been deemed “inactive” -- forthe record retention period as dictated by predicate rule requirements (such as CGMP and GLPregulations).14 In most paperless recorders, several channels of data recorded every one (1) second, forexample, will quickly consume very large blocks of primary and secondary memory storage. Prior to apaper-to-paperless transition, users should consult with their company’s information systemprofessionals to help prepare for the electronic data storage as computer files replace the paper records.

COMMUNICATION WITH EMPLOYEES

Employers should be mindful that, just as with all other organizational and assignment changes,communication with the employees is very important. The employees may be concerned about possiblejob or assignment changes as a result of the technology change. The paperless solutions – computersystems and paperless recorders – are often advertised as being ‘maintenance-free,’ and this is largelytrue. Paperless solutions do not have consumables (pens and paper) needing to be changed, nor do theyhave moving parts that wear and need replacing. Although secondary memory (diskettes, memory cards,

tape backup, etc.) needs to be changed with some frequency, many employees will have concerns thattheir job may change, or may be eliminated altogether, in a videographic recording environment.Management-Employee communications regarding the technology change and its associated impact ontraining needs and job assignments will be important as always. Without acceptance from the operatorsthemselves, the transition to any paperless solution will be difficult.

CONCLUDING REMARKS

Pharmaceutical, biotechnology, and food & beverage industries are guided by several regulatorydocuments such as CGMP (21 CFR 210 and 211) and the PMO. These and other documents representthe guiding regulations for Federal, State, and local departments and agencies. Many producers still relyupon traditional paper chart recorders and are not benefiting from paperless solutions. Regulation 21CFR Part 11 outlines requirements if users choose to maintain electronic records for submittals toregulatory agencies, and CPG 160.850 begins to outline the enforcement policy for FDA personnel.Several paperless solutions are advertised as meeting Part 11 requirements. Videographic recorders inparticular offer several advantages compared to alternative methods for meeting Part 11 requirements inregulated applications. One of the most optimal solutions for transitioning producers from paperrecording to paperless recording will include products with both hardware and software designedspecifically for regulated applications. Paperless recorders will offer ease of use in setup and operation,and they can be installed in close proximity to the process (rather than to a remote control roomlocation). These advantages will contribute to giving State and local regulators, in addition to users,increased confidence in the validity and security of paperless recording systems. Videographic recorderscustomized specifically for regulated applications offer the greatest benefits and will provide users aneasy and relatively intuitive transition to Part 11 solutions in sanitary-related and other regulatedenvironments.

REFERENCES

1. “Title 21, Parts 1 to 99,” Code of Federal Regulations, Food and Drugs, Office of the FederalRegister, National Archives and Records Administration, U.S. Government Printing Office,Washington, D.C., Part 11, 4-01-2000 edition.

2. Owen, Terry, “Paperless Data Transmission Gains Ground,” Control, Volume 23, Number 3, April1998, Terry Owen, pp. 65-68.

3. “Title 21, Parts 200 to 299,” Code of Federal Regulations, Food and Drugs, Office of the FederalRegister, National Archives and Records Administration, U.S. Government Printing Office,Washington, D.C., Parts 210 and 211, 04-01-1999 edition.

4. Harrold, David, AFAB Group technical consultant “21 CFR Part 11 Awareness Poll Results: Whatwe learned from our 21 CFR Part 11 awareness survey,” AFAB Group website,(http://afabgroup.com/21_CFR_Part_11/report_21_CFR_Part_11.html ), .AFAB Group, Avon,Indiana, Site Awareness Survey, March 26, 2002.

5. Polischuk, Tom, “New data acquisition solutions increase functionality, decrease costs,” ControlSolutions, PennWell Publishing Company, Tulsa, Oklahoma, Volume 73, Number 9, September2000, pages 39-42.

6. Harrold, Dave “I’m from the Government and I’m Here to Help You!”, Control Engineering,Cahners Business Information, Cleveland, Ohio, Volume __, Number __, (date), pages __-__.

7. Neff, Jack, “Paper Work,” Food Processing, Putman Publishing Company, Itasca, Illinois, Volume59, Number 3, March 1998, pages 79-82.

8. Department of Health and Human Services, Food and Drug Administration “21 CFR Part 11Electronic Records; Electronic Signatures; Final Rule, Electronic submissions; Establishment ofPublic docket; Notice,” Federal Register, U.S. Government Printing Office, Washington, D.C.,Volume 62, Number 54, Thursday, March 20, 1997, pages 13429-13466. (Note: this document iscommonly referred to as 21 CFR Part 11 “Preamble.”)

9. Dotzel, Margaret M., Acting Associate Commissioner for Policy, “Enforcement Policy: ElectronicRecords; Electronic Signatures—Compliance Policy Guide; Guidance for FDA Personnel,” FederalRegister, U.S. Government Printing Office, Washington, D.C., Volume 64, Number 139,Wednesday, July 21, 1999, pages 39146-39147.

10. United States Public Health Service, Grade ‘A’ Pasteurized Milk Ordinance, 1999 Revision, U.S.Department of Health and Human Services, U.S. Government Printing Office, Washington, D.C.,pages 59-80, Appendices H-I.

11. Department of Health and Human Services, Food and Drug Administration, Center for Food Safetyand Applied Nutrition, “HACCP: A State-of-the-Art Approach to Food Safety,” Hazard Analysisand Critical Control Point, BG01-4, (http://www.cfsan.fda.gov/~lrd/bghaccp.html), October 2001.

12. Townsend, Kate, “21 CFR Part 11: Current industry position”, Pharmaceutical Online (AVerticalNet Marketplace for Industry Professionals), Taratec Development Corporation,Bridgewater, New Jersey, March 27, 2001.

13. Schlesser, J.E. et.al., “Acquisition, Storage, and Review of Safety Data from a Commercial Systemfor High Temperature, Short Time Pasteurization,” Journal of Dairy Science, American DairyScience Association, Savoy, Illinois, Volume 81, Number 1, January 1998, pages 25-30.

14. Canale, Mike, Taratec Development Corporation, Bridgewater, NJ, “Part 11 Compliance in theLaboratory – A Practical Approach for Securing Data Files,” Cahners Scientific Features(http://www.cahnersscientific.com), Morris Plains, NJ, reprint from Scientific Computing &Instrumentation, Volume 19, Number 6, May 2002, pages 64-66.

FIGURE 1 – HTST PROCESS MAP WITH SELECTED CONTROL POINT OUTPUTS TOLEGAL CONTROLS IN FOOD AND BEVERAGE APPLICATION

APPENDIX 3

FIGURE 3 – SEVEN PRINCIPLES OF HACCP

Seven (7) principles of HACCP

•Analyze hazards. Potential hazards associated with a food and measures to control those hazards areidentified. The hazard could be biological, such as a microbe; chemical, such as a toxin; or physical, suchas ground glass or metal fragments.

•Identify critical control points. These are points in a food’s production--from its raw state throughprocessing and shipping to consumption by the consumer--at which the potential hazard can be controlledor eliminated. Examples are cooking, cooling, packaging, and metal detection.

•Establish preventive measures with critical limits for each control point. For a cooked food, forexample, this might include setting the minimum cooking temperature and time required to ensure theelimination of any harmful microbes.

•Establish procedures to monitor the critical control points. Such procedures might include determininghow and by whom cooking time and temperature should be monitored.

•Establish corrective actions to be taken when monitoring shows that a critical limit has not beenmet--for example, reprocessing or disposing of food if the minimum cooking temperature is not met.

•Establish procedures to verify that the system is working properly--for example, testing time-and-temperature recording devices to verify that a cooking unit is working properly.

•Establish effective recordkeeping to document the HACCP system. This would include records ofhazards and their control methods, the monitoring of safety requirements and action taken to correctpotential problems. Each of these principles must be backed by sound scientific knowledge: for example,published microbiological studies on time and temperature factors for controlling fooborne pathogens.

Source: Center for Food Safety and Applied Nutrition (CFSAN)U.S. Food and Drug Administration

TABLE 1 - ADVANTAGES AND DISADVANTAGES OF PAPER RECORDERS

ADVANTAGES DISADVANTAGES

� Familiarity, years of experience with paper chartrecorders

� Highly flexible - accepted practice ofhandwritten notes and signatures onto charts

� Existing inventory of consumables and sparesfor recorders already in operation

� Frequent pen and paper changes necessitatefrequent monitoring (also a disadvantage),insuring that the process and instruments areoperating satisfactorily

� Mechanical nature – parts wear and tear

� Frequent pen and paper changes consumevaluable resource time

� Patterns across lengthy time periods (multiplecharts) are difficult to determine

� Data searches between charts are cumbersome

� Special handling is required for paper records,including climate controlled environments andrisk of misfilings

FIGURE 5 – VIDEOGRAPHIC RECORDER FEATURES

Graphic displayshows trends and

event marks

Drop down menuselections and help

screens

Green (forward flow)and Red (divert)LED’s for diary

pasteurization

Buffer memory +econdary memory(e.g. diskettedrive, PC memorycard)

Setup andoperation pushbuttons

FIGURE 3 –CIRCULAR PAPER CHART WITH HANDWRITTEN NOTATIONS

FIGURE 2 – FERMENTER PROCESS MAP WITH SELECTED INSTRUMENTATION ANDCONTROL POINTS

FIGURE 4 – AUDIT TRAIL IN VIDEOGRAPHIC RECORDER SCREEN DISPLAY

Appendix 1

TITLE 21CODE OF FEDERAL REGULATIONS

PART 11--ELECTRONIC RECORDS; ELECTRONIC SIGNATURES

Subpart A--General ProvisionsSec.11.1 Scope.11.2 Implementation.11.3 Definitions.

Subpart B--Electronic Records11.10 Controls for closed systems.11.30 Controls for open systems.11.50 Signature manifestations.11.70 Signature/record linking.

Subpart C--Electronic Signatures11.100 General requirements.11.200 Electronic signature components and controls.11.300 Controls for identification codes/passwords.

AUTHORITY: Secs. 201-903 of the Federal Food, Drug, and CosmeticAct (21 U.S.C. 321-393); sec. 351 of the Public Health Service Act(42 U.S.C. 262).

Subpart A--General Provisions

Sec. 11.1 Scope.(a) The regulations in this part set forth the criteria under which the agency considers electronic records, electronic

signatures, and handwritten signatures executed to electronic records to be trustworthy, reliable, and generally equivalent topaper records and handwritten signatures executed on paper.

(b) This part applies to records in electronic form that are created, modified, maintained, archived, retrieved, or transmitted,under any records requirements set forth in agency regulations. This part also applies to electronic records submitted to theagency under requirements of the Federal Food, Drug, and Cosmetic Act and the Public Health Service Act, even if suchrecords are not specifically identified in agency regulations. However, this part does not apply to paper records that are, orhave been, transmitted by electronic means.

(c) Where electronic signatures and their associated electronic records meet the requirements of this part, the agency willconsider the electronic signatures to be equivalent to full handwritten signatures, initials, and other general signings asrequired by agency regulations, unless specifically excepted by regulation(s) effective on or after August 20, 1997.

(d) Electronic records that meet the requirements of this part may be used in lieu of paper records, in accordance with Sec.11.2, unless paper records are specifically required.(e) Computer systems (including hardware and software), controls, andattendant documentation maintained under this part shall be readily available for, and subject to, FDA inspection.

Sec. 11.2 Implementation.(a) For records required to be maintained but not submitted to the agency, persons may use electronic records in lieu of

paper records or electronic signatures in lieu of traditional signatures, in whole or in part, provided that the requirements ofthis part are met.

(b) For records submitted to the agency, persons may use electronic records in lieu of paper records or electronic signaturesin lieu of traditional signatures, in whole or in part, provided that:

(1) The requirements of this part are met; and(2) The document or parts of a document to be submitted have been identified in public docket No. 92S-0251 as being the

type of submission the agency accepts in electronic form. This docket will identify specifically what types of documents orparts of documents are acceptable for submission in electronic form without paper records and the agency receiving unit(s)(e.g., specific center, office, division, branch) to which such submissions may be made. Documents to agency receivingunit(s) not specified in the public docket will not be considered as official if they are submitted in electronic form; paperforms of such documents will be considered as official and must accompany any electronic records. Persons are expected toconsult with the intended agency receiving unit for details on how (e.g., method of transmission, media, file formats, andtechnical protocols) and whether to proceed with the electronic submission.

Sec. 11.3 Definitions.(a) The definitions and interpretations of terms contained in section 201 of the act apply to those terms when used in this

part.(b) The following definitions of terms also apply to this part:(1) Act means the Federal Food, Drug, and Cosmetic Act (secs. 201-903 (21 U.S.C. 321-393)).(2) Agency means the Food and Drug Administration.(3) Biometrics means a method of verifying an individual's identity based on measurement of the individual's physical

feature(s) or repeatable action(s) where those features and/or actions are both unique to that individual and measurable.(4) Closed system means an environment in which system access is controlled by persons who are responsible for the

content of electronic records that are on the system.(5) Digital signature means an electronic signature based upon cryptographic methods of originator authentication,

computed by using a set of rules and a set of parameters such that the identity of the signer and the integrity of the data can beverified.

(6) Electronic record means any combination of text, graphics, data, audio, pictorial, or other information representation indigital form that is created, modified, maintained, archived, retrieved, or distributed by a computer system.

(7) Electronic signature means a computer data compilation of any symbol or series of symbols executed, adopted, orauthorized by an individual to be the legally binding equivalent of the individual's handwritten signature.

(8) Handwritten signature means the scripted name or legal mark of an individual handwritten by that individual andexecuted or adopted with the present intention to authenticate a writing in a permanent form. The act of signing with awriting or marking instrument such as a pen or stylus is preserved. The scripted name or legal mark, while conventionallyapplied to paper, may also be applied to other devices that capture the name or mark.

(9) Open system means an environment in which system access is not controlled by persons who are responsible for thecontent of electronic records that are on the system.

Subpart B--Electronic Records

Sec. 11.10 Controls for closed systems.Persons who use closed systems to create, modify, maintain, or transmit electronic records shall employ procedures and

controls designed to ensure the authenticity, integrity, and, when appropriate, the confidentiality of electronic records, and toensure that the signer cannot readily repudiate the signed record as not genuine. Such procedures and controls shall includethe following:

(a) Validation of systems to ensure accuracy, reliability, consistent intended performance, and the ability to discern invalidor altered records.

(b) The ability to generate accurate and complete copies of records in both human readable and electronic form suitable forinspection, review, and copying by the agency. Persons should contact the agency if there are any questions regarding theability of the agency to perform such review and copying of the electronic records.

(c) Protection of records to enable their accurate and ready retrieval throughout the records retention period.(d) Limiting system access to authorized individuals.(e) Use of secure, computer-generated, time-stamped audit trails to independently record the date and time of operator

entries and actions that create, modify, or delete electronic records. Record changes shall not obscure previously recorded

information. Such audit trail documentation shall be retained for a period at least as long as that required for the subjectelectronic records and shall be available for agency review and copying.

(f) Use of operational system checks to enforce permitted sequencing of steps and events, as appropriate.(g) Use of authority checks to ensure that only authorized individuals can use the system, electronically sign a record,

access the operation or computer system input or output device, alter a record, or perform the operation at hand.(h) Use of device (e.g., terminal) checks to determine, as appropriate, the validity of the source of data input or operational

instruction.(i) Determination that persons who develop, maintain, or use electronic record/electronic signature systems have the

education, training, and experience to perform their assigned tasks.(j) The establishment of, and adherence to, written policies that hold individuals accountable and responsible for actions

initiated under their electronic signatures, in order to deter record and signature falsification.(k) Use of appropriate controls over systems documentation including:(1) Adequate controls over the distribution of, access to, and use of documentation for system operation and maintenance.(2) Revision and change control procedures to maintain an audit trail that documents time-sequenced development and

modification of systems documentation.

Sec. 11.30 Controls for open systems.Persons who use open systems to create, modify, maintain, or transmit electronic records shall employ procedures and

controls designed to ensure the authenticity, integrity, and, as appropriate, the confidentiality of electronic records from thepoint of their creation to the point of their receipt. Such procedures and controls shall include those identified in Sec. 11.10,as appropriate, and additional measures such as document encryption and use of appropriate digital signature standards toensure, as necessary under the circumstances, record authenticity, integrity, and confidentiality.

Sec. 11.50 Signature manifestations.(a) Signed electronic records shall contain information associated with the signing that clearly indicates all of the

following:(1) The printed name of the signer;(2) The date and time when the signature was executed; and(3) The meaning (such as review, approval, responsibility, or authorship) associated with the signature.(b) The items identified in paragraphs (a)(1), (a)(2), and (a)(3) of this section shall be subject to the same controls as for

electronic records and shall be included as part of any human readable form of the electronic record (such as electronicdisplay or printout).

Sec. 11.70 Signature/record linking.Electronic signatures and handwritten signatures executed to electronic records shall be linked to their respective electronic

records to ensure that the signatures cannot be excised, copied, or otherwise transferred to falsify an electronic record byordinary means.

Subpart C--Electronic Signatures

Sec. 11.100 General requirements.(a) Each electronic signature shall be unique to one individual and shall not be reused by, or reassigned to, anyone else.(b) Before an organization establishes, assigns, certifies, or otherwise sanctions an individual's electronic signature, or any

element of such electronic signature, the organization shall verify the identity of the individual.(c) Persons using electronic signatures shall, prior to or at the time of such use, certify to the agency that the electronic

signatures in their system, used on or after August 20, 1997, are intended to be the legally binding equivalent of traditionalhandwritten signatures.

(1) The certification shall be submitted in paper form and signed with a traditional handwritten signature, to the Office ofRegional Operations (HFC-100), 5600 Fishers Lane, Rockville, MD 20857.

(2) Persons using electronic signatures shall, upon agency request, provide additional certification or testimony that aspecific electronic signature is the legally binding equivalent of the signer's handwritten signature.

Sec. 11.200 Electronic signature components and controls.

(a) Electronic signatures that are not based upon biometrics shall:(1) Employ at least two distinct identification components such as an identification code and password.(i) When an individual executes a series of signings during a single, continuous period of controlled system access, the first

signing shall be executed using all electronic signature components; subsequent signings shall be executed using at least oneelectronic signature component that is only executable by, and designed to be used only by, the individual.

(ii) When an individual executes one or more signings not performed during a single, continuous period of controlledsystem access, each signing shall be executed using all of the electronic signature components.

(2) Be used only by their genuine owners; and(3) Be administered and executed to ensure that attempted use of an individual's electronic signature by anyone other than

its genuine owner requires collaboration of two or more individuals.(b) Electronic signatures based upon biometrics shall be designed to ensure that they cannot be used by anyone other than

their genuine owners.

Sec. 11.300 Controls for identification codes/passwords.Persons who use electronic signatures based upon use of identification codes in combination with passwords shall employ

controls to ensure their security and integrity. Such controls shall include:(a) Maintaining the uniqueness of each combined identification code and password, such that no two individuals have the

same combination of identification code and password.(b) Ensuring that identification code and password issuances are periodically checked, recalled, or revised (e.g., to cover

such events as password aging).(c) Following loss management procedures to electronically deauthorize lost, stolen, missing, or otherwise potentially

compromised tokens, cards, and other devices that bear or generate identification code or password information, and to issuetemporary or permanent replacements using suitable, rigorous controls.

(d) Use of transaction safeguards to prevent unauthorized use of passwords and/or identification codes, and to detect andreport in an immediate and urgent manner any attempts at their unauthorized use to the system security unit, and, asappropriate, to organizational management.

(e) Initial and periodic testing of devices, such as tokens or cards, that bear or generate identification code or passwordinformation to ensure that they function properly and have not been altered in an unauthorized manner.

Dated: March 11, 1997.William B. Schultz,Deputy Commissioner for Policy.[FR Doc. 97-6833 Filed 3-20-97; 8:45am]BILLING CODE 4160-01-F

Appendix 2

Office of Regulatory AffairsCOMPLIANCE POLICY GUIDE Section 160.850

COMPLIANCE POLICY GUIDE

Section 160.850

Title: Enforcement Policy: 21 CFR Part 11; Electronic Records; Electronic Signatures (CPG 7153.17)

Background:

This compliance guidance document is an update to the Compliance Policy Guides Manual (August 1996 edition).This is a new Compliance Policy Guide (CPG) and will be included in the next printing of the Compliance PolicyGuides Manual. The CPG is intended for Food and Drug Administration (FDA) personnel and is availableelectronically to the public. This guidance document represents the agency's current thinking on what is requiredto be fully compliant with 21 CFR Part 11, "Electronic Records; Electronic Signatures" and provides that agencydecisions on whether or not to pursue regulatory actions will be based on a case by case evaluation. The CPGdoes not create or confer any rights for or on any person and does not operate to bind FDA or the public. Analternative approach may be used if such approach satisfies the requirements of the applicable statute,regulation, or both.

In the Federal Register of March 20, 1997, at 62 FR 13429, FDA issued a notice of final rulemaking for 21 CFR,Part 11, Electronic Records; Electronic Signatures. The rule went into effect on August 20, 1997. Part 11 isintended to create criteria for electronic recordkeeping technologies while preserving the agency's ability toprotect and promote the public health (e.g., by facilitating timely review and approval of safe and effective newmedical products, conducting efficient audits of required records, and when necessary pursuing regulatoryactions). Part 11 applies to all FDA program areas, but does not mandate electronic recordkeeping. Part 11describes the technical and procedural requirements that must be met if a person chooses to maintain recordselectronically and use electronic signatures. Part 11 applies to those records required by an FDA predicate ruleand to signatures required by an FDA predicate rule, as well as signatures that are not required, but appear inrequired records.

Part 11 was developed in concert with industry over a period of six years. Virtually all of the rule's requirementshad been suggested by industry comments to a July 21, 1992 Advance Notice of Proposed Rulemaking (at 57 FR32185). In response to comments to an August 31, 1994 Proposed Rule (at 59 FR 45160) the agency refined andreduced many of the proposed requirements in order to minimize the burden of compliance. The final rule'sprovisions are consistent with an emerging body of federal and state law as well as commercial standards andpractices.

Certain older electronic systems may not have been in full compliance with Part 11 by August 20, 1997, andmodification to these so called "legacy systems" may take more time. As explained in the preamble to the finalrule, Part 11 does not grandfather legacy systems and FDA expects that firms using legacy systems will begintaking steps to achieve full compliance.

Policy:

When persons are not fully compliant with Part 11, decisions on whether or not to pursue regulatory actions willbe based on a case by case evaluation, which may include the following:

Nature and extent of Part 11 deviation(s). FDA will consider Part 11 deviations to be moresignificant if those deviations are numerous, if the deviations make it difficult for the agency toaudit or interpret data, or if the deviations undermine the integrity of the data or the electronicsystem. For example, FDA expects that firms will use file formats that permit the agency to makeaccurate and complete copies in both human readable and electronic form of audited electronicrecords. Similarly, FDA would have little confidence in data from firms that do not hold theiremployees accountable and responsible for actions taken under their electronic signatures.

Effect on product quality and data integrity. For example, FDA would consider the absence of anaudit trail to be highly significant when there are data discrepancies and when individuals denyresponsibility for record entries. Similarly, lack of operational system checks to enforce eventsequencing would be significant if an operator's ability to deviate from the prescribed order ofmanufacturing steps results in an adulterated or misbranded product.

Adequacy and timeliness of planned corrective measures. Firms should have a reasonabletimetable for promptly modifying any systems not in compliance (including legacy systems) tomake them Part 11 compliant, and should be able to demonstrate progress in implementingtheir timetable. FDA expects that Part 11 requirements for procedural controls will already bein place. FDA recognizes that technology based controls may take longer to install in older systems.

Compliance history of the establishment, especially with respect to data integrity. FDA willconsider Part 11 deviations to be more significant if a firm has a history of Part 11 violations orof inadequate or unreliable recordkeeping. Until firms attain full compliance with Part 11, FDAinvestigators will exercise greater vigilance to detect inconsistencies, unauthorized modifications,poor attributability, and any other problems associated with failure to comply with Part 11.

Regulatory Action Guidance:

Program monitors and center compliance offices should be consulted prior to recommending regulatory action.FDA will consider regulatory action with respect to Part 11 when the electronic records or electronic signaturesare unacceptable substitutes for paper records or handwritten signatures, and that therefore, requirements of theapplicable regulations (e.g., CGMP and GLP regulations) are not met. Regulatory citations should reference suchpredicate regulations in addition to Part 11. The following is an example of a regulatory citation for a violation ofthe device quality system regulations.

Failure to establish and maintain procedures to control all documents that are required by 21 CFR 820.40, andfailure to use authority checks to ensure that only authorized individuals can use the system and alter records, asrequired by 21 CFR 11.10(g). For example, engineering drawings for manufacturing equipment and devices arestored in AutoCAD form on a desktop computer. The storage device was not protected from unauthorized accessand modification of the drawings.

Issue date: 5/13/99