If a computer system is for clinical research it is critical, and the cost of not validating and testing may be more than the cost of a clinical study or drug application: the reputation and future of a company are at stake. Adoption of the principles of computer validation may contribute to the ability of a company to achieve required quality standards, but will also show benefits in a business sense in assuring the integrity of scientific testing and reliability of data submitted in an application. Applying these principles early in system design is a cost contributing to achieving reliability throughout the life cycle. In other words, this is a benefit, which usually outweighs the cost of system or data loss. Important factors include using these principles early; looking at interface activities between groups of personnel or data; and focusing on critical areas. This paper includes a selected bibliography of useful reference tools for computer validation.
Commission of the European Communities.CPMP working party on efficacy of medicinal products, Note for Guidance: Good Clinical Practice for Trials on Medicinal Products in the European Community. III/3976/88-EN, Final. Brussels: European Commission, 4/5/1990.
2.
Commission of the European Communities.Good Manufacturing Practice for Medicinal Products. In: Rules Governing Medicinal Products in the European Community, Vol. IV. Brussels: European Commission, 1992. CO-71–91–760-EN-C.
3.
International Standards Organization.Standard ISO-8402: Quality Vocabulary. (See also under “British Standards.“).
4.
International Standards Organization. Standard ISO-9000:1987: Quality management and quality assurance standards — Guidelines for selection and use.
5.
International Standards Organization. Standard ISO-9001:1987: Quality systems-Model for quality assurance in design/development, production, installation, and servicing.
6.
International Standards Organization. Standard ISO-9002:1987: Quality Systems—Model for quality assurance in production and installation.
7.
International Standards Organization. Standard ISO-9003:1987: Quality Systems — Model for quality assurance in final inspection and test.
8.
International Standards Organization. Standard ISO-9004:1987: Quality management and quality system elements —Guidelines.
9.
British Standard 7229: “Quality systems auditing,” Parts 1 (ISO 10011 1), 2 (ISO 1011 1), and 3 (ISO 10011 3), 1991.
10.
ClarkAS. Computer systems validation: An investigator's view. Pharm Tech. 1988;12: 60, 62, 64–66. The development, implementation, testing, documentation, maintenance and revalidation of procedures involved in the validation of computer hardware and software are discussed. Potential areas of evaluation during an FDA inspection of automated manufacturing systems are noted. (4 REFS).
11.
EdwardsCM. FDA inspections of systems in a pharmaceutical manufacturing establishment. Drug Development and Indus Pharm. 1984;19(2):165–189. Systems inspections presented from the vantage point of an experienced FDA investigator.
12.
FryEM. Parenteral drug industry: Recent findings. J Parenter Sci Technol. 1982;36: 55–58. Problem areas found in the parenteral drug industry by FDA inspection for compliance to the good manufacturing practice regulations are discussed. The need for adequate monitoring of the air and interpretation of results in aseptic processing areas; the question of validation processes versus end product testing as a means of quality control; and the use of computers in documenting manufacturing operations, are noted.
13.
FryEM. FDA Regulation of computer systems in drug manufacturing. Pharm Engin. 1988;9/10: 47–50.
14.
GuerraJ.Audits of computer systems in analytical laboratories. Pharm Tech. 1988;12(9):142, 144–147, 150, 152. Approaches to computer quality assurance and relevant concepts in hardware and software validation for computer systems are discussed, and an auditing strategy for analytical laboratory systems is outlined. (5 REFS.).
15.
GuerraJ.CGMPs in the chemistry laboratory. Pharm Tech. 1986;10(11):38–42.
16.
GuerraJ.Practical application of CGMPs to gas and high performance liquid chromatographic systems. Pharm Tech. 1984;8: 81, 84. Regulatory requirements for system validation related to HPLC analysis of drug products are discussed. The interaction of computers in the analytical system and means of process validation are included.
17.
GuerraJVassosBHColonMA. Safeguarding instrument reliability. Pharm Tech. 1987;11: 102, 104–106, 108. The use of electrical circuitry (automated power controller and power failure detector) in validation processes for analytical equipment is described.
18.
KahanJS. Legal implications of software validation. Drug Inf J. 1987;21(4):481–486. The statutory and regulatory basis of the FDA's jurisdiction over software used by the pharmaceutical industry is discussed. The legal implications of the FDA's activities in this area are also noted. (13 REFS.).
19.
MastersGFigaroleP.Validation principles for computer systems—FDA's perspective. Pharm Tech. 1986;10: 44, 46. Definitions of computer systems and computer system validation acceptable to the Food and Drug Administration are presented and minimum requirements for computer validation are given. The necessary documentation for validation is discussed for each stage of the validation procedure. (1 REF.).
20.
MotisePJ. What to expect when FDA audits computer controlled processes. Pharm Manuf. 1984;1: 32–35. Principle objectives of an FDA investigator relating to the evaluation of computer system configuration, potential hardware and software problems, system performance, manual backup systems, and hardware and software validation are discussed.
21.
MotisePJ. Computer systems for the production of drug products. Pharm Engirt. 1982;7/8: 32–38.
22.
MotisePJ. Validation of computerized systems in the control of drug processes: FDA perspective. Pharm Tech. 1984;8: 40, 42–45. The validation of computer hardware and software, used in the control of drug production, is discussed. Five areas are considered: defining the task to be performed; identifying computer operational limits; testing the system; preparing documentation; and establishing systems to detect changes and precipitate revalidation. (4 REFS.).
23.
SchwemerWL. Validation: Foundation of GMP. Pharm-Eng. 1990;10: 44–46. The good manufacturing practice regulations leading to the development of process validation guidelines issued by the Food and Drug Administration are discussed, including some validation concepts, an update on drug enforcement, and future trends.
24.
TetzlaffRF. GMP documentation requirements for automated systems: Part I. Pharm Tech. 1992: 112–124. Reprints of the three-part article for $15 (plus mailing) from Aster Publishing Corp., Beverly Sisseck, PO Box 10460, Eugene, OR 97440. This article describes current issues in documenting computer system validation and operation from the perspective of an FDA investigator, and reviews documentation requirements and FDA guidelines on documentation. (66 REFS.).
25.
TetzlaffRF. GMP documentation requirements for automated systems: Part II. Pharm Tech. 1992: 60–72. This article offers some practical experiences and ways to ensure that automated system documentation will conform to the intent of the GMP regulations.
26.
TetzlaffRF. GMP documentation requirements for automated systems: Part III. FDA Inspections of Computerized Laboratory Systems. Pharm Tech. 1992;70–82. This article describes some of the potential problems found during FDA inspections of laboratory computer systems, emphasizing the importance of developing appropriate specifications that can be measured and tested to demonstrate performance.
27.
TrillT.Inspector's thoughts on pharmaceutical production. Manuf Chem. 1990;61: 31, 33, 35. The design of computerized control systems for use in the manufacture of pharmaceutical products is considered. Key considerations in the system/software development life cycle are outlined. Resource planning, establishing standards, and system validation are also covered. Flow charts are provided.
28.
U.S. Food and Drug Administration,* CDER.Guide to Inspection of Computerized Systems in Drug Processing. Rockville, MD: U.S. Dept of Health and Human Services: Division of Drug Quality Compliance and Field Investigations; February 1983.
29.
U.S. Food and Drug Administration.Software Development Activities. Technical Report; Reference materials and training aids for investigators. Rockville, MD: U.S. Dept of Health and Human Services, Division of Field Investigations; July 1987.
30.
U.S. Food and Drug Administration.Compliance Policy Guides. Guide 7132a.07. Computerized Drug Processing: Input-Output Checking. (Available from FDA FOI Staff [HFI 35], 5600 Fishers Lane, Rockville, MD 20857, USA).
31.
U.S. Food and Drug Administration. Compliance Policy Guides. Guide 7132a.08. Computerized Drug Processing: Identification of ‘Persons’ on Batch Production and Control Records. Rockville, MD: U.S. Dept of Health and Human Services.
32.
U.S. Food and Drug Administration. Compliance Policy Guides. Guide 7132a.11, Chapter 32a. Drugs—Adulteration, Computerized Drug Processing: CGMP Applicability to Hardware and Software. Rockville, MD: U.S. Dept of Health and Human Services; December 1984.
33.
U.S. Food and Drug Administration. Compliance Policy Guides. Guide 7132a.12, Chapter 32a. Drugs—Adulteration. Computerized Drug Processing: Vendor Responsibility. Rockville, MD: U.S. Dept of Health and Human Services; January 1985.
34.
U.S. Food and Drug Administration. Compliance Policy Guides. Guide 7132a.15, Chapter 32a. Drugs—Adulteration. Computerized Drug Processing; Source Code for Process Control Application Programs. Rockville, MD: U.S. Dept of Health and Human Services; April 16, 1987.
35.
U.S. Food and Drug Administration.Regulations, Guidelines, Recommendations and Agreements. 21 CFR Section 10.90. Washington, DC: U.S. Government Printing Office.
36.
U.S. Food and Drug Administration.Current GMP in the Manufacture, Processing, Packing, or Holding of Large Volume Parenterals. Federal Register41(6), 22202–22219 (1976).
37.
U.S. Food and Drug Administration.The Computer in FDA Regulated Industries. Inspection Technical Guide Number 23, May 1976.
38.
U.S. Food and Drug Administration.The Computer in FDA Regulated Industries—Part II Computer Hardware. Inspection Technical Guide Number 29, Rockville, MD: U.S. Dept of Health and Human Services; September 1977.
39.
U.S. Food and Drug Administration.Guideline on General Principles of Process Validation. Rockville, MD: U.S. Dept of Health and Human Services; May 1987.
40.
U.S. Food and Drug Administration. Preapproval Inspections/Investigations, Compliance Program 7346.832.
41.
U.S. Food and Drug Administration.Medical Device Good Manufacturing Practice Manual, 5th ed.Div. of Small Business Assistance, Center for Devices and Radiological Health. (Available from U.S. Government Printing Office, Washington, DC, ISBN 0-16-035884-2.).
42.
U.S. Food and Drug Administration.Application of the Medical Device GMPs to Computerized Devices and Manufacturing Processes— Medical Device GMP Guidance for FDA Investigators. Rockville, MD: U.S. Dept of Health and Human Services.
43.
U.S. Food and Drug Administration.Reviewer's Guidance for Computer-Controlled Medical Devices Undergoing 510(k) Review. Rockville, MD: U.S. Dept of Health and Human Services.
44.
AgallocoJ.Validation of existing computer systems. Pharm Tech. 1987;11(1):38–39, 42. Steps required in the validation process for computer systems in use before recognition of the need for such procedures are discussed. The method outlined parallels those used for new systems with different emphasis due to the inherent acceptability of an established system for its intended use. (2 REFS.).
45.
NATO Software Quality Control System Requirements, Allied Quality Assurance Publication, AQAP-13, August 1981, NATO Unclassified. NACISA, rue de Genève 8, Brussels, Belgium. This document may be used as a supplement to AQAP-1 in stipulating a software quality control (SQC) sub-system which will be considered a part of the quality control system prescribed by AQAP-1, or as a stand-alone document.
46.
ANSI/IEEE Standard 729–1983.“Glossary of Software Engineering Terminology.”The Institute of Electrical and Electronics Engineers, Inc., 345 East 47th Street, New York, NY 10017, U.S.A. (American National Standard).
47.
ANSI/IEEE Standard 730–1984.“Software Quality Assurance Plans.” The purpose of this standard is to provide uniform, minimum acceptable requirements for preparation and content of software quality assurance plans (SQAP).
48.
ANSI/IEEE Standard 828–1983.“Software Configuration Management Plans.”.
49.
ANSI/IEEE Standard 829–1983.“Software Test Documentation.”.
50.
ANSI/IEEE Standard 830–1984.“Software Requirements Specifications.”.
51.
BerklandRD. Validatable software design. Pharm Tech. 1991;15: 160–165, 196. Methods for the design and development of control, monitoring, and reporting software for processes subject to FDA validation requirements are discussed. The documentation produced should be the result of sound design practices, because by doing so a drug manufacturer can achieve a reasonable measure of confidence that functional requirements will consistently be met. (16 REFS.).
52.
BozenhardtH.The validation life cycle applied to software development: New concepts or simply good business. Drug Dev IND Pharm. 1988;14(18):2717–2723. The methods, procedures, and concepts of software development for process controls used in several industrial environments and the current evolution of control software development methods of the batch processing industry are examined. The life cycle concepts applied to the pharmaceutical industry and the validation concepts as imposed by regulations are discussed.
53.
British Standard 4778.“Glossary of Terms used in Quality Management.”British Standards Institution, 2 Park Street, London, W1A 2BS.
54.
British Standard 5515.“Code of Practice for Documentation of Computer Based Systems.”.
55.
British Standard 5750. Parts 0 (ISO 9000), 1 (ISO 9001, EN 29001), 2 (ISO 9002, EN 29002), 3 (ISO 9003, EN 29003), and 4. “Quality Systems.”.
56.
British Standard 5750. Part 13:1991 (ISO 9000 3). “Guide to the application of BS 5750: Part 1 to the development, supply and maintenance of software.”.
57.
British Standard 5750. Part 8:1991 (ISO 9004 2). “Guide to quality management and quality systems elements for services.”.
58.
British Standard 5760.“Reliability of Systems, Equipment and Components.”.
59.
British Standard 6719.“Guide to Specifying User Requirements for a Computer Based System.”.
60.
British Standard 6488.“Code of Practice for Configuration Management of Computer Based Systems.”.
61.
BronsteinRJ. Concept of a validation plan. Drug Inf J. 1986;20(1):37–42. A validation plan was developed to show that a computer program, software system, or hardware configuration would consistently perform as intended within preestablished operational limits. (7 REFS.).
62.
BrownEH. Standard operating procedures for computer systems validation. Drug Inf J. 1987;21(2): 193–200. Based upon FDA's requirements, the documentation of standard operating procedures to describe and define the manner in which scientific computer systems are validated and how that validation is documented both in the pharmaceutical manufacturing and research areas of McNeil Pharmaceutical are discussed.
63.
Quality Assurance Program for the Development of Software Used in Critical Applications. Ontario, Canada: Canadian Standards Association. CAN/CSA-Q396.1.1–89. This standard specifies the software quality assurance program requirements to be planned, developed, implemented, and maintained in order to assure that software to be developed for critical applications conforms to customer requirements.
64.
ChapmanKG. A history of validation in the United States. Part 2. Validation of computer-related systems. Pharm Tech. 1991;15: 54–56, 58, 60, 62, 65–66, 68, 70. An overview of the development of computer system validation, discussing contributions from the FDA, the pharmaceutical industry, and also from the vendor community is presented. (26 REFS.).
65.
ChapmanKGHarrisJRBluhmARErricoJ J.Source code availability and vendor user relationships. Pharm Tech. 1987;11(12):24–26, 30, 32–35. The extent to which members of the pharmaceutical industry must have access to source code information for their computer software is discussed, and implications for complying with good manufacturing practices in the area of computer system validation are described. (21 REFS.).
66.
ChowTS. Software Quality Assurance. A Practical Approach (Tutorial). New York, NY: IEEE Comp Soc1985, 0-8186-0569-3. (The Institute of Electrical and Electronics Engineers, Inc.).
67.
Computerized Data Systems for Nonclinical Safety Assessment. Maple Glen PA: Conference report. 1988.
68.
DunnRUllmanR.Quality Assurance for Computer Software. New York: McGraw-Hill; 1982, 0-07-018312-0.
69.
FosterRA. Introduction to Software Quality Assurance. New York: Richard A. Foster; 1983.
70.
FryJDDrewRT. Creation and implementation of a computer validation program. Drug Inf J. 1992;26(1):103–108. The need to develop and implement a computer validation program to ensure that systems and programs perform their intended functions is discussed; the process of computer validation is broken down into 10 components: administration, requirements, design, testing, operation, security, maintenance, change control, record retention, and periodic review. The implementation of such a program, which involves creating awareness, providing training and education, and developing an auditing method to determine level of compliance and enable appropriate adjustment, is also presented. (3 REFS.).
71.
GorenLJ. Computer validation, Part I: Testing and verification of applications software. Bio-Pharm. 1988;1(11/12):28–35.
KiefferRNallyJ.Implementing total quality in the pharmaceutical industry. Pharm Tech. 1991;15: 130, 132, 134, 136, 138. Differences between traditional quality philosophy and the total quality approach in the pharmaceutical industry are explored and one company's change from a good manufacturing practice (GMP) driven approach to a total quality approach is described. The traditional approach has been shaped by GMPs, which emphasize inspections and testing. The total quality approach emphasizes having a quality philosophy in every part of the business. (8 REFS.).
74.
KlinglerDE. Documentation and management of configurable software. Drug Inf J. 1987;21(3):283–287. A management approach and documentation format (the software configuration specification) to aid in the control of configurable software in an industrial environment are described. The software configuration specification that can be used to document and control purchased systems is discussed. (3 REFS.).
75.
KlinglerDE. Role of rapid prototypes in software validation. Drug Inf J. 1987;21(4):431–439. The importance of validation throughout the software life cycle in a pharmaceutical firm was discussed. The use of rapid prototyping techniques for facilitating requirements definition and validation, and user acceptance testing, were emphasized. (34 REFS.).
76.
KosmalaRM. Relationship between functional requirements and software design. Pharm Tech. 1990;15(11):66–68.
77.
KovachSA. Control systems project phases, including validation. Pharm Eng. 1990;10: 17–21. A discussion is presented of the many aspects involved in the successful implementation of a control system with computer hardware and software, including an understanding of what level of support and documentation is provided by the vendor for validation, proper preparation by the buyer, successful communication and interaction among all team members, and good project management skills practiced by the purchaser. (1 REF.).
78.
KuzelNR. Fundamentals of computer system validation and documentation in the pharmaceutical industry. Pharm Tech. 1985;9: 60, 62, 66, 68, 72, 76. A general discussion of types of validation projects; a set of recommended measures for validating and documenting computer hardware and software; and the installation, operation, and review of computerized systems for use in the pharmaceutical industry is presented.
79.
LaposkiEJ. Planning and managing the computer automation project. Pharm Manuf. 1985;2: 30–36. A 10-step system for the implementation and validation of a computer automation project is presented. Discussion includes: (1) user requirements and proposal preparation; (2) computer model and simulation; (3) rough system block diagram; (4) final system block diagram; (5) design basis; (6) design engineering and programming; (7) testing; (8) hardware and software validation; (9) installation and start up; and (10) validation of the installed system.
80.
LienEBSchultzB.Structured approach to validation. Pharm Eng. 1991;11: 17–18, 20–21. The validation of hardware and software computer systems and engineering and integration services in the pharmaceutical and health care industries is described.
81.
LiskinM.Can you trust your database?Personal Computing. June 29, 1990: 129–134. Warning: Relying blindly on the integrity of your database can be hazardous to your company's health. A thorough database audit can find errors before they find you.
82.
MaloneM.Managing the validation process. Drug Inf J. 1987;21(4):487–494. The methodology used in software validation, which took place during a year-long laboratory automation project, is described. Using the described techniques the automation and the validation were completed at the same time; this allowed the software package to be put into production without delay.
83.
MyersGJ. Software Reliability: Principles and Practices. New York: Wiley-Interscience; 1979.
84.
MyersGJ. The art of software testing. New York: Wiley-Interscience; 1979.
85.
PassingHUnkelbachHD. Software validation considered from the GLP and GMP Guidelines. Pharm Ind. 1987;49(6):590–595. The meaning of the term “software validation” is discussed with reference to the good manufacturing practices (GMP) and good laboratory practices (GLP) guidelines. (6 REFS.).
86.
SalazarJM. Computer migration and validation: Vendor's perspective. Pharm Tech. 1991;15(6):46, 48, 52. Computer migration and validation strategies in implementing technological advances for the control of manufacturing equipment in the pharmaceutical industry are examined for benefits versus risks, implementation factors, functions, and vendor qualification. The benefits involve support, bug fixes, and performance. The risks include effects on all parts of the company. The vendor's qualification can help define the level of revalidation effort. This migration strategy should be defined before the control system is placed in service and periodically evaluated for its effectiveness. (3 REFS.).
87.
StotzRW. Applications of CASE tools in the pharmaceutical industry. Pharm Tech. 1990;14: 84, 86, 88, 90, 92, 94–96. Computer aided (or computer assisted) software engineering (CASE) is discussed as an emerging technology that will assist in the planning, development, validation, and maintenance of computerized systems in less time and at a lower cost. These tools have been widely used in nonpharmaceutical applications. However, this new technology presently has few practical applications or examples in the pharmaceutical industry. (10 REFS.).
88.
TeagardenCJ. A Stepwise Approach to Software Validation. Pharm Tech. 1989;13(9):98–112.
89.
VaisT.Selecting a high-performance database for clinical research. Pharm Technol Int. 1991;3: 44–48. The characteristics of high-performance database management systems for clinical drug trials are described, and a seven-step checklist to help ensure selection of the proper system is included.
90.
WallaceDRFujiiRU. Software verification and validation: An overview. IEEE Software. May 1989;10–17. Properly applied throughout the life cycle, verification and validation (V&V) can result in higher quality, more reliable programs. This article introduces the V&V method and standards to support it. (6 REFS.).
91.
AndersonW.Software validation techniques. Drug Inf J. 1987;21:(4)461–469. A framework for software validation was discussed with reference to the five main areas of concern in verifying the quality of software. The use of information control and static and dynamic software analyses was also described. This framework is intended to increase productivity and the likelihood of success during the initial software validation period and for the lifetime of the software system. These methods were based upon experience developing and supporting a major laboratory data management software product. (11 REFS.).
92.
HerrickSS. Validation of computer systems. Clin Res Pract Drug Regul Aff. 1984;2(3):231–258. The validation of laboratory computerized equipment was discussed with reference to hardware, software, and regulatory requirements. (13 REFS.).
93.
JohnsonR.Good Automated Laboratory Practices (GALPS). 1991. U.S. Environmental Protection Agency, Office of Information Resources Management ME 34, Alexander & Highway 54, Research Triangle Park, NC 27711.
94.
SmithMartin MRuddDR. Importance of proper validation of the analytical methods employed in the quality control of pharmaceuticals. Acta Pharm Jugosl. 1990;40(1–2):7–19. The requirements for proper validation of the analytical methods employed in the quality control of pharmaceuticals are reviewed in appreciation of the fact that the results obtained from application of these methods stand in substitution for any direct demonstration of the therapeutic efficacy or the patient safety of the batches concerned. A computer based system, computer assisted method validation in situ (CAMVIS) is described which provides a means of checking the validity of a high performance liquid chromatographic method as it is being applied to the assay of a series of samples. (17 REFS.).
95.
MartinPAGaunnacGLTsujiK.Automation of microtiter plate chromogenic substrate LAL endotoxin assay method by use of a modified Cetus Pro/Pette Express System. J Parenter Sci Technol. 1986;40: 61–66.
96.
RiceJXStollFP. Validation of a computer system for chromatographic data acquisition in a quality control laboratory. Pharm Eng. 1989;9: 15–19. A strategy was designed to implement and validate a computerized data acquisition system for chromatographic analysis according to current good manufacturing practices. (11 REFS.).
97.
ToddMLandauRKoziolTDwyerRNitaharaK.Validation of the bioanalytical computer system. Drug Inf J. 1987;21(4):503–514. A systems development life cycle is described which incorporates prototyping, validation, documentation, and management control of a computer system used in an analytical laboratory.
98.
U.K. Department of Health.Good Laboratory Practice, United Kingdom Compliance Program. “The Application of GLP Principles to Computer Systems.” December 1988.
99.
AdamsC.Validating computer systems. Manuf Chem. 1990;61(59):61–63. The importance of validating computer systems in the pharmaceutical industry is discussed. It was noted that proper validation can provide real benefits through better, more cost effective systems.
100.
AgallocoJP. Practical considerations in retrospective validation. Pharm Tech. 1983;7(88):90. Problems associated with computerized retrospective process validation in the areas of set up, presentation of data, and interpretation are discussed, and some solutions are given. (5 REFS.).
101.
AlfordJSClineFL. Computer system validation—staying current: Installation qualification. Pharm Tech. 1990;14: 88, 90, 92, 94, 96, 98, 100, 102, 104. Installation qualification, a systematic approach in which qualified representatives of appropriate disciplines are involved in the installation and validation of computer system hardware for use in the pharmaceutical industry, is discussed. It was noted that hardware includes field measurement and control devices, transducers, wiring, the computer system, and the environment in which each of these is installed and operated. (12 REFS.) Reprints: T. Savage, Pharm. Manufacturers Assoc, 1100 Fifteenth St. N.W., Washington, D.C. 20005, USA.
102.
AlperinG.Validation considerations in pharmaceutical processes and plant design. Pharm Eng. 1984;4: 15–20. A brief commentary on the regulatory aspects of validation procedures was presented. The major suggestion concerns involvement of the process validation team in a formal cost savings program aimed ultimately at achieving a smooth transition to automated or semiautomated processes.
103.
BellDFarrellPSSmallDC. Simple, inexpensive implementation of the Fo concept of autoclave cycle validation using a portable data logger with a remote microcomputer. J Clin Pharm Therap. 1987;12:157–163. The conversion of an autoclave, previously controlled by a bottle simulator and monitored using master temperature records, to one controlled by a bottle probe and monitored using Fo values, was described. Temperatures were recorded with a portable data logger and a microcomputer was used to calculate Fo values and produce batch reports. (7 REFS.).
104.
BirrenbachGKoepkeW.Machine diagnosis for improved productivity and GMP conform production control. Pharm Ind. 1982;44: 951–955. A system for the monitoring of pharmaceutical production according to good manufacturing practices, based on microprocessor technology and combined with a video terminal, is described. The system is capable of analyzing production lines, preventing faults within the manufacturing process, and providing documentation of conformance with good manufacturing practices. The economics of the system are also discussed. (2 REFS.).
105.
BowieS.Implementing an automated material-dispensing system. Pharm Tech. 1991;15(4): 64–74. An automated weighing and dispensing system used in the pharmaceutical industry is described, including implementation, operational procedures, security features, training, and validation.
106.
CarrJM. Systematic procedure for the development of batch process control systems. Pharm Eng. 1991;11: 23–29. Proven techniques that can reduce the time and problems associated with the design of batch process control systems in the pharmaceutical industry are presented. Steps in the development of a successful batch process control system are summarized. The use of the time sequence diagrams for design of the batch control system and the use of a process simulator for testing of the final control system software can help produce a successful project. (9 REFS.).
107.
DavisM.Validation of computer software in process control applications. J Parenter Sci Technol. 1986;40: 18–24. The components of a validation package for a computerized process control system in the pharmaceutical industry are discussed. The role of each component is discussed, and functional test procedures which focus on system performance are shown to effectively simplify testing while satisfying the requirements for validation. (3 REFS.).
108.
DigginsK.Development standards for software used in drug production. Pharm Tech. 1987;11: 56–62. An overview of computer software development standards for systems used in the pharmaceutical industry and methods of validation are discussed. (3 REFS.).
109.
DoubleME. Ongoing evaluation of a validated computer system: QA perspective. Pharm Eng. 1990;10: 22–24. The components of the maintenance operations phase of the computer software cycle are described and the role of the quality control department of a pharmaceutical company in conducting periodic inspections of the validated system is discussed.
EttorreLM. Retrospective validation of existing computer systems. Drug Inf J. 1988;22(4):547–551. The approach that McNeil Pharmaceuticals has taken to retrospectively validate one of its computer systems in use since 1979 is described. The outcome was a retrospective validation document consisting of 11 sections: introduction, summary, background, computer validation, raw data retention, program operations, hardware, inspection/audits, training, conclusions, and signature page. It is concluded that retrospective validation takes some time and hard work, but if the results are positive it can save a firm a lot of unnecessary time spent revalidating an existing system that has been operating successfully for years.
112.
FerociMPicciniSSferruzzaG.Computerized weighing for the pharmaceutical industry: Theory, achievement and validation. Boll Chim Farm. 1987;126: 20–24. An error-proof weighing system is described that eliminates the problems in controlling raw materials during use in the pharmaceutical industry. After weighing of the materials, the batch record is printed along with the control sheets and the manufacturing method. A description of the hardware, the software and the validation of the system during six months of production is presented. (3 REFS.).
113.
FetteW.Fette presses for integrated systems. Manuf Chem. 1991;62: 21, 23. Computerized total process integration in tableting lines, from raw material to the packing of the final product, as a step forward to meet quality control and validation demands in tablet production is discussed. Reprints: from company. Wilhelm Fette GmbH, Postfach 1180, D 2053 Schwarzenbek, Germany.
114.
GeschwandtnerRHamblochHHempelHELanzWWiesenthalK. Validation of computer-assisted production processes in pharmaceutical manufacturing. Pharm Ind. 1989;51(8):911–913. The objectives, definition, planning, and implementation of validation of computer assisted production processes in pharmaceutical manufacturing are described. Prospective and retrospective validation processes are included.
115.
JerzewskiRLRudnicEM. Development of a low cost intelligent tablet compression monitor using a personal computer. Pharm Tech. 1986;10: 32, 34, 36, 38–41. The development of a low-cost, computer based monitoring system for monitoring instrumented tablet presses is described. The software programs were written in BASIC and a sample program is given. To avoid the cost of custom written programs, it is stated that judicious selection of an A/D converter with prewritten software packages can reduce the time and cost of constructing computer programs for data acquisition and processing. (25 REFS.).
116.
KeaneJA. Computers and quality assurance in a regulated industry. Washington: Medical Devices, Diagnostics & Instrumentation Reports (Grey Sheet). 1981;10: 45–77.
117.
KunzeKH. Description of a weighing unit for the weighing of pharmaceutical ingredients. Drugs Made Ger. 1976;19: 36–41. The establishment of a centralized weighing unit for processing materials in pharmaceutical production plants is described. The following points are covered: (1) the design of the weighing unit, (2) a description of the functioning of this unit, and (3) the preparation of the necessary documentation of the weighing operations carried out pursuant to proper GMP guidelines. The system employs automated balances which print labels and record weights. The unit weighs ingredients from 2g to 1000kg. A central console for controlling all of the balances is described.
118.
LiszkayM.Qualification and validation in pharmaceutical packaging. Pharm Ind. 1985;47(3);303–306. The benefits and necessity of qualification and validation in pharmaceutical packaging are demonstrated with examples of some problems which may arise in the use of fully automated packaging lines. (5 REFS.).
119.
MastersonPM. Applying automated process control to lyophilization. Pharm Tech. 1989;13: 48, 50, 52–54. Practical issues relating to automating a lyophilization process are discussed, and the selection of the automation system and how that system relates to the methodology for the validation of the control system are described. Incorporating an automated control and data acquisition system into a pharmaceutical or biotechnology operation requires detailed knowledge of the process being automated and familiarity with required procedures. A project team approach, comprehensive testing procedures, and thorough documentation should be emphasized, and a well defined methodology for validation of the control system should be established. (3 REFS.).
120.
MillerGR. Validation testing of hardware and software: Using a real time simulator. Pharm Eng. 1990;10: 17–20. A method of validation testing of computer hardware and application software using a real time simulator developed for use in the pharmaceutical industry is described, including software specifications, application software, simulation, testing protocols and the various types of real-time simulation testing.
121.
MyersTKasicaTChraiS.Approaches to cycle development for clean-in-place processes. J Parenter Sci Technol. 1987;41: 9–15. Factors affecting clean-in-place processes for manufacturing equipment are discussed, and an automated process cycle, with validation procedures, is described. (4 REFS.).
122.
PaulsonDSVogelDG. Preparatory software documentation for validation of computer controlled manufacturing operations. Pharm Manuf. 1984;1: 36–38,56. A guide for managers in the generation of data that will lead to successful software validation of computer controlled manufacturing processes is presented. Documentation requirements, manufacturing and software specifications, and software architecture are discussed. (2 REFS.).
123.
Pharmaceutical Manufacturers Association's (PMA) Computer Systems Validation Committee.Computer system validation —Staying current: Introduction. Pharm Tech. 1989;13(5): 60–66.
124.
PMA's Computer Systems Validation Committee.Computer system validation—Staying current: Installation qualification. Pharm Tech. 1990;14(9):89–102.
125.
PMA's Computer Systems Validation Committee.Computer System Validation—Staying current: Software development testing strategies. Pharm Tech. 1989;13(9):142–156.
126.
PMA's Validation Advisory Committee.Process validation concepts for drug products. Pharm Tech. 1985;9(9):78–82.
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PMA's Validation Advisory Committee. Validation concepts for computer systems used in the manufacture of drug products. Pharm Tech. 1986;10(5):24, 26–27, 30, 32, 34. Fundamental concepts for the validation of computer systems used in good manufacturing practices related pharmaceutical operations are presented by the Pharmaceutical Manufacturers Association.
128.
PMA. Proceedings: Concepts and principles for the validation of computer systems used in the manufacture and control of drug products. Seminar. Chicago IL, April 20–23, 1986.
129.
PittsJRiccaJRehbeinD.Data integration in the process industry. Pharm Eng. 1989;9: 34–36. The use of a batch historian program for the management of data in the process industry is described, including the use of relational database basis, data documentation, statistical process control, and validation. (2 REFS.).
130.
RayTKrietensteinJ.Streamlining warehouse processing with a lot status segregation system. Pharm Manuf. 1985;2: 12, 14–15. A computer controlled lot status segregation system, used by a pharmaceutical manufacturer to keep track of acceptance or rejection status of raw materials in a warehouse, is described. Systems controls, validation, and benefits are discussed.
131.
RiceIXSextonFA. Validating an automated dispensing system —case study. Pharm Tech. 1988;12: 44, 46, 48, 50, 52, 54. The methodology and documentation structure used in the development and validation of an automated system for the dispensing area in pharmaceutical industry are discussed. Procedures that were followed for initiating the project, developing and validating the software, and documenting the progress of the validation procedures are discussed. Applicability to the validation of any automated system within the industry is noted. (16 REFS.).
132.
SechovecKS. Validation of an automated filter integrity tester for use in bubble point testing. J Parenter Sci Technol. 1989;43: 23–26. The basic principles of filter integrity testing (bubble point test) are explained. An automatic filter integrity testing machine was validated by challenging the unit's ability to differentiate between integral (intact) and nonintegral filters using a manual method as a standard. (3 REFS.).
133.
SiebertER. Use of robotics in tablet sample preparation. Pharm Manuf. 1985;2: 24–29, 54. The design of a robotics system for oral contraceptive tablet analytical sample preparation is presented. Problems encountered during the validation process and results of precision and accuracy tests demonstrating that the automated system is comparable to manual methods are discussed. (2 REFS.).
134.
StapleyD.High speed video aids fault finding. Manuf Chem. 1984;55: 41, 43. A high speed video system is described which can be applied to automated filling and packaging operations of pharmaceutical products; application of the computerized system to various stages of a tablet vial packaging line is demonstrated.
135.
StefanDALeesmanGDPatelMRMoreheadWT. Computer interfaced instrumentation of a rotary tablet press. Drug Dev IND Pharm. 1985;11: 83–100. The instrumentation and design of a computer interfaced, 25-station rotary tablet press are described. The abilities of the computer interface to simultaneously monitor precompression, compression, and ejection forces, and store data for later analysis is discussed. System validation for sensitivity and reproducibility is also described. (4 REFS.).
136.
Stefanini-OresicLGrdinicV.Computer aided pharmaceutical control. Part 1. PC versus GLP. Farm Glas. 1990;46: 101–104. The need for the development of good laboratory practices for a computer system, and the validation of a computer hardware and software system, including relevant documentation, are discussed. (4 REFS.).
137.
TrottmanD.Applying GMP to computerization in a solid oral dosage form factory. Drug Dev IND Pharm. 1989;15(10):1693–1713. Applications of computerized systems and good manufacturing practices in the manufacturing of solid oral dosage forms are described, including hardware, software, and computer security.
138.
VogelDGSchmidtWCSanfordBG. Computer interface for sterilization validation. Pharm Tech. 1983;7: 64, 66, 68. A simple interface of validation instrumentation with a microcomputer was developed for the acquisition, sorting, reduction, and statistical analysis of the evaluation of sterilization cycles.
139.
WolberPBeechDMcAllisterM.Validation of computerized membrane integrity test systems. J Parenter Sci Technol. 1988;42: 106–110. The priorities and problems associated with the validation of computerized membrane integrity test systems and the FDA guidelines for inspection of computerized systems in drug processing are discussed. Automated integrity test devices are highly specialized forms of computerized systems which do not easily conform to existing qualification parameters. Verification of equivalence to the existing validated method provides a path that is least time consuming and offers a proven test method which is already employed as a reference point. (12 REFS.).
140.
WolffKPloschH.Electronic data processing based production in the hospital pharmacy: Practice — legitimate conversion of the GMP guidelines. Krankenhauspharmazie. 1987;8: 442–446. An electronic data processing program for use in the hospital pharmacy for the production and documentation of drugs, which conforms to the good manufacturing practices guidelines, is discussed. (12 REFS.).
141.
YelvigiM.Principles of process automation for liquid and solid dosage forms. Pharm Tech. 1984;8: 47–50, 52, 55–56. Basic concepts involved in process automation for liquid and solid dosage form manufacturing are discussed, with emphasis on the process development and brief discussion on quality assurance and validation principles. (6 REFS.).
142.
DukeEL, V&V of flight and mission critical software. IEEE Software. May 1989;39–45. The aeronautics agency's flight research facility has adapted V&V to meet its special needs. The methodology's cornerstones are shared responsibility and flexibility. (10 REFS.).
143.
DunhamJR. Experiments in software reliability: Life-critical applications. IEEE Transactions on Software Engineering: Vol. SE-12, No. 1, January 1986. The paper discusses four reliability data gathering experiments which were conducted using a small sample of programs for two problems having unreliability requirements, n version programming for fault detection, and repetitive run modeling for failure and fault rate estimation. (29 REFS.).
144.
OliverDP. Lessons learned in the application of software safety. Washington: Medical Devices, Diagnostics & Instrumentation Reports (Grey Sheet). 1991;6: 158–161.
