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Computer System Validation An Overview of Official Requeriments
Computer System Validation An Overview of Official Requeriments
ACTA
HEWETIAE
ELSEVIER Pharmaceutics Acta Helvetiae 72 (1998) 317-325
Abstract
A brief overview of the relevant documents for companies in the pharmaceutical industry, which are to be taken into consideration to
fulfil computer system validation requirements, is presented. We concentrate on official requirements and valid standards in the USA,
European Community and Switzerland. There are basically three GMP-guidelines, their interpretations by the associations of interests like
APV and PDA as well as the GAMP Suppliers Guide. However, the three GMP-guidelines imply the same philosophy about computer
system validation. They describe more a what-to-do approach for validation, whereas the GAMP Suppliers Guide describes a how-to-do
validation. Nevertheless, they do not contain major discrepancies. 0 1998 Elsevier Science B.V.
.O 0
Production Requirements
5 ) 1 ...‘...
and Maintanance ..-..., and Design
t
Validation
Testing
I
Installation :. Coding
Testing
mines the resources required for validation. The system tem design documents should be available for review and
specifications have to be defined. The detailed description updates.
of the final computerised system has to be documented. (4) Installation testing: The end user performs the sys-
During this phase the documents to be produced while tem’s task with his/her own data and procedures. System
validating are identified. This covers protocols and reports. failure leads to new documentation and re-design.
The system documentation might be updated due to valida- (5) Production maintenance: The system is released for
tion efforts. production. System changes (software or hardware) have
(2) Coding: At the beginning of this phase, the valida- to be documented and controlled in a predefined manner.
tion plan should be finished off. Information about the The first and second step can be linked to the earlier
validation test environment, assumptions, exclusions and mentioned design qualification, step three and four will be
limitations about the system as well as installation proce- validated in installation qualification and the task of per-
dures should be clarified. This phase covers the implemen- formance will be linked to step five of the above life-cycle
tation of software and construction of hardware. model.
(3) Testing: Th’1s complex phase can be divided into This life-cycle model is explicitly mentioned in the
several phases. All single modules whether they are hard- APV Guideline ‘Computerised Systems’ based on Annex
ware or software have to be tested. Afterwards an integra- 11 of the EC-GMP-Guidelines (APV, 1996), which will be
tion test has to be performed. While the developers con- discussed further in this paper.
duct unit, system and integration testing, the Validation
2.2. The V-model
Committee is in a position to define test cases and data
running the acceptance test. Several documents such as, The Forum for Good Automated Manufacturing Prac-
requirement documents, functional specification and sys- tice introduced guidelines (GAMP, 1996) for suppliers
Level I
User Requirement Specification . . . . . . . Automated Performance Qualification
1 Level 2 T
System Function Specification . . . . . . System Acceptance Testing
1 Level 3 T
Hardware Design Specification Hardware Acceptance Testing
1 Level 4 T
Software Design Specification Software Integration Testing
1
1 Level 5 T
Software Module Specification .-.-.--.-.---..-.-. Software Module Testing
1 T
I Code Modules
Fig. 3. The V-model: The left part of the V-model concerns on constructing the system whether the right part focuses each step of the system validation
process.
320 A. Hojinann et al./ Phamaceutica Acta Helvetiae 72 (1998)317-325
Validation is part of quality assurance. Miiller et al. Fig. 4. European community legislation.
3.1.2. Switzerland
3. Governmental regulations and guidelines The manufacturing and quality control of medicinal
products is regulated by the Cantons. Switzerland is di-
Regulation in this field is many fold and it is not always vided into 26 Cantons. These 26 Cantons have founded a
easy to have an overview of it, since its status in the legal concordat called Interkantonale Vereinbarung (IKV), from
hierarchy may spread from law to strong recommendation. where the Intercantonal Office for the Control of Medicines
A brief overview is presented for the EC, Switzerland and (Interkantonale Kontrollstelle fur Heilmittel) (IKS)
the USA. emerged. IKS, on behalf of the cantons, is mainly respon-
sible for the registration of medicinal products. In the field
3.1. Governmental regulations of GMP the IKS has issued manufacturing guidelines
(IKS, 1995) which adopt the guide to good manufacturing
3.1. I. European community practice issued by PIC (PIC, 1989) and also consider
The requirement to follow good manufacturing practice recommendations of the World Health Organisation (WHO,
in EC-countries is laid down in the EC directive 1992). European directives and guidelines but also intema-
75/319/EEC (EC, 1975). Differences concerning the con- tional regulations (e.g. WHO, European Pharmacopoeia)
tent and number of national GMP-guidelines in EC-coun- are considered in Swiss legislation and they are often
tries led to the publication of the EC directive accordingly adapted into Swiss law. These IKS-manufac-
91/356/EEC (EC, 1991) on the principles of good manu- turing guidelines are not applicable to the production of
facturing practice and the homogenous EC-GMP-guide- pharmaceutical goods in public or hospital pharmacies.
lines (EC, 1989) belong to it. Hence, these guidelines are The legislation in Switzerland is depicted in Fig. 5.
now mandatory for all EC-members. The main document Due to the very complex legal framework it is in the
of the EC-GMP-guidelines has been amended by several authority of the Cantons to issue manufacturing authorisa-
annexes, one of which is number 11 which provides tions whereas GMP-certificates for instance are issued by
A. Hoffmann et al./Phamaceutica Acta Helvetiae 72 (1998) 317-325 321
3.2.1. APV
the IKS. GMP-matters are therefore a shared responsibility The International Association for Pharmaceutical Tech-
leading to several inspectorates, one at the IKS and the nology (Arbeitsgemeinschaft Pharmazeutische Verfahren-
others cantonal or regionally structured. In the near future stechnik, APV) is originally a German association. This
four regional areas will be constructed and IKS will use its organisation founded the board of Information Technology
position as co-ordinating institution. which discusses the problems and chances of modem
information technology. This specialist section published a
3.1.3. USA detailed interpretation of Annex 11 (APV, 1996).
Muller et al. (1996) state that the regulations and points
of view of the US regulatory authority Food and Drug 3.2.2. PDA
Administration (FDA) are certainly important for manufac- The Parenteral Drug Association (PDA) is an American
turers all over the world exporting into the USA. There- association which founded a committee Validation of
fore, an overview is presented how quality related FDA Computer Related Systems. This board assembled a guide-
regulations concerning the production of drugs are organ- line for the qualification of computer systems and com-
ised. The congress enacts the Food, Drug and Cosmetic puter related systems as a Technical Report (PDA, 19951,
Act and FDA’s existence is due to the mandate to approve which is now an important document for computer system
drugs based on the demonstration of safety, efficacy and validation in the USA.
quality. The legislation in the USA is depicted in Fig. 6.
The contents of the FDA-GMP-guidelines (FDA, 1987) 3.2.3. GAMP-Forum
is conceptionally comparable with the EC-/PIC-GMP- In 1990 an informal group, the UK Pharmaceutical
guidelines but there are differences in the content. For Industry Computer System Validation Forum (PICSVF)
example, the FDA-GMP-guidelines do not have a supple- was set up to establish a compendium concerning the
ment chapter explicitly about validation of computer sys- validation of automated systems in pharmaceutical manu-
tems whereas the EC-GMP-guidelines contain a special facture. In the following drafts and versions the EC-GMP
annex. On the other hand the FDA recently issued supple- Annex 11 and further comments of companies from all
mentary regulations concerning i.e. electronic signatures over Europe and the USA were incorporated. This led to
CFR (1995). version 2.0 of the GAMP Supplier Guide (GAMP, 1996)
Changes in the pharmaceutical field lead to a reaction which was published by the Good Automated Manufactur-
by the authorities. The guidelines should keep up with the ing Practice Forum in May 1996.
new trends in industry. Therefore, since 1987 the FDA-
GMP-guidelines have been frequently revised as so called
current GMP-guidelines, (cGMP) and the guide is still in
the revision process. Proposed changes have been already
published in the Federal Register, CFR. This Code of
Federal Regulations, CFR 210/211 (CFR, 19961, is on a
Code of Federal Regulations
higher legal level compared to the guidelines and guides
(ZICFR 210+2ll)
which have the status of recommendations, however, most
stringent recommendations.
The earliest document dealing with computer validation
was the Blue Book (FDA, 1983). It is usually applied as and other Guidelines
guidance for inspectors. The valid document for validation
in the computer-related environment for pharmaceutical Fig. 6. USA legislation.
322 A. Ho@zann et al. /Pharmaceutics Acta Helvetiae 72 (1998) 317-325
regarded with caution. The customer has to consider the do. However, there is no existence of an overall regulatory
cost of this option. guide for validation, that is why the interpretations by
For newly developed computer software, validation can non-governmental organisations are important.
be seen as a concept of quality assurance in electronic data In the USA the PDA Technical Report No. 18 (PDA,
processing. In most companies there is a parallel develop- 1995) is the most essential document, whereas in Europe
ment of quality assurance and information technology. the APV-guidelines (APV, 1996) reflect an important in-
Quality assurance has been applied from production and terpretation of Annex 11. Both documents show what-to-do
analytics, whereas information technology rather comes to achieve the objectives of computer system validation in
more from the administrative parts. It can often be seen detail. This what-to-do is accepted and seen as being
that the information technology is not adequately covered sufficient, especially by large companies. These companies
by quality assurance. In companies with long-time use of view the flexibility of this approach as an advantage.
computers, it also occurs that standards in quality assur- The capacity of smaller companies demands a compre-
ance are used but they are not carried through for all hensible description and guide about how-to-do validation.
computer applications. Therefore it can be said, that the The GAMP-guide (GAMP, 1996) takes this demand con-
validation of computer systems is often not given the cerning prospective validation into account. Nowadays, the
importance it should be. Another problem is that docu- GAMP Supplier Guide is the most comprehensive and
ments which were required for validation frequently do not most detailed guide for the qualification of all kinds of
exist and companies rely strongly on the competence of computer systems and has considerable international sig-
their employees. nificance. The document can be designated broadly as a
Many user systems have been installed before valida- general guide to achieve a validated computerised system
tion was required by law in Europe. Despite the non-paral- and should be regarded as a very important document.
lel development and validation, practice shows that most The lack of governmental procedures in great detail can
of these systems perform their tasks reliably. Nevertheless, also be seen as a chance. It allows flexibility to move
these systems do not always fulfil the requirements of a within the legal requirements. Standards set by customers
modem computer validation. The substitution of such ex- and suppliers of computer systems come closer to require-
isting software or hardware results often in big efforts even ments in the real world than detailed regulations made by
if only a part is substituted. For every changed module a authorities.
validation is required. An overall retrospective validation In the near future, the described standard documents
of the system will lead to the lawful acceptance of the will receive more importance. The groups of interests
system as a validated system. nowadays focus on standardisation guides for detailed
questions, i.e. electronic signature.
4.2. Guidelines
4.3. Aspects of inspections
In the USA the FDA-cGMP-guidelines (CFR, 1996)
require a validation of computerised systems. The guid- The publication of the Blue Book (FDA, 1983) is the
ance to performing this validation is still under develop- only official document that contains guidance for inspec-
ment, since computer validation is a new field in valida- tors. However, the authorities provide support for inspec-
tion. The objective of transferring what is desirable in tors and the trend to harrnonise the level of inspections is
theory must be applied in practice. made by joint-inspections and discussions on conferences
The EC directive (EC, 1991) and its corresponding like PIC (1996).
EC-GMP-guidelines (EC, 1989) as well as the PIC-guide- Neither the FDA nor another authority published a
lines (PIG, 1989) require also a validation of computerised checklist or a guidance for industry so far. Because the
systems. Here, Annex 11 describes additional cornerstones topic of computer system validation is relatively new,
and points which have to be taken into consideration while many aspects have not been fixed yet. The FDA an-
validating computerised systems. In brief it can be said nounced a guide, which should be published in 1997 and
that the GMP-guidelines on Good Manufacturing Practice so did PIC. As declared, the PIC-guide will be an overall
for Medicinal Products are mandatory in the countries of document, covering all important papers published by
the European Union as well as in Switzerland. various non-governmental organisations. Switzerland will
There are basically two approaches to give guidelines deal without an own guideline but the authorities will
for validation. First is the description of a how-to-do accept the international standard. In addition, there is the
validation, while the second gives a guideline for what-to- intention to create a checklist for the industry.
324 A. H&inann et al. / Pharmaceutics Acta Helvetiae 72 (1998) 317-325
Currently the GAMP-guide and the publications from tion of all partners and the aim to have world-wide har-
PDA and APV represent the only sources for requirements monisation is a declared objective for the future intema-
checked at an inspection, but there exists flexibility for tional work.
interpretations by inspectors. A validation extent of differ-
ent topics is given in the GAMP Supplier Guide, chapter
10: Validation Strategy for Different Types of Software Acknowledgements
Products.
In the sense of documented evidence it is important to We thank Dr. Annette Beck-Sickinger, Dr. G. Imanidis
complete the documentation for all steps of the life-cycle and Dr. S. Marrer for organising the seminar and for their
model. Even during a retrospective validation this model competent guidance. Our special thanks go to Dr. S.
should be followed as far as possible. Particular critical Marrer, F. Hoffmann-La Roche AG Basel, for his useful
points in computer system validation and therefore possi- advice concerning the manuscript and for kindly reviewing
ble starting-points for an inspection are the risk-analysis, it.
planning, the specifications, the security of access, the
security of data and the hole change control.
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