Reference Section

The Future of Computer Systems Validation in the Pharmaceutical

Industr y: Red Herrings , Old Chestnuts and Silver Bullets
a report by
Guy Wingate

Quality Director, GlaxoSmithKline

Computer technology plays an ever-increasing role in of the computer system. The principle is to build in
the pharmaceutical industry. It is used throughout the quality rather than rely solely on testing. A high degree
whole supply chain with varying degrees of potential of assurance is sought rather than absolute proof of
impact on patient safety. Computer validation is operability. It is hard to argue that this approach is
typically treated as a technical speciality of little interest flawed, but regulatory guidance has struggled to keep
to those not directly involved. Indeed I have written up with technological changes and consequently it is
many detailed papers and technical books on all too easy to declare validation standards out of date
computer validation myself as a so-called ‘validation even though the principles they preach are still valid.
Guy Wingate is a Quality Director
with GlaxoSmithKline. He is a expert’. Now however, I believe the time is now right The main US regulatory guidance document remains
recognised international expert on to instead examine the future direction of computer the Blue Book, first published 20 years ago.7 European
the topic of computer validation
validation from an advanced industry perspective. regulatory guidance is more recent but continues to
and electronic records and
signatures. He currently chairs focus on custom-built developments rather than
ISPE/GAMP that brings together The theory behind the US Food and Drug managing today’s highly integrated configurable
computer validation experts from
around the world and is responsible Administration (FDA) paper outlining the future of systems.8 Even the most recent Good Automated
for the GAMP Guides cited in 21st century Good Manufacturing Practice (GMP) Manufacturing Practice (GAMP4) guidelines do not
regulatory guidance issued by FDA for the pharmaceutical industry is becoming reality.1 appear, at first sight, to sanction the use of modern,
and PIC/S. Dr Wingate has written
a number of books on computer The issue of complementary standards such as ICH rapid application development techniques.9
validation, regularly speaks and Q82, ICH Q93, ICH Q104 and ASTM E555 has
chairs conferences, and is a visiting
lecturer for MSc courses accredited
aided this process, supported by the industry and the Secondly, computer validation is inherently
by Dublin Institute of Technology EU, Japanese and US regulatory authorities. All inefficient and ineffective. Two commonly quoted
and Manchester University. aspects of quality assurance (QA) are impacted, examples revolve around the role of the quality
including computer validation. There has been much assurance (QA) department and their demand for the
written advocating great change. Equally many duplication of work by pharmaceutical companies
people share unease about some of the ideas being that has already been done by their suppliers.
proposed. With questions about practical Practitioners have had a rough ride for well over a
implementation being hotly debated I believe it is decade over the efficiency and effectiveness of
timely to reflect on why and how we use computer computer validation. Consequently, there has been
validation and to take a look at the real issues being significant work in leaning validation and applying
faced. This is dangerous territory and my opinions Six-Sigma methodology. There is no reason why the
may upset both traditionalists and modernists alike. problem of excessive paperwork and duplication of
There is a need to generate wider awareness and effort cannot be remedied. Pharmaceutical companies
understanding of some of the main issues before us do not need to retest system operability, which has
and to reach a consensus on the future of computer already been verified and suitably documented by
validation. I will start by reviewing three common supplier testing. Indeed, many firms have now
criticisms of current validation practice and then successfully addressed these and other similar
outline some thoughts on the way forward. assumptions. There are many examples of current
validation costs being only a fraction of what they
Firstly, the concept of computer validation is outdated once were, when compared to overall project costs. It
and no longer relevant. It is important to realise that was not that long ago, the end of the 1990s, when
computer validation was introduced for a reason, to best in class validation would mean 10% of project
address operational failures of computer systems that cost.10 More recent experiences have claimed costs as
impacted patient safety.6 Validation is based on taking low as 2% for validation of complex systems that have
a structured life-cycle approach to managing the subsequently passed rigorous regulatory inspections.11
whole process. This takes in the initial planning and These improvements have been achieved by applying
specification of the project through development, the principles of lean manufacturing and Six-Sigma.12
testing and release to final operation and maintenance Thirdly, computer validation techniques and

1 DRUG MANUFACTURING & SUPPLY 2006

 Reference Section

terminology hinder the paradigm shift needed to • quality-critical parameters in manufacturing;

support the implementation of 21st century GMP. It is • product release;
suggested that many constraints are self-imposed by • recall; and
over-zealous interpretation of regulatory expectations • adverse events or complaints.
(requirements or guidance). We should try and keep to
the spirit of what computer validation lifecycle is trying The amount of validation through the computer
to achieve. GAMP4 is compatible with modern, rapid system life-cycle and amount of associated
application development techniques and is founded on documentary evidence should be commensurate
a risk-based approach; however, this is not the with risk. This concept is not new but we need to
immediate impression given when reading the exploit it. Regulatory authorities such as the FDA
guidance. Another contributory factor to whether and the UK Medicines and Healthcare products
computer validation will support 21st century GMP Regulatory Agency (MHRA) have already
has been confusion over terminology. It is important to indicated they are comfortable with this approach.
remember that computer validation brings together a It should also be possible to use supplier
fusion of disciplines from laboratory analysts, engineers, assessments, not necessarily audits, to determine the
IT professionals and QA personnel. acceptability of supplier documentation without
the need to repeat supplier testing. Further, the role
Whilst a common terminology has become established of QA units within a pharmaceutical company can
over the years it is now being challenged by be limited to establishing policies and procedures,
technologists trying to implement Process Analytical approving acceptance criteria, and approving
Technology (PAT).13 For example, the US based reports. This is only true so long as there is
standards authority ASTM who are developing a series sufficient confidence in the capability of whoever is
of PAT standards are promoting dropping the concept doing the remaining validation activities. The work
of ‘validation’ for facilities, equipment and computer culture is extremely important and generally needs
systems in favour of focusing on ‘qualification’ and more attention. As long as managers and
‘good practice’.14 Great care is needed when placing practitioners alike have the right quality mindset
emphasis on these without defining exactly what level when it comes to making decisions then patient
of control is expected. PAT applications will require safety and regulatory compliance will not be
high integrity if they are to be exploited and hence the compromised. At the end of the day people make
principles behind computer validation are more the difference. Good people deliver not just short-
necessary than ever. There will be confusion as existing term results but results that hold up to scrutiny
practitioners try to transfer between the established long-term too.
language of validation and a new taxonomy, which
will still have some shared words, but with different In conclusion, whilst the concepts and principles
meanings. A significant and widespread re-education behind computer validation remain convincing and
programme will be needed if such new terminology is relevant, it is clear that computer validation
to stick. Surely prudence would say it is better to practices need to be updated to reflect modern
continue to improve the current understanding of computer technology and development techniques.
existing terminology used over the past 25 years to A risk-based approach must be evident to protect
meet the needs of 21st century GMP. Indeed new patient safety but also allow for efficient and
terminology such as the finalised version of the PAT effective ways of working to deliver systems that
standards might even be at odds with EU GMP Annex deliver business benefits. Industry groups like
11 on Validation.15 We need to be wary of voices that ISPE/GAMP, the Parenteral Drug Association
offer an alternative silver bullet to validation without (PDA) and the Pharmaceutical Research and
fully examining the pros and cons that such a change Manufacturers of America (PhRMA) that draw
would invoke. together recognised experts in this topic area have a
responsibility to lead this change.
It might appear that everything in the field of
computer validation is fine and there is no need for As an industry we cannot afford to see a repeat of
any change; however, this is not the case. Computer the problems that electronic records and electronic
validation does need to change but through significant signatures caused at the end of the 1990s when
evolution not revolution. In particular it needs to take inappropriate practice diverted industry investment
risk management to its heart. The main focus should from delivering real business improvement.16 ■
be on critical computer systems that have an impact on
patient safety, i.e. those used for controlling:
The views expressed in this article are personal reflections
• data supporting regulatory safety and efficacy and do not necessarily represent the views of Dr Wingate’s
submissions; employer nor any industry groups with which he is affiliated.

2 DRUG MANUFACTURING & SUPPLY 2006

 The Future of Computer Systems Validation in the Pharmaceutical Industr y

References

1. FDA, Pharmaceutical cGMPs for the 21st Century – A Risk-Based Approach (2002).
2. ICH, Pharmaceutical Development, Approved ICH Consensus Guideline Q8, International Conference on Harmonisation
of Technical Requirements for Registration of Pharmaceuticals for Human Use (2005).
3. ICH, Quality Risk Management, Approved ICH Consensus Guideline Q9, International Conference on Harmonisation
of Technical Requirements for Registration of Pharmaceuticals for Human Use (2005).
4. ICH, Pharmaceutical Quality System, Draft ICH Consensus Guideline Q10, International Conference on Harmonisation
of Technical Requirements for Registration of Pharmaceuticals for Human Use (2006).
5. ASTM Technical Standards on Pharmaceutical Application of Process Analytical Technology, Technical Committee E55,
www.astm.org
6. HSE, Out of Control: Why Control Systems Go Wrong and How to Prevent Failures, U.K. Health & Safety Executive
(2003).
7. FDA, Guide to Inspection of Computerised Systems in Drug Processing, Technical Report, Reference Materials and
Training Aids for Investigators (1983).
8. Pharmaceutical Inspection Co-operation Scheme, Good Practices for Computerised Systems in Regulated GxP
Environments, Pharmaceutical Inspection Convention (2003);PI 011-1.
9. GAMP Forum, GAMP Guide for Validation of Automated Systems (known as GAMP4), published by International
Society for Pharmaceutical Engineering (2001).
10. Wyrick ML, “Assessing Progress Towards Harmonisation of Validation Governance in the Global Pharmaceutical
Industry”, Business Intelligence (2000).
11. GAMP Forum, Informal Survey of Validation Costs at Public Meeting (unpublished) (2005).
12. Wingate GAS, Computer Systems Validation: Quality Assurance, Risk Management and Regulatory Compliance for
Pharmaceutical and Healthcare Companies (2004), Interpharm/CRC.
13. FDA, Process Analytical Technologies Initiative (2002).
14. ASTM, Standard Guide for Specification, Design, and Verification of Pharmaceutical and Biopharmaceutical Manufacturing
Systems and Equipment, Draft Standard E55.03.WK9864 (2006).
15. EU GMP Annex 11, Qualification and Validation, effective 2001.
16. ISPE, “Risk-Based Approach to 21 CFR, Part 11”, White Paper (December 2002), published by ISPE.

DRUG MANUFACTURING & SUPPLY 2006 3