Features | March / April 2021

The History & Future of Validation

By Anthony J. Margetts, Ph.D., Line Lundsberg-Nielsen, PhD

Across every industry today, digitalization is driving the use and value
of data to disrupt traditional business models and ways of working. In
pharmaceuticals, the promises of Industry 4.0 are expected, and
needed, to nally modernize the legacy approaches that have
evolved since the 1970s. Validation is an obvious target for digital
disruption because of the ine cient, document-heavy methods in
place and the huge costs and time wasted, and because it is a barrier
to e cient and e ective technologies that can advance safer and
better quality products. This article re ects on the history of validation
and anticipated future directions.

The lead author of this account has used personal experiences to help tell the story. For this
reason, the article uses the rst person in parts of the narrative.

THE FIRST 50 YEARS

This history begins with the perspective of a leading gure in validation, James Agalloco, who just
achieved a great milestone: four decades of being involved with ISPE. He has stated that the
origins of validation in our industry can be traced to terminal sterilization process failures in the
early 1970s.1 One case was the 1971 Devonport incident, in which a batch of 5% dextrose IV
bottles that were not correctly sterilized reached the market and were administered to patients.
Sadly, ve patients at a Devonport, England, hospital died after receiving the contaminated
solution.2 I knew the manager involved, and such tragedies refocused everyone in the industry
on the fundamental importance of the safety of our drug manufacturing processes.

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The rst UK “Orange Guide,” titled “Guide to Good Pharmaceutical Manufacturing Practice,” was
published in 1971. The edition released in 1983 included wording on validation. Today, the UK
Orange Guide covers EU GMP, rather than British GMP.3 Such international e orts have
encouraged the standardization of regulations.

In the US, the GMPs for drugs (21 CFR Parts 210 and 211) and medical devices (21 CFR Part 820)
were rst published in 1978 and, like the Orange Guide, included validation as a central term in
1983. Current versions of the GMPs are available from the US FDA website.4

At the Parenteral Drug Association Annual Meeting in 1980, Ed Fry of the US FDA gave a talk
titled “What We See That Makes Us Nervous,” in which he expressed the need to improve
pharmaceutical manufacturing processes. The FDA recognized that processes were not robust,
and throughout the 1980s, the regulators considered how to make companies more e ectively
validate their processes and published a series of seminal guidance documents, such as the 1983
guide to inspection of computerized systems in drug processing.5 The FDA’s discussions
included concepts of scienti c understanding based on process development. Despite these
discussions, when the FDA published “Guidance for Industry: Process Validation: General
Principles and Practices” in 1987, the guidelines did not mention the design of the process.6

In 1984, however, Ken Chapman published a paper about process validation,7 which introduced
the life-cycle concept and explained that the ability to successfully validate commercial
manufacture depends on knowledge from process development. Chapman was also very active
in the early days of computer validation, and he developed the idea that a computerized system
consists of software, hardware, operating procedures, people, and equipment—and sits in an
operational environment that has to be managed. This model is very important and relevant
today.

In 1987, with increased understanding that computer systems were being used in manufacturing,
the US FDA sent four inspectors to a master of science program in applied computing at the
University of Georgia, Athens. In 1991, an FDA inspector visited Glaxo and Imperial Chemical
Industries Pharmaceuticals manufacturing sites in the UK and Italy and, for the rst time, the
regulators raised concerns about the lack of validation of computer systems. These inspections
led to the formation of the GAMP® Community of Practice to develop an industry-wide response
to meet the US FDA’s expectations. (For a history of GAMP, see reference.8 )

Table 1: Stages in US and EU guidance on the process validation life cycle.

Stage US EU

Pharmaceutical development or process design

1 Process design
(ICH Q8)

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 Stage US EU

2 Process quali cation (PQ) Quali cation and validation

Quali cation (Annex 15)

Quali cation of equipment and Installation quali cation (IQ)
2.1
utilities Operational quali cation (OQ)
Performance quali cation (PQ)

Process validation (PV)

Process performance Traditional
2.2
quali cation (PPQ) Continuous process veri cation (CPV)
Hybrid

Continued process veri cation

3 Ongoing process veri cation (OPV)
(CPV)

In the early 1990s, the FDA launched their preapproval inspections to a rm that commercial
materials had their basis in the pivotal clinical trial process and materials. I had the experience of
witnessing an inspector stop an audit because we could not demonstrate that the process being
operated was the one used for the clinical trials. In the same inspection, the inspector asked
speci cally for validation plans and validation summary reports, now considered a central
element of the quality system needed for manufacture of drug products.

A sequence of FDA investigations of Barr Laboratories that started in 1989 became a huge
problem for the company, as inspectors repeatedly ob-served Barr’s failure to follow cGMPs while
the company disputed those ndings. Ultimately, the con ict landed in the US District Court of
New Jersey. In the 1993 case, United States v. Barr Laboratories, Inc., Judge Alfred Wolin
declared that process validation is required by GMPs.9

In 2004, the FDA published “Pharmaceutical cGMPS for the 21st Century—A Risk-Based
Approach.”10 This included a reference to the revised compliance policy guide (CPG) for process
validation.11 Then, in 2011, 30 years after Ed Fry raised concerns and 25 years after Ken Chapman
published his paper, the FDA published “Guidance for Industry: Process Validation: General
Principles and Practice.”12 In this guidance, the FDA adopted a life-cycle approach, moving from
process quali cation to validation in three stages, Stage 1: Process Design, Stage 2: Process
Quali cation, and Stage 3: Continued Process Veri cation.

Between 2005 and 2009, the International Council on Harmonisation (ICH) produced a series of
quality guidelines emphasizing the importance of pharmaceutical development, the life cycle, and
the framework of quality risk management:13

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 ICH Q8 Pharmaceutical Development (2005; minor updates 2009)
ICH Q9 Quality Risk Management (2005)
ICH Q10 Pharmaceutical Quality System (2008)

Among the ICH quality guidelines, Q6 (1999), Q7 (2000), Q9, and Q10 speci cally require
assessment and approval of suppliers. Use of approved suppliers is an important part of the
quality process. Q7 covers the life-cycle approach for active pharmaceutical ingredients.

In 2007, the American Society for Testing and Materials (ASTM) with ISPE involvement published
standard ASTM E2500, Speci cation, Design, and Veri cation of Pharmaceutical and
Biopharmaceutical Manufacturing Systems and Equipment.14 This introduced a risk-based
approach to quali cation of unit operations in GMP manufacturing that leverages engineering
activities to reduce quali cation risk.

In 2015, Annex 15: Quali cation & Validation was published as part of the EU Guidelines for Good
Manufacturing Practice for Medicinal Products for Human and Veterinary Use.15 The next year,
the EMA published two process validation guidelines.16 ,17 These guidelines used a similar life-
cycle approach to the one used by the FDA; however, staging terminology varies (see Table 1).

In FDA guidance, activities covered by “continued process veri cation” include routine monitoring
of process parameters, trending of data, change control, retraining, and corrective and preventive
actions (CAPA). In EMA de nitions, “continuous process veri cation” operates in place of process
validation.

At the same time that regulatory authorities were producing guidelines and standards, the
pharma industry and others introduced many improvement initiatives, including operational
excellence, lean manufacturing, and Six Sigma. Around the world, companies outside of pharma
adopted ISO 9000 quality management standards18 as a basis for their quality system
improvements, and they could see the bene ts in the supply chains. Some companies could see
the bene t of understanding the process as part of validation, but this was in complete contrast to
many pharmaceutical companies around the world. In the pharma industry, most did not see
process validation as a bene t. Instead, they saw only a necessity to perform three consecutive
process validation batches and document that performance.

Throughout the early decades of validation history, I watched the battles between regulatory
teams trying to get processes registered with as much information as possible, and production
teams that did not want to be too speci c because they knew that they might fail in process
validation, or later during commercial manufacturing. Much of the resistance to speci city
stemmed from the burden of ling regulatory variances for what should be minor process
changes operating as part of continuous improvement.

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Since the new millennium, with the help of the FDA process analytical technology (PAT) initiative
and ICH, more of us in the pharma industry have realized the importance of process
development, risk assessment, and process understanding, and have come to understand that
allowable limits for critical quality attributes (CQAs) and critical process parameters (CPPs) can
establish a rational validation framework to help manufacture safe and e ective products reliably.

In the era of science-based process validation and personalized medicine, the number of process
performance quali cation or process validation (PPQ/PV) batches must be justi ed for small
molecules, large molecules, and advanced therapy medicinal products. We now realize that these
processes require real-time monitoring of each batch to maintain them in a state of control.
Fortunately, the EMA has stated that continuous process veri cation may provide a practicable
method of managing batch-to-batch consistency, quality assurance, and quality control.16

ISPE’S CONTRIBUTIONS
No history of validation can overlook the signi cance of ISPE’s role in establishing GAMP and
commissioning and quali cation (C&Q) concepts.

GAMP
GAMP introduced a number of concepts that are important in validation today:

The life-cycle model concept, which is now seen as fundamental for process validation.
The expectation to see validation activity de ned upfront in validation plans and closed o by
formally signed validation reports produced by the regulated company.
The concept of the user requirement speci cation (URS) as a basis of quali cation. This was
developed further by ASTM E250014 and by the ISPE commissioning and quali cation guide.19
The concept of using approved suppliers, introduced in 1994.
The concept of risk assessment, introduced in 2001.
The V model to link speci cations to veri cation, introduced in 1994. At that time, some
companies wrote installation quali cation (IQ) and operational quali cation (OQ) documents
that did not refer to any speci cations. This link between speci cations and veri cation is an
important part of validation today.
Key terms to help to focus risk assessment, including patient safety, product quality, and data
integrity. In 2017, GAMP published an important guide dealing with data integrity,20 which is a
fundamental part of process validation.

C&Q Concepts
The ISPE Baseline Guide Vol. 5: Commissioning and Quali cation, originally published in 2001,
was revised in 2019.19 The

guide describes how systems are commissioned and critical aspects (CAs) and critical design
elements (CDEs) are quali ed. Critical aspects and critical design elements are linked to QCAs

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and CPPs. Facilities, equipment, and systems supporting processes should be quali ed using
these concepts to reduce the burden of non-quality-impacting documentation, and repeat testing,
which were notable in the past.

Key aspects of C&Q include:

Commissioning is executed and documented as Good Engineering Practice (GEP).21

Good engineering practice veri es that the URS requirements are all incorporated, have been
approved in the design review, and have been tested and documented as working in the
acceptance and release report or quali cation report.
In good engineering practice, everything is tested to ensure the system is t-for-purpose.
Systems are 100% (GEP) tested during commissioning, with approximately 10% of testing
focused on the CAs/CDEs for quali cation.
The focus for quali cation is on robust testing and documentation of the CAs/CDEs as
appropriate to the level of risk controls applied.
Lists of tests, test scripts, acceptance criteria, and traceability are all covered by Good
engineering practice.
Computer systems controlling equipment are quali ed with the equipment.
The commissioning and quali cation guide is clear that quality does not approve
commissioning documents. The guide notes that quality will approve the commissioning and
quali cation plan and the acceptance and release report.
Typically, major pharmaceutical companies cover all the engineering associated with a new
project in one commissioning and quali cation plan and in the nal acceptance and release
report, so the role of quality assurance is limited to approval of these documents and the use
of approved subject matter experts who oversee the quali cation work.
Much of the quali cation supporting data can be provided by approved suppliers. The supplier
assessment is an important step to deciding the validation strategy, and the validation plan
should refer to the use of supplier quali cation practices as much as possible.

LOOKING FORWARD
The following are important to incorporate into the proposed new “Validation 4.0” framework that
will enable Industry 4.0 changes in the pharmaceutical industry.

Leveraging the Product Life Cycle

The life-cycle model concept builds on the importance of data from pharmaceutical development
as a fundamental for process validation. Requirements are an output from development and
needed as a baseline for everything—including processes, facilities, utilities, systems, and
equipment—to de ne the CQAs, CPPs, CAs, and CDEs so that these can be veri ed later.
Requirements can be handled as processes and more clearly understood by describing them
using illustrative process maps. Processes are further detailed using data maps showing the ow
and relevance of information at each step and activity across the end-to-end product life cycle.

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Risk Assessment and Controls at Design
This part of the Validation 4.0 framework focuses on aspects of the process or system that are
important to patient safety, product quality, and data integrity, and it allows the validation e ort to
be focused on critical areas.

Process and data maps are used to better understand the risks to the process, and the risks to
data. Risk assessment and controls analysis should be started as early as possible during process
and system development and speci cation. The control strategy is an important part of the
design, and doing this work early allows for generation of suitable options that lower risk and a
clear identi cation of the data that must be measured to ensure the state of control. Risk
assessment can be used to evaluate data integrity to show where controls are needed to ensure
that processes are operating correctly.

Data-Driven Process Validation

As noted previously in Table 1, the US FDA’s structure for process validation has three stages:

Stage 1 is the essential link to the development stage, covering process design and
establishing the control strategy. It also includes the design of equipment and automation
systems, assessment of input material attributes, process dynamics and variability, and
development of strategies for process monitoring and control.
Stage 2 has two parts: Stage 2.1, quali cation of the equipment, utilities, and facility,
demonstrates the equipment and systems work as intended. Stage 2.2 demonstrates the
robustness of the manufacturing process and the adequacy of the control strategy (i.e.,
veri cation of the control strategy).
Stage 3, continued process veri cation, provides continual assurance that the process remains
in a state of control during commercial manufacture.

Annex 15 of the Pharmaceutical Inspection Convention/Pharmaceutical Inspection Co-Operation

Scheme (PIC/S) GMP guide22 describes the requirements for process validation in some detail
and includes the points described earlier from US regulations. The PIC/S guide also states that for
products developed by a quality by design approach, where it has been scienti cally established
during development that the control strategy provides a high degree of quality assurance,
continuous process veri cation can be used as an alternative to traditional process validation.

CONCLUSION
Validation is here to stay—it is an integral part of regulatory requirements and of the
manufacturing component of the healthcare environment. The added value of validation must be
to demonstrate that the manufacturing system is t for the intended use, and that the control
strategy clearly reduces the risk to patient safety. Also, validation in itself should not be a barrier
to innovation.

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Continuous process veri cation is a key target for Validation 4.0. We need to develop methods
that encompass the continuous monitoring of data, from the process and the risks to the control
strategy, to ensure our processes are always valid. By building in feedback to the process, we
enable a control model that can develop and respond to change, and we can monitor processes
in real-time.

Because parts of the model may change during operation, monitoring of the process and risks is
necessary and will ensure that we constantly learn more about the process as it becomes mature
through the product life cycle. Establishing this concept early and systemizing it in tools is
expected to be an e ective way to move toward the application of digital twins. A digital twin is a
replica of an intended or operating process, which can be used to plan and analyze the process
and understand the e ect of design and proposed changes.

A stated goal of Validation 4.0 is to potentially eliminate Stage 2 of process validation (veri cation
of the control strategy by testing). By bringing R&D and Stage 3 operations closer together and
moving to continuous veri cation from real-time data, we can speed up the validation process,
keep up with innovation in the new digital world, and reduce risks to patient safety.

Available in Russian

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ABOUT THE AUTHORS

Anthony J. Margetts, Ph.D.

Principal Consultant

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 Factorytalk Co., Ltd.
Dr. Anthony Margetts is Principle Consultant for Factorytalk’s Compliance department and a
highly experienced and leading international Pharmaceutical and Chemical engineering
practitioner and project manager...

Line Lundsberg-Nielsen, PhD

Managing Consultant, Compliance Consulting
NNE
Line is a physicist and holds a Ph.D. in PAT. Her background is pharmaceutical manufacturing
and development, and she is passionate about the Control Strategy...

REFERENCES

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2 Dabin, K. “Remembering the Devonport Incident–50 Years On.” Science Museum (blog). Published 20 September
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https://journal.pda.org/content/56/3/137
3 Medicines Complete. “The Orange Guide.” Royal Pharmaceutical Society. Accessed 8 January 2021.
https://about.medicinescomplete.com/publication/the-orange-guide
4 US Food and Drug Administration. “Current Good Manufacturing Practices for Finished Pharmaceuticals.” Code of
Federal Regulations. Title 21, Chapter 1, Part 211.
https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=211
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compliance.org/ les/guidemgr/ucm074869.pdf
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May 1987. https://www.fda.gov/ les/drugs/published/Process-Validation--General-Principles-and-Practices.pdf
7 Chapman, K. “The PAR Approach to Process Validation.” Pharmaceutical Technology 8, no. 12 (1984): 22–36.
8 Clark, C., and S. Wyn. “The GAMP® Community Celebrates 21 Years.” Pharmaceutical Engineering 33, no. 4
(July/August 2013): 94–95, 97.
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https://law.justia.com/cases/federal/district-courts/FSupp/812/458/1762275
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September 2004. https://www.fda.gov/media/77391/download
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Active Pharmaceutical Ingredients Subject to Pre-Market Approval.” March 2004. https://www.fda.gov/regulatory-
information/search-fda-guidance-documents/cpg-sec-490100-process-validation-requirements-drug-products-and-
active-pharmaceutical-ingredients
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13 International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. “ICH
Quality Guidelines.” Accessed 8 January 2021. https://www.ich.org/page/quality-guidelines

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 ab
14 ASTM International. ASTM E2500-07: Standard Guide for Speci cation, Design, and Veri cation of
Pharmaceutical and Biopharmaceutical Manufacturing Systems and Equipment. West Conshohocken, PA: ASTM
International, 2007. doi:10.1520/E2500-07
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Human and Veterinary Use. Annex 15: Quali cation & Validation.” March 2015.
https://ec.europa.eu/health/sites/health/ les/ les/eudralex/vol-4/2015-10_annex15.pdf
ab
16 European Medicines Agency. “EMA Guideline on Process Validation for Finished Products—Information and
Data to Be Provided in Regulatory Submissions.” November 2016.
https://www.ema.europa.eu/en/documents/scienti c-guideline/guideline-process-validation- nished-products-
information-data-be-provided-regulatory-submissions_en.pdf>
17 European Medicines Agency. “Process Validation for the Manufacture of Biotechnology-Derived Active Substances
and Data to Be Provided in the Regulatory Submission.” November 2016.
https://www.ema.europa.eu/en/documents/scienti c-guideline/guideline-process-validation-manufacture-
biotechnology-derived-active-substances-data-be-provided_en.pdf
18 International Organization for Standardization. “ISO 9000 Family: Quality Management.” Accessed 8 January 2021.
https://www.iso.org/iso-9001-quality-management.html
ab
19 International Society for Pharmaceutical Engineering. ISPE Baseline Guide, vol. 5. Commissioning and
Quali cation, 2nd ed. North Bethesda, MD: International Society for Pharmaceutical Engineering, 2019.
20 International Society for Pharmaceutical Engineering. ISPE GAMP® Guide Records & Data Integrity. North Bethesda,
MD: International Society for Pharmaceutical Engineering, 2017.
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Bethesda, MD: International Society for Pharmaceutical Engineering, 2008.
22 Pharmaceutical Inspection Convention/Pharmaceutical Inspection Co-Operation Scheme (PIC/S). “Guide to Good
Manufacturing Practice for Medicinal Products Annexes.” July 2018. https://picscheme.org/docview/1946
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