September / October 2021

PQLI®: Advancing Innovation &

Regulation
Christine M. V. Moore, PhD, Nina S. Cauchon, PhD, Gabriella Dahlgren, PhD
Maria L. Hoffman, Maurice B. Parlane, B Tech MIT, Roger W. Quan, PhD, Wyatt
J. Roth, PhD, Eli Zavialov, PhD

A unique aspect of the pharmaceutical industry is the pairing of innovation and

regulation. For nearly two decades, ISPE’s Product Quality Lifecycle Initiative
(PQLI®) has worked at the nexus of pharmaceutical manufacturing technology and
regulation to bring forward solutions that help advance new regulatory and
technology approaches. This article summarizes the historical and current PQLI work
in realizing this mission, thus supporting medicines reaching patients around the
globe.

PQLI initiated in the early 2000s, concurrent with the advancement of the pharmaceutical quality by
design paradigm and ICH guidelines ICH Q8 on pharmaceutical development, ICH Q9 on quality risk
management, ICH Q10 on pharmaceutical quality systems, and later ICH Q11 on development and
manufacture of drug substances. The early PQLI technical teams sought to clarify how practitioners
can implement the new quality by design concepts in a way that would benefit both regulators and
industry.

PQLI teams authored several seminal papers, 1, 2, 3, 4 culminating in PQLI Good Practice
Guides5, 6, 7, 8 that include detailed illustrative examples. These articles and guides formed a solid
foundation for quality by design and have been influential for both industry and regulators to this day.

PQLI’S PROGRESSION
ISPE and PQLI have transformed through the years to stay current with emerging technology and
regulatory trends. Today’s PQLI technical teams cover a broad range of topics related to new
regulatory and technology approaches. A view of current and past PQLI teams reflecting their role in
pharmaceutical product life cycle is depicted in Figure 1. Although the topics may be diverse, each
PQLI technical team has a common mission to deliver state-of-the-art content that advances
regulatory science for pharmaceutical chemistry, manufacturing, and controls (CMC).
The current PQLI teams include Continuous Manufacturing, Transportable & Point of Care
Manufacturing, Patient Centric Specifications, ICH Q12 Implementation, and Process Validation.

Each PQLI team has its own life cycle. PQLI topics are identified through ISPE regulatory committees
and developed through small teams of subject matter experts (SMEs) who are ISPE members. The
PQLI technical teams work to understand the current landscape and to form consensus approaches
for these emerging topics, identifying the relevant regulatory and technical questions and potential
solutions.

Their findings are made available through ISPE and other conferences, ISPE white papers,
and Pharmaceutical Engineering® articles. As PQLI topics develop and fully mature, they may be
“retired” from PQLI or reshaped into a format where SMEs can more broadly share their knowledge
and experience, such as through an ISPE Community of Practice (CoP). Alternatively, a PQLI team
can evolve into a writing team for an ISPE Good Practice Guide. One such example is the recently
retired PQLI technical team on Knowledge Management, which recently published an ISPE
Knowledge Management Good Practice Guide.9

Today’s technical teams in PQLI address some of the greatest current regulatory and technical
challenges of pharmaceutical manufacturing as they strive to shape the regulatory landscape for the
successful implementation of new technology and regulatory approaches. A brief discussion of each
current PQLI topic follows.

PQLI CONTINUOUS MANUFACTURING WORKING GROUP

Continuous manufacturing (CM) is emerging as the new and next generation of pharmaceutical
manufacturing processes. The technology is amenable to helping resolve current needs within our
industry such as drug shortage, variable demand in production volume from issues such as a
pandemic, faster transfer to manufacturing, and more local or regional manufacturing. Continuous
manufacturing is supported by other advanced technologies such as process analytical technology,
modeling, real-time release testing, and continuous process verification. The draft FDA guidance on
continuous manufacturing defines continuous manufacturing as “an integrated process that consists of
a series of two or more unit operations (‘the system’). In such a process, the input material(s) are
continuously fed into and transformed within the process, and the processed output materials are
continuously removed from the system.”10
Implementation of continuous manufacturing introduces some unique challenges related to
manufacturing process controls and assurance of product quality, especially for multinational
companies that are trying to obtain global regulatory approvals without the benefit of harmonized
regulatory guidance documents. Addressing these challenges has been and still is the focus of the CM
team within PQLI.

As with any new technology, it is important that early adopters have opportunities to share their
successes as well as pain points to help expand use of the technology and close gaps. The PQLI
continuous manufacturing team has addressed these issues through biennial ISPE continuous
manufacturing workshops. The inaugural continuous manufacturing workshop in 2016 focused on the
business benefits and regulatory and technical challenges of the newly emerging technology. 11 This
workshop led to the initiation of the PQLI continuous manufacturing team. In 2018, the focus was on
small molecule API and drug product, which was the more mature platform for continuous
manufacturing at that time, with multiple products having gained regulatory approvals. The workshop
brought together regulators, industry members, and academics from across the globe. Building on the
success of the 2018 workshop, a virtual ISPE Continuous Manufacturing Workshop was held in 2020.
As a sign of the maturation and expanded use of the technology, the workshop featured two parallel
tracks for small molecules and biologics.

To ensure a broader reach beyond workshops, the team has also focused on publishing papers to
address novel elements of continuous manufacturing. Two theme issues of Pharmaceutical
Engineering® have been published. In May-June 2019, the focus was on holistic control strategy,
process validation, sampling, and regulatory progress globally. 12 The current issue13 focuses on the
progress in the past two years, highlighting the advancement of continuous manufacturing for
biologics, the global acceptance of continuous manufacturing, development and validation of a
continuous manufacturing process, and summary of the work that is being done within ISPE in support
of continuous manufacturing equipment development.

With the progression of ICH Q13 Continuous Manufacturing of Drug Substance and Drug
Products,14 there will be opportunities for the PQLI continuous manufacturing Working Group to
comment on the draft guidance document and to generate working products to support the successful
implementation of the guide-line across our industry and around the world.
PQLI TRANSPORTABLE AND POINT OF CARE (POC) WORKING

GROUP
Transportable and point of care manufacturing is the subject of the newest PQLI technical team; it is
emerging as an enabler for speed to market by providing decentralized manufacturing and distribution
closer to the patient. See Table 1 for different types of mobile manufacturing and the applications they
support.

Process intensification creates opportunities for facilities with a smaller footprint that can be replicated
cost-effectively, reducing supply risk through redundancy and allowing flexibility to respond to changes
in market demand. Mobile manufacturing affords the opportunity to change the regulatory pathway in a
science- and risk-based manner. The potential for portable manufacturing is immense with possible
manufacturing applications for small molecule, biotechnology, and cell and gene therapy products,
especially if utilizing smaller equipment such as with continuous manufacturing. Regulatory flexibility
and speed can be achieved with strong collaboration between industry and regulators, as shown
during the COVID-19 pandemic. The question for mobile manufacturing then becomes: can elements
from this experience become part of the normal business process?

Risks to product quality for transportable manufacturing tend to be lower than traditional site changes
due to the sameness or similarity of equipment and scale. Two scenarios are envisioned that avoid
traditional scale-up and technology transfer issues: (a) the same transportable unit can be relocated
from one location to another, and (b) the transportable unit can be replicated or cloned using the same
design and equipment. However, in many regions the regulatory framework is not in place to provide
benefit from the lowered risk related to transportable manufacturing. The lack of regulatory framework
leads to unique challenges, especially for multinational companies that are trying to obtain global
regulatory approvals without the benefit of harmonized regulatory guidance documents. Addressing
these opportunities and challenges is the focus of the Transportable and POC team.

The adoption of new technology must start with a level of understanding of the benefits and challenges
that exist with implementation. To that end, the team will introduce the different types of mobile
manufacturing and drive an understanding of the technical, quality, and regulatory aspects of the
technology at various forums.

Table 1: Types of modular, mobile, and point of care manufacturing configurations.

Manufacturing Type Volume Supported Applications
Clinical
Portable on-demand modular cleanrooms
Low to moderate Commercial
(PODs)
Lab
Clinical
Manufacturing trailers Low Lab
Some commercial
Clinical
Portable skid Low to moderate
Commercial
Clinical
Suitcase manufacturing Single dose
Commercial

PQLI ICH Q12 WORKING GROUP

ISPE PQLI ICH Q12 Working Group was formed in 2019 with the focus on supporting the adoption of
ICH Q12 guideline on pharmaceutical product life cycle management 15 by regulatory agencies and
enabling the implementation of the ICH Q12 principles by pharmaceutical and biopharmaceutical
companies. ICH Q12 is a transformational guideline that has a wide scope of applicability. ICH Q12
builds on the framework laid down in ICH Q8–Q11 guidelines and has the potential to remediate key
remaining technical and regulatory hurdles that prevented the full adoption and implementation of
flexible science- and risk-based approaches to postapproval CMC change management.

The progress to date on implementation of ICH Q12 has been slow. ICH is currently completing the
preparation of training materials and is planning the initiation of a training program in fall 2021. The
EMA published a note on EU implementation of ICH Q12 in March 2020, 16 while the FDA was
expected to issue its ICH Q12 implementation guidance in May 2021. 17 Many other global health
authorities such as Japan, Brazil, Canada, and China have discussed similar plans for issuing
guidance for implementation of ICH Q12 in the next year or two.

Among the ISPE PQLI ICH Q12 Working Group’s recent accomplishments was a feature article in
ISPE’s Pharmaceutical Engineering May-June 2020 issue that discussed key aspects of ICH Q12 and
highlighted major changes from Step 2 (draft) to Step 4 (final) guideline document. 18 The working
group has also played a leading role in organizing ICH Q12–focused sessions at conferences and
workshops featuring a diverse group of speakers from both the biopharmaceutical industry and
regulatory agencies at the 2020 ISPE Biopharmaceutical Manufacturing Conference, 2020 ISPE
Annual Meeting & Expo, and 2021 FDA-Xavier PharmaLink conference. Some of the key themes that
emerged from these meetings included the importance of robust criticality assessments and the
effective communication of their results and data to regulators in support of proposed established
conditions (ECs); a wide variety of terminology and approaches used by the applicants and the need
for greater alignment in this area; and a better understanding of what constitutes a robust
pharmaceutical quality system and how it should be conveyed to regulators. Significant interest arose
around key lessons learned from the recent FDA Pilot on Established Conditions and how the FDA
plans to implement ECs and product life cycle management (PLCM) documentation in the future.
Some of these questions and concerns have been addressed in the recently published FDA draft
guidance on ICH Q12 implementation.17

Going forward, the working group plans to continue its efforts to drive global ICH Q12 adoption, define
key opportunities and challenges with Q12 implementation, and develop examples and trainings that
help improve the understanding of the key guideline principles. ICH Q12 is a complex guide-line with
novel tools and approaches, some of which are currently not fully compatible with the existing legal
frameworks in certain markets. Therefore, for the full potential of ICH Q12 to be realized, it is critical to
foster a robust global dialogue around current implementation challenges and to share the best
implementation practices. To achieve its ambitious mission, the working group seeks to expand its
partnerships with other cross-industry groups, including those under ISPE PQLI initiative, as well as
ICH and other global regulatory bodies.

PQLI PATIENT CENTRIC SPECIFICATIONS WORKING GROUP

Patient-centric specifications are those focused on delivering a quality product based on patient
needs. Historically, regulatory agencies evaluated a marketing application’s proposed manufacturing,
drug substance, and drug product specifications by relying on the developmental work and the clinical
batch history. The challenge is that often there are only a few clinical lots, especially if the marketing
application was submitted under an accelerated developmental program. Limiting the evaluation
criteria to the clinical batches does not take into consideration the process understanding or prior
knowledge from similar products, animal studies, publications, and process controls/attributes risk that
are also relevant to the product quality.

In the past three years, this PQLI team has been involved with sharing the patient-centric
specifications topic in different conferences and forums. 19 The feedback from the presentations has
been very positive from the pharmaceutical community and the regulatory attendees. Pharmaceutical
company representatives acknowledge that they have all faced the same challenges to obtain a
globally accepted specification approach, which has resulted in complexity within the pharmaceutical
companies’ regulatory and operations groups to support the divergent marketing application details.
The FDA has also acknowledged that a patient-centric specification approach is acceptable. In fact,
the FDA has created an internal procedure document for their assessors to drive a more consistent
approach in determining approvability of specifications and controls based on all of the relevant data
and not just on the manufacturing history 20 However, the team fully recognizes that to be successful,
patient-centric approaches need to be adopted worldwide.

As the team looks to continue the conversations about this topic, they are focused on three goals. The
first goal is to host an ISPE webinar to broaden exposure to the topic to ex-US regulatory agencies. An
FDA representative will also be among the speakers to provide the regulators’ perspective. Second,
the team plans to publish a discussion paper in support of changing the ICH Q6A/B documents’
language to be consistent with the patient-centric specification approach. Part of the confusion about
appropriate specifications can be attributed to the current language in both ICH Q6A and
6B,21, 22 which are now over 20 years old. Some of the text is conflicting even within the guidance
documents when viewed from a patient-centric perspective. In contrast, more recent ICH guidelines,
such as ICH M7 on mutagenic impurities and ICH M9 on biowaivers, have elements that are
consistent with patient-centric specification setting. Finally, the team is looking to continue to advance
the topic through publications. The PQLI Working Group published a paper for small molecule
considerations of patient-centric quality standards 23 and is working on a paper specific to biologic
specification setting. Even though new biological entities are more complex than their small molecule
new chemical entities, there are still opportunities to support a patient-centric approach in the biologics
marketing applications.

PQLI PROCESS VALIDATION WORKING GROUP

The Process Validation (PV) Working Group is the most mature of the PQLI teams; it was founded
about 10 years ago and remains very active. The process validation team is focused on the practical
implementation of life cycle approaches to process validation. Because of its broad nature, process
validation has natural linkages to many other PQLI and ISPE topics under development.

Initially, the team was focused on understanding challenges in practical implementation of process
validation to the product life cycle arising out of the regulatory guidance such as the FDA’s 2011
Process Validation guide.24 Questions addressed included use of statistics, implementation of control
strategy, planning and management of continued/ongoing process verification, application of process
validation to legacy products, and techniques to determine the number of batched required for process
performance qualification (PPQ).

The process validation team has been active in presenting best practices from ISPE member
organizations, hosting work groups and discussions on challenging topics, and disseminating
information through published articles and presentations. The team has published nine discussion
papers over the past decade covering a wide range of process validation-related topics, including
“Stage 3 Process Validation: Applying Continued Process Verification Expectations”; “Lifecycle
Approach to Biotech Process Validation”; “Implementing Lifecycle Validation Practices at Contract
Manufacturing Organizations”; “Determining Number of Process Performance Qualification Batches
Using Statistical Tools”; and “Process Validation in Context of Small Molecule DS and DP Continuous
Manufacturing Processes.”25 These discussion papers are provided free to ISPE members.

The process validation team regularly holds sessions at the ISPE Annual Meeting on process
validation-related topics. Additionally, the team has conducted five well-attended stand-alone process
validation workshops between 2012 and 2019, where both industry SMEs and regulators shared their
experience on this subject. Despite process validation being a more mature topic, there is still
enormous demand for some of the original concepts developed by the team, especially in a webinar
format. Members of the process validation team developed ISPE’s Process Validation Training course
and have contributed to many regulatory and affiliate conferences around the world. ISPE instructors
have also provided multiple trainings to regulators worldwide on process validation topics.
In 2019, a subgroup of the process validation team authored ISPE’s Process Validation Good Practice
Guide.26 This guide built on the work of the team and contains practical guidance covering all three
stages of the process validation life cycle as it is interpreted worldwide. It discusses process validation
in the US and EU and in emerging markets such as Asia Pacific and other parts of the world. The
guide contains six detailed appendices covering case studies and application of statistical techniques
to process validation.

The process validation team is still very active, with 50 members that meet monthly. The team
continues to work on evolving new process validation content and delivering knowledge. Topics of
current interest include applying science- and risk-based thinking to emerging process validation
challenges for new modalities such as cell and gene therapy, products under accelerated
development, and continuous verification.

CONCLUSION
Although much has changed since PQLI was initiated, one constant is the ability of PQLI technical
teams to advance new regulatory approaches based on current science and technology. The life cycle
aspect of PQLI covers not only pharmaceutical product life cycle, but also the life cycle for the
technical teams themselves. New topics are added to PQLI as they emerge and sunsetted as they
mature into standard practice. The chairs of PQLI and the team leads welcome ideas for new topics
and nominations of experts who are ISPE members and willing to contribute to technical teams. ISPE
members with deep subject matter expertise should contact [email protected] if interested in
participating in PQLI teams as contributors.

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ABOUT THE AUTHORS

Christine M. V. Moore, PhD

Global Head and Executive Director, GRACS CMC Policy
Merck & Co, Inc.
Dr. Christine Moore is Global Head and Executive Director, GRACS CMC – Policy at Merck. Christine
joined Merck after more than a decade in various...
More

Nina S. Cauchon, PhD

Director Regulatory Affairs - CMC
Amgen Inc.
Nina S. Cauchon, PhD is Director Regulatory Affairs CMC at Amgen Inc in Thousand Oaks, CA, and
leads RA-CMC Advocacy and External Engagement. She has...
More

Gabriella Dahlgren, PhD

Senior Manager, Strategy Deployment and Excellence, PQM
Janssen Supply Group LLC
Gabriella has been part of the Global Janssen Product Quality organization since 2015 leading the
development of new procedures and processes to support PAT, Real...
More

Maria L. Hoffman
Executive Director, Engineering
Merck & Co., Inc.
Maria Hoffman is the Advanced Manufacturing Technology Head and Executive Director, Small
Molecule Science and Technology at Merck. Maria has held various positions within Merck...
More

Maurice B. Parlane, B Tech MIT

Principal/Director
New Wayz Consulting Ltd/CBE Pty Ltd
Maurice Parlane is Principal of New Wayz Consulting Ltd in New Zealand and a Director of CBE Pty
Ltd in Australia. He is a professional...
More

Roger W. Quan, PhD

Regulatory Affairs Consultant
Regtel Consulting LLC
Roger Quan, PhD, is a Regulatory Affairs Consultant for Regtel Consulting, LLC. Last year, Roger left
Abbott/AbbVie after a 20-year career that included stints in...
More

Wyatt J. Roth, PhD

Director
Eli Lilly & Co.
Wyatt Roth is a director within the Small Molecule Design and Development organization at Eli Lilly
and Company, Indianapolis, IN. He received B.S. degrees in...
More

Eli Zavialov, PhD

Scientific Director
Johnson & Johnson
Eli Zavialov, PhD, is Scientific Director, Regulatory CMC Dossier Development and Operations, at
Johnson & Johnson. Eli joined J&J in 2011, where he made significant...
More

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