Pedro E. Hernandez-Abad Jun Huang Saly Romero-Torres
Associate Director, Wyeth Principal PAT Scientist II, Wyeth Principal PAT Scientist, Wyeth
QbD and PAT:
From Science to Compliance
Boards of health like the Food and Drug Administration and European Medicines Agency and ICH
guidelines Q8, Q9 and Q10, provide a framework for Quality by Design (QbD) that fully integrates drug
substance and drug product development with the principles of Quality Risk Management (QRM),
Process Analytical Technology (PAT) and Quality Systems (QS). QbD may begin as early as drug substance
engineering and could extend to formulation and process development.
QbD combined with Process Analytical system should assure not only the product CPAC, established at the University of
Technology (PAT) tools enable process control quality, but also should guarantee integrity of Washington in 1984:
and increase the assurance that product quality the data and compliance.
attributes are achieved consistently, and/or that A consortium of Industrial, National Laboratory
manufacturing efficiencies are obtained. QbD and PAT and Government Agency Sponsors addressing
In recent years Quality by Design (QbD) QbD: “A systematic approach to development multidisciplinary challenges in Process
and Risk and Science Based Initiatives have that begins with predefined objectives Analytical Technology (PAT) and
been the topics of many meetings and and emphasises product and process Process Control through fundamental and
conferences within the pharmaceutical understanding and process control, directed academic research.
community. The new paradigm of building based on sound science and quality risk
quality into the process and product, as management.” ICH Q8(R1, 2008) PAC: “The goal of process analytical chemistry
opposed to policing quality in the final dosage is to supply quantitative and qualitative
form, is fast becoming the norm, particularly for PAT is one of the many tools or enablers of information about a chemical process.
new products in the pipeline. Scientific based QbD. PAT can be an invaluable tool through life Such information can be used not only to
quality analytical technologies are finding their cycle management. During product and process monitor and control a process, but also
way from the lab to the manufacturing line. But development it can enhance prior knowledge to optimise its efficient use of energy,
even though the science is proven, the path to and improve process understanding, help with time, and raw materials.” Callis, Illman,
implementation is not so clear. process mapping and monitoring, model Kowalski (1987).
Synthetic chemistry research and building and along with QRM, help establish a
development teams have been using QbD and design space and a control strategy. During PAT: “The Agency considers PAT to be a system
PAT principles for decades. These principles manufacturing operations PAT can help ensure for designing, analysing, and controlling
have been named differently throughout the process robustness and consistent output, as manufacturing through timely
years and have been championed by many well as enabling operational flexibility through measurements (i.e., during processing) of
different business or quality drivers. Industries adaptive process controls, based on process critical quality and performance attributes
such as food, semi-conductors, oil and many understanding, and ultimately Real Time of raw and in-process materials and
more, owe their profit and very existence to the Release (RTR) through a science/risk based processes, with the goal of ensuring final
QbD and PAT principles. approach and Quality Systems. For continual product quality.” Food and Drug
A strategy for PAT implementation in a improvement, PAT tools, such as multivariate Administration PAT Guidance (2004).
QbD environment has to be developed in order data analysis and process control systems,
to achieve the final goal of process control. The enable historical data tracking and trending Terminology
challenge is not demonstrating proof of for continual improvement and consistent The language of QbD and PAT is in constant
concept or reliability; the real challenge is patient outcome. flux. Control space to control strategy, Design
integrating PAT into a QbD system that assures Space or Normal Operating Ranges (NOR),
quality and continuous process improvement From PAC to PAT Proven Acceptable Ranges or (PAR), Experience
in a commercial manufacturing process. This PAC: Center for Process Analytical Chemistry Space, Knowledge Space, Continuous
www.europeanpharmaceuticalreview.com European Pharmaceutical Review Issue 4 2009 55
Figure 1 PAT to understand and manage raw material and process variability, and ensure final product quality
Improvement to Continual Improvement, challenges to QbD and PAT development and variability existing from raw materials,
Multivariate Data Analysis (MVDA) or implementation. processes, intermediates to final product. A
Chemometrics…and the list goes on. successfully implemented PAT system should
Practitioners should have a clear Champion, goal, value be able to:
understanding of the terminology. and opportunities 1) Identify, understand and manage the
When it comes to MVDA and Champion: QbD and PAT need Champions. sources of variability;
Chemometrics, the list of acronyms increases QbD and PAT can not be developed, 2) Establish relationship between raw
exponentially and is influenced by the software implemented and sustained as a part time material, process parameters and final
package involved and the scientist experience. effort. It has to be a serious commitment product quality attributes;
supported by management in order to achieve 3) Control raw material/processes to ensure
PAT misconceptions an effective cultural transformation. CQAs as specified.
A true PAT platform should provide timely
measurements! PAT is Dynamic, Real Time and Goal: It has to be identified, commonly Variability of a single quality attribute of
Process Based, with the capability of process accepted/acknowledged by the team, and in-coming raw material can be represented
correction and potential open or close loop embraced by the organisation as desirable, using a normal distribution with specification
control. The latter would be the ideal scenario. achievable and realistic. Some of the previous limits, while a combination of multiple quality
Close loop process controls are old school to PAT’s unfulfilled promises are the worst attributes of raw material can be summarised
process/control engineers in other industries, obstacles to overcome. in a multivariate chart, e.g. PCA Scores plot.
but pharma industry has a long way to go. The goal of PAT development and Pharmaceutical processes are multivariate by
Spectroscopy Alone is Not PAT! Even though implementation should be aligned with the nature, with many variables impacting
spectroscopic techniques such as Raman and scope of a QbD plan. A PAT system is processes and product quality attributes.
NIRS can be part of a Holistic QbD approach, developed to measure critical process It is important to monitor and evaluate batch
they are considered chemical and physical parameters and critical quality attributes, process performance by modeling multiple
characterisation techniques when they are not understand product and process variability, variables simultaneously, instead of looking at
in a dynamic real time production environment. and thus control manufacturing processes to each variable individually. Multivariate control
Early adopter’s disappointments of new help achieve a predefined target product chart, e.g. Scores control chart, derived by
techniques, concomitant failures of profile and/or bring robustness to the process. multivariate statistical process control (MSPC),
implementation and lack of understanding of can be used to represent a process signature or
the true nature of QbD and PAT, have added The flow diagram in Figure 1 depicts the fingerprint of the process, and detect/diagnose
56 European Pharmaceutical Review Issue 4 2009
faults as the batch evolves. What is often further assessments to define the potential two scales; (1) laboratory (small) and (2)
neglected is that process trajectory of a CQA of risks, opportunities, alternatives, and commercial scale (large).
intermediate is also important. For instance, solution/recommendations for the PAT tool During the in-process application
drying too fast or too slow during the drying development and implementation. The development, the method should be optimised
process may lead to batch failure. With all assessment should be based on an outline and scientifically validated. That is, tested for
upstream variability well understood and design of system requirements in terms of the merits of a validation like: specificity,
managed, final product quality attributes can Input, Processes, Output (IPO) and Procedures. linearity, range, accuracy, precision,
then be controlled as specified. The outcome of the feasibility will be repeatability, intermediate precision,
The authors recommend that PAT confirmed by the solution of the intended use robustness, detection limit, quantitation limit,
teams are engaged early on in the of the method implementation. It is important etc. to ensure that the method is fit for
process development stages, in order to to mention that the feasibility study is purpose. The term scientifically validated, in this
understand and evaluate the critical process preferably performed in a developmental or context, refers to a validation in an R&D
parameters and quality attributes. For R&D environment. non-GMP environment in order to assess
existing products, PAT efforts could be directed Application Development may require method feasibility and appropriateness.
to processes that have shown a need for Design of Experiments (DoE). A DoE is a Method deployment at scale may still
improvement. Do not do PAT for the sake of PAT. structured, organised method for require an Application Development approach
determining the relationship between factors using DoE. Scale up and equipment changes
Value and opportunities: ROI considerations that affect the process and the output of that may be factors to consider, as well as commercial
initial cost might be high, but the cost of process. The DoE may be performed in scale supply sourcing related variability.
quality is priceless. At the end of the day, the
cost of a sensor and allied IOQ and
implementation will be justified by the first
batch saved or recall averted. Build a business
case, do the maths and take it upstairs. If there
is not a champion, ask for one! Again, do not do
PAT for the sake of PAT.
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Monitoring: The method validation in a working. No more Quality by Inspection! A QbD systems approach to QbD that is being
cGMP compliant environment usually takes culture will require champions, trainers and implemented for all new products across the
place during the monitoring stage. educators and empowered operators, manufacturing divisions, aligned with R&D as
Plant site quality systems may impact PAT supervisors, engineers, IT/S and quality personnel. part of a holistic QbD approach.
deployment and monitoring even under “Safe It is everyone’s responsibility to get on board.
Harbor” when monitoring data will not have an New SOPs, guides and skill sets will be Regulatory Aspects
impact on commercial, clinical or development required. The mindset has to change from a Early communication with the Boards of Health
batch disposition. culture of fixed unalterable processes, to (BOH) and engaging them as partners in this
For Implementation, an Implementation adaptive process controls, science and risk new paradigm is key to successful
Team and a Validation Team should be based processes and regulatory flexibility. implementation. In the end, no surprises, better
assembled to categorise the implementation Many technical business units have to be understanding and co-development are all
and validation requirements and propose engaged in the process. Engineering, critical components to positive outcomes.
acceptance criteria for each stage, based on the information technology, physical
application or intended use of the PAT Tool and characterisation and statistics teams (to Utilisation of PAT in process control
method. The intended use of each could be mention a few) should be incorporated in the and continual improvement
established during the DoE developed for PAT groups. Again, it is everyone’s responsibility This is the final frontier! Real Time Release
the method. These requirements and criteria to get on board. (RTR), continual improvement and other
will be ultimately in a validation protocol regulatory or financial benefits may be initially
and described in the validation report. PAT at Wyeth driven by the desire of increasing quality,
The acceptance criteria must be in-line At Wyeth, QbD and PAT has been a cross decreasing cost and improving manufacturing.
with the expected specification, protocol functional and inter departmental effort across There are several ways to look at this new
requirements, development experience and business and product units. The approach has paradigm. Should we do all or most of the PAT
manufacturing practice. been to replicate successful implementation and process understanding during
strategies and technology platforms in order to development and implement manufacturing/
Cultural Change, Education and reduce learning curves, improve manufacturing engineering process controls during
Infrastructure efficiencies and harmonise technology manufacturing? Or should we identify and
QbD, QRM, PAT etc have to be understood, platforms and quality systems. implement PAT in manufacturing to control and
accepted and embraced as the new ways of Wyeth has a consistent, well-defined, optimise? The possibilities are endless, it is in
58 European Pharmaceutical Review Issue 4 2009
many ways unchartered territory and the pharmaceutical industry
and the BOH are working on a path forward.
The main challenge at this stage is the development and
deployment of the Quality Systems to support QbD and PAT in full
compliance in a GMP environment.
Pedro Hernandez-Abad is Associate Director at Wyeth Pharmaceuticals,
where he leads the QbD/PAT Team at Wyeth’s Pharmaceutical
Development Center, Pearl River NY. The PAT team supports projects
emerging out of R&D and into early Phase II development all the way to
launch. Pedro gained his PhD in synthetic organic chemistry from the
University of Pennsylvania with Prof. KC Nicolaou and completed his
postdoctoral studies at Oxford University with Prof George Fleet. Since
2005 he is part of the team responsible for PAT implementation for what
will be Wyeth’s first product seeking real time release (RTR) approval
from the FDA.
Jun Huang is Principal PAT Scientist II at Wyeth’s Pharmaceutical
Development Center, Pearl River NY. His primary responsibility is to
implement QbD/PAT in pharmaceutical development and manufacturing.
Prior to joining Wyeth, he worked at GlaxoSmithKline, PerkinElmer, and
CAMO. He received his PhD in chemometrics from the Norwegian
University of Science and Technology in Norway, 2001, with Prof. Kim
Esbensen, a M.Sc and a B.Sc from China. His experience and interests
involve chemometrics, multiple analytical techniques (NIR, Chemical
imaging, Raman, GC/LC/MS, and ICP-OES etc), and process engineering.
Saly Romero-Torres is currently working as Principal PAT Scientist at
Wyeth Pharmaceuticals. She holds a PhD in Analytical Chemistry which
she completed at Purdue University (West Lafayette, IN) in 2006. Her
dissertation title is "Raman and Chemometrics for Pharmaceutical Process
Analysis". Before joining Wyeth, she worked at Schering-Plough
Pharmaceuticals as a spectroscopist in a physical characterisation team.
At Schering Plough, she developed new spectroscopic (IR, NIR and
Raman) and chemometrics based analytical methods aimed to characterise
and understand chemical and physical attributes that were critical to the
quality of pharmaceutical materials.