Reprinted from

PHARMACEUTICAL ENGINEERING

research and development

THE OFFICIAL TECHNICAL MAGAZINE OF ISPE

SEPTEMBER/OCTOBER 2014, VOL 34, NO 5

Pharmaceutical Product Quality

Copyright ISPE 2014

www.PharmaceuticalEngineering.org

Symposium Summary Report:

The Use of Process Capability to
Ensure Pharmaceutical Product
Quality
by Daniel Y. Peng,* Richard Lostritto, Dafni Bika, Jean-Marie Geoffroy,
Thomas Shepard, Brian Eden, Kenneth Cot, Alpesh Patel,
Michael Choi, and Lawrence X. Yu*
*The views presented in this article by the authors do not necessarily
reflect those of the Food and Drug Administration.

This article presents summary report of the main points from the 28th IFPAC
Annual Meeting Process Capability Symposium.

he symposium, Use of Process Capability to Ensure Pharmaceutical Product

Quality, was held on 23 January 2014,
in Arlington, Virginia (USA) during the
28th International Forum on Process
Analytical Chemistry (IFPAC) annual
meeting.1 More than 75 participants
from worldwide innovator and generic
pharmaceutical companies, academia,
regulatory agencies, and professional societies attended this
symposium. Pharmaceutical scientists from both the innovator and generic pharmaceutical industries and the Food and
Drug Administration (FDA) presented their perspectives on
the potential applications of process capability to monitor pharmaceutical product quality. The panel discussion
provided an excellent source of information regarding the
challenges and opportunities when using process capability
indices. This summary report documents the main points
from the symposium and intended to stimulate further discussion on the use of process capability.

Opening Remarks
On behalf of symposium chair Dr. Lawrence Yu (Acting
Director, Office of Pharmaceutical Science, Center for Drug
Evaluation and Research (CDER)/FDA), Dr. Daniel Peng
delivered opening remarks. Dr. Peng began with a quotation
from H. Thomas Johnson: What you measure is what you
get. More likely, what you measure is all youll get. What
you dont (or cant) measure is lost.2 This highlights the importance of measuring the right things and measuring them
correctly. Dr. Peng emphasized that, in the past, it was usual
and customary to set acceptance criteria based on process
capability (the variability observed in the data). However,
this practice unintentionally allows manufacturers with
poor manufacturing and process controls to have products
with relatively wider acceptance criteria compared to good
manufacturing and controls with tight specifications. This
also could be one of the fundamental reasons why the pharmaceutical industry only gets 2-3 sigma since, the specification is set based on process capability.3 To break the vicious
cycle, our view may need to be fundamentally changed so
that the role of specifications is to confirm (control) product
quality rather than process robustness. Therefore, prior to

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further discussion on process capability, it is important for

all of us to understand that acceptance criteria should be independently established based on product safety and efficacy
(patients needs), not process capability.

Clinically Relevant Specifications: A

Regulatory Perspective
Dr. Richard Lostritto (Acting Deputy Director for Science
and Policy and Acting Biopharmaceutics Lead, Office of New
Drug Quality Assessment (ONDQA), CDER/FDA) discussed
the regulatory perspective on Clinically Relevant Specifications (CRSs).
Dr. Lostritto first introduced the working definitions of
some vocabulary related to CRSs:
CRS: in vitro test methods that reject batches that are
likely to exhibit inadequate clinical performance.
Adequate Clinical Drug Product Performance:
appropriate pharmacological action and safety for a given
drug, indication, route of administration, and patient
population.
Equivalent Quality: equivalence between test and reference drug products based on in vitro specifications and
bridging studies.
Bioequivalence: equivalence between test and reference drug products based on drug independent pharmacokinetic criteria (e.g., Cmax, Tmax, AUC).
Clinical Equivalence: equivalence between test and
reference drug products based on drug dependent criteria
of safety and efficacy.
The longstanding problem is that end product testing is
asked to fulfill two conditions: to serve as a quality control
tool (precise and accurate manufacture) and to serve as a
predictor of in vivo performance. In the current state, there
is often not enough focused data and knowledge on this
issue to be sure that both of these conditions are met at the
time of initial approval. Dr. Lostritto stated that This is just
an observation, not a limitation, and he suggested that with
some thoughtful modification of development programs
with CRSs in mind, this may be achievable earlier on without
a huge increase in total work.
Today, we have additional tools to help us address this
situation, such as In Vitro/In Vivo Correlation (IVIVC), In
Vitro/In Vivo Relationship (IVIVR), Biopharmaceutics Classification System (BCS), guidance documents, modeling/
prediction software, and published research findings. The
time is right to use these tools of greater mutual benefit in
developing and implementing CRSs. There are also industry,
regulatory, and professional standards, as well as societal
expectations of quality, purity, and potency, to consider that
may reasonably transcend other less sensitive factors (e.g., a
very wide therapeutic index).

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Benefits of CRSs include: 1. reject batches with likely

inadequate in vivo performance would be rejected, 2. follow
up actions after a reject are better clarified to be patient
relevant, 3. related in vitro quality standards are more likely
to have clinical relevance, and encourages meaningful innovation, and 4. post-approval changes are better linked to
meaningful product performance requirements.
Challenges to developing and implementing CRSs include: 1. an organic and multicultural resistance to change,
2. to be there at initial approval may require some shift in
development focus, and 3. uncertainty in the balance of opportunity costs to gains.
Dr. Lostritto presented four case studies to illustrate the
benefits of and challenges to setting up clinically relevant
dissolution specifications for immediate release and extended release products. He closed with a view of future developments in CRSs: 1. CRSs are needed in the modern world, 2.
the benefits of CRSs are worth investing in, 3. compartmentalizing the problem on a risk basis can facilitate progress,
4. CRSs will exploit and in turn further stimulate other
advances such as quality by design (QbD), and 5. consider
more supportive data to support CRSs at initial submission.

Use Process Capability to Ensure

Pharmaceutical Product Quality
Dr. Daniel Peng (Senior Product Quality Reviewer/QbD
Liaison, Office of Pharmaceutical Science, CDER/FDA)
gave an overview on how to use process capability to ensure
pharmaceutical product quality. Dr. Peng first introduced
the definition and calculation formula of the four process
capability indices according to the ASTM E2281 standard
guide.4 Dr. Peng then discussed the difference between
process capability indices (Cp and Cpk) and process performance indices (Pp and Ppk). Process performance indices
(Pp and Ppk) account for the overall variability in the system
and do not require the process to be in a state of statistical
control. Hence, process performance indices address how
the process has performed and cannot be used to forecast future batch failure rate. On the other hand, process
capability indices (Cp and Cpk) only account for the inherent
variability (noise) due to common cause of a stable process.
It represents the potential (theoretical) capability (i.e., how
well a given process could perform when all special causes
have been eliminated). In order to evaluate if the process
reaches a statistical control state and estimate the inherent
variability, Shewhart control charts and the eight Western
electric rules are often used.5,6 Dr. Peng then further discussed different types of control charts and used examples to
illustrate their uses in the pharmaceutical industry.
To facilitate the discussion and collect industry feedback,
Dr. Peng used questions to ask the audiences opinion on
the potential applications of these process capability indices
during the product development stage, process scale up/

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technology transfer/process qualification stage, and routine

commercial manufacture stage. The general consensus is that
process capability indices can be a powerful tool during late
stage commercialization (e.g., technology transfer, process
qualification, and routine commercial manufacture). During
the development stage, the preliminary index has its limitations due to limited batches and equipment scale. Dr. Peng
also shared a case study in which the Agency performed a
process capability analysis of eight generic products and their
Reference List Drug (RLD) of an anti-epilepsy drug product.
The batch release data of the annual stability batches (ranged
between 10 and 18 batches based on data availability) were
collected. All generic products and the RLD met current
USP quality standards. However, process capability indices
provided quantitative metrics by which to rank manufacturing process performance and help FDA focus its surveillance
efforts on the manufacture sites that had the lowest performance (especially when the Ppk 95% confidence bound
was below 1). Dr. Peng also proposed a vision that it may
be possible to use these indicators as Real-Time Quality
Surveillance tools to monitor process performancesimilar
to how credit card companies monitor abnormal transactions
nowadaysin the future with advances in IT infrastructure.

Finally, Dr. Peng summarized the advantages of the process

capability indices: 1. it considers not only the process mean
and variability, but also considers these in relation to the
specification that is established based on patient needs (safety and efficacy), 2. it is quantitative and action enabling, 3. it
can apply to cross sectors (brand, generic, OTC, and biotech
products), and 4. no additional testing is required since the
commercial batch release data are available at the manufacture site per current regulations. Hence, Dr. Peng believes
process capability indices provide a simple and powerful tool
by which to ensure product quality and process robustness
while not adding too much burden to industry to implement
the tool.

Product Robustness: Reducing Variability

and Ensuring Delivery of Superior Quality
Products to Patients

Dr. Dafni Bika (Vice President, Global Manufacturing Science and Technology, Bristol-Myers Squibb) provided an
innovator pharmaceutical company perspective on how to
use process capability indices as a tool by which to drive
operational excellence at Bristol-Myers Squibb (BMS).
Dr. Bika started the presentation by describing that
process robustness is the ability of a
process to demonstrate acceptable
quality and performance while tolerThe symposium, Use of Process Capability to Ensure Pharmaceutical
ating input variability. Then, Dr.
Product Quality, was held on 23 January 2014, in Arlington, Virginia
Bika discussed that product robustness
(USA) during the 28th International Forum on Process Analytical Chemis a holistic and comprehensive strategy
istry (IFPAC) annual meeting. This symposium provided an opportunity
at BMS that is used to ensure product
for pharmaceutical scientists to discuss the potential applications of
quality, compliance, and uninterrupted
supply. The process capability concept is
process capability indices to ensure product quality. Various presentatherefore applied across the value chain
tions from both the innovator and generic pharmaceutical industries
from raw materials to manufacturing
and the Food and Drug Administration (FDA) were included. The panel
processes and distribution to reduce varidiscussion provided an excellent source of information regarding the
ability from different sources (materials,
challenges and opportunities when using process capability indices.
equipment, methods, processes, etc).
This summary report documents the main points from this symposium:
Process robustness monitoring plans
are applied to many new, growth, and
1. clinically relevant specifications (CRSs) are needed in the modern
mature products. This is supported by
world, and are worth investing in because of their benefits, 2. process
automated data gathering and analysis
capability indices can be a powerful tool by which to ensure drug
at the growth and launch manufacturing
product quality and process robustness, 3. case studies from both the
sites with future technology implemeninnovator and generic pharmaceutical industries demonstrated that
tation planned for most sites. Product
process capability indices can be an useful tool by which to drive oprobustness and process capability analyses also have been extended to analytical
erational excellence and ensure delivery of superior product quality, 4.
methods, equipment, distribution, and
use of process capability indices should always go hand-in-hand with
selected external manufacturers. BMS
enhanced scientific understanding, and 5. some technical and culture
has updated its business processes and
challenges in implementing these tools still exist. Hence, further discusquality systems and engaged employees
sion and broadly engaging industry and other stakeholders on details
in developing the required skills and setof the implementation are still needed.
ting the expectations.

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Dr. Bika then discussed the application of process monitoring plans and data analysis (including process capability) across all stages of validation lifecycle, with emphasis
on early and routine commercial manufacturing (Stage
3).7 Product performance across the network is tracked by
leading indicators (e.g., process capability) and resulting
business outcomes such as reduction of product recalls,
batch rejections, and investigations. Dr. Bika also presented
specific process monitoring examples, robustness improvement cases, and future applications.
Dr. Bika concluded that even with some challenges that
exist, the return on investment is evident and manifests
itself every day across BMSs manufacturing network in
savings from yield and cycle time improvements, avoidance
of rejects, write offs, and time lost on investigations. It also
continues to building an engaging and proactive culture
where monitoring data and related metrics are used to anticipate and prevent manufacturing issues.

Control Charting Drives Value Creation

by Identifying Opportunities for Reducing
Product Defects and Confirming Enhanced
Performance*
*Dr. Jean-Marie Geoffroy and Thomas Shepard from Hospira were not in attendance to deliver their presentation
due to unforeseen conflicts.
Dr. Jean-Marie Geoffroy (Vice President Quality, Pharmaceutical Engineering and Analytical Services, Hospira) and
Thomas Shepard (Director of Manufacturing Science and
Technology, Hospira) prepared a case study on how control
charting drives value creation by identifying opportunities for reducing product defects and confirming enhanced
performance.
Control plan strategies for parenteral drugs and their
containment are evolving with the industrys regulatory environment. The ability to use leading indicators to predict field
performance remains our industrys best option for reducing
customer and patient risk. This case study is one example of
how mature product control plans can be developed using the
concepts of QbD and how overall quality can be improved.
The overall strategy for controls is structured to progressively monitor critical response variables that indicate the
performance and quality of the IV container. Control is
obtained by identifying critical parameters that correlate to
the overall quality of the product, then monitoring the parameters, and finally acting on changes in parameters. Each
phase of product maturity requires control planning and is
part of an overall control strategy. The phases of product
maturity are raw components, in-process preassemblies,
pre-sterile product, and finally released product. The historical performance of each phase is used to generate baseline
control parameters and limits.

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The control plan for mature products starts with the lagging variable and moves upstream to define design Critical
Quality Attributes (CQA) for the product, and progresses to
Critical Control Parameters (CPP) for the manufacture and
incorporates the component CQA. Component CPP was not
included in this study.
Phase 1: identify primary areas of field performance and
monitor for variance over time with Pareto analysis and
control charting.
Phase 2: online process inspection is trended by lot to indicate overall capability of the process to produce defect-free
containers. Defects at the form fill seal pre-sterile inspection
were identified as a leading indicator for field performance.
Phase 3: identify if average performance or product consistency is the primary driver for pre-sterile defects. Average performance of the container is defined by the design of
the device, while the degree of variability in the container is
dependent upon the overall compounded variability of the
process as measured by temperature, equipment alignment,
pressure, and component performance variability. Compounded variability was identified as a leading indicator for
pre-sterile defects.
Phase 4: identify areas of contribution to compounded
variability. Unscheduled process interruption (equipment
failure, intermittent operator intervention, process readjustment, etc.) and component dimensional variability were
identified as primary contributors to process variability.
The interrelationship between component and unscheduled
process interruption was observed when the process steady
state was disturbed by a disruption in component supply or
placement.
A continual improvement project was initiated to standardize component placement and add upstream component
dimensional monitoring at the component supplier. Implementation of the project resulted in a reduction of unscheduled process interruption. Effectiveness of the improvement
was then monitored and was substantiated by a significant
improvement in field performance. By using an integrated
control plan of leading performance variables to provide
indicators for field performance productivity, overall quality
was improved.

Process Capability Applications: Mylans

Perspective
Brian Eden (Vice President, Global Operational Excellence,
Mylan Inc. (absent due to business travel)) and Kenneth
Cot (Operational Excellence Leader, North America Technical Operations, Mylan Inc.) described the applications of

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process capability indices to drive operation excellence in

Mylan.
Cot first gave a brief summary on what industry is
hearing about process capability (Cpk/Ppk) as a tool from
worldwide regulatory guidances.7,8,9,10 Then, Cot discussed
their current status. Even though the commercial batch
manufacture data, in-process control data, and batch release
data are collected in the Annual Product Review (APR) at the
manufacture site in accordance with Current Good Manufacturing Practices (CGMPs), the raw data tend to be tabular
without statistical analysis and the full potential of the dataset is not best utilized. Hence, Cot believes it can be greatly
beneficial for industry to use statistical process control tools,
control charts, monitor and trending, and Cpk/Ppk calculations to improve drug product quality. These tools can
provide a more detailed understanding of product trends
and transform from the reactive trouble shooting paradigm
to a proactive failure reduction or prevention paradigm. Cot
also emphasized that it is important to monitor not only the
output measures (e.g., product critical quality attributes),
but also the high-risk input material attributes and process
parameters.
Cot then discussed the practical procedure of process
capability analysis in Mylan:
Collect raw data data source (Laboratory Information
Management System (LIMS) and manual collection)
Refine data filter/sort/pool with Microsoft Excel
Perform statistical analysis verify assumptions and
perform process capability analysis using Minitab16
Prepare report annotate and provide commentary
analysis for business decisions to be made using Microsoft PowerPoint
Cot then shared an oral solid dosage form Content Uniformity (CU) example to illustrate the procedures and how
these tools were used to quantitatively evaluate product
quality and identify continual improvement opportunities.
Due to non-normal distribution of the CU data, data transformation was discussed. Cot also shared process capability
analysis results of an injectable product assay (18 commercial batches between January 2011 and June 2012).
Cot closed with suggestions on how to make these initiatives more sustainable:
Standardize documentation through global directives and
annual product review templates and Standard Operating
Procedures (SOPs)
Provide education to employees and stakeholders, for
example via workshops on basic statistics, statistic software, Statistical Process Control (SPC) tools, and lean/six
sigma black belt trainings.

Process Capabilities Cp and Cpk

Generic Industry Perspective
Dr. Alpesh Patel (Vice President, Global Regulatory Affairs,
Amneal Pharmaceuticals of NY LLC) described Amneals
generic industry perspective on the current status and
practices of using process capability indices to improve drug
product quality over product lifecycle.
Dr. Patel started his presentation by quoting from
Socrates, The unexamined life is not worth living. He modified the quotation to be An unexamined
manufacturing process is not worth implementing to remind the audience how important it is to control
the process to the target with minimum variation. Then, Dr.
Patel discussed the definition in process capability indices
in layman language by using the parable of parking a car
(mean and variability) into a garage (fixed specifications) to help the audience understand the concept. Further, Dr. Patel discussed a process capability roadmap based
on Amneals current practice. To illustrate the roadmap, Dr.
Patel first shared a case study for a transdermal patch process understanding of the coating step: 1. perform initial risk
assessment to select potential high-risk process parameters,
2. conduct multivariate studies using formal experimental
design to identify critical process parameters (CPPs), 3.
optimize CPP ranges to achieve the desired product performance with minimum variability, and 4. demonstrate process robustness by using the statistical process control tools
(individual control charts, Xbar-Range charts) and process
capability analysis (Cp and Cpk). Then, Dr. Patel shared
another case study for an oral tablet compression unit operation process understanding and control by using batchto-batch tablet weight data as part of continual improvement
to demonstrate process capabilities during product lifecycle
management. Dr. Patel concluded that Process Capability indices (Cp/Cpk, Pp/Ppk) are excellent tools that can be
used during development and throughout product lifecycle
to ensure the drug product quality.

Process Capability: Understanding the

Science and the Statistics
Dr. Michael Choi (General Manager, Johnson & Johnson
HyangNam Pharmaceutical Plant, Korea) gave a presentation on how to link QbD to process capability using science
and statistic tools (e.g., process capability indices).
First, Dr. Choi gave a brief introduction on process capability and discussed the benefits and limitations of using
process capability indices in manufacturing process control.
Then, Dr. Choi shared an example case study for tablet druglayering process understanding and how science and process
capability tools can be used to improve process robustness.11 A process capability equation is derived from the first
principles for a precision tablet coating process to illustrate
the scientific and statistical relationship between the critical

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quality attribute composite assay, material attributes, and

process parameters. By isolating the true process capability from the overall process capability, the noise (from
sampling, analytical methods, etc.) can be quantified. If the
noise is a significant portion of the overall process capability, opportunities exist to improve the overall process capability by examining and reducing this noise. The true
process capability may be improved by adjusting the process
according to the mechanistic relationship.
Dr. Choi further discussed the potential applications of
process capability indices in risk assessment and control
strategy establishment. For example, process capability
indices and scientific relationships can be used to assign
objective values to the severity, probability, and detectability for failure mode and effects analysis (FMEA)-type risk
assessments. Dr. Choi concluded that the use of process capability indices should always go hand-in-hand with process
understanding. This provides a better way by which to link
QbD to process capability and yield superior product quality.

Panel Discussion
Audience: How do we establish clinical relevant specification, for example, dissolution specification, for a generic
product that generally does not have as much clinical data
as the new drug during Phase 1-3 clinical studies?

Panel: As highlighted in Dr. Lostrittos presentation, a

risk-based approach can greatly facilitate progress in this
area. For example, standard dissolution media and acceptance criteria would be appropriate for an immediate release
oral solid dosage form of a highly soluble (BCS I or III) and
non-narrow therapeutic index drug substance. On the other
hand, for some high-risk drug products (e.g., extended
release oral drug product or immediate release drug product
formulated with poorly soluble drug substance), the applicant should make every reasonable effort to develop a
dissolution test that is predictive of in vivo performance.
The applicant may use USP methods or FDA-recommended
methods as a starting point. As the applicant gains additional experience during product development (including any pilot bioavailability or bioequivalence studies), the dissolution
methods should be iteratively modified to have appropriate
discriminating power. The applicant may explore a different apparatus, media compositions, speeds, etc., to develop
the appropriate discriminating conditions. The panel also
referred to the FDA/Office of Generic Drugs Example Pharmaceutical Development Report for an immediate release
(IR) dosage form12 and modified release (MR) dosage form,13
which illustrate these principles in details.
With that said, the panel also pointed out that the dissolution approaches used today are often non-robust in that
they may be inherently over-sensitive to minor changes in

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the method which do not reflect relevant in vivo performance. For example, it is well documented in the literature
that the dissolution vessels hydrodynamics are poorly reproducible and very heterogeneous.14 Minor mechanical and
other changes in dissolution apparatus may have dramatic
effects on dissolution results. Its a persistent limitation of
current approaches that has hindered both in vitro quality
control testing and the development of clinically relevant
dissolution methods and specifications. It would be useful to develop new dissolution apparatus that are simple,
reproducible, robust, and linkable to clinical performance to
improve the antiquated vessel methodology.

Audience: Do the data have to be normally distributed to

use process capability indices?

Panel: In general, the answer is yes, since data normality is one of the three prerequisites to use process capability indices (Cp/Cpk) to estimate future batch failure rate.
However, there are some remedies when the data are not
normally distributedfor example, data transformation, distribution fit, or reference interval calculation (also known as
the percentile method). The ISO 21747 guidance document15
is cited for readers to gain further detail, as it is beyond the
scope of this paper.
The panel also highlighted that it is important to meet
another two prerequisites to use process capability indices
(Cp/Cpk) to forecast future batch failure rate: 1. sufficient
number of the subgroups is included, and 2. the process is
in a state of statistical control, which means that all special
causes have been eliminated from the systemand therefore
there are no detectable patterns or trends exhibited and the
variation observed in the data is only due to common cause
(process noise) of the system.5,6
The audience also commented that content uniformity
(acceptance value) in general is not normally distributed due
to standard deviation calculation. However, assay data are
generally normally distributed. It is good practice to graph
the raw data to see the shape of the distribution curve and
use science and product understanding to figure out if it is
outliers or any scientific reason that caused the non-normal
distribution.
The panel and audience also further discussed the drawbacks and limitations of the current USP content uniformity
test.16 Other alternative approaches may be considered, for
example the ASTM E2709 where tolerance for variability
(% RSD) is based on the sample size, confidence level, and
sample mean.17 Of course, the sampling plan is also critical
to ensure the samples taken are representative of the batch.
The panel and audience further discussed the distribution
of dissolution data. There is no general agreement about the
shape of the distribution of the dissolution data. Saccone,
et al., assumed the normal or lognormal distribution and

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gave the following rationale:18 Normal distribution is a

good model of the distribution since the amount dissolved
by each unit is a function of a large number of variables.
Lognormal distribution seems suitable to simulate a physical limit to the amount dissolved due to the amount of drug
product in the pharmaceutical dosage form.

Audience: What are the challenges in implementing process capability analysis?

Panel:
1. Many different data sources are collected manually or
through automated systems. It is quite challenging to
refine the data to be usable for process capability analysis and ensure data integrity during format change and
transformation.
2. Both technical knowledge (statistical analysis and SPC)
and cultural gaps (how to manage a change) need to be
addressed.
3. A sizable investment is needed to ensure data gathering,
analysis, and integrity (i.e., appropriate IT platforms).
4. Apart from the technical challenges and accountability,
the firms quality management systems need to be updated accordingly to drive the expectations (SOPs,
validation directives, statistic analysis manuals, procedures
for locking and updating statistic control limits, etc.)
5. It is a cross-functional effort that requires many parts of
the organization to collaborate and align (process, analytical, engineering, quality, regulatory, and procurement).

Audience: How do we evaluate within batch variability of

legacy products?

Panel: The traditional quality control tests based on the

current regulatory paradigm do not address this issue. Some
companies test 10-30 samples from each drum of a large
production batch to estimate the within batch variability.
Some companies use the assay data from different package configurations to estimate within batch variability. The
panel also mentioned that the concept of using subgroups
(samples taken and tested periodically during a large production batch manufacturing) to construct a control chart
is also applicable to evaluate the within batch variability.5,6
The control charts can then be used to evaluate whether the
process for manufacturing this batch is in a state of statistical control, and the process capability indices can be used to
evaluate whether the process for this batch is capable.
The audience also mentioned that stratified sampling of inprocess dosage units based on the Product Quality Research
Institutes (PQRIs) blending uniformity working group
recommendation is an alternative way by which to estimate
the within batch variability.19

Audience: Does the generic industry also need to adopt

this approach?

Panel: We are all here for one reason: to ensure that medicines available to the American public are of the highest
quality. It is very important to ensure both generic and innovator drug products meet the same quality standardsan
expectation even more relevant because generic products
account for more than 80% of U.S. medicines.20 It has been
and will continue to be the FDAs policy to ensure the same
quality standard between innovator and generic products.
This will be further supported in the proposed Office of
Pharmaceutical Quality (OPQ) by integrating review and
inspection across product lifecycle.

Audience: What is the difference between in a state of

control versus in a state of statistical control?

Panel: A process is in a state of statistical control when

all special causes have been eliminated and the variation
seen in the data is random and inherent to the process itself
(process noise). In order to evaluate if a process is in a state
of statistical control, it is often associated with the use of a
control chart and the eight Western Electric Rules for special
cause tests. However, there is no general agreement on
which rule or rules should be strictly applied. Each company may have different practices for when to use the eight
Western Electric Rules. Nevertheless, it should be noted that
a control chart is only used to evaluate whether a process is
in a state of statistical control and does not address whether
the process is acceptable or not since the control chart itself
is not related to the specification. A process can be very
stable (i.e., in a state of statistical control), but not meet
customer needs (out of specification). Vice versa, a process
may be out of statistical control, but still be well within
the specifications. These two terms describe two different
aspects of a process.5,6

Audience: What is the relationship between QbD and

process capability? How do we evaluate process capability
during the development stage?

Panel: During the development stage, the objective is

to ensure that the product and process are appropriately
designed and any aspects (e.g., drug substances, excipients,
formulation, container closure systems, manufacturing
processes, in-process material, and final product) that are
critical to product quality, safety, and efficacy are identified.
To achieve this goal, a number of input material attributes
and process parameters are deliberately varied across a
range of values according to experimental design. Based on
the impact of these parameters on the drug product intermediates and finished drug product Critical Quality Attributes

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(CQAs), critical attribute of input materials and CPPs can be

identified and an appropriate control strategy can then be
established. In most cases, the process is not in a statistical
control state during the early development phase; therefore,
Cpk is not the appropriate index. However, if sufficient
development batches are produced, preliminary Ppk and its
confidence bound can be calculated. The data can be used to
assess how the designed product and process can approximately achieve the target quality attributes in the desired
range. If not, fundamental changes of the product and/or
process design may be necessary to achieve the predefined
target. This can significantly help the company identify
incapable process during the early stage and avoid wasting
resources. It is well known, however, that these development studies are often conducted at the laboratory or pilot
scale. Therefore, the preliminary Ppk obtained from the
laboratory or pilot scale cannot be extrapolated to production scale unless the process can be demonstrated to be
scale independent or that scale up of the process can be well
predicted with a high certainty. As such, extra cautions need
to be taken to interpret these preliminary indices obtained
during the development stage. Nevertheless, enhanced understanding of the formulation and process builds the solid
foundation needed to ultimately obtain high Cpk and Ppk
for commercial manufacture. Therefore, increasing process
capability and reduce product variability and defects is one
of the QbD objectives.21

Audience: If we implement process capability indices, is it

possible to gain regulatory flexibility?

Panel: The short answer would be, yes, it is possible, but

we are not there yet. For this exact reason, we are having
this symposium to facilitate scientific discussion and collect
industry feedback and input. If some common ground can
be reached, it is possible to achieve the well-sought regulatory flexibility in the future with the following prerequisites:
1. the commercial manufacture process can demonstrate a
state of statistical control and achieve the desired process capability (e.g., Cpk 95% confidence bound > 1 or any value to
be agreed on between industry and regulatory agency), 2. the
applicant commits to continue using statistical process control tools to monitor the process and ensure that the process
remains in a state of statistical control, 3. a healthy pharmaceutical quality system is in place to ensure that correct
and preventive actions are available when any unplanned or
undesired departures are observed from the process, and 4.
the applicant calculates and reports in the subsequent annual report the trending of Cpk/Ppk for all CQAs to confirm
there is no negative trend or observation.

Summary
Key highlights from the symposium were as follows: 1.

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Clinically Relevant Specifications (CRSs) are needed in the

modern world, and are worth investing in because of their
benefits, 2. process capability indices can be a powerful
tool by which to ensure drug product quality and process
robustness, 3. case studies from both the innovator and generic pharmaceutical industries demonstrated that process
capability indices can be an useful tool by which to drive
operation excellence and ensure delivery of superior product
quality, 4. use of process capability indices should always
go hand-in-hand with enhanced scientific understanding of
the product and process, and 5. some technical and culture challenges in implementing these tools still exist. The
panel discussion provided an excellent source of information regarding the strengths and some of the considerations
when using process capability indices. Further discussion
and broadly engaging industry and other stakeholders would
greatly benefit increased adoption and implementation of
this powerful tool.

References
1. 28th International Forum on Process Analytical Chemistry (IFPAC) Annual Meeting, http://www.ifpac.com/cgibin/IFPACProgram2014.pl, accessed 10 February 2014.
2. http://www.isixsigma.com/community/blogs/what-youmeasure-what-you-get/,accessed 10 February 2014.
3. Vase, P., Achieving Six Sigma Quality in Medical Device
Manufacturing by use of Design of Experiments and Statistical Process Control, Pharmaceutical Engineering,
Vol. 27, No. 2, 2007, pp. 1-9, www.PharmaceuticalEngineering.org.
4. ASTM E2281: Standard Practice for Process and Measurement Capability Indices.
5. ISO 8258: Shewhart Control Charts.
6. ASTM E2587: Standard Practice for Use of Control
Charts in Statistical Process Control, www.astm.org.
7. U.S. FDA Guidance for Industry on Process Validation:
General Principles and Practices, 2011, www.fda.gov.
8. ICH Q9 Quality Risk Management, www.ich.org.
9. ICH Q10 Pharmaceutical Quality System, www.ich.org.
10. World Health Organization (WHO) GMP and Inspection
for Pharmaceutical Products: Main Principles, http://
whqlibdoc.who.int/publications/2007/9789241547086_
eng.pdf, accessed on 10 January 2014).
11. Choi, M., Determining the Manufacturability of Druglayered Tablets, Pharmaceutical Manufacturing, No. 4,
2007, pp. 34-42.
12. Quality by Design (QbD): An Example Pharmaceutical Development Report for an Immediate Release (IR)
Dosage Form, (http://www.fda.gov/downloads/Drugs/
DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/UCM304305.pdf,
accessed 10 February 2014.

research and development

Pharmaceutical Product Quality

13. Quality by Design (QbD): An Example Pharmaceutical Development Report for a Modified Release (MR)
Dosage Form (http://www.fda.gov/downloads/Drugs/
DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/UCM286595.pdf)
(accessed 10 February 2014).
14. Baxter, J.L., et al., Hydrodynamics-induced Variability in the USP Apparatus II Dissolution Test, Int. J.
Pharm., Vol. 292, No. 1-2, 2005, pp. 17-28.
15. ISO 21747: Statistical Methods -- Process Performance and
Capability Statistics for Measured Quality Characteristics.
16. USP<905> Uniformity of Dosage Units.
17. ASTM E2709: Standard Practice for Demonstrating Capability to Comply with an Acceptance Procedure, www.
astm.org.
18. Saccone, C. D., et al., Statistical Properties of the Dissolution Test of USP, Dissolution Technologies, Vol. 11,
No. 4, 2004, pp. 25-28.
19. The Use of Stratified Sampling of Blend and Dosage Units
to Demonstrate Adequacy of Mix for Powder Blends
(http://www.pqri.org/pdfs/DTC/Articles/Final_BUWG_
Stratfied_Sampling.pdf) (accessed 10 February 2014)
20. Declining Medicine Use and Cost: For Better or Worse?
(www.imshealth.com) (accessed 10 February 2014).
21. Yu, L.X., et al., Understanding Pharmaceutical Quality
by Design, AAPS J., Vol. 16, 2014, pp. 771-783.

Acknowledgments
Andre Raw, Sau (Larry) Lee, Chengjiu Hu, Khalid Khan,
Leila Wieser, Alex Viehmann and Karthik Iyer.

About the Authors

Daniel Y. Peng, PhD is currently a Senior
Product Quality Reviewer and QbD Liaison
in the Office of Pharmaceutical Science
(OPS), CDER/FDA. Previously, Dr. Peng
served as a Senior Formulation Scientist/
Project Lead for late stage Product Development at AstraZeneca (Wilmington, DE) and an Instructor
(faculty) at College of Pharmacy, University of Tennessee
Health Science Center (Memphis, TN). Dr. Peng obtained
his PhD in pharmaceutics from West China University of
Medical Sciences (Chengdu, China). He has published three
book chapters, 16 peer reviewed papers and four US patents. Dr. Peng has extensive experience in formulation and
process development for solid oral dosage forms and novel
drug delivery systems. He is also skilled in applying Design of
Experiments (DOE), Multivariate Analysis (MVA), Statistical
Process Control (SPC), and Artificial Neural Network (ANN)
software for pharmaceutical product development.

Food and Drug Administration, Office of Pharmaceutical

Science, 10903 New Hampshire Avenue, Silver Spring, MD
20993, USA.
Richard (Rik) Lostritto, PhD joined the FDA in 1995
and currently serves as Acting Deputy Office Director for
Science and Policy and Acting Biopharmaceutics Lead in the
Office of New Drug Quality Assessment (ONDQA). Previously, Dr. Lostritto served as Director, Division-I, which
includes Chemistry, Manufacturing, and Controls (CMC)
responsibility for oncology, hematology, cardio-renal, neurology, and psychiatric drug products. He had also served as
CMC Team Leader successively collocated in the Divisions
of Oncology Drug Products and Pulmonary and Allergy Drug
Products. Before joining the Agency, Dr. Lostritto worked
at Boehringer Ingelheim Pharmaceuticals leading a group
that developed medical aerosol formulations after serving as
Assistant/Associate Professor of Pharmacy at The University
of Connecticut (1983-1992). He received his MS and PhD
in pharmaceutical chemistry and pharmaceutics from the
University of Michigan and his BS in pharmacy from The
University of Connecticut.
Food and Drug Administration, Office of Pharmaceutical Science, 10903 New Hampshire Ave., Silver Spring, MD
20993, USA.
Dafni Bika, PhD is a technology innovation and change leader with more than 20
years of international experience at top-tier
companies. Dr. Bika industrializes new
products by uniquely balancing technical
expertise with business understanding,
while developing others and inspiring discretionary performance. She is currently Vice President with Bristol-Myers
Squibb leading the Global Drug Product Manufacturing
Science and Technology organization located in New Brunswick, NJ. Dr. Bika joined Bristol-Myers Squibb in 2009 after
spending 10 years with Merck in West Point, PA on a similar
science and technology role. Prior to joining Merck, Dr.
Bika was in roles of increasing responsibility as a Development and Technology Manager with Procter and Gamble in
the European Technical Center in Brussels, Belgium, and
Viochrom in Athens, Greece. She holds a PhD in materials
science and engineering from the University of Pennsylvania, an MS in materials science and engineering from the
University of Rochester, New York, and a Diploma in chemical engineering from the National Technical University of
Athens.
Bristol-Myers Squibb, Global Drug Product Manufacturing Science and Technology, 1 Squibb Dr., New Brunswick,
New Jersey 08903, USA.

PHARMACEUTICAL ENGINEERING

SEPTEMBER/OCTOBER 2014

research and development

Pharmaceutical Product Quality

Jean-Marie Geoffroy, PhD is currently

Vice President Quality, Pharmaceutical
Engineering and Analytical Services at
Hospira. He is a registered pharmacist
from the University of Rhode Island,
and obtained his PhD in pharmaceutics
from the University of Wisconsin, Madison. His 24 years of
technical experience include process analytical technology,
formulation development and marketed product support,
focusing on technology transfer, process validation, and process optimization. He is an internationally recognized expert
and speaker in the areas of advanced analytics, quality by
design, risk management, process optimization and Process
Analytical Technology (PAT). He has trained FDA reviewers
and compliance officers in these areas. He is a member of
Parenteral Drug Association (PDA), American Association
of Pharmaceutical Scientists (AAPS), and ISPE. Prior to
Hospira, he has held various management positions within
Takeda, TAP Pharmaceuticals, Abbott Laboratories, Marion
Merrell Dow and CIMA Labs.
Hospira, Corporate Quality, Pharmaceutical Engineering
and Analytical Services, 275 N Field Dr., Lake Forest, Illinois
60045, USA.
Thomas A. Shepard is Director of
Manufacturing Science and Technology at
Hospira since 2012. He has 25 years of experience in medical device and pharmaceutical industry: research and development
and operations. His primary areas of focus
are biomaterials, drug containment, and drug delivery. He is
the PDA Task Force Leader for Technical Report: Identification and Classification of Integrity Defects in Large Volume
Plastic Containers.
Hospira, Corporate Quality, Pharmaceutical Engineering
and Analytical Services, 275 N Field Dr., Lake Forest, Illinois
60045, USA.
Brian Eden has more than 20 years of
operations, continuous improvement and
leadership experience in a range of industries, including energy, consumer goods,
food and pharmaceuticals. He holds a BS in
physics from the University of Connecticut
and an MS in engineering from Purdue University. Following eight years of service as an officer and Nuclear Engineer
in the US Navy, Edeb held a series of high impact roles with
General Electric Company, earning credentials in Six Sigma,
Lean and Reliability Engineering and is certified by GE as
Master Black Belt. Since 2004, he has specialized in startup
and deployment of global-scale Lean Six Sigma programs

10

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PHARMACEUTICAL ENGINEERING

with a particular focus on holistic methodology and detailed

financial analysis. Within pharmaceutical deployments,
Eden is also recognized as an expert in the area of quality by
design and other applications of problem solving and analytical tools to pharmaceutical quality and product development. He currently leads the Global Operational Excellence
program for Mylan, one of the worlds leading generics and
specialty pharmaceutical companies.
Mylan Pharmaceuticals, Global Operational Excellence,
781 Chestnut Ridge Rd., Morgantown, West Virginia 26505,
USA.
Kenneth Cot holds a BS in systems
management, Colorado Technical University, and was trained at the GE Capital
Center for Learning and Organizational
Education (CLOE). He worked as a Six
Sigma Black Belt in supply chain with
Penske Logistics. Three years later, he was certified at GE
Capital with Master Black Belt, and began teaching Six
Sigma full time. He was interested in healthcare and helping
people, and was recruited by Ethicon the surgical division
of Johnson & Johnson (J&J) in 2003. During this time, he
also started work on a graduate degree in biostatistics from
Rutgers University. Cot put his education on hold though,
because he was transferred to J&J Vision Care in London,
England. In 2011, he joined Mylan Pharmaceuticals and is
now the Senior Director for Operational Excellence, managing strategic projects for the North America region and
directly support four manufacturing locations, a repackaging
site and our regional distribution center.
Mylan Pharmaceuticals, Global Operational Excellence, 781
Chestnut Ridge Rd., Morgantown, West Virginia 26505, USA.
Alpesh Patel is working as Global Vice
President, Regulatory Affairs in Amneal Pharmaceuticals of NY LLC. Patel
is responsible for all strategies related to
US and Global Product Portfolio including effective communicates with Global
Regulatory Authorities (US FDA, MHRA etc.) and interprets
and communicates to the management about the changes in
strategies of regulatory authorities and guidances as they
relate to Amneal products on the global market. In addition, he is a core member of US FDA GPhA, TAC, SARB, API
Committee, IFPAC, QbD and Stability Committee and other
professional organizations such as DIA, PQRI, and Inactive
Ingredient Committee.
Amneal Pharmaceuticals, Global Regulatory Affairs, 85
Adams Ave., Hauppauge, New York 11788, USA.

research and development

Pharmaceutical Product Quality

Michael Choi, PhD is General Manager

for Johnson & Johnson HyangNam Pharmaceutical plant in the Janssen Supply
Chain. Previously, he served as Head of
Process Robustness for Americas Technical Operations at Teva, Senior Principal
Scientist for Consumer Healthcare R&D at Schering Plough,
and Senior Process Engineer for Pharmaceutical Technology
and Engineering at Merck & Co., Inc.
Johnson & Johnson HyangNam Pharmaceutical Plant, 45
Jeyakgongdan 2-gil Hyangnam-Eup, Hwasung-si, Gyeonggido, 445-937, Korea.
Dr. Lawrence X. Yu is the Director
(acting), Office of Pharmaceutical Science,
Food and Drug Administration, overseeing
the Office of New Drug Quality Assessment, Office of Generic Drug Quality Assessment, Office of Biotechnology Products, and Office of Testing and Research. He is also adjunct
Professor of Pharmaceutical Engineering at the University of
Michigan. Dr. Yu is a fellow and the past section Chair of the
American Association of Pharmaceutical Scientists and an
Associate Editor of the AAPS Journal. Dr. Yu has authored/
co-authored more than 120 papers, presented more than 100
abstracts, and given more than 180 invited presentations.
He is a co-editor of the book entitled, Biopharmaceutics Applications in Drug Development.
Food and Drug Administration, Office of Pharmaceutical
Science, 10903 New Hampshire Ave., Silver Spring, Maryland 20993, USA.

PHARMACEUTICAL ENGINEERING

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