AAPS Introductions in the Pharmaceutical Sciences

Ajay Babu Pazhayattil

Naheed Sayeed-Desta
Emilija Fredro-Kumbaradzi
Jordan Collins

Solid Oral
Dose Process
Validation
The Basics, Volume 1
AAPS Introductions in the Pharmaceutical
Sciences

Series Editor:
Robin M. Zavod
Midwestern University, Downers Grove, IL, USA
Springer and the American Association of Pharmaceutical Scientists (AAPS) have
partnered again to produce a second series that juxtaposes the AAPS Advances in the
Pharmaceutical Sciences series. It is a set of introductory volumes that lay out the
foundations of the different established pockets and emerging subfields of the
pharmaceutical sciences. Springer and the AAPS aim to publish scholarly science
focused on general topics in the pharma and biotech industries, and should be of
interest to students, scientists, and industry professionals.

More information about this series at http://www.springer.com/series/15769

Ajay Babu Pazhayattil • Naheed Sayeed-Desta
Emilija Fredro-Kumbaradzi • Jordan Collins

Solid Oral Dose Process

Validation
The Basics, Volume 1
Ajay Babu Pazhayattil Naheed Sayeed-Desta
Eurofins Alphora Reserach Inc. (Canada) Apotex (Canada)
Toronto, ON, Canada Toronto, ON, Canada

Emilija Fredro-Kumbaradzi Jordan Collins
Apotex (Canada) IQVIA (Canada)
Toronto, ON, Canada Toronto, ON, Canada

ISSN 2522-834X     ISSN 2522-8358 (electronic)

AAPS Introductions in the Pharmaceutical Sciences
ISBN 978-3-030-02471-0    ISBN 978-3-030-02472-7 (eBook)
https://doi.org/10.1007/978-3-030-02472-7

Library of Congress Control Number: 2018961586

© American Association of Pharmaceutical Scientists 2018

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Preface

Solid dose pharmaceutical drug manufacturing process validation has evolved since
introduction of the first FDA guidance in 1987. The current thinking on process
validation reflects FDA’s Pharmaceutical cGMPs for the twenty-first-century risk-­
based approach. Since introduction of the current science and risk-based life cycle
approach to process validation in 2011, there have been multiple strategies proposed
to support the concepts discussed. Solid dosage products remain mainstay of the
overall drug market and among new molecular entities. Further, generic products
make up the majority of the prescription market share totaling approximately 91%
of the prescriptions filled. The drive to develop Introductions book series on Solid
Oral Dose Process Validation emanated from this fact. The two-part series will
address the basic concepts of process validation with a focus on high-volume
generic solid dose manufacturing processes. The insights discussed in the books are
directly associated to the regulatory guidances that can be practically applied in
academic and business settings. The subject matter has been researched and sub-
stantiated with scientific evidences. The authors have carefully considered the
approaches to ensure that they are practically applicable in generic solid dose manu-
facturing. We hope that the reader gains a comprehensive understanding on solid
dose manufacturing process validation while enjoying the carefully selected con-
tents. Thank you for selecting Introductions book series on Solid Oral Dose Process
Validation for your learning needs!

Toronto, ON, Canada Ajay Babu Pazhayattil

 Naheed Sayeed-Desta
 Emilija Fredro-Kumbaradzi
 Jordan Collins

v
Acknowledgment

The authors would like to thank Dr. Robin Zavod, PhD., editor-in-chief, Currents in
Pharmacy Teaching and Learning, professor, Pharmaceutical Sciences, Midwestern
University Chicago College of Pharmacy, 555 31st Street, Downers Grove, IL
60515, for her encouragement in bringing the textbook on Solid Oral Dose Process
Validation. The process validation concepts have undergone significant changes in
the past decade. We would also like to express our gratitude to all past and present
colleagues at Apotex Inc. who have inspired us in collaborating and completing a
comprehensive work.

vii
Contents

1 Life Cycle Approach to Process Validation����������������������������������������������  1

Process Validation Stages����������������������������������������������������������������������������  3
Stage 1 – Process Design (Stages 1A and 1B)����������������������������������������  3
Stage 2 – Process Qualification (Stages 2A and 2B) ������������������������������  4
Stage 3 – Continued Process Verification (Stages 3A and 3B)����������������  5
Auxiliary Programs Supporting Life Cycle Process Validation������������������  6
Regulatory Requirements����������������������������������������������������������������������������  6
References����������������������������������������������������������������������������������������������������  7
2 Solid Dose Formulations����������������������������������������������������������������������������  9
Introduction��������������������������������������������������������������������������������������������������  9
Tablets����������������������������������������������������������������������������������������������������������  10
Tablets Manufacturing Processes����������������������������������������������������������������  12
Direct Compression ��������������������������������������������������������������������������������  12
Granulation����������������������������������������������������������������������������������������������  14
Dry Granulation ��������������������������������������������������������������������������������������  14
Wet Granulation ��������������������������������������������������������������������������������������  16
Selection of Granulation Process ������������������������������������������������������������  21
Compression/Tabletting ��������������������������������������������������������������������������  22
Capsules ������������������������������������������������������������������������������������������������������  23
Capsule Manufacturing Process������������������������������������������������������������������  26
Soft Gelatin Capsules������������������������������������������������������������������������������  26
Hard Gelatin Capsules ����������������������������������������������������������������������������  26
References����������������������������������������������������������������������������������������������������  28
3 Stage 1A Process Design: Quality by Design ������������������������������������������  29
Quality Target Product Profile (QTTP)��������������������������������������������������������  32
Critical Quality Attribute (CQA) ����������������������������������������������������������������  33
Critical Material Attribute (CMA) ��������������������������������������������������������������  33
Critical Process Parameter (CPP)����������������������������������������������������������������  33
Design of Experiments (DoE)����������������������������������������������������������������������  34

ix
x Contents

Control Strategy (CS)����������������������������������������������������������������������������������  34

Process Capability and Continual Improvement������������������������������������������  34
References����������������������������������������������������������������������������������������������������  35
4 Knowledge Management and Risk Assessment for Life
Cycle Stages������������������������������������������������������������������������������������������������  37
Knowledge Base for Development��������������������������������������������������������������  38
ICH Q9 Quality Risk Management��������������������������������������������������������������  39
Risk Assessment��������������������������������������������������������������������������������������  39
Risk Control ��������������������������������������������������������������������������������������������  39
Risk Communication ������������������������������������������������������������������������������  40
Fit for Purpose Risk Assessment Tools for Life Cycle����������������������������  40
Risk Assessment in Life Cycle Stages ��������������������������������������������������������  41
Risk Assessment at Stage 1����������������������������������������������������������������������  42
Systematic Experiments��������������������������������������������������������������������������  45
Design Space������������������������������������������������������������������������������������������������  45
References����������������������������������������������������������������������������������������������������  51
5 Stage 1B Process Scale-Up Considerations����������������������������������������������  53
Process Scale-Up Studies����������������������������������������������������������������������������  53
Blend Time Analysis��������������������������������������������������������������������������������  54
Compaction����������������������������������������������������������������������������������������������  55
Summary of DoE Influence of Process Parameters on CQA������������������  56
Tablet Compression���������������������������������������������������������������������������������  56
Control Strategy Components����������������������������������������������������������������������  58
References����������������������������������������������������������������������������������������������������  59
6 Stage 2A and Stage 2B: Process Qualification����������������������������������������  61
Stage 2A: Design and Qualification of the Facility, Equipment,
and Utilities��������������������������������������������������������������������������������������������������  61
Design Qualification (DQ)����������������������������������������������������������������������  63
Installation Qualification (IQ)������������������������������������������������������������������  63
Operational Qualification (OQ) ��������������������������������������������������������������  64
Performance Qualification (PQ)��������������������������������������������������������������  64
Impact of Product and Process on Facilities, Utilities,
and Systems ��������������������������������������������������������������������������������������������  65
Technology Transfer Considerations ����������������������������������������������������������  66
Checklist Prior to Initiating Stage 2B����������������������������������������������������������  68
Stage 2B: Process Performance Qualification ��������������������������������������������  68
Process Performance Qualification Protocol ������������������������������������������  70
Sampling and Testing Plan (Stage 2B)����������������������������������������������������  70
Process Analytical Technology (PAT)������������������������������������������������������  71
Acceptance Criteria (Stage 2B) ��������������������������������������������������������������  71
Incidents, Failures, and Deviations (Stage 2B)����������������������������������������  72
Process Performance Qualification Report����������������������������������������������  72
Statistical Tools (Stage 2B)����������������������������������������������������������������������  73
Contents xi

Type of Studies����������������������������������������������������������������������������������������  73

Approaches to Consider��������������������������������������������������������������������������  74
PPQ for Legacy Products������������������������������������������������������������������������  75
Qualification of Changes��������������������������������������������������������������������������  75
References����������������������������������������������������������������������������������������������������  78
7 Stage 3A and Stage 3B: Continued Process Verification������������������������  79
Benefits of Continued Process Verification Program ����������������������������������  80
Regulations Requiring CPV Program������������������������������������������������������  81
Continued Process Verification Stage 3A����������������������������������������������������  81
Continued Process Verification Stage 3B����������������������������������������������������  84
Use of Product/Process Data��������������������������������������������������������������������  85
ICH Guidance’s Working in Tandem ����������������������������������������������������������  86
References����������������������������������������������������������������������������������������������������  89

Index��������������������������������������������������������������������������������������������������������������������  91
About the Authors

Ajay Babu Pazhayattil,  M.Pharm, PhD (Candidate), is an industrial pharmacist

successful in conceiving, implementing, and promoting novel methodologies in
pharmaceutical quality assurance, regulatory affairs, technical operations, and man-
ufacturing operations based on sound scientific principles. His industry experience
extends through solid dose, liquids, and parenteral dosage forms. Ajay has been in
leadership roles with Eurofins Alphora, Apotex, Pharmetics, WellSpring, NBTY,
Patheon, Marcan, and Accord Pharma. He has implemented a comprehensive life
cycle management system supporting ICH Q8 to Q12 for global sites. He holds an
MPharm in medicinal chemistry and is currently working on his PhD.  He has
authored multiple pharmaceutical journal articles.

Naheed  Sayeed-Desta,  MBA (Candidate), has been responsible for providing

strategic directions on life cycle management of biopharmaceuticals in a GMP envi-
ronment. Naheed champions delivery of science and risk-based approaches from
traditional to novel processing technologies. She is a proven leader in technology
operations. Her expertise in providing pragmatic operational solutions is well rec-
ognized. She has been the lead author of journal articles. Naheed is active in bio-
pharmaceutical industry organizations including PDA, AAPS, and IFPAC.

Emilija  Fredro-Kumbaradzi,  MSc, PhD, is manager of Biowaivers and

Biocorrelation team within the Formulation Development Department at Apotex
Inc., Toronto, responsible for biopharmaceutical aspects of drug product. She has
extensive experience in formulation development of generic formulations for imme-
diate and modified release products intended for various markets. Prior to Apotex,
she has held a position of professor of pharmaceutical technology at Faculty of
Pharmacy at University of Skopje, Macedonia. She has received her BSc in phar-
macy from the University of Skopje, MSc from the University of Belgrade, Serbia,
and PhD in pharmaceutical sciences from the University of Skopje, Macedonia. Her
current research interests include solid dosage forms of low soluble drugs and vari-
ous approaches and technologies in drug formulation to remediate solubility and
stability issues, selection of bio-indicative dissolution and in silico modeling.

xiii
xiv About the Authors

Jordan Collins,  MSc, MA, PhD, is senior solutions architect at Privacy Analytics,

an IQVIA Company, responsible for leading client engagements assessing the risk
of reidentification of individuals and supplying guidance on anonymization for data
sets shared for secondary purposes. He also currently provides statistical consulting
services, primarily to healthcare researchers and pharmaceutical companies. He has
extensive experience in performing statistical analyses across a wide variety of
industries. Prior to privacy analytics, he held the position of manager, Statistical
Support at Apotex Inc. He received his BSc (honors) in mathematics from Mount
Allison University, MSc in mathematics from McMaster University, MA in applied
statistics from York University, and PhD in philosophy from the University of
Auckland, New Zealand. His current research interests include the application of
Bayesian statistics to industrial decision making and the development of machine
learning techniques for use in process optimization.
Chapter 1
Life Cycle Approach to Process Validation

Abstract  Process validation activities align with the product lifecycle concept of
ICH Q8, Q9, and Q10 (ICH, International Conference on Harmonisation of techni-
cal requirements for the registration of pharmaceuticals for human use (ICH) guid-
ance document: Q8 (R2): pharmaceutical development, Geneva, 2009; ICH,
International Conference on Harmonisation of technical requirements for the regis-
tration of pharmaceuticals for human use (ICH) guidance document: Q9: quality
risk management, Geneva, 2005; ICH, International Conference on Harmonisation
of technical requirements for the registration of pharmaceuticals for human use
(ICH) guidance: Q10: pharmaceutical quality system, Geneva, 2008) that link prod-
uct and process development, qualification of commercial manufacturing and main-
tenance of the process in a state of control during routine production. The regulators
and industry have been adopting process validation lifecycle concepts.

Keywords  Process validation · Life cycle · Process design · Process performance

qualification · Continued process verification

As defined by the US FDA Process Validation Guidance [1], process validation is

the collection and evaluation of data, from the process design stage through com-
mercial production, which establishes scientific evidence that a process is capable
of consistently delivering quality product. Process validation involves a series of
activities taking place over the lifecycle of the product and process: Process
design (Stage 1), process qualification (Stage 2), and continued process verifica-
tion (Stage 3).
An effective process validation program ensures quality, safety, and efficacy are
designed and built into the product through its lifecycle. This is achieved by ensur-
ing all manufacturing steps are controlled, measured, and quantified by finished
product quality attribute specifications. Sound scientific principles, good knowledge
management, documentation, and pharmaceutical quality systems are required to
efficiently utilize data from all stages. This is a dramatic shift from the previous
guidance and requirements to declare a process validated. Sources of variation,
impact of the variation on the process and quality attributes, and control of the varia-
tion are required (Fig. 1.1).

© American Association of Pharmaceutical Scientists 2018 1

A. B. Pazhayattil et al., Solid Oral Dose Process Validation, AAPS Introductions
in the Pharmaceutical Sciences, https://doi.org/10.1007/978-3-030-02472-7_1
2 1  Life Cycle Approach to Process Validation

Fig. 1.1  Life cycle approach

Each phase of the process validation lifecycle is distinct as per a normal course
of development activities that occur for a product. Stage 1 or process design stage is
the initial development stage where the commercial manufacturing is defined. Stage
2 or process qualification is where the process design is evaluated and verified to
determine if the manufacturing process is capable and reproducible. Stage 3 or con-
tinued process verification [2] is where ongoing assurance of a state of control is
gained through monitoring of routine commercial batches. In some instances, activ-
ities for products may occur in multiple stages.
Some preparative Stage 2B activities may be initiated in parallel with those from
Stage 1B. However, a readiness assessment needs to be conducted to determine the
timing of sufficient information and completion of activities to support moving for-
ward with Stage 2 manufacturing. Available Stage 1 data make it unnecessary to
execute Stage 2 over the operating ranges.
The following sequence of activities is conducted as preparation for Stage 2B:
• Review of technology transfer report(s) and associated documentation
• Creation and approval of process performance qualification (PPQ) protocols
• Execution of PPQ Protocols
• Documentation, review, and acceptance of results
• Creation and approval of PPQ reports
• Notify change owner
Homogeneity within a batch and consistency between batches are goals of PPQ
activities. PPQ batches will be manufactured under conditions that reflect routine
production settings for process parameters. Challenging process ranges as part of
the PPQ exercise are included in cases where there is insufficient development data
Process Validation Stages 3

to support the proposed parameters. PPQ batches are prevented from being released
to the market before all criteria prescribed in the PPQ Protocol have been satisfied.
Process development (formulation development), optimization, and/or demonstra-
tion batches (technical operations) will not be releasable for sale, as these studies
are designed to collect data for establishment of PPQ criteria. PPQ and continued
process verification batches will be releasable for sale provided all predetermined
criteria are satisfied.
A manufacturer must gain and provide a high degree of assurance that the pro-
cess validated is capable of consistently producing drug product that meets its qual-
ity attributes relating to identity, strength, quality, purity, and potency. The degree of
assurance provided depends on sufficient scientific understanding of the product by
the manufacturer. Objective data and information can be gathered and evaluated
from trials, pilot or laboratory scale, demonstration, and commercial batches. This
is done through activities from process design, process qualification, and continued
process verification stages of the product’s lifecycle as established by a successful
validation program. Information and knowledge are used to understand a product’s
performance and establish a control strategy to ensure the manufacturing process
results in products with the desired quality attributes are met. The control strategy
includes the process, raw materials, equipment, production environment, personnel,
and procedure changes.
In order to establish an effective control strategy, it is important for manufactur-
ers to understand sources of variation, detect and measure the degree of variation,
understand the impact of the variation on the process and attributes, and control the
variation. These activities can occur over the three stages and enables a risk-based
decision-making of the process lifecycle. Criticality of attributes and parameters is
to be determined by the manufacturer and communicated to the agency. Reevaluation
of the criticality is continuous and can be done as more knowledge is gained on the
process. Parameters and attributes that pose a higher risk require a higher degree of
control. Process validation activities should provide assurance that a production
output is protected against all sources of variability, hence reducing negative impacts
on production outputs, supply chain, and patient health.

Process Validation Stages

Stage 1 – Process Design (Stages 1A and 1B)

The first stage of the process validation lifecycle includes activities that define a
process suitable for commercial manufacturing that consistently delivers a product
that meets its quality attributes. Product development studies, generally performed
in non-Good Manufacturing Practice (GMP) small-scale laboratories, provide key
inputs of the process design stage such as intended dosage form, quality attributes,
and manufacturing path. All studies are to be documented and verified internally for
4 1  Life Cycle Approach to Process Validation

use at a later stage of the lifecycle following ICH Q10 recommendations. During
development limitations of commercial equipment should be considered, and any
future variability that may be contributed from different sources such as materials
(raw materials), man (operators and procedures), machine (equipment), measure-
ment (testing methods and systems), and mother nature (environmental conditions)
can be estimated in Stage 1.
In order to design an efficient process with effective controls, process knowledge
and understanding are desired. This can be gained through design of experiment
(DOE) studies that can reveal any relationships or interactions between input vari-
ables and output attributes. The studies can help determine operating ranges and
specifications for in-process controls required to maintain the finished product qual-
ity attributes. In lieu of DOE studies, computer simulations and historical data from
similar processes can be used to understand the process and mitigate any risks fore-
seen for commercial manufacturing. All activities resulting in process understand-
ing and identification of variables and controls are to be documented and justified.
The information is vital for establishing a strategy for process control that addresses
variability to assure product quality. A process control strategy for commercial pro-
duction based on early risk assessments from Stage 1 may be improved as experi-
ence is gained for a product. Risk assessment tools are to be utilized to mitigate any
residual risks and determine Stage 2 requirements for sampling and testing to assure
product quality and minimal variability of future batches.

Stage 2 – Process Qualification (Stages 2A and 2B)

The second stage of the process validation lifecycle is process qualification where
the process design of a product is evaluated to determine if it is capable of reproduc-
ible commercial production. As per 501(a)(2)(B) of the Act, any product distributed
commercially is legally required to successfully complete Stage 2 activities. This
stage has two components: Stage 2A, design of the facility and qualification of the
equipment and utilities, and Stage 2B – process performance qualification (PPQ).
Stage 2 is expected to follow compliant final commercial process. Facility, util-
ity, system, and equipment qualification stage (Stage 2A) should precede the PPQ
activities. These activities are generally termed as qualification activities.
Qualification stage includes specific activities such as defining the equipment oper-
ating principles, construction of material, performance standards etc. which are fit
for purpose. The qualification ensures that they are created and installed meeting the
user requirements specifications and/or design specifications. The installation quali-
fication, operational qualification, and performance qualification are requirements
at this stage. The commissioning activities such as factory acceptance testing (FAT)
and site acceptance testing (SAT) are to be completed prior to the initiation of quali-
fication activities [3]. Typically, the activities are conducted as an overall project
Process Validation Stages 5

plan which will include the types of studies included, timing of the qualification
steps, and the acceptance criteria.
Process performance qualification (Stage 2B) is the second stage of Stage 2.
With completion of PPQ, the process design will be confirmed and ensures that the
manufacturing process can be commercially applied with a high degree of confi-
dence. Application of scientific principles and statistical methods is pivotal in PPQ
studies. Stage 2B or PPQ will have a heightened level of sampling and testing to
justify the commercial process. The PPQ sampling and testing plans should be
based on statistics with previous credible experiences considered. Completion of
PPQ stage is a major landmark in process validation lifecycle as it marks the com-
mencement of commercial distribution of the product. PPQ studies are generally
performed in a prospective manner and in certain circumstances concurrent PPQ
studies are also acceptable. The outcome of PPQ study will demonstrate the manu-
facturer’s level of product and process understanding thus demonstrating control
over the manufacturing process.

Stage 3 – Continued Process Verification (Stages 3A and 3B)

Continued process verification is a significant addition to the process validation

lifecycle concept. The first US FDA validation guidance dates back to 1987. The
Guideline on General Principles of Process Validation (1987) primarily pertained to
the current Stage 2: process performance qualification stage of process validation
lifecycle. The 1987 guidance described elements such as the validation prerequi-
sites, protocol, and report requirements. The guidance document had provisions for
postvalidation activities such as the need for quality systems to identify revalidation
requirements during changes. The significant change including addition of Stage 3
or continued process verification (CPV) stage came through with the 2011 US FDA
process validation guidance. The guidance formalized the CPV approaches that
developed and evolved through the years after the first guidance.
Stage 3 (CPV) uses the continual data collected to maintain the product quality.
The data includes process trends, critical quality attributes, and critical material
attribute, in process quality attributes. The application of statistical methods in
CPV is important. The selected trending methods should ensure minimal opportu-
nities for overreaction and underdetection. The information collected should dis-
play the level of control as the process is commercially utilized. The sources of
variability are identified though a robust CPV program. Once identified it triggers
the continuous improvement measures for product/process. Tools used for detect-
ing variability include statistical methods such as control charts. Understanding of
intra- and interbatch variability is of particular importance in batch processes.
Being an ongoing monitoring CPV ensures applying preventive measures prior to
encountering a failure mode; therefore, such programs cannot be coupled with an
annual assessment such as annual product review. However, CPV data can be used
for other quality system applications. Stage 3 can be subcategorized as Stage 3A
and Stage 3B.
6 1  Life Cycle Approach to Process Validation

Auxiliary Programs Supporting Life Cycle Process Validation

All personnel responsible for the process validation and operation of production
processes will need sufficient education, experience, and/or training to perform
the required tasks. Training is to be performed according to approved standard
operating procedures, work instructions, and documents. Process validation team
will undergo training on process validation master plan (PVMP), job-specific
Standard Operating Procedure (SOP), Work Instruction (WI) and GMP, safety,
and HR learning and development training programs as stipulated in the role-
specific training plan. Equipment cleaning procedures and routine monitoring
procedures are to be validated. Cleaning validation needs to be completed prior to.
Analytical methods that are used in the quality control (QC) laboratories to sup-
port process validation programs must be validated in accordance with the analyti-
cal quality by design concepts. PPQ batches should be placed on stability. Process
validation activities can be also triggered by regulatory/client audits and commit-
ments. The root cause of the observation is investigated and a corrective action
plan with a due date is determined prior to initiation of a study.

Regulatory Requirements

Process validation is a legally enforceable requirement under section 501(a)(2)(B)

of the Act (21 U.S.C 351(a)(2)(B)) as well as current Good Manufacturing Practices
(cGMP) requirements under 21 Code of Federal Regulations (CFR) parts 210 and
211 for finished pharmaceuticals and components. Manufacturing processes are
required to be designed, controlled, and maintained to assure that in-­process and
finished product predetermined specifications and quality attributes are met consis-
tently and reliably. Specifics for process validation are outlined in 211.100 (a) for
process design, operations, and controls that are used to ensure products meet

Fig. 1.2  Regulatory harmony

References 7

predetermined attributes. In-process specifications are required to be established,

controlled, and consistent with final drug product specifications. The specifications
established should be determined using statistical procedures if applicable and data
from previous acceptable process mean and process variability estimates. The reg-
ulations also define activities for all stages of the process validation life cycle.
Section 211.180 9 (e) requires periodic review and ongoing feedback of product
quality and process performance to determine if any changes are needed to main-
tain the product quality (Fig. 1.2).
The regulations also require that the facilities and equipment used to manufac-
ture drug products are of suitable size, construction, and location to facilitate suit-
able operations. All equipment used that is automated, mechanical, and electronic is
required to have written programs for calibration, inspection, and maintenance to
assure proper performance.

References

1. US FDA. Guidance for industry, process validation: general principles and practices. White
Oak: US Food and Drug Administration; 2011. www.fda.gov/downloads/Drugs/Guidances/
UCM070336.pdf
2. Alsmeyer D, Pazhayattil A. A case for stage 3 continued process verification. Pharma Manuf
J.  2014.; http://www.pharmamanufacturing.com/articles/2014/stage3-continued-process-
verification
3. European Commission (EC). Guidelines on good manufacturing practice for medicinal
products, Annex 15. 2014.
Chapter 2
Solid Dose Formulations

Abstract  Among the solid dosage forms, tablets and capsules take by far the
largest fraction of drug products taken by oral route. The chapter discusses tablet
and capsule formulations and the traditional manufacturing processes. New tech-
nologies such as 3D printing are currently emerging as an alternate manufacturing
process. Continuous solid dose manufacturing utilizes technology such as process
analytical technology (PAT), process modeling to enhance pharmaceutical solid
dose manufacturing processes.

Keywords  Formulation · Solid dose · Tablets · Granulation · Soft gelatin capsules

· Hard gelatin capsules

Introduction

Oral route of administration is the most frequently used route as it is simple,

convenient, and noninvasive. Some drug substances are intended to be dissolved
and absorbed in the mouth cavity for achieving rapid onset of action; others are
expected to have local effect in the mouth. The dosage forms to be administered via
oral route can be liquid forms (solutions or suspensions) or solid forms (powders,
tablets, and capsules).
Majority of the drug substances are to be transported into gastrointestinal tract
where the drug is to be dissolved and absorbed. However, pure drug substances are
not suitable to be directly ingested for various reasons. For instance, dose of the
drug may be too low (fraction of milligram), the taste of the drug may be unpleas-
ant, stability of the drug substance may be poor and may require stabilization, or
solubility of the active on its own may be poor and may require solubilization in
order to become available for absorption from the gastrointestinal tract. Hence, in
order to be delivered to the desired site of its absorption or action, the drug sub-
stance needs to be formulated in a dosage form by combining the active pharma-
ceutical ingredient with inactive ingredients, and processing it using specific
manufacturing processes.

© American Association of Pharmaceutical Scientists 2018 9

A. B. Pazhayattil et al., Solid Oral Dose Process Validation, AAPS Introductions
in the Pharmaceutical Sciences, https://doi.org/10.1007/978-3-030-02472-7_2
10 2  Solid Dose Formulations

Tablets

Tablets are compressed dosage forms obtained by pressing the powder mixtures into
solid compacts of a desired shape. They are most popular dosage forms that repre-
sent about 70% of the pharmaceutical products on the market. Their popularity can
be attributed not only to the convenience of use by the patients but also to accurate
dosing, simple packaging, ease of transportation, and cost-effective mass
manufacturing.
Tablets can be categorized by route of administration, drug release rate, type/
formulation design (Table 2.1).
Not every powder can form solid compact under exposure to compression force.
Powder ingredients should be able to bond and undergo plastic deformation forming
a solid compact. Hence formulation design of a tablet dosage form encompasses
careful selection of powder ingredients and processing steps to modulate their phys-
ical properties to achieve desired bonding into a solid compact. However, upon
administration, the reversed process of release of the entrapped drug substance is
required. The composition should ensure release and dissolution of the active ingre-
dient at the site of absorption in the gastrointestinal tract for those that should have
systemic effect or on the site of action for those intended to act locally in the selected
part of the gastrointestinal tract.
Inactive ingredients used in tablet formulation can be categorized in several cat-
egories based on their role in formulation. Main categories are:
• Diluents (fillers)  – bulking agents which are considered “inert” are added to
achieve desired size of the tablet. Typically, in a case of low dosed products
where the active ingredient amount is too small, they are added to increase the
weight so the tablet form can be made. Examples are sugars, mainly lactose,
sugar alcohols (mannitol, sorbitol), salts such as dicalcium phosphate or sodium
chloride, cellulose derivatives such as microcrystalline cellulose.However, they
may also function as cohesive component that aid in formation of the solid com-
pact, disintegrant, taste modifier, or as a stabilizer. Current trends in pharmaceu-
tical excipients are directed toward modifying of their properties so they can
display multiple roles in the formulation, thus allowing for compositions with
fewer ingredients.
• Binders – materials that bind the powder particles together into agglomerates,
i.e., granules, and also in further adherence of granules to each other during com-
pression into tablets. They can be utilized as dry powders in dry granulation
processes or as a solution in wet granulation process. Granulation processes will
be discussed in later parts of this section. Examples of dry binders are cellulose
derivatives, while wet binders that form sticky viscous solutions are gelatin,
starch, sucrose, glucose, polyvinylpyrrolidone, and acacia gum.
• Disintegrants – components that facilitate tablet break up upon exposure to aque-
ous media. They have capillary structure that leads to absorption of water and
swelling, thus causing tablet to fall apart into pieces. Commonly used d­ isintegrants
are cellulose derivatives (croscarmellose sodium, microcrystalline c­ellulose),
starch, cross-linked polyvinylpyrrolidone.
Table 2.1  Type of tablets
Route of Site of drug
administration release Release rate Type of tablet Characteristics
Tablets

Per oral Stomach Immediate Conventional Shape and size suitable for swallowing
(stomach and Intestine Modified
intestine) Immediate Multicompartmental Multilayer or tablet in tablet
Modified Each compartment contains different drug substance.
Combination of the Separation may be driven by incompatibility between the
two active ingredients or by the need to achieve different release
characteristics from each layer (e.g., immediate and delayed)
Immediate Dispersible To be dispersed in water before administration

Immediate Effervescent To be dispersed in water before administration. Disintegration

is facilitated by release of carbon dioxide in reaction of an
acidic component and carbonate or bicarbonate salt
Oral cavity Oral cavity Immediate Chewable To be grinded by chewing before swallowing

Immediate release Buccal Flat shape. Placed in buccal pouch (between gums and cheek)
and absorption via where it disintegrates slowly by erosion
buccal mucosa
Immediate release Sublingual Small size. Placed under the tongue where it disintegrates
and rapid absorption slowly by erosion
Immediate Oral dispersible To be placed in mouth where they rapidly disintegrates

Body cavity Vagina Immediate release Vaginal Elongated shape. Disintegrates and dissolves in vaginal cavity
for local action
Rectum Immediate release Rectal Torpedo shape. Disintegrate or dissolve in rectal cavity
for local or systemic
action
Implant into Subcutaneous Modified Implant Sterile form to be implanted under the skin for drug release
tissue over prolonged period of time
Ocular Modified Implant Sterile form of very small size to be implanted in the eye for
11

local action
12 2  Solid Dose Formulations

• Glidants  – components that improve powder flow by reducing the friction

between the particles. They spread onto surfaces of particles, smooth them and
reduce the friction. Most common glidant is colloidal silicon dioxide.
• Lubricants – components that prevent adherence of the powders and granules to
the metal surfaces of tableting machine, specifically, punches and dies. Thus,
they enable formation of intact tablet and facilitate tablet ejection from the die
cavity. Most commonly used lubricant is magnesium stearate. Stearic acid, talc,
sodium stearyl fumarate also aid in lubrication. All lubricants have glidant prop-
erties to a lesser extent and vice versa.

Tablets Manufacturing Processes

Processes employed in tablet manufacturing can be categorized as [1]:

• Direct compression  – where powder mix components possess inherited
compressibility.
• Granulation – properties of the mix components are modulated to achieve desired
compressibility.

Direct Compression

Direct compression is the simplest manufacturing process where the excipients are
to be blended and compressed without a granulation step. It involves very few man-
ufacturing steps (milling, mixing, and compression), and hence, it is time efficient.
It possesses high cost-effective advantage over other processes not only due to sig-
nificantly shorter processing time but also due to significant saving on equipment.
In addition, since there is no solvents or heating involved, the risk for moisture or
heat-driven degradation or moisture-induced change to the drug substance polymor-
phic form is minimized. However, this is not a feasible approach for all formula-
tions. Powder composition should possess directly compressible properties to be
able to form a tablet by simple application of pressure. Since drug substance proper-
ties are given and cannot be modified, the inactive ingredients have to be carefully
selected as they should not only be directly compressible themselves, but also capa-
ble to compensate for poor compressibility of the drug substance. In addition, they
have to possess good flowability to ensure uniform filling of die cavities during
tableting, thus eliminating risk of weight variation. Capacity of the directly com-
pressible diluents to carry noncompressible materials is an important quality attri-
bute. Normally, drug substance is considered noncompressible. In such a case, the
quantity of active ingredient that can be incorporated in the formulation for direct
compression is limited to maximum of about 25%, so the remaining 75% of the
inactive ingredients with directly compressible properties can compensate for
Tablets Manufacturing Processes 13

noncompressible drug substance properties. However, if the drug substance itself

possesses some compressibility, the load of active ingredient in directly compress-
ible formulation can increase accordingly.
Considering industry interest in formulating the solid dosage forms as directly
compressible products, there are many excipients that have been developed to have
desired compressibility and capacity that allows for incorporation of a noncom-
pressible drug substance and other noncompressible ingredients. By far, most popu-
lar and most efficient directly compressible ingredient is microcrystalline cellulose
(MCC) [2]. The crystalline lattice easily undergoes plastic deformation and forms
solid compacts. Further beneficial characteristic of microcrystalline cellulose is its
affinity to absorb water due to its porous capillary structure, which facilitates disin-
tegration of the tablet once exposed to hydrophilic media. Hence, although insolu-
ble, it enables tablet disintegration which makes it suitable for immediate release
formulations. That means, it can aid in formation of the solid compact but also in its
disintegration once tablet is exposed to gastrointestinal fluids.
Dibasic calcium phosphate is also suitable for direct compression. It is free flow-
ing and compressible material, but it is not soluble and does not disintegrate upon
exposure to hydrophilic media. Hence, tablet formulations containing dibasic cal-
cium phosphate have to contain disintegrants to ensure tablet disintegration if
desired. Rapid disintegration as a prerequisite for drug release is typical require-
ment for tablets intended for immediate release of the drug substance. In a case of
modified release products, rapid disintegration is not required.
The third most popular ingredient is lactose. Special grades of lactose anhydrous
and lactose monohydrate obtained by spray drying process possess adequate com-
pressibility, but also aid in tablet disintegration by mechanism of erosion as the
sugars slowly dissolve in aqueous media.
In order to meet industry needs for wider selection of directly compressible
ingredients, manufacturers of excipients have developed techniques for modulating
the properties of the existing ingredients by their combining and coprocessing.
Coprocessing provides functional synergy as well as masks the undesired properties
of the individual components [3]. Coprocessing may be done by cocrystallization,
coprecipitation, spray congealing, hot-melt extrusion, or agglomeration.
Coprocessed combination of MCC-calcium carbonate, MCC-mannitol, mannitol-­
sorbitol, sucrose-sorbitol, sorbitol-calcium diphosphate are some of the examples of
compressible materials available on the market (Fig. 2.1).

Drug substance, directly Milling/De- Blending

compressible ingredients agglomeration

Coating (optional) Tableting

Fig. 2.1  Steps of tablet manufacture by direct compression process

14 2  Solid Dose Formulations

Granulation

Granulation is a process of formation of larger multiparticulate formations, gran-

ules, by adherence of primary powder particles to each other. During this process
powder particles are forced to bond to each other generally by mean of incorpora-
tion of binding agent. There are several reasons for granulation:
• Poor flow and poor compressibility of powder mix  – granules have improved
flowability and form much stronger compacts when exposed to pressure. This is
a result of close proximity of powder particles to each other within the granule
and the presence of binding agent in each granule.
• Poor powder flow – particles of small size with cohesive properties do not flow
well which results in uneven fill of die cavities and weight variation. Increase of
the particle size by granulation yields in less interparticulate interactions and
improved flow.
• Poor mix homogeneity and susceptibility to powder segregation – granulation
can “lock” the small particles in place resulting in uniform blend with reduced
tendency to segregation. Segregation occurs during further processing of the
powder mixes as a result of shaking and vibrations (material transfer, powder in
hopper of tableting press, encapsulation machine, etc.). It is driven by different
density and particle size of the mix components. Since granules will have same
density and fairly uniform shape and size, the tendency for segregation is signifi-
cantly reduced.

Dry Granulation

Dry granulation process is the second process of choice in development of the solid
dosage forms. It is used in cases where direct compression is not feasible, e.g., high
load of noncompressible drug substance and presence of noncompressible ingredi-
ents (e.g., release rate controlling polymers). Also, compositions with low active
content may need dry granulation to overcome challenges in achieving drug homo-
geneity or to bring robustness in cases where direct mix is susceptible to segregation
during further processing. Dry granulation process does not involve any wetting nor
heating to evaporate the solvent, which makes it suitable for drug substances sensi-
tive to moisture or heat. Product manufactured with dry granulation process is less
likely to generate during stability degradation products associated with residual
moisture or exposure to heat during drying. In addition, dry granulation process is
unlikely to impact the polymorphic form of the active ingredient or trigger transi-
tion into another form.
Dry granulation encompasses formation of aggregates from smaller powder par-
ticles [4]. The bonding mechanisms involve van der Waals forces, mechanical inter-
locking, and formation of solid bridges. The bonding process undergoes through
several sequential steps:
Tablets Manufacturing Processes 15

• Particle rearrangement – particles move to fill void spaces and come closer to
each other.
• Particle deformation – change of the shape (plastic deformation) under higher
force that increases contact area between the particles.
• Particle fragmentation – as force further increases, particles fracture and create
additional contact points.
• Particle bonding – at contact areas bonding takes place in plastically deformed
material due to van der Waals forces.
Dry granulation process is conducted by means of roller compaction. Powder
mix is pushed in between the two heavy rollers that rotate toward each other, thus
pulling the material to pass through. The rollers exert pressure onto material which
gradually densifies, deforms, and creates a ribbon. The ribbon that comes out is
further broken into granules by milling and passing through the screen.
Major drawback to the compaction process that can reduce the throughput and
affect density of the ribbon is the entrapped air. This is particularly the case when
compacting mixes containing fine particles. Hence, equipment design may account
for tampering the material to expel the air and/or deaerating the material before
reaching to the rollers by applying vacuum via vacuum port (Fig. 2.2).
Assuming material flows between the rollers without disruption in horizontal
layers, the volume will decrease proportionally to the decrease of the distance
between the rollers. Volume of the material entrapped in the volume space defined
by arc lengths will have to compress into smaller volume. Accordingly, the final
density of the compact (ribbon) is mainly defined by the distance (gap) between the
rollers at tip point (lowest distance point) [5].
In fact, advanced equipment design allows for continuous compaction process
with consistent ribbon quality that is not affected by fluctuation of critical process
parameters. The equipment Human-Machine Interface (HMI) system maintains and

Fig. 2.2  Roller compactor

16 2  Solid Dose Formulations

Drug Substance, Milling/De- Blending

Ingredients agglomeration

Blending of Granules Ribbon Roller Compaction

Milling/Screening

Tableting

Fig. 2.3  Steps of tablet manufacture by dry granulation process

controls constant feeding rate for the incoming materials, constant compaction
force, roller speed, and constant roller gap. Furthermore, milling of the ribbon and
screening through a screen are integral parts of the compaction equipment. Roller
compactors are equipped with oscillating granulator mounted above a screen,
which breaks the ribbon and forms dry granules of defined size. The size of the
granules will depend not only on ribbon mechanical properties and screen size but
also on the angle of oscillation and rotation speed of the oscillator along with its
distance from the screen (Fig. 2.3).

Wet Granulation

Wet granulation process involves use of solvent where powder mix particles are
agglomerated by wetting with binder solution followed by mixing or kneading.
Drug substance may be incorporated into the granulation liquid or added to the
powder mix. Sometimes pure solvent may be used as a granulating liquid while the
dry binder is incorporated in the powder mix. Granulating liquid forms a film around
the particles which acts as an adhesive. Adhesion is facilitated by the forces of sur-
face tension at liquid-air interface and the hydrostatic suction pressure. The liquid
displaces the air between the particles and the particles are held together by the
capillary suction forces. The liquid forms liquid bridges that are only temporary
formations. During the drying process, solvent will be evaporated, and the wet gran-
ules will be dried. In place of liquid bridges, solid bridges will be formed as a result
of adhesive properties of the binder or due to partial dissolving of some of the solid
materials in the granulating liquid during processing. Upon removal of the solvent
by drying, binders form solid bridges once they harden or crystallize. Similarly, if
solid materials dissolve in the granulating liquid, they will crystallize and harden
upon drying.
Solid bridges are held together by the action of van der Waals forces but can also
involve electrostatic forces. It is important to note that these forces will become
stronger upon compression as a distance at contact surface areas will decrease.
Tablets Manufacturing Processes 17

Granulation solvent for pharmaceutical use can be water but can also be an organic
solvent (mainly alcohols) or combination of the two (hydroalcoholic systems).
The equipment for wet granulation can be categorized:
• Low shear granulators
• High shear mixer granulator (HSMG)
• Medium shear granulators (fluid bed granulator)
Low shear granulators are used for wetting and kneading of the wet mass. They
contain mixing element of different shape that moves through the mass (ribbon mix-
ers, paddle mixers, rotating auger mixers, planetary mixers). At the end of the gran-
ulation, wet mass needs to be passed through a screen to form wet granules that
would be transferred into a drying oven or fluid bed driers for drying. This means
the granulation process is discontinuous and comprises of several individual pro-
cessing steps.
High shear mixer granulator (HSMG) consists of stainless steel mixing bowl of
typically cylindrical shape, equipped with a three-bladed mixing element, impel-
ler, that rotates at high speed and auxiliary mixing element, chopper. Granulator
bowl is designed with heating/cooling jacket system that can control the tempera-
ture of the material loaded into the granulator. Impeller rotates at high speed of
100–500 rpm. Based upon the position of the rotational axis of the impeller, HSMG
can have vertical or horizontal design. During the granulation process, while
impeller is mixing the loaded powder material, granulating liquid is being added
via solution port and sprayed over powder material. Wetted mass is mixed by the
impeller to achieve uniform distribution of the solution. The role of the chopper,
which is mounted on the side of the bowl or on the lid is to break the wet lumps and
push the material back toward the impeller for proper mixing. Rotational speed of
the chopper is also very high – 1000–3000 rpm. Depending on the nature of the
granulation solvent and its boiling temperature, wet mass can also be dried in the
granulator. Through the heating jacked around the bowl, wet mass is heated to
evaporate the solvent thus resulting in dry granulation at the end. This means that
the granulation and drying process are combined into one continuous processing
stage. If the heating jacket temperature is not sufficient for elimination of solvents
of high boiling temperature, such as water, the wet mass can be transferred onto
trays or loaded into fluid bed dryer for drying stage, i.e., the granulation process
would be discontinuous.
Typical process of wet granulation in high shear granulator has the following
sequential steps:
• Loading of the powder ingredients into the granulator bowl.
• Premixing the ingredients for a short period of time at high speed.
• Liquid addition while mixing at lower speed; chopper may be turned on half way
during liquid addition, once the material starts to become wet.
• Wet mixing at medium to high speed for uniform distribution of the liquid (end
point of wet granulation is often determined through monitoring the power con-
sumption of the impeller).
18 2  Solid Dose Formulations

Fig. 2.4  High sheer wet

granulator

Granulation solvent

Powder ingredients Granulation (mixing, Drying

wetting, nucleation,
densification)

Tableting Blending of granules Milling

Fig. 2.5  Steps of tablet manufacture by wet granulation process

• Drying of the wet mass while mixing at high impeller speed with chopper
turned on.
• Unloading of dried material.
• Milling of the dried material.
There are few advantages of granulation in HSMG – capability to process vis-
cous masses, higher densification, consistent determination of the end point, repro-
ducible granule size, and, last but not the least, shorter processing time (Figs. 2.4
and 2.5).

Hot-Melt Granulation

Hot-melt granulation process is based on melting one or more ingredients which

then become binding agents for the nonmelted powder particles. Binders are in
solid state at room temperature but should melt between 30 and 100 °C. The mol-
ten binder should be tacky, so it can adhere to the powder particles and create
homogeneous molten mass. Upon cooling, the solidified agglomerated mass
should be broken into granules of desired size for further processing. Hot-melt
Tablets Manufacturing Processes 19

granulation can be done in high shear mixer granulators equipped with heating
jacket or in specifically designed auger extrusion systems.
If the melting process takes place in the high shear granulator, the molten mass
should be partially cooled, so the soft mass can be passed through the screen to form
granules. Granules will further solidify upon complete cooling. Optionally, unloaded
mass can be left to completely cool and solidify (without screening) and then the
solid mass will be milled for particle size reduction.
Hot-melt extrusion (HME) technique [6], widely used in plastic material indus-
try, has gained popularity in pharmaceutical manufacturing. It is a process that
can yield in formation of solid dispersion and it does not require solvent. HME
was found suitable for increasing solubility and bioavailability of poorly soluble
drugs. Hence, it is a granulation technique that can modulate properties of powder
materials to make them suitable for further processing, such as compression into
tablets, but at the same time modulating the solubility and/or release rate of the
active ingredient to achieve desired bioavailability. HME is widely used for con-
trolled release formulations.
Process involves combination of melting and extrusion, resulting in formation of
extrudate of desired characteristics. Equipment consists of a barrel with heating
capabilities and a conveyer system with auger design. Mixture of powder materials
is continuously loaded into the heated barrel where it will be moved longitudinally
by a rotating screw. Material will gradually soften and melt while being mixed and
pressured along the way. The temperature in the melting zone should be at least
15 °C higher than the melting point of semicrystalline materials or above the glass
transition temperature for amorphous polymers. Toward the end of the barrel, tem-
perature is reduced (cooling zone) and molten mass is being extruded through die
cavities of defined shape and size. The extrudate slightly expands and increases its
cross section upon leaving the extruder. The strains of extruded material are then
chopped into small pieces to form granules. Critical process parameters that can be
controlled are feeding rate, screw speed, and temperature in different barrel zones.
They affect the melting process by modifying the residence time and shear stress.
Extrusion can be complemented with spheronization step, where the extruded gran-
ules are rotated onto a plate to form spherical pellets.
Process of HME is very complex as it involves many process variables which
need to be well understood during process development. The variables also interact
with each other which may further impact the quality attributes of the extrudate.
However, once process is well developed and understood, it offers advantage of a
robust and continuous granulation with major benefits in development of controlled
release formulations as well as enhanced bioavailability of poorly soluble com-
pounds (Figs. 2.6 and 2.7).

Fluid Bed Granulation

Fluid bed granulation is process of forming granules by spraying the granulation

liquid onto powder particles that are fluidized in a stream of air. Based on the inten-
sity of shear, it is considered medium shear granulation process. Use of fluid bed
20 2  Solid Dose Formulations

Fig. 2.6 Hot-melt extruder

Powder ingredients Melting Extrusion or screening

Tableting Blending of granules Spheronization

(optional)

Fig. 2.7  Steps of tablet manufacture by hot-melt extrusion process

technique for pharmaceutical manufacture began with Wurster in the early 1960s
[7], where he reported possibility to coat and granulate the material, while it is fluid-
ized by heated air.
The equipment consists of large chamber where the hot air is blown from the
bottom in upward direction. Powder material is loaded into the chamber and lifted
by the heated air stream. Granulating liquid is introduced through a spraying nozzle
which spreads the liquid onto moving powder particles. When particles collide,
binder from the solution causes them to adhere to each other thus slowly growing
into granules. At the same time, the solvent is evaporated resulting at the end in
dried granules. The bonding starts with liquid bridges which gradually transform
into solid bridges upon solvent evaporation. The main process parameters are air
flow, temperature, spraying rate, and atomizing pressure. They control the air veloc-
ity (and thus material movement), the temperature of the fluidized air, droplet size,
and rate of granulation. Process requires careful optimization of processing param-
eters, as it can easily result in either lack of granulation or formation of wet lumps.
The equipment is expensive which makes the cost of manufacture fairly high
compared to other granulation techniques. It requires auxiliary equipment such as
air preparation system with heater and humidifier/dehumidifier, filter system to pre-
vent particle loss through the exhaust, and solvent collection system particularly for
organic solvents.
There are numerous advantages of the fluid bed process. Granulation and drying
happen in oneunit operation. Process results in uniform granulation and uniform
drying. Drying efficiency is high due to high surface area and flow of the heated air,
and therefore, it requires much lower temperature for solvent evaporation.
Tablets Manufacturing Processes 21

Fig. 2.8  Fluid bed

granulator

Granulation liquid

Powder ingredients Granulation Blending of granules

(Spraying, drying)

Tableting

Fig. 2.9  Steps of tablet manufacture by fluid bed granulation process

It requires much less liquid compared to other processes. Process can be fully
automated. Disadvantages, besides the high equipment cost, are long resident time,
high porosity of granules, and risk of explosion due to buildup of static charge
(Figs. 2.8 and 2.9).

Selection of Granulation Process

There are multiple options for granulation, each one offering its own advantages
and disadvantages. The manufacturing process should be selected taking into con-
siderations properties of the drug substance and the target product profile to be
achieved. Two main critical drug substance properties are solubility and stability.
22 2  Solid Dose Formulations

Poor solubility will govern selection of process where the drug substance will
dissolve or melt and potentially achieve enhancement of the solubility through
interaction with functional ingredients of the formulation. Susceptibility of the drug
substance toward degradation in presence of moisture, or elevated temperature will
narrow down the selection of manufacturing processes to avoid solvents and heat.
Desired target product profile such as drug release rate will determine selection of
the excipients in conjunction with the manufacturing process. For instance, hot melt
technology with selected polymer may achieve enhanced formulation through for-
mation of solid dispersion, where the drug substance will display solubility over the
saturation solubility of the drug substance on its own.
More than one granulation option may be viable for manufacture of the product.
Understanding the theory of granulation along with knowledge on available tech-
niques will help the formulator to select the optimal one, taking into consideration
the drug substance properties and the goal of the formulation. Selection of appro-
priate granulation process should always be complemented with right choice of
excipients. When multiple processes are proven feasible, the simplest but robust
process with appropriate controls in place should be selected, keeping the cost
effectiveness in mind.
Although the granules as such may represent the dosage form, they are typically
an intermediate product intended to be further processed to produce a finished dos-
age form. Most often, granules are mixed with extragranular excipients and then
compressed into a tablet or encapsulated into a capsule dosage form.

Compression/Tabletting

Tabletting represents process of compression of the granulation or powder mix into

solid compacts of desired shape by applying pressure onto powder. Compression
takes place into the die cavity filled with powder where punches penetrate and exert
pressure onto powder. The sequence of compression process is presented below.
• Die filling – lower punch moves down to create a cavity where powder from the
hopper will fill in. Volume of the die cavity determines the weight of the tablet.
• Compression – upper punch gets into position above the die and moves down-
ward into the die. Particles are entrapped between the lower and upper punches.
As punches penetrate into the cavity, particles first pack closer together and then
under the applied force aggregate into solid compacts.
• Ejection – upper punch moves out and solid compact is expelled from the die
cavity by rising movement of the lower punch. Once tablet is out of the cavity,
surface plate moves it out of the compression table.
Compression machines can have different design and number of compression
stations:
• Single station machine has one compression station  – one die and one set of
upper and lower punches. Force is exerted by upper punch only, while the lower
Capsules 23

punch is stationary. The output is fairly low – up to 200 tablets per minute. Single
station machines are used for experimental purpose only and may be operated
manually or by electric motor.
• Multiple station machines are called rotary presses as they have multiple dies on
a rotary table and multiple sets of upper and lower punches. As the table rotates,
punches pass under or over the pressure rolls which thus apply pressure on
punches. During one rotation, die filling, compression, and ejection step are
completed and tablet is discharged from the press. Considering multiple station
design, at any given moment there are multiple tablets undergoing compression
at different sequence; each station completes compression after one full rotation.
Speed of rotation and number of stations determine the output of rotary presses
which can go very high, up to 10,000 units per minute.
Size and shape of the tablet is determined by the size and shape of the die and
punches. Tablet tooling, i.e., dies and punches are shown in figure (Fig. 2.10).
Dwell time is defined as duration of exposure of the materials to pressure during
compression and it is controlled by the rotation speed and number of stations on
rotary press. Dwell time directly impacts tablet mechanical properties. A main
characteristic of the tablet is the hardness, which is function of cohesiveness of the
materials, force applied during compression, and the dwell time. Tablet hardness is
expressed as force required for breaking the tablet. It will directly affect tablet fri-
ability and it is also correlated to the disintegration of the tablet.

Capsules

Capsules are old dosage forms made with intention to mask unpleasant tastes and
separate unit doses in small “boxes” (lat. Capsula  – box) suitable to be ingested
along with the drug substance. Hence, in general, they consist of the capsule shell
(container) and capsule content with drug substance. The first capsules were made of
starch by French pharmacist St. Limousin. However, due to hygroscopicity of starch,
they were found unsuitable and they were later replaced by gelatin made capsules.
Gelatin capsules are made of gelatin as major ingredient and plasticizer to allevi-
ate brittleness and aid in flexibility. Commonly used plasticizers are glycerol, sorbi-
tol, and propylene glycol. In addition, coloring agents and opacifiers may be added
to achieve the desired appearance. Gelatin capsule can be soft (elastic) or hard cap-
sules. Even though they are essentially the same and differ only in amount of plas-
ticizing agent and water in the shell, they are made with very different processes
(Fig. 2.11).
Soft (elastic) capsules are characterized by sealed continuous gelatin shell. The
shell is elastic as it contains higher amount of plasticizer and water. They are mainly
used for encapsulating liquid (oily) fills, or semisolid content. The formation of the
shell, capsule filling, and sealing happens simultaneously in the same unit operation
using specialized equipment. The shape is spherical, oval, or oblong.
24 2  Solid Dose Formulations

Fig. 2.10  Dies and punches (a) Compression process (b) Rotary tablet press (Source: Jeff Dahl:
https://commons.wikimedia.org/wiki/File:Tablet_press_animation.gif)
Capsules 25

Fig. 2.11  Soft gelatin (a)

and hard gelatin (b)
capsule

5 4 3 2 1 0 00 000

Size Dimensions (mm) Approximate volume

(length ´ body diameter) (ml)

5 11.1 ´ 4.91 0.13

4 14.3 ´ 5.32 0.20

3 15.9 ´ 5.82 0.27

2 18.0 ´ 6.35 0.37

1 19.4 ´ 6.91 0.48

0 21.7 ´ 7.34 0.67

00 23.3 ´ 8.18 0.95

000 26.1 ´ 9.55 1.36

Fig. 2.12  Hard gelatin capsule sizes

Hard gelatin capsules are produced in two separate stages. One is formation of
the empty hard gelatin shell and the second step is filling of the shells with content.
Content is typically powder or granules but can also contain pellets, tablets, smaller
capsules, and rarely semisolids or liquids.
Hard gelatin shells are made by specialized manufacturers. Hard shells made of
alternate materials, such as hypromellose, are also available; however, gelatin made
shells represent the majority on the market. Shells have cylindrical shape and con-
sist of two pieces: capsule body and cap. They come in eight standard sizes to
accommodate for filling of different amount of material (Fig. 2.12).
26 2  Solid Dose Formulations

Capsule Manufacturing Process

Soft Gelatin Capsules

Soft (elastic) capsules are characterized by manufacturing process that simultane-

ously forms the shell, inserts the liquid fill, and seals the shell in the same unit
operation. It requires specialized equipment. Gelatin material and fill material are
prepared separately, and both fed into the machine. Gelatin material is supplied as
warm solution that is dispersed into a thin layer over cooling rollers to form two
ribbons of soft film. The two films come over the die rollers where the films will
take a shape of the die cavities, representing the two halves of the capsule. The die
rollers rotate toward each other. Fill material is injected in the film cavities between
the rollers just before the two halves are hermetically sealed together by aligning to
each other and pressed by the die system. The filled and sealed capsules are released
underneath the die system (Fig. 2.13).

Hard Gelatin Capsules

For hard shell capsules, shells are produced separately by specialized manufacturers
and encapsulation consists of filling the content into the shells. Capsule can be filled
with powder material but also with smaller tablets, soft gelatin capsules, or combi-
nations thereof. Powder filling is the most common type of capsule fill. Hard cap-
sule encapsulation process encompasses several sequential steps:
• Shell opening – detaching the cap from the body
• Filling – powder material is filled into capsule body
• Closing of the filled body by attaching the cap
• Weight checking – to eliminate empty, under filled or overfilled capsules

Fig. 2.13  Soft gelatin

manufacturing process
Capsule Manufacturing Process 27

Similar to powder mixes for tableting, the fill material has to have good flow-
ability to ensure uniform fill weight. Material for encapsulation can be prepared by
simple mixing process, but it can also utilize granulation. Granulation would be
method of choice for improving the flow, densifying fluffy materials, or achieving
and maintaining homogeneity of low dose products. Selection of the ingredients and
process is also driven by the desired drug release profile or necessity to improve the
bioavailability of poorly soluble drug substances.
Encapsulation equipment design can vary to accommodate for the nature of the
fill material. For powder encapsulation as the most common case, powder material
is being picked up by immersing the cylindrical tubes (pistons) into the powder
mass of defined depth (i.e., powder bed). The filled pistons emerge from the
powder bed holding the material within the tube by principle of suction. Then they
move to transfer and release the content into the capsule body. The last step is
aligning the cap and body and applying pressure to close the filled capsule
(Figs. 2.14 and 2.15).

Fig. 2.14  Hard gelatin encapsulation process

Capsule Shells

Capsule fill Encapsulation Weight sorting

(Powder, granules,
pellets, tablets etc.)

Fig. 2.15  Steps of capsule manufacture – hard gelatin capsules

28 2  Solid Dose Formulations

References

1. Lachman L, Lieberman HA, Kanig JL.  The theory and practice of industrial pharmacy.
Philadelphia: Lea & Febiger; 1970.
2. Hasegawa M. Direct compression microcrystalline cellulose grade 12 versus classic grade 102.
Pharm Technol. 2002;26:50–61.
3. Block LH, Morreton A, Apte SP, Wendt RH, Munson EJ, Creekmore JR, Persaud IV,
Sheehan C, Wang H.  Excipients for direct compaction—an update. Pharm Dev Technol.
2009;11:111–24.
4. Shanmugham S. Granulation techniques and technologies: recent progresses. Bioimpacts.
2015;5(1):55–63.
5. Acevedo D, Muliadi A, Giridhar A, Litster JD, Romañach RJ. Evaluation of three approaches
for real-time monitoring of roller compaction with near-infrared spectroscopy. AAPS
PharmSciTech. 2012;13(3):1005–12.
6. Patil H, Tiwari RV, Repka MA. Hot-melt extrusion: from theory to application in pharmaceuti-
cal formulation. AAPS PharmSciTech. 2016;17(1):20–42.
7. Teunou RE, Poncelet D. Batch and continuous fluid bed coating—review and state of the art.
J Food Eng. 2002;53(4):325–40.
Chapter 3
Stage 1A Process Design: Quality
by Design

Abstract  Quality by design (QbD) (US FDA, Quality by design for ANDAs: an
example for immediate-release dosage forms, 2012) approach in product develop-
ment has become a norm as Regulatory Agencies are basing their decisions on sub-
mitted product on the review of the scientific information generated and presented
in a systematic way. It reduces the issues and burden at process validation stage and
throughout the commercial manufacture. Consequently, it reduces the need for post
approval changes driven by processing issues but also facilitates approval of process
improvement changes that may fall within the originally studied design space.

Keywords  Quality by design · Process design · Quality target product profile ·

Critical quality Attributes · Critical process parameter · Control strategy ·
Design space

“The aim of pharmaceutical development is to design a quality product and its

manufacturing process to consistently deliver the intended performance of the prod-
uct. The information and knowledge gained from pharmaceutical development
studies and manufacturing experience provide scientific understanding to support
the establishment of the design space, specifications, and manufacturing controls”
(ICH Q8(R2)). International Conference on Harmonization (ICH) covers QbD prin-
ciples in product development in several Guidance documents  – ICH Q8 (R2)
(Pharmaceutical Development), ICH Q9 (Quality Risk Management), and ICH Q10
(Pharmaceutical Quality System) which have been imposed by Regulatory
Agencies. Each Guidance discusses QbD aspects at different stages of product
development and product life cycle, as illustrated in Fig. 3.1.
Development of a product starts with defining the goal to be achieved, i.e. sum-
mary of desired attributes of a new product. This is quality target product profile
(QTTP). Some of the desired attributes may not be critical for product quality and
its selection may be driven by preference (e.g., color or shape of the tablet).
However, there are attributes that are critical to product performance, i.e. critical
quality attributes (CQA) of the drug product. In order to ensure they are adequate
and consistently met, series of studies are to be done to properly understand fac-
tors that may have an impact on CQA, its magnitude and acceptable boundaries.

© American Association of Pharmaceutical Scientists 2018 29

A. B. Pazhayattil et al., Solid Oral Dose Process Validation, AAPS Introductions
in the Pharmaceutical Sciences, https://doi.org/10.1007/978-3-030-02472-7_3
30 3  Stage 1A Process Design: Quality by Design

Quality Drug Product

process
manufacturing
monitoing and
product design process design process
continued
qualification
verification
ICH Q8 (R2) Pharmaceutical Development

ICH Q9 Quality Risk Management

ICH Q10 Pharmaceutical Quality Systems

Fig. 3.1  Drug product development

• route of admiistration
• dosage form
Define QTPP • desired PK profile (efficacy)
• safety

Formulation • composition
design • process

CQA of • identify CMA of active, excipients

Product • identify CPP

Control • CMA
strategy • CPP

Product development

Commercial implementation

Fig. 3.2  Overview of QbD process

Accordingly, controls over these factors are to be established. These factors may
be associated with critical material attributes (CMAs) for the active and inactive
ingredients or critical process parameters (CPP) for the drug product. Accordingly,
for all CMA and CPP that affect drug product CQA, appropriate ranges are pro-
posed as an outcome of the studies, representing the control strategy (CS) for
product manufacture (Fig. 3.2).
3  Stage 1A Process Design: Quality by Design 31

The QbD principle in product development is based on establishing a correlation

between formulation and manufacturing variables on the one side and CQA of the
product on the other. Formulation and the selected manufacturing process can have
impact on each other. Material attributes of active and inactive ingredients may
have an impact on the selection of the type of manufacturing process and process
parameters. Likewise, the manufacturing process is essentially a tool to alter mate-
rial attributes toward desired behavior. Establishing these relationships requires a
series of systematically planed experiments, i.e., design of experiments (DoEs).
Data collected during the experiments are to be carefully evaluated, using statistical
tools, in order to arrive at the right conclusion on the criticality of each studied
parameter. Consequently, acceptable ranges for all critical parameters of the materi-
als (active ingredient and excipients) and ranges for critical process parameters for
all processing steps are derived. This will ensure consistent quality performance of
the drug product with minimum batch-to-batch variability in CQAs (Fig. 3.3).
Following are the elements of the QbD approach:
1 . Quality target product profile (QTPP)
2. Critical quality attributes (CQAs)
3. Critical material attributes (CMAs)
4. Critical process parameters (CPPs)
5. Design of experiments (DoE)
6. Control strategy over CMA and CQA
7. Process capability and continual improvement

FORMULATION
Critical Material
Attributes (CQA) for
drug substance &
excipients)
DRUG PRODUCT
Critical Quality
Attributes (CQA)

MANUFACTURING
Critical Process
Parameters (CPP)

Fig. 3.3  Components of QbD approach

32 3  Stage 1A Process Design: Quality by Design

Quality Target Product Profile (QTTP)

Quality target product profile determines the strategy in development of the product.
The main goal is to develop a product which will primarily have desired therapeutic
efficacy, but at the same time be safe for the patient population. There are multiple
elements to be considered while defining the target for product development. They
are all connected and need to be considered collectively:
• Intended use in clinical setting
• Route of administration
• Dosage form
• Delivery system
• Dosage strength
• Intended release of the therapeutic ingredient
• Container closure system
• Drug product quality criteria
Route of administration is select based on the intended use in a clinical setting.
For instance, if it requires rapid onset, it may be administered as inhalation, or onto
oral mucosa (e.g., sublingual tablet, oromucosal spray), but if it is for local action
on skin, it can be administered topically. Next, depending on the route of adminis-
tration and desired bioavailability profile, a suitable dosage form should be selected.
For example, if intended for peroral application, it could be in the liquid (solution,
suspension) or solid dosage form (tablet, capsule, etc.). While selecting the dosage
form, target patient population should be considered. If it is intended for young
children, it will be preferably liquid form for ease of administration. If it is intended
for elderly people, size of dosage form should be small for ease of swallowing, or
alternatively it should allow for sprinkling over food. An example would be a cap-
sule product filled with pellets or mini-tablets that can be opened and sprinkled onto
food before swallowing.
Based on the desired release profile of the therapeutic ingredient, the target
release profile will be defined. Quality attributes of the product will be selected
dependent of the type of dosage form and desired release profile. Last but not the
least is container closure system which should be carefully selected. The system is
not only a “holding” container but a key factor that ensures a suitable environment
for maintaining drug product attributes over the shelf life. In some cases, container
closure system is an integral part that defines the dosage form and serves as a device
for drug product administration (e.g., nasal spray product).
In a case of development of a generic product, QTPP is largely defined by the
profile of the innovator’s product. Noncritical attributes (appearance, color, shape)
can be different, but attributes critical to product performance must be met. Generic
products should be pharmaceutically equivalent, encompasing the same active
ingredient, same dosage form, route of administration, and strength. Again, certain
differences are allowed, (e.g., different release profile due to difference in the
­formulation design) as long as they do not impact safety and efficacy that have to be
demonstrated similar to the innovator.
Critical Process Parameter (CPP) 33

Critical Quality Attribute (CQA)

Once the target product profile is defined, quality attributes for the drug product
should be identified. Quality attributes are identity, purity (degradation product,
microbial contamination, residual solvents), assay, content uniformity, dissolution,
water content, or physical attributes (color, size, shape of the tablet, score line, hard-
ness, etc.). Quality attributes can be identified [1] as critical or noncritical based
upon the severity to cause harm to the patient if not met. Consequently, CQAs are
properties of the drug product that need to be met at all times during product shelf
life to ensure the therapeutic efficacy and safety of the product.

Critical Material Attribute (CMA)

Critical Material Attributes are properties of the drug substance and inactive ingre-
dients that may have an impact on CQA of the product. Knowledge and understand-
ing of the drug substance’s physical, chemical, and biological properties are
fundamental to the development of a quality drug product. The formulator should
consider physical characteristics of the drug substance, such as polymorphic form
and particle size, as they may significantly impact the solubility rate for poorly
soluble compounds. Chemical stability and factors that may trigger or facilitate
unwanted degradation reactions should be well understood to be able to be sup-
pressed or controlled. For example, if the drug substance is sensitive to heat, manu-
facturing processes that involve heating, such as wet granulation, should be avoided.
Each of the CMA for the drug substance should be studied to establish acceptable
ranges for drug product performance. Excipients and components are selected such
that they are compatible with the drug substance and serve the purpose of designing
a dosage form with the desirable product profile. The formulator has to have thor-
ough understanding of their properties, functionality, and criticality, not only to
achieve the target product performance, but also to ensure that the product is robust.
For instance, viscosity of the release rate controlling polymer can impact the drug
product dissolution and, therefore, its effect on this product CQA should be studied
during product development. Hence, during the product design stage, CMAs for
each of the components in the formulation have to be identified, in order to study
their impact and establish appropriate controls that will ensure consistent product
performance.

Critical Process Parameter (CPP)

The chosen manufacturing process can impact the quality attributes of a drug prod-
uct as each unit operation can affect product quality. Hence it is important to evalu-
ate each manufacturing step, define potential impact of each of the process
34 3  Stage 1A Process Design: Quality by Design

parameters against different CQAs, and based on the risk assessment, select those
that requires to be studied to establish their acceptable operational ranges.

Design of Experiments (DoE)

Formulation development process is essentially based on knowledge and under-

standing of the two major elements – materials and manufacturing process. During
the product design stage, they need to be studied to determine their impact on drug
product CQA. In order to facilitate the development process and arrive at unbiased
study conclusions, Design of Experiments (DoE) is used [2]. It represents a system-
atic approach used in initial screening experiments to select the critical factors as
well as to study the impact of selected CMA and CPP on product performance. In
ICH Q8(R2), DoE is defined as “a structured, organized method for determining the
relationship between factors affecting a process and the output of that process”.
DoE employs statistical tools in knowledge-based product development. Prior
knowledge and experience with similar products and formulations are comple-
mented with DoE. Methodology can vary – full factorial, fractional factorial, central
composite Placket-Burman, Box-Behnken design [3]. Key factors are systemati-
cally varied and their effect on predefined output parameters is assessed. Ultimately,
the CMAs and CPPs are identified and their optimal ranges that ensure product
quality are established. Thus, the design space for the product is created.

Control Strategy (CS)

Based upon studies on CMA and CPP, a set of predefined controls for the materials
and manufacturing process parameters are derived. This set of controls represents a
control strategy that will ensure a robust and reproducible manufacturing process
resulting in a product of consistent quality. Control strategy encompasses specifica-
tions for drug substance, inactive ingredients and components, operating parameters
for each manufacturing step, in-process controls, as well as finished product
specifications.

Process Capability and Continual Improvement

The robustness of the manufacturing process is assessed by calculating the process

capability index, derived from the six sigma concept. The calculation is based on
analysis of available data from manufactured batches and serves to predict risks
associated with future product manufacture. Process capability index is calculated
based on the difference of the actual observed data from the upper and lower limit
References 35

of specification, divided by six times standard deviation. Index values higher that 1
suggest the process is robust. During the life cycle of the product, product quality
parameters and product performance indicators are continuously monitored and
analyzed. Accumulated data is used for trend analysis. Considering the additional
experience with the product, changes to the product may be introduced as continual
improvement. This may include changes to material attributes or process parame-
ters. Changes may be done within the previously established design space, or the
design space may be expanded based on additional knowledge gained.

References

1. Maguire J, Peng D.  How to identify critical quality attributes and critical process parame-
ters, Office of Process and Facility (OPF) OPQ/CDER/FDA, FDA/PQRI 2nd conference,
North Bethesda, MD. 2015.
2. Torbeck LD.  Pharmaceutical and medical device validation by experimental design.
Boca Raton: CRC Press; 2007.
3. Cavazzuti M.  Optimization methods: from theory to design. Berlin, Heidelberg: Springer-­
Verlag; 2013.
Chapter 4
Knowledge Management and Risk
Assessment for Life Cycle Stages

Abstract The foundation of pharmaceutical development is knowledge and

understanding. However, the general knowledge is not sufficient for making scien-
tifically sound decisions for the specific product, but rather a starting point of prod-
uct development. International Conference on Harmonization (ICH) Q9 provides a
systematic approach to quality risk management. It gives the principles and tools
of quality risk management to make risk-based critical decisions in process valida-
tion life cycle. The tools proposed are recognized across the industry for risk man-
agement purposes. Assessment of risk to quality is based on sound scientific
knowledge and based on patient impact. FDA process validation guidance high-
lights the need to using risk-based decision-making. The level of risk assessment is
determined by the complexity of the scenario. Quality risk management tools are
enabling tools (Stocker et al., J Pharm Sci 106:278–290, 2017). Selection of fit for
purpose tools (Strong, The risk of trusting risk priority numbers. AAPS
Newsmagazine, 2017) and use of the appropriate tools are critical at each stage of
the process validation life cycle.

Keywords  Knowledge management · Product development · Risk assessment ·

Knowledge space · Process design

Knowledge management (KM) [1] is a method of capturing, storing, distributing,

and utilizing explicit, implicit, and tacit knowledge to improve product knowledge
and process understanding. Big data allows harnessing the magnitude of informa-
tion generated by pharmaceutical organizations across the product life cycle [2].
The manufacturing data including process parameters, equipment, facility, calibra-
tion, environmental conditions, and qualification ensures continuous improvement
of product development, and process enhancements. Knowledge gained across
Stage 1. Stages 2 and 3 ensure continuous improvement resulting in minimal
potential for process failures. The data on sufficiently similar products and pro-
cesses at commercial scale provides confidence of product quality. US FDA pro-
cess validation guidance and Annex 15 of European Medicine Agency recommend
commercialization once the Stage 2 data has established a high degree of product
and process understanding and demonstrated adequate process controls.

© American Association of Pharmaceutical Scientists 2018 37

A. B. Pazhayattil et al., Solid Oral Dose Process Validation, AAPS Introductions
in the Pharmaceutical Sciences, https://doi.org/10.1007/978-3-030-02472-7_4
38 4  Knowledge Management and Risk Assessment for Life Cycle Stages

Fig. 4.1  Knowledge management through life cycle stages

Knowledge management is an enabler as per International Conference on

Harmonization (ICH) Q10 Pharmaceutical Quality System. KM ensures that the
product control strategy is current while enabling continuous improvement. KM of
all three stages of the process validation life cycle ensures a risk-based and data-
driven decision-making process as desired by the regulators (Fig. 4.1).

Knowledge Base for Development

Knowledge base incorporates facts, skills, scientific literature, and experience. It

encompasses knowledge of drug substance (DS), available inactive materials that
may be chosen for the formulation, understanding of pharmaceutical processes
and packaging components, and, most importantly, how they may correlate to the
quality attributes of drug products (DPs). Even though it is a necessary prerequi-
site for pharmaceutical development, it should never be considered as substitute
for conducting experiments and performing data analysis. General knowledge
should be combined with experiments and data analysis to be able to objectively
assess all the factors and arrive to conclusions for the specific product. Its primary
role would be in assessing the risks associated with each of the factors (CMA and
CPP) in order to plan and design appropriate studies for confirmation of the poten-
tial impact. Accordingly, knowledge is only an initial tool in pharmaceutical QbD
development that is complemented with systematic approach in assessing the risk
factors, performing experiments, and arriving with unbiased conclusions based on
data analysis.
ICH Q9 Quality Risk Management 39

ICH Q9 Quality Risk Management

The systematic approach identified by ICH Q9 quality risk management includes

risk identification, risk analysis, and risk evaluation, outlined for developing risk
control strategies. A risk is a combination of probability of occurrence, its harm and
severity. Effective risk management strategies need to be applied to life cycle pro-
cess validation for quality outcomes. The application of the risk assessment meth-
odologies is across the product’s life cycle. Risk management provides a means to
control and manage the risks associated with developing and commercializing drug
products. As per ICH Q9, quality risk management is a systematic process for the
assessment, control, communication, and review of risks to the quality of the drug
(medicinal) product across the product life cycle. A model for quality risk manage-
ment is outlined in the diagram. The emphasis on each component of the frame-
work might differ from case to case but a robust process will incorporate
consideration of all the elements at a level of detail that is commensurate with the
specific risk (Fig. 4.2).

Risk Assessment

The assessment involves identification of the hazards. The assessment of risks with
the exposure to hazards gives the sense of magnitude. The risk question should be
very clear prior to embarking on a risk assessment exercise. Risk identification
involves a systematic information application to identify the hazards with respect
to the risk question. The information applied can be similar product/process data,
theoretical constructs, and experience. Risk analysis is the estimation of the risk
associated with the hazards identified. It links with the likelihood of its happening.
The risk evaluation compares the identified risks against given risk criteria.

Risk Control

Risk control includes decision-making to reduce the risks. The risks are reduced to
an acceptable level. The steps take to reduce the risk should commensurate with the
level and significance of the risk identified. The risk control strategy can be devel-
oped by multiple methodologies. Risk reduction is the mitigation steps for quality
risks when it’s beyond the acceptable levels. Risk reduction typically includes the
steps taken to minimize severity and probability. The detection methods can be used
to reduce quality risks as part of the risk control strategy. Risk reduction plans can
also introduce additional risks to the process. Therefore, additional risk assessment
measures are to be taken upon such activities. The acceptance act of risk is termed
as risk acceptance. The acceptance of residual risks is done in certain cases.
However, for drug products the risk reduction should be maintained at an acceptable
level before proceeding with advanced stages of process validation life cycle.
40 4  Knowledge Management and Risk Assessment for Life Cycle Stages

Fig. 4.2  ICH quality risk management

Risk Communication

When the risk management information is shared with the decision-makers, it

becomes risk communication. The different stages of risk management are com-
municated. This communication is well documented as decision-maker’s act on
such notices. Such communication in process validation life cycle stages includes
the ones to regulators, industry, patients, etc. Risk acceptance is always done
through communication to decision-makers.

Fit for Purpose Risk Assessment Tools for Life Cycle

Many innovative risk assessment tools are available. Some of these tools include:
• Failure mode effects analysis (FMEA) [3]
• Failure mode, effects, and criticality analysis (FMECA)
• Fault tree analysis (FTA)
R isk Assessment in Life Cycle Stages 41

• Hazard analysis and critical control points (HACCP)

• Hazard operability analysis (HAZOP)
• Preliminary hazard analysis (PHA)
Basic risk management facilitation methods include:
• Flowcharts
• Check sheets
• Process mapping
• Cause and effect diagrams (also called an Ishikawa diagram or fish bone
diagram)

Risk Assessment in Life Cycle Stages

Risk assessment is performed across all life cycle stages (Fig. 4.3). In particular,
preformulation risk assessment, technical risk assessment prior to scale-up, and pre-­
PPQ risk assessments are part of Stage 1 activities. The approach to each PPQ study

Fig. 4.3  Risk assessments at stages – flowchart

42 4  Knowledge Management and Risk Assessment for Life Cycle Stages

will be tailored to the needs of the product, as defined in a detailed risk assessment
performed prior (Stage 1B) to the drafting of the study protocol (Stage 2B). The
principle being applied is that the number of batches, sampling plans, acceptance
criteria, and ongoing monitoring will reflect the outstanding risks identified. Launch
products will receive an initial risk assessment following publication of the formu-
lation development package. This is a systematic examination of all aspects of the
potential risk arising from formulation, process, and packaging for their impact on
critical quality attributes of the product. The output from this risk assessment is
documented in the technical risk evaluation (TRE) along with details of develop-
ment studies performed as part of the Phase 1 validation cycle. The TRE outline the
approach to scale-up, whose details are specified in the Technology Transfer
Protocol (TTP). Once executed, the demonstration batches are reported in the tech-
nology transfer report (TTR). The TTR contain an updated version of the earlier risk
assessment which captures any risks which have been modified or mitigated based
on the completion of one or more full-scale batches. The TTR then propose the
approach to Stage 2B PPQ for launch.
PPQ studies of previously validated product will also begin with a risk assess-
ment, based on past history and the nature of the proposed changes. Where a change
has been made to the formulation, process, or packaging as a result of a remediation
study, the report (technical summary report, TSR, or experimental report, EXR) will
incorporate the risk assessment of that change and will propose a Stage 2B PPQ
strategy. Additionally, cumulative effect of all changes is also evaluated through risk
assessment. In all cases where a previous risk assessment exists, any further valida-
tion activity will prompt a review and need to be updated based on the most recent
information.

Risk Assessment at Stage 1

Quality risk management is covered in ICH Q9 guideline. ICH Q9 is defining sys-

tematic approach in quality risk management in pharmaceutical industry and does
not specifically discuss the risk assessment for pharmaceutical development.
However, principles of risk assessment management and tools available are appli-
cable to product development stage. Process of risk assessment involves risk identi-
fication, risk analysis, and risk evaluation. At the initial stage of product development,
risk assessment is performed to identify factors that may have an impact on CQA of
the drug product and to assess the level of risk that is anticipated. At this stage, it is
the knowledge that guides the scientist during the assessment.
At initial risk assessment stage, CMAs are assessed with regard to identified
CQAs of the drug product. Examples of initial risk assessment for identified CMA
of the drug substance and excipients on drug product CQA are shown in Tables 4.1,
4.2, 4.3, and 4.4.
Each of the assessments (low, medium, high risk) should be supported with
scientific rationale. If the risk is ranked as low, there is no need for further inves-
tigation. However, medium- and high-risk attributes require further studies to
R isk Assessment in Life Cycle Stages 43

Table 4.1  Example of risk assessment for CMA of the drug substance on drug product CQA

DS CMA
Particle Chemical Residual
Polymorphism Impurities
size stability solvents
DP CQA

Assay Low Low N/A Low Low

Content
Medium Low N/A Low Low
uniformity

Impurities Low Medium N/A Medium Low

Disintegration
Low Low N/A Low Low
time

Dissolution High Low N/A Low Low

Relative risk ranking:

Low risk: No further investigation is needed
Medium risk: Further investigation may be needed
High risk : Further investigation is needed
N/A: Not applicable

establish a correlation with CQA of the drug product. As an outcome of the stud-
ies, design space and/or control space will be derived. Establishing the control
space means defining the control strategy over CMA that may impact the CQA of
the drug product. Control strategy mitigates the risk as it ensures the identified
medium- and high-risk CMAs are maintained within the range of values where
they will not jeopardize any of the CQAs of the drug product and the CQAs will
consistently meet desired target product profile. Control strategy is a risk mitiga-
tion strategy.
Accordingly, upon completion of the studies, formulation risk assessment for the
CMA of the drug substance and excipients is updated.
Critical process parameters (CPPs) that may impact drug product CQA should
be identified for each unit operation/processing step. Figure 4.4 shows an example
for capsule product manufactured using dry granulation process by roller compac-
tion. Once CPPs are identified, risk assessment will assign an appropriate risk level.
Example of risk assessment for the encapsulation step is shown in Table 4.5.
Based upon initial risk level assigned, studies will be designed to explore the
impact of each factor and establish correlation between each input parameter with
corresponding output parameter (CQA of the drug product). Based upon data
­analysis of these studies, operating ranges for CPPs that will result in acceptable
CQAs of the drug product will be established. These ranges represent the control
strategy for the identified CPP and they define the control space. Operating within
44 4  Knowledge Management and Risk Assessment for Life Cycle Stages

Table 4.2  Example of risk assessment for CMA of the excipients on drug product CQA

Drug product CQAs

Excipients material Content Disintegration

Assay Impurities Dissolution
attributes uniformity time

Diluent type Low Low Low Medium Medium

Diluent level Low Low Low Medium Medium

Binder type Low Low Low High High

Binder grade Low Low Low High High

Binder level Low Low Low High High

Disintegrant type Low Low Low High High

Disintegrant level Low Low Low High High

Lubricant level Low Low Low Low Medium

Glidant level Low Low Low Low Low

Relative risk ranking:

Low risk: No further investigation is needed.
Medium risk: Further investigation may be needed
High risk: Further investigation is needed.
N/A: Not applicable

this range mitigates the risk of drug product failures for any of the CQAs. In addi-
tion, depending on the study design and extent, an operating space wider than the
one defined with control strategy may be established that may be of use as support
for any future changes, i.e., design space for the operating parameters. Upon com-
pletion of the studies, risk assessment for the CPP is updated (Table 4.6).
Design Space 45

Table 4.3  Example of updated risk assessment for the CQA of drug substance

DS CMA
Particle Chemical Residual
Polymorphism Impurities
size stability solvents
DP CQA

Assay Lowa Lowa N/A Lowa Lowa

Particle
Content
size Lowa N/A Lowa Lowa
uniformity
controlled

Impurity Impurity
Impurities Lowa level N/A level Lowa
controlled controlled

Disintegration
Lowa Lowa N/A Lowa Lowa
time

Particle
Dissolution size Lowa N/A Lowa Lowa
controlled

aLow risk: Low risk from initial risk assessment

Systematic Experiments

DoE is an excellent tool to plan experiments for evaluation of the identified factor.
Each factor is changed within predefined range in planned manner and the impact
on identified CQA is measured. DoE allows studying a combined effect of multiple
input parameters as they may impact jointly the same CQA.  Of course, it is the
knowledge that will provide a basis for selecting the factors to be evaluated in com-
bined manner during the risk assessment stage. Similarly, based on knowledge, cer-
tain extreme combinations of input parameters can be omitted as they may not be
feasible and/or unlikely to yield a product.
Mechanistic models are used to establish correlation between input and output
parameters. Significance of the change of the output with changing the inputs is
objectively assessed through statistical parameters. Also, interaction between the
parameters can be studied and objectively evaluated using statistical tools.

Design Space

An extensive study of interrelationship between the CMAs, CPPs, and CQAs dur-
ing product development can lead to defining a design space. ICH Q8(R2) defines
the design space as multidimensional combination and interaction of input
46 4  Knowledge Management and Risk Assessment for Life Cycle Stages

Table 4.4  Example of updated risk assessment for the CQA of excipients

Drug product CQAs

Content Disintegratio
Excipients material Assay Impurities uniformit n time Dissolution
Attributes y

Diluent type Diluent type Diluent type

Lowa Lowa Lowa
fixed fixed

Diluent level Diluent level Diluent type

Lowa Lowa Lowa
fixed fixed

Binder type Binder type Binder type

Lowa Lowa Lowa
fixed fixed

Binder grade Binder grade Binder grade

Lowa Lowa Lowa
fixed fixed

Binder level Binder level Binder level

Lowa Lowa Lowa
fixed fixed

Disintegrant type Disintegrant Disintegrant

Lowa Lowa Lowa
type fixed type fixed

Disintegrant level Disintegrant Disintegrant

Lowa Lowa Lowa
level fixed level fixed

Lubricant level Lubricant

Lowa Lowa Lowa Lowa
level fixed

Glidant level Lowa Lowa Lowa Lowa Lowa

aLow risk: Low risk from initial risk assessment

variables (e.g., material attributes) and process parameters that have been demon-
strated to provide assurance of quality. Any combination of parameters that falls
within the design space is expected to result in quality product. Design space and
control space (defined by proposed control strategy) are not to be considered the
same (Fig.  4.5). Design space incorporates the control space but also spreads
beyond it. Defining the design space is not a regulatory requirement but brings
many benefits. Proposed design space is subject to regulatory assessment and
approval during the review process. Once approved, during the life cycle of the
product, if any parameter is to be changed outside the control space but within the
design space, it is not considered a change that requires regulatory approval. It is an
intention of product development to determine the design space and allow for flex-
ibility in modifying the CQA or CMA during product life cycle as a part of continu-
ous process improvement. Hence, it is in industry interest to establish the design
space. This will not only aid in managing the life cycle changes to the product, but
Design Space 47

Fig. 4.4  Identification of CPPs

Table 4.5  Example of risk assessment of CPPs for CQAs of the drug product – encapsulation step

Unit Operation CPP ENCAPSULATION

Compression adjustment Encapsulation speed

CQA

Particle size distribution of the

N/A N/A
blend

Bulk density of the blend N/A N/A

Blend uniformity N/A N/A

Weight variation Low High

Disintegration Low Low

Dissolution Low Low

Assay Low Med

Content uniformity Low High

Relative risk ranking:

Low risk: No further investigation is needed
Medium risk: Further investigation may be needed
High risk : Further investigation is needed
48 4  Knowledge Management and Risk Assessment for Life Cycle Stages

Table 4.6  Example of updated risk assessment of CPP for CQA of the drug product  –
encapsulation step

Unit Operation , CPP ENCAPSULATION

Compression adjus tment Encapsulation speed

CQA

Particle size distribution of the

N/A N/A
blend

Bulk density of the blend N/A N/A

Blend uniformity N/A N/A

Weight variation Critical,

Lowa
PAR identified

Disintegration Lowa Lowa

Dissolution Lowa Lowa

Assay Lowa Critical,

PAR identified

Content uniformity Lowa Critical,

PAR identified

PAR: Proven acceptable range

N/A: Not applicable

aLow risk: Low risk from initial risk assessment

also help to get better understanding on robustness of the product manufactured

within the control space. Operating the processes close to borders of the design
space is risky, as normal process variations may bring the process outside the
boundary. Nevertheless, control space is always tighter than design space to prevent
unexpected outcomes. Wider the design space relative to control space, product is
more robust.
Design space encompasses several elements. Composition or formulation of
design space is defined by experiments conducted by varying the composition com-
ponents, their grades, or levels. Likewise, process design space will be defined by
acceptable ranges of process parameters established based upon planned study on
impact of process parameters on product CQAs.
Defining the design space combines the results of all DoE studies for CMA and
CPP. Each factor can affect the CQA independently. In order to obtain design space,
effect of multiple independent factors should be considered in combined manner
(Fig. 4.6).
Design Space 49

Control
Design
Knowledge space
space
base

Fig. 4.5  Design space vs. control space

900
900
800
800
700
700
Factor 2

Factor 2

600
600
500 Dissolution 500
Design Space Hardness
400 Design
400
Space
300
300
0.1 0.2 0.3 0.4 0.5
0.1 0.2 0.3 0.4 0.5
Factor 1
Factor 1

900

800

700
Factor 2

600

500
Combined
400
Design Space
300
0.1 0.2 0.3 0.4 0.5
Factor 1

Fig. 4.6  Combined design space

50 4  Knowledge Management and Risk Assessment for Life Cycle Stages

Formulation element of the design space is not likely to be dependent on

batches scale. However, process design space may depend on the scale as the
equipment proposed for scale-up manufacture will be different than the laboratory
scale. Larger scale equipment will have different process parameters. Hence,
design space established at laboratory scale may not be directly applicable to
large-scale manufacture. The ranges for CPP established at laboratory scale would
need to be extrapolated to large-scale equipment. At this stage, again knowledge
base is fundamental. Proposed scaled-up ranges should be derived scientifically
using comparison of the laboratory scale and large-scale equipment. Various fac-
tors are taken into consideration. First, the design and operating principle of the
equipment should be similar. Geometric similarity of the laboratory and large-
scale equipment is essential for some processes. Keeping the same percentage fill
(occupancy) of the material in the equipment is required for maintaining compa-
rable processing conditions. Similarity of kinematic factors such as rotational
speed that would dictate movement of the material during the processes should be
considered. When it comes to processes that require heating, transfer of the heat
should also be compared. Accordingly, process design space for scale-up process
may be defined. However, at this point, risk assessment tools are to be utilized to
assign the level of risk associated with the scale-up. Prior experience with similar
processes may be useful to understand the risks and extrapolate the design space.
Adequacy of the theoretically derived scaled-­up operational ranges is subject to
verification at large scale. Of course, it is not feasible to reestablish the entire
design space at larger scale. If confirmed for selected settings at larger scale, it
increases assurance in mathematical approach and scientific justification used in
scaling-up of the design space. Accordingly, scale-up correlation for the design
space is based on semiempirical approach in extrapolating the data from experi-
mentally based laboratory-scale studies. Consequently, it reduces the risk where a
change needs to be implemented within the scaled-up design space, or the control
space needs to be relaxed.
Fact that pharmaceutical processes involve multiple unit operations increases
the complexity and multiplies the risk. Each one brings its own risk that may also
impact consecutive processes or unit operations. Not all the unit operations need
to have established design space. It is matter of decision made during risk assess-
ment to fully explore only selected unit operations that are considered most criti-
cal. However, when interpreting the data, possible impact on changes to selected
unit operation on downstream processes must be considered for potential
interactions.
Design space can be modified or expanded during the product life cycle as
more data become available for analysis. Sometimes, change to the design space
may require additional verification. For instance, if new equipment is introduced
to replace the original one, or manufacturing site is changed, verification will be
needed. The additional data collected may support further expansion of the
design space.
References 51

References

1. Koenig ME. What is KM? Knowledge management explained. KM World Magazine. 2018.

2. Pazhayattil AB, Ingram M, Sayeed-Desta N. Cross-sector intelligence: the prospects for data
convergence in biopharma. Life Science Connect. 2018.
3. Bhattacharya J. Quality risk management –understanding and control the risk in pharmaceuti-
cal manufacturing industry. Int J Pharm Sci Invent. 2015;4:29–41.
Chapter 5
Stage 1B Process Scale-Up Considerations

Abstract  Processes ready for commercialization post Stage 1A need to demon-

strate capability for commercial scaling. Commercial scale-up studies are con-
ducted as part of Stage 1B process design activities. The manufacturing process is
evaluated to estimate effect of scale. Product control strategy is optimized post
Stage 1B studies. The successful completion of the stage ensures readiness for
process performance qualification.

Keywords  Scale-up · Process design · Critical process parameter · Stage 1A ·

Manufacturing process

A quality by design approach to new product development based on ICH Q8 defines

a product’s design space. An initial risk analysis, in accordance with ICH Q9, is
used to establish which variables and unit operations are likely to have the greatest
impact on product quality. This effort establishes all critical process parameters and
their proven acceptable ranges for new products. The processes are challenged at
the edges of failure and demonstrated evidence of product quality within PARs is
provided. Process parameters should be identified as critical when a change can
result in failure to meet the QTPP. Process parameters should not be considered
critical when there is no trend of failure and there is no evidence of significant inter-
actions within the proven acceptable range (PAR). Trials are carried out to establish
appropriate control strategies to minimize the effects of variability in material attri-
butes and process parameters on CQAs.

Process Scale-Up Studies

The manufacturing process (e.g., an immediate release solid dose product) should
be evaluated at scale wherein sufficient quantity of material is used to demonstrate
the capability of the commercial scale manufacturing equipment. A series of opti-
mization batches should be created to evaluate critical stages in the process.
Manufacturing steps should be evaluated in order to determine the steps that most

© American Association of Pharmaceutical Scientists 2018 53

A. B. Pazhayattil et al., Solid Oral Dose Process Validation, AAPS Introductions
in the Pharmaceutical Sciences, https://doi.org/10.1007/978-3-030-02472-7_5
54 5  Stage 1B Process Scale-Up Considerations

significantly impact the quality attributes of the finished product. At each critical
process stage, parameters should be explored over a range of settings, with appro-
priate sampling and testing, in order to determine settings for commercial manufac-
ture. Proposed acceptance criteria for quality attributes and processing parameters
should be established for all manufacturing stages based on the demonstrated ability
to meet the desired requirements.
Summary of a solid dose manufacturing process design, as an example:
• Screen active and excipients using a Comil fitted with 0.032R screen
• Blend the milled materials in a suitable-sized in blender
• Compact the blended material using a compactor, evaluating the compaction
parameters during the compaction study
• Add screened material and over blend, evaluating parameters blend time
analysis
• Compress the granulation into tablets, evaluating the press parameters through
Compression Specification Range Determination studies.

Blend Time Analysis

Blending steps are critical in the manufacture of all pharmaceutical solid dosage
forms containing multiple ingredients. It ensures blend homogeneity. All blending
stages are performed in bin blenders of similar design. For commercial use, a scale-
­up was proposed to an 80 ft3 (900 kg) bin blender; no other changes were required.
Extensive prior knowledge experience with the use of the bins in the manufacture
has demonstrated that blend times are transferable. The FDA PV guidance recom-
mends use of previous credible data with sufficiently similar products and pro-
cesses. A PV life cycle management software solution enables identification of like
products, determination of similar processes with comparable formulation (%
active), screening of raw materials with similar physical characteristics, identifica-
tion of products with common blend batch size/bin fill, comparable blend bulk den-
sity, acceptable blend uniformity (BU) results etc. This ability to retrieve essential
information thus negated the need for determining blend process parameters by
acquiring additional raw materials for multiple full-scale batches, additional manu-
facturing floor time for trial purposes, and associated resources. The approach based
on sound science ensured establishing the blend process parameters prior to Stage
2. Similar formulations in 80  ft3 bin blender were assessed. The blend process
parameters were similar for six formulations. There is low risk therefore to adapt the
same process parameters for this scale-up total of 15 min of mixing at 10 rpm. The
product characteristics were also considered. A bin fill-level of 67% was chosen to
have optimal mixing in the 80 (900 kg) bin as the increase is close to the optimum
recommended level of 70% helps in having relatively better sheer among particles
in addition to axial/radial mixing, improving mixing dynamics. The blending pro-
cesses with kinematic (same number of revolutions) similarity were adapted. In
order to verify suitability if blend times, demonstration batches were initiated.
Process Scale-Up Studies 55

Table 5.1  Blend time analysis results summary

Blend Blend
80 ft3 bin 4 ft3 bin
Batch # 1234 Batch # 5678
Measure 5 min 10 min 15 min 10 min 15 min
Minimum (%) 96.9 98.2 97.5 98.7 98.4
Mean (%) 98.7 98.6 98.2 99.4 99.1
Maximum (%) 99.5 99.1 98.8 99.9 99.7
SD (%) 0.8 0.3 0.5 0.4 0.4
Development specification
Individual results 90.0–110.0%, SD NMT 3.0%

Samples were removed to verify that the manufacturing process is capable of

producing a suitably homogeneous blend. The results of these blend studies, as
indicated in the Table 5.1, suggest that in the 4.0 and scaled up 80 ft3 bin blender
provide adequate blending with the estimated parameters, demonstrating the scal-
ability of the blending stage. Assessment of BU variability – product to product and
within product – batch to batch may be statistically determined [1].

Compaction

Compaction was identified as a critical step in the manufacturing process as the

physical properties of the granulation have been demonstrated to affect powder flow
and compressibility during tablet compression. Control of the compaction process
is provided by three main parameters:
1 . The force applied to the compact being formed (compaction force)
2. Roller gap width
3. Speed at which the compact is formed (compaction roller speed)
In order to evaluate the range and optimum value for each of these settings,
experimental studies were performed to explore both the values for each parameter
systematically using a design of experiments which will produce a granulation
which can be successfully compressed. Granulations produced according to the
design of experiments were compressed into tablets and tested against the proposed
acceptance criteria. The compactors used during process optimization are the same
model as the compactors used for manufacturing commercial batches; therefore, the
results obtained at this stage are directly transferable to commercial scale
manufacture.
In addition to the equipment settings, the sieve profile and density of the granula-
tion produced at this stage must remain similar between manufactured batches in
order to minimize variation during the dosing of the granulation into the final dos-
age units. In order to ensure similarity of granulations between manufactured
batches, in-process acceptance criteria for the granulation were established through
56 5  Stage 1B Process Scale-Up Considerations

Fig. 5.1  Parameter estimates

Table 5.2  Compaction CPPs

Setting Target Proven acceptable range (PAR)
Compaction force (kN/cm) 10 4.0–18.0
Roll speed (rpm) 3.0 2.0–8.0
Roll gap width (mm) 2.5 2.0–4.0
Screen size (μm) 800 Fixed

evaluation of results of the granulations produced using design of experiments for

compaction parameters in combination with test results of granulations produced
during manufacture of all other experimental trials and batches. Different granula-
tion parameter ranges were evaluated. The design of experiments was conducted
using a 23−1 fractional factorial design for the critical compaction parameter ranges.
The blend uniformity results and % SD values depict that all the DoE batches had
uniform blend distribution.

Summary of DoE Influence of Process Parameters on CQA

A statistical model incorporating interactive and polynomial terms was used to eval-
uate the effect of the independent variables on the dependent variables. The analysis
can be conducted by linear regression using statistical software such as JMP [2].
There was no impact of compaction parameters on granule attributes. Example
below shows that it does not have a significant effect on the dissolution of the tablets
(Fig. 5.1 and Table 5.2).
As a result of these studies and data from all other applicable trials, targets and
ranges were established for the compaction critical process parameters, as
presented.

Tablet Compression

Compression was identified as a critical manufacturing stage as this unit operation

creates the dosage form. The compression speed range is optimized for a specific
tablet press, as this speed range can affect the ability of the press to ensure that
individual tablet weights are maintained within limits. Tablet press speed also
Control Strategy Components 57

Table 5.3  Summary of compression force versus tablet in-process CQAs

Compression force Hardness Thickness Friability Dissolution (%)
(kN) (kp) (inches) (%) @60 min
10.5 1.2 0.154 0.3 99
11.0 1.3 0.151 0.2 100
11.7 2.3 0.148 0.1 99
12.4 2.8 0.146 0.1 98
12.9 2.9 0.143 0.2 101
13.2 3.2 0.143 0.2 99
13.6 3.8 0.143 0.2 98

impacts the compression dynamics such as the time available for powder to fill into
the die cavity, the dwell time during compression, and the application of force
between upper and lower punches. These parameters are press specific, though
inferences can be made between similar presses. Acceptance criteria for hardness
and thickness were established during a Compression Specification Range
Determination study [3]. During the study, the blend was compressed into tablets
over a range of compression forces, producing tablets of minimum and maximum
hardness while still maintaining other relevant physical attributes such as accept-
able friability and appearance (free from any sticking, picking, capping, etc.).
These tablets were also tested for dissolution, content uniformity, and assay, veri-
fying the ability of tablets manufactured at the extremes of these ranges to meet the
predetermined quality attributes. Tablets were also manufactured at low weight and
high weight, verifying the ability of tablets within the determined acceptable
weight range to meet all other acceptance criteria. As a result of these studies,
optimized tablet press speeds for compression using the presses were established.
Acceptance criteria for hardness and thickness were also established based on the
extremes of the observed values. Should the product be manufactured on another
tablet press, the press speed is re-­evaluated during Stage 2B, while the physical
acceptance criteria will remain constant. Further, compression force was gradually
increased to achieve the hardness and samples were withdrawn at intermediate
stages. The effect of compression force and hardness on the critical quality attri-
butes is summarized (Table 5.3).
The compression force (10.5–13.6 kN) and hardness (1.2–3.8 kp) do not have
any significant impact on the dissolution of the finished product. The press speeds
(10–45 rpm) were confirmed to produce tablets of acceptable weight variation and
other critical properties. Based on evaluation of data from all relevant batches, the
originally proposed ranges were considered suitable.
58 5  Stage 1B Process Scale-Up Considerations

Table 5.4  Proposed control strategy

Critical process
Equipment parameters PAR Target NOR Justification
Initial blending process variables
Comil Comil screen 0.032R 0.032R 0.032R Ensure de-agglomeration of
Blending blend
Blending time (min) 10, 15 15 15 To ensure blend uniformity
Blending speed (rpm) 10 10 10 To ensure blend uniformity
Compaction process variables
Compactor Compaction force 4.0– 10.0 6.0– To ensure CQA’s are
(kN) 18.0 12.0 consistently met
Roller speed (rpm) 2.0–8.0 3.0 2.0–6.0
Screen size (um) 800 800 800
Roller gap (mm) 2.0–4.0 2.5 2.0–4.0
Final blending process variables
Bin Screen 0.032R 0.032R 0.032R To ensure blend uniformity
blender Blending time (min) 5 5 5
Blending speed (rpm) 10 10 10
Compression process variables
Tablet Compression speed 10–45 45 10–45 To ensure CQA’s are
press (rpm) consistently met

Control Strategy Components

A product control strategy is derived from current product and process understand-
ing as well as prior knowledge to ensure process performance and product quality.
The strategy includes:
• Control of starting material attributes, in terms of critical quality attributes
• Control of equipment
• Control on operating ranges (Critical Process Parameters)
• Specification of critical quality attributes of in-process materials
• Specifications on critical quality attributes of the finished product
The following table provides an example of a proposed control strategy for the
identified critical process parameters (Table 5.4).
A QbD-based product and process characterization allows for development of an
effective control strategy. Further, a Stage 3 CPV program allows for continued
improvement of the control strategy during the life cycle. A Stage 3a program is
integral in enhancing control strategy for newly launched products. Guidance’s such
References 59

as ICH Q12 proposes tools such as Post Approval Change Management Protocols
(PACMP) [4] for changes including revision of equipment process parameters,
within the proven acceptable ranges of the design space. The product/process owner
is responsible to define any potential impact based on scale-up and post approval
changes (SUPAC) guidance [5], the product/process understanding gained, and
studies performed.

References

1. Sayeed-Desta N, Pazhayattil AB, Collins J, Doshi C.  A science and risk based prag-
matic methodology for blend and content uniformity assessment. AAPS PharmSciTech.
2018;19(3):1483–92.
2. SAS. Statistics for FDA process validation using JMP software, SAS. 2018.
3. Nayak BK, Elchidana P, Dixit M, Sahu PK. QbD approach: tablet compression process optimi-
zation using design of experiments. Int J Pharm Sci. 2016;38(2):45–53.
4. Pazhayattil A, Sayeed-Desta N, Iyer V. ICH Q12 post approval change management protocol:
advantages for consumers, Regulators and Industry, RAPS. 2017.
5. US FDA.  Guidance for Industry: Immediate release: solid oral dosage forms scale-up and
post approval changes: chemistry, manufacturing, and controls, in vitro dissolution testing, and
in vivo bioequivalence documentation, CDER, CMC. 1995.
Chapter 6
Stage 2A and Stage 2B: Process
Qualification

Abstract The process qualification stage verifies that the commercial process

developed is capable of reproducible commercial manufacturing. Stage 2 is required
prior to product commercialization and establishes the process with scientific evi-
dence that it is capable of consistently delivering quality drug products. Qualification
activities for facility, equipment, and utilities (Stage 2A) are conducted prior to use
in commercial Stage 2B activities.

Keywords  Process qualification · Stage 2A · Stage 2B · Commercial distribution ·

Statistical assessment acceptance criteria · FDA

 tage 2A: Design and Qualification of the Facility, Equipment,

S
and Utilities

Preceding commercial manufacturing of products for distribution, all facilities,

utilities, and equipment used are to be qualified for their design, installation, and
operation for intended use, cleaning, maintenance, and performance suitably. This
includes facility design and commissioning prior to Stage 2B or process perfor-
mance qualification. Qualification activities for facilities, utilities, systems, manu-
facturing, and packaging equipment include risk management to determine impact
on product quality attributes. To determine the level of activities required on the
performance and documentation of qualification activities depends on the potential
risk associated. ASTM 2500 “Applied Risk Management for Commissioning and
Qualification” may be used to assess the criticality of each equipment, utility, and
system on the potential to impact product quality attributes. General qualification
activities of any equipment intended for manufacture of drug products prior to pro-
cess qualification activities include installation qualification (IQ), operational quali-
fication (OQ), and performance qualification (PQ) [1].
Documents and procedures necessary to properly operate and maintain the sys-
tem need to be in place prior to use in production of pharmaceutical products.
Qualification should be executed by trained personnel with maintained training
records and in accordance with predetermined and approved qualification protocols

© American Association of Pharmaceutical Scientists 2018 61

A. B. Pazhayattil et al., Solid Oral Dose Process Validation, AAPS Introductions
in the Pharmaceutical Sciences, https://doi.org/10.1007/978-3-030-02472-7_6
62 6  Stage 2A and Stage 2B: Process Qualification

and standard procedures. Results of qualification activities should be recorded in

approved qualification reports. Validation Master Plan (VMP) should specify the
overall policy, organization, planning, scope, and stages applied in qualification of
all equipment, systems, utilities, and facilities that impact the quality of a drug prod-
uct as agreed by management.
The four qualification stages that are needed to determine if processes are deemed
suitable need to follow a logical sequence:
1 . Design qualification (DQ)
2. Installation qualification (IQ)
3. Operational qualification (OQ)
4. Performance qualification (PQ)
All utilities and equipment should be maintained in a qualified state and periodi-
cally reviewed for requalification need. Changes made need to be assessed through
appropriated change control systems and the impact of the change assessed as per
quality risk management principles to determine testing required to maintain the
qualification status (Fig. 6.1).
All processes used to manufacture pharmaceutical product should be validated
on qualified equipment to ensure batch to batch consistency. Equipment released
for routine use requires documented evidence of its successful qualification status.
Where not all stages of qualification are required for new systems, documented
impact assessment and scientific justification are required to support the decision.
Systems such as computerized systems, water purification systems, steam systems,
production and quality control of equipment and instruments. In cases where some
stages of qualification are conducted by third parties, it is the responsibility of the
manufacturer to ensure qualification is completed in accordance with GMPs.

Fig. 6.1  Model for direct impact systems

Stage 2A: Design and Qualification of the Facility, Equipment, and Utilities 63

Predelivery inspections (PDI) and factory acceptance tests (FAT) that occur before
delivery to the manufacturing site support qualification activities. FAT may be per-
formed at the supplier’s location prior to shipping the equipment. This process
allows for a timely remediation of potential issues prior to equipment delivery
hence maintaining scheduled qualification activities. As recommended in the
International Society for Pharmaceutical Engineering (ISPE) Baseline guidance
[2], efforts should be made to incorporate both PDI and FAT. One of the first steps
in FAT is verification of documentation, specifications and components, alarms,
and controls. In addition to the test cases, a placebo batch is run to establish the
tablet press capability at controlling tablet weight. In-process checks for tablet
thickness, hardness, and weight are verified during the test. FAT results are reviewed
prior to acceptance.

Design Qualification (DQ)

This is the first stage of the qualification process, whereby the documented evidence
that the premises, supporting systems, utilities, equipment, and processes have been
designed in accordance with the requirements of good manufacturing practices.
Suitable suppliers should be selected and approved for the facility, utility, system, or
equipment based on definitive requirements assessment.

Installation Qualification (IQ)

IQ is the first step in qualifying any equipment and is the process of verifying the
installation of the equipment and that the critical components are installed correctly
and meet the design requirement specifications. It is a formal and systematic check
of all installed equipment against the supplier’s specifications and additional criteria
identified by the user. IQ activities should be carried out in accordance with an IQ
protocol and the execution documented in an IQ report. The IQ protocol outlines the
roles and responsibilities, approach, equipment description, functional description,
utility requirements, critical instruments, and devices. Sufficient design detail
should be available, including:
1 . Process and instrumentation diagram (P&ID)
2. Instrument list
3. Material certifications
4. Spare parts list
5. Change parts list
6. Installation check sheets
7. Lubricants schedule
64 6  Stage 2A and Stage 2B: Process Qualification

Any instrument or device that can impact the safety, integrity, strength, and
purity (SISPQ) [3] of a drug product is considered critical and should be calibrated
and tested appropriately during IQ.  The tests and challenges should be repeated
enough times to provide assurance of reliability of results. Preventative mainte-
nance schedule including calibration, maintenance, and cleaning for the equipment
is developed during this stage. Documented PDI and FAT of systems, or major
components, are normally carried out prior to delivery to the site.

Operational Qualification (OQ)

OQ of equipment is part of final qualification activities before performance qualifi-

cation or process validation activities can begin. It is documented verification pro-
cess that ensures the individual components and systems operate as specified within
established limits and tolerances of parameters. OQ verification includes tests that
challenge and verify operating ranges and key process parameters that regulate the
process or product quality simulating routine commercial production. All tests are
performed in accordance with an approved protocol. OQ plans may include, but not
limited to:
1 . Power failure and restoration test
2. Equipment alarms and faults confirmation test
3. Security testing
4. Sequence testing
5. Operational testing
6. Instrument/control devices OQ
The OQ protocol should clearly list all critical operating parameters and their test
functions. Standard operating procedures (SOPs) and training program need to be in
place prior to the execution of the OQ protocol. The critical process parameter
ranges for a process being developed are established within the equipment qualified
ranges. The completion and approval of the OQ reviewed results as a formal sum-
mary report is required prior to the start of performance qualification.

Performance Qualification (PQ)

Performance qualification step of equipment qualification is conducted where

required. In this phase procedures, personnel, systems, and materials are integrated
and their combined performance to produce the required output is verified. This step
demonstrates that the process will produce acceptable product under normal operat-
ing conditions. PQ testing should cover the operating range of the intended process,
unless documented evidence from the development phases confirming the opera-
tional ranges is available. PQ may be conducted in parallel with OQ with clear
documentation to differentiate.
Stage 2A: Design and Qualification of the Facility, Equipment, and Utilities 65

Through all stages of qualification, design, construction, commissioning,

changes are to be managed through a quality management system. Appropriate
quality oversight and approvals are required for any changes made to equipment,
systems that impact product quality. Impact assessments from appropriate func-
tional groups need to be documented. The ongoing qualified state throughout the
life of the facility, equipment, and systems involved need to be maintained.

I mpact of Product and Process on Facilities, Utilities,

and Systems

Introduction of a new product and/or process has an impact on the existing or newly
commissioned facilities, utilities, and systems. Multiple factors should be consid-
ered for new product launch or site transfers to a new or existing facility. This sec-
tion describes the industry best practices and factors to consider when introducing a
new product and/or process that impacts facilities, utilities, and other systems. The
direct impact system is designed and commissioned in line with the good engineer-
ing practices as well as qualification practices. Per Good Engineering Practices
(GEP) [4] related to facilities, utilities, and equipment the following factors should
be considered:
1. cGMP design and installation with health, safety, environmental, operational,
maintenance, statutory, and regulatory requirements
2. Documentation of design, drawings, tests, manuals, inspections, and

certifications
3. Construction management, standard procurement practices, installation, and

commissioning

Impact Assessments During Commissioning and Qualification

Commissioning entails a well-planned and managed engineering approach to estab-

lish facilities that meet the design requirements in a safe and functional environ-
ment. The impact assessment begins with an enhanced design review that reduces
business risk. An enhanced design review (EDR) ensures the conformance of opera-
tional and regulatory expectations. The EDR provides a structured review of the
design of facilities, utilities, and equipment. Since the EDR is performed early in
the process design, problems at the IQ, OQ, and PQ qualification stages are mini-
mized. Manufacturer manuals are evaluated to ensure feasibility on the basis of
facility, utility, and system requirements.
Systematic commissioning execution activities assure that there is adequate
planning and preparation associated to successfully manage the project between
physical completion and turnover to qualification. The V-Model is applicable
for systems requiring qualification. The model mandates that the performance,
construction, operational requirements should be known for qualification, which is
66 6  Stage 2A and Stage 2B: Process Qualification

Fig. 6.2  HVAC system

in alignment with the ASTM E2500 requirement [5]. Installation qualification veri-
fies the construction and installation, operational qualification verifies the functional
requirements, and performance qualification verifies the user requirements and
challenges a collection of systems working together with specific tests. Part of
reconfiguring a cGMP suite for a new equipment, a system impact assessment is
required. As an example, the heating, ventilation, and air conditioning (HVAC) sys-
tem, a critical facility requirement, is discussed. The system works on the principle
of air volume exchange by varying the temperature of supplied air with a fixed fresh
and recirculated air volume. The critical parameters for the system are differential
room pressure, temperature, relative humidity, and particulates. An HVAC system
includes duct work, prefilters, heating coils, chilling coils, fans, and high efficiency
particulate air (HEPA) filters (Fig. 6.2).
When new products and processes are introduced, the HVAC requirements for
the room such as air changes and HEPA filters are evaluated.

Technology Transfer Considerations

The introduction of new products or processes requires good understanding of the

product formulation as multiple input variables (e.g., raw material) introduce poten-
tial complexities that determine the system operating parameters. To assure minimal
impact to facilities, utilities, and systems, a planned evaluation for each of the key
areas is required. The technical transfer project should consider the risks associated
with the transfer of product/process from R&D to commercial or the transfer of
product/process between sites. A gap analysis between the product control strategy
Technology Transfer Considerations 67

Table 6.1  Gap analysis for new products

Task Components
Facility assessment Review of:
 Technical risk assessment and product control strategy for
understanding of CPPs
Gap analysis on:
 Plans and layouts of facility
 Building (construction and finish)
 Qualification status (DQ, IQ, and OQ)
Equipment selection and transfer Gap analysis on:
 List of all equipment and associated utilities, systems
 Make, model
 Qualification status (DQ, IQ, OQ, PQ)
 Drawings and manuals
 Standard operating procedures (setup, operation, cleaning,
maintenance, calibration, storage)
Process transfer: Manufacturing Development history and report:
and packaging  Process description
 Process flow chart
 Rationale for specifications
 Change control assessment
 Critical process parameters
 Master Batch Manufacturing and packaging record

and the facility should be performed to identify the requirements associated with
adapting existing equipment or the need for acquiring new equipment. Assessment
tasks are summarized (Table 6.1).
The building facility and location of all equipment should be considered when
the process maps/process flow charts are determined. This includes flow of person-
nel and material. The impact of manufacturing the new products on currently manu-
factured products that will utilize the same equipment should be determined.
A technology transfer strategy is initiated with risk assessment of key areas. The
assessment includes facilities, utilities, and systems. The risk evaluation should
include the layout, construction, and finish of building and services (e.g., HVAC,
temperature, relative humidity, water, power, and compressed air) as specific prod-
uct and process requirements are different. Similarly, a risk assessment of the equip-
ment make and model involved in the manufacture, filling, packaging, and control
of the product/process should be performed. Steps should be defined to mitigate
identified risks. In addition, the impact of product and process on health, safety, and
environment should be assessed. This includes an understanding of the risks associ-
ated with handling of equipment and utilities. cGMP requirements should be satis-
fied and the intended production volumes and batch sizes should be considered.
Select factors for evaluation include:
1 . Minimum and maximum capacity
2. Material of construction
3. Critical operating parameters
4. Critical equipment components (e.g., filters, screens, sensors)
68 6  Stage 2A and Stage 2B: Process Qualification

5 . Critical quality attributes

6. Range of intended use
The technology transfer activities (R&D to commercial or between sites) follow
the ASTM E2500 recommendations for risk-based approach [6]. Critical quality
attributes (CQAs), critical process parameters (CPPs), process control strategy
information, and prior production experience are all considered for product technol-
ogy transfer.

Checklist Prior to Initiating Stage 2B

Prior to initiating the Stage 2 studies, a thorough technical risk assessment (deter-
mining impact of individual material attribute or process parameter to finished prod-
uct quality attributes) should be performed. Information from similar products can
be utilized to perform the scale-up risk assessment. A fit for purpose risk assessment
methodology need to be applied. All critical risks need to be identified and miti-
gated or an adequate control strategy implemented prior to proceeding with Stage
2B activities.
The below functional checklist may be used, as applicable, to assure prerequi-
sites is complete prior to Stage 2B (Table 6.2).

Stage 2B: Process Performance Qualification

The process designed in Stage 1 is confirmed and demonstrated in Stage 2B to

perform as expected for commercial manufacturing to meet all quality attributes
with demonstrated control. At this stage of the life cycle, the facility, utilities,
equipment, personnel, control procedures, components, and manufacturing process
used to manufacture commercial product are qualified. Supporting data from all
relevant studies including Stage 1 is evaluated. Process robustness, consistency,
and controls are part of the scientific evidence required to declare the process per-
formance qualification as successful providing assurance of delivering quality
commercial batches.
During PPQ studies, heightened sampling and testing than routine commercial
manufacturing is required to confirm process consistency through all process stages.
Experience with similar processes may be used to determine the frequency and
sampling points during the process. The complexity of the process and experience
with similar products and processes are some of the factors that can be used to deter-
mine the appropriate validation strategy and testing requirements for the PPQ
batches. A protocol is required that specifies the manufacturing conditions, controls,
processing parameters, limits, testing requirements, verification of input materials,
analytical methods, and acceptance criteria. The protocol is to be reviewed and
Stage 2B: Process Performance Qualification 69

Table 6.2  Prestage 2B checklist

# Documentation/requirements Yes/no
1 Enhanced design review ✓
2 Preinspection delivery ✓
3 Factory acceptance test ✓
4 System impact assessment ✓
5 Commissioning report ✓
6 Operating manual ✓
7 Installation qualification protocol/report ✓
8 Operational qualification protocol/report ✓
9 Performance qualification protocol/report ✓
10 Preventive maintenance schedule ✓
11 Calibration reports ✓
12 Validation master plan ✓
13 Product development report (CPP, NOR, CS) ✓
14 Technology transfer report ✓
15 Standard operating procedure (operation, cleaning, PM, ✓
calibration)
16 Quality management system (change control) ✓
17 Continued process verification procedure ✓
18 Utilities qualification (HVAC, compressed air) ✓
19 Technical risk assessment report ✓
20 Personnel training records ✓

approved by appropriate areas, including the quality, unit prior to execution of PPQ
batches. Based on risk assessment of the product a sampling plan needs to be derived
that provides good statistical confidence of quality within and between batches
throughout the process. Number of batches required to estimate this confidence
statistically is recommended [7]. The protocol should include a detailed sampling
plan that specifies the sampling points, number of samples, and the frequency of
sampling at each unit operation. Process performance indicators and statistical
methods to evaluate intrabatch and interbatch variability need to be described.
PPQ batches should be executed under normal commercial production condi-
tions and trained personnel who are expected to routinely perform each processing
step as per routing procedures. The evaluation of data should be based on sound
science and the manufacturers understanding of the product and process. Statistical
methods and tools may be used to derive meaningful analysis and objective mea-
sure of product quality based on the criteria and process performance indicators.
Any departures from the protocol, procedures or acceptance criteria are investi-
gated and discussed in the report. The report is to evaluate all data and clearly
conclude if the data indicates the process is considered to be in a state of control.
The documented justification and approval of the report by appropriate depart-
ments and the quality unit are used to release lots to market and produce future
commercial batches.
70 6  Stage 2A and Stage 2B: Process Qualification

Process Performance Qualification Protocol

The PPQ Protocol is a written, preapproved plan stating how a PPQ study will be
conducted. PPQ Protocols are generated according to internal standard operating
procedures or work instructions. The typical sampling and testing requirements as
well as the typical equipment parameters monitored during validation of specific
manufacturing processes are generally outlined in the SOP or work instruction.
Exceptions to the typical sampling/testing plan may be included in the PPQ
Protocol along with appropriate justification. Any changes to validated processes
are evaluated as described and necessary revalidation measures initiated. The PPQ
strategy is established at Stage 1B, and documented in an approved report.
Evaluation of in-­process holding times, where necessary, will typically be detailed
as a separate protocol, appended to the main document. Submission Protocols are
generated for the purpose of regulatory submissions. Submission protocols follow
the general requirements as described under PPQ Protocol; however, they may not
contain as much detail as PPQ Protocols since they might be written prior to scale
up activities.
The PPQ Protocol defines the PPQ study requirements. The protocol considers
the Stage 1 activities and provides directives and criterial for the study. They
include:
1. The purpose and objectives of the study
2. Determine number of batches for PPQ study
3. The materials used in the study
4. Roles and responsibilities for execution of PPQ batches
5. Acceptance criterial including statistical criteria
6. Directives on change and deviations during PPQ study
7. Specifications, master documents, and methods to be used in the study
8. Facilities, equipment, and utilities
9. Training requirements
10. Reporting and interpretation of results

Sampling and Testing Plan (Stage 2B)

Sampling plans are developed to demonstrate that the process can be considered
in-control and reproducible. Internal standard operating procedures (SOPs) and
work instructions (WIs) outline the typical PPQ sampling requirements for each
manufacturing process as well as the process parameters typically monitored during
the PPQ study. The standard sampling plan detailed in the WIs may be modified for
each individual product based on the risk evaluation performed on the process,
batch size, and run time to ensure sufficient samples are obtained to represent all
significant portions of the batch and their respective risks. Blend sample sizes are
generally approximately 3 unit doses; however, in some cases a larger blend sample
Stage 2B: Process Performance Qualification 71

sizes may be required for low active (<25% active) products or where sampling bias
due to smaller sample size is suspected based on historical development data and/or
previous PPQ data. These additional requirements are specified in the individual
product-specific protocol.
Sampling of the production processes is performed according to the PPQ
Protocols and In-Process Sampling Work Instructions; the samples are tested as per
the validated analytical method for each product. Where ongoing routine commer-
cial blend sampling has been submitted and is required, this sampling may not be
performed on the PPQ blend batches provided the extent of the validation sampling
exceeds the requirement for blend sampling of routine commercial batches. This
will be documented in the PPQ Protocols. Data will be obtained from the dosing
process in a stratified manner from beginning to end of the dosing process and
include a determination of the tailing end point by sampling for uniformity at
increased frequency from the end of each dosing run. This exercise can be com-
pleted during the verification and/or optimization study and referenced in the PPQ
protocol.

Process Analytical Technology (PAT)

It is allowed for the substitution of conventional sampling and analysis with process
analytical technology (PAT) [8] based alternative technique, governed by approved
standard operating documents. The PAT methods for the in-process product mea-
surement and process adjustment should be validated and equipment and instru-
mentation used are qualified. PAT provides continuous process verification;
evaluation of PAT derived data will be part of the APR trending.

Acceptance Criteria (Stage 2B)

Processes are considered validated if they comply with the acceptance criteria
developed within each PPQ Protocol. Any deviation from the protocol’s acceptance
criteria is documented via the quality deviation reporting system or in the report and
investigated to determine root cause and corrective action required.
As required, additional acceptance criteria may be included in a PPQ Protocol
depending on risk assessment of changes being made to manufacturing processes.
Statistical analysis will be performed on the PPQ batch results to determine the
confidence level for future specification compliance. Tools and techniques will be
used in the analysis, in order to support conclusions such as interbatch consistency
and process control. Individual protocols may also include a similar requirement
where submissions to regulatory agencies reflect the individual requirements par-
ticular to a specific market.
72 6  Stage 2A and Stage 2B: Process Qualification

Incidents, Failures, and Deviations (Stage 2B)

Any test failures during process validation must be documented and investigated
to determine the cause of failure and whether the failure or deviation impacts the
PPQ study. Where the failure can be attributed to an occurrence which is not
intrinsic to the process, for example, an equipment failure or a faulty raw material,
then it can be agreed to complete the validation exercise substituting another batch
for the one that failed, for example, if there is an equipment failure during the
manufacturing of the second batch, then it is only necessary to include an addi-
tional batch in the study. This investigation and the subsequent action and justifi-
cation shall be included in the validation report. Where the failure may be attributed
to a process failure, or where the process-related investigation is inconclusive, the
validation study will be closed and process remediation will be initiated, as
required. Repeating the validation exercise with no justifiable changes to the pro-
cess is not acceptable. Unless there is a demonstrable process change, the vali-
dated state of the process must be evaluated referencing the failed batch(es) and
corrective actions.

Process Performance Qualification Report

PPQ study of production processes is completed when all aspects of the PPQ
Protocols are executed and acceptable results are obtained. A PPQ report is written
upon completion of the study (or interim report if Stage 2 concurrent release) and
includes all predetermined data gathered during the study, investigations, evaluation
of the results, process capability. The PPQ report documents the decision to con-
sider the production successfully completing Stage 2B stage. A certificate may be
issued to define the milestone. Report addendums are meant for the purpose of
revising an approved report. An addendum will discuss the justification for and
details of the changes with reference to the original document. Executable protocols
are acceptable and are meant for special projects encompassing multiple strengths
or products.
The report summarizes the PPQ study. The primary objective of the PPQ report
is to justify that the manufacturing process consistently delivers quality products. It
confirms that the manufacturing process as designed is reproducible during com-
mercial manufacturing. The following sections are included in a PPQ report:
1. Discussion on the overall study run
2. The batches, equipment, and components used in the study
3. The parameters and settings applied
4. Scope of the study including the hold times and run details, dates
5. Equipment make and model, qualification, and calibration status
6. Yield of operations
7. API summary
8. Results discussions of each unit operations
Stage 2B: Process Performance Qualification 73

9. Run charts and assessments

10. Overall summary of the study
11. Deviations and incidents
12. Change control requirements
13. Statistical assessments
14. Conclusion of the study

Statistical Tools (Stage 2B)

The process validation Stage 2B report will include discussions around any inter-
batch variability: results of the demo batch may also be included in these calcula-
tions. Statistical process capability (Cpk) and other tools can be applied to the
process and results if sufficient data is available. This will encompass blend unifor-
mity, content uniformity, dissolution, as well as any critical parameter, as appropri-
ate, specific to the manufacturing process of the product.

Type of Studies

Prospective PPQ Study

Process validation PPQ study needs to be completed successfully (full execution of

Stages 1A, 1B, 2A, and 2B) and a high degree of assurance in the process achieved
before commercial distribution of either a new product or a product made under a
modified production process, where the modifications are significant and may affect
the product’s characteristics.

Concurrent PPQ Study

PPQ study can, in exceptional circumstances, be designed to release one or more

batches for distribution before complete execution of the protocol requirements. In
order to qualify for concurrent release, a product must have a history of good per-
formance at the scale proposed for validation: it will not be considered for launch of
new products. If this criterion is met, concurrent release may be permissible in the
following special circumstances:
1 . Products for which there is limited demand.
2. Products that have short shelf-lives.
3. Products that are medically necessary and are being manufactured in coordina-
tion with a regulatory authority.
The justification for conducting concurrent release must be fully described in the
protocol and rarely used. Where a concurrent release approach is used, an interim
74 6  Stage 2A and Stage 2B: Process Qualification

PPQ report shall be prepared and approved prior to the distribution to market of
each batch, and a final report shall be prepared and approved after the completion of
all study batches.

Approaches to Consider
Matrix Approach

A matrix approach may be applied to a prospective PPQ study for a product family
which has a number of strengths, or strength combinations, where the formulations
are closely related. The protocol will be based on sound scientific principles, com-
prehensive product risk assessment, and thorough understanding of product and
process. Similar products and processes can be considered for a matrix approach
(sampling, testing, monitoring) during validation. The intent of such an approach is
to gain sufficient assurance of future product performance through a focus on the
products which represent the highest risks which includes the extremes of strengths
or ratios of strengths.

Market Equivalency

Market equivalency studies can be performed to compare the validation status of

one market to new market poised for launch based on equivalency of formulation,
manufacturing process, testing methods, acceptance criteria, and API source. A
market equivalency study may conclude that no additional validation is required or
that any specific differing part of a process require for validation which will be
executed in accordance with a written and preapproved market equivalency
protocol.

Site Transfers

A risk assessment will be performed for site transfers to determine the requirements
for PPQ. The quality systems and standard operating procedures used at both facili-
ties within the company will be compared. A prospective study is required; how-
ever, validation strategy will be based on the outcome of process risk assessment
and a regulatory strategy regarding the site changes.

Unacceptable Validation Approach

Retrospective validation is no longer considered as an acceptable PPQ approach.

Where this had been applied previously, a prospective PPQ approach will be used
to gain the necessary assurance of future product performance. Data from
Stage 2B: Process Performance Qualification 75

previous retrospective validation studies as well as historical data from the com-
mercial batches manufactured may, however, be used as a source on which to
perform a product risk analysis in order to determine an appropriate prospective
validation strategy.

PPQ for Legacy Products

In the case of legacy products where the process was not necessarily developed in
accordance with ICH Q8 principles, revalidation activities require a different
approach. Gaps in the historic validation studies need to be identified and opportu-
nities to close those gaps need to be planned. The criticality and quality risk of the
identified gaps need to be understood and prioritized. A firm’s quality system,
change management system, risk management system, and process knowledge of
the product are important elements in defining the validation strategy for legacy
products. Based on the current and historic product data and information, it is pos-
sible to establish the CPPs and CQAs for a given process in order to monitor and
control it through its life cycle. The number of batches required for revalidating a
legacy product for changes depends on the firms continued process verification
program. The intent of validation is to provide assurance that a process is capable
of producing quality product that meets all predetermined requirements. Availability
of monitoring data will provide the assurance of process variation and control
which can further be complimented with Stage 2B data. Application of the life
cycle approach to legacy products is just as instrumental as its application to new
products (Fig. 6.3).

Qualification of Changes

Any change to a validated process is made in accordance with the internal Change
Control Program. Critical process changes will trigger a Stage 1 and Stage 2 study
and will be completed under a unique change control reference number. Batches

Fig. 6.3  Stage 3–1–2

approach [9]
76 6  Stage 2A and Stage 2B: Process Qualification

Table 6.3  Change types – PPQ

Type of change PPQ review
Formulation
Change to a formulation
 Addition of raw material (e.g., addition of minor excipient) x
 Removal of raw material (e.g., removal of minor excipient) x
 Substitution of one raw material for another (e.g., change in critical
excipient, change to different excipient) x
 Substitution of one grade or standard of raw material for another x
 Alteration of the concentration of a raw material x
 Alteration of the absolute quantities of raw materials (e.g., same
excipient, different proportions) x
Process change
Change to a manufacturing, filling, or packaging process
 Scale-up or scale-down of batch size x
 Addition of equipment x
 Removal of equipment x
 Substitution of equipment x
 Modification of equipment x
 Modification of computer-controlled equipment x
 Change in the sequence of steps x
 Addition of a processing step x
 Deletion of processing step x
 Modification of a processing step x
 Addition of a control parameter (e.g., time, speed, and temperature) x
 Deletion of a control parameter x
 Modification of a control parameter x
 Change in tooling specifications x
Raw material change
Change to an active raw material or excipient
 Change of manufacturer X
 Change of manufacturing process or scale X
 Change in specification X
 Substitution of one grade or standard of raw material for another X
 API manufacturing site change X
Component change
Change to a primary packaging component
 Substitution of one component for another X
 Substitution of one grade or standard component for another X
 Change in pack size X
 Change to more/less protective pack X
 Change of manufacturer X
 Change of manufacturing process X
 Change of specification X
(continued)
Stage 2B: Process Performance Qualification 77

Table 6.3 (continued)
Product change
Change to the specification of a finished product
 Change in analytical specification of the product X
 Addition of packaging component to the BOM X
 Removal of a packaging component from the BOM X
Facility or service change
Change to a facility housing quality-related operation, or to a service
system which may affect product quality
 Change in manufacturing site X

will not be released for commercial sale until all the testing is completed, reports
reviewed, and approved by quality. Circumstances that involve unplanned changes
in batch size or yields but do not involve in-process, material, intermediate or fin-
ished product failures, or changes in the processing methods (how) and/or step
objectives (why) may be justified through an investigation report.
Proposed changes are assessed by a qualified validation group. Validation
requirements are documented on the Change Control Form as per internal SOP. PPQ
Protocol number will be assigned for the study. A risk assessment will be performed
to determine the strategy. In all cases, the results will be compared with the most
recent process performance and/or appropriate PPQ study completed for the prod-
uct to ensure the new process is equivalent or better than the past performance of the
original process. Changes in bin/batch size of a mixed material (or “blend”) will be
evaluated based on the amount of active in the formulation as well as the type of
manufacturing process used, e.g., common/proportional blend vs. unique mix. A
risk assessment for the effect of API change on the process will be conducted within
and a material assessment report generated. Any process modifications necessary to
accommodate the new API source will be determined in protocol-controlled trials
and documented. Multiple unique supplier lots will be used to manufacture the
initial PPQ batches whenever practical and applicable and these batches must be
placed on the stability program. Changes that alter the original intent of the study
must be made either through a PPQ Protocol Addendum or in the report.
Annual product review provides a mechanism to periodically determine if there
has been gradual variation from the validated state due to the cumulative effects of
small changes, regulatory changes or due to the passage of time. Validation
­recommendations from APR will be considered. Assessment of monitoring batches
in Stage 3A and real time batch to batch monitoring in Stage 3B are the other
mechanisms.
The following is a guide to the types of changes which will likely have an impact
on product quality and which will be evaluated and the need for PPQ studies
(Table 6.3).
78 6  Stage 2A and Stage 2B: Process Qualification

References

1. Tartal J. Quality system regulation process validation FDA small business regulatory education
for industry (REdI), Silver Spring, MD. 2015.
2. ISPE. Commissioning and qualification baseline guide. Tampa: ISPE; 2018.
3. Drapala P. Deviation investigation format and content: a guide for inspection success. Pharm
Technol. 2017;41:108–10.
4. ISPE. Good engineering practices (GEP). Tampa: ISPE; 2008.
5. JVT. ASTM E2500: the end of validation? J Valid Technol. 2014. http://www.ivtnetwork.com/
article/astm-e2500-end-validation.
6. ASTM. E2500: standard guide for specification, design, and verification of pharmaceutical and
biopharmaceutical manufacturing systems and equipment. Philadelphia: ASTM; 2013.
7. Pazhayattil A, Alsmeyer D, Chen S, Hye M, Ingram M, Sanghvi P.  Stage 2 process perfor-
mance qualification (PPQ): a scientific approach to determine the number of PPQ batches.
AAPS PharmSciTech. 2016;17:829–33.
8. US FDA. Guidance for industry PAT – a framework for innovative pharmaceutical develop-
ment, manufacturing, and quality assurance, Pharmaceutical CGMP. 2004.
9. ISPE. Process validation conference, Bethesda. 12–14 Sept 2017.
Chapter 7
Stage 3A and Stage 3B: Continued Process
Verification

Abstract  Monitoring adds assurance that during routine commercial production of

drug products, the process remains in a state of control. Through life cycle Stage 1,
critical material attributes and CQAs are established; critical process parameters
(CPPs) and process control strategies are defined. CPPs and CQAs are verified in
Stage 2. As the product moves to Stage 3, the body of data grows significantly. At
Stage 3A and 3B, CPV data continues to be generated until the product is discontin-
ued. As data is available in real time, it allows immediate action for continuous
improvement upon signal detection.

Keywords  Continued process verification · Ongoing process verification ·

Continuous improvement · Stage 3 · Variability · Statistical assessment

Continued process verification is a significant addition to the process validation life

cycle concept. The first US FDA validation guidance dates back to 1987 [1]. The
Guideline on General Principles of Process Validation (1987) primarily pertained to
the current Stage 2: process performance qualification stage of process validation
life cycle. The 1987 guidance described elements such as the validation prerequi-
sites, protocol, and report requirements. The guidance document had provisions for
post validation activities such as the need for quality systems to identify revalidation
requirements during changes. The significant change including addition of Stage 3
or CPV stage came through with the 2011 US FDA process validation guidance.
The guidance formalized the CPV approaches that developed and evolved through
the years after the first guidance.
Regulators and industry recognized that a mere three-batch validation procedure
may not be ideal in ensuring manufacturing control and consistent assurance that
the process maintains a validated state. The restrictive process qualification step
was not inclusive enough to capture all potential variabilities possible during the
life cycle of the product. The new definition of process validation per the revised
US FDA process validation guidance [2] is the collection and evaluation of data,
from the process design stage through commercial production, which establishes
scientific evidence that a process is capable of consistently delivering quality prod-
ucts. The new approach identifies process validation as a life cycle concept that

© American Association of Pharmaceutical Scientists 2018 79

A. B. Pazhayattil et al., Solid Oral Dose Process Validation, AAPS Introductions
in the Pharmaceutical Sciences, https://doi.org/10.1007/978-3-030-02472-7_7
80 7  Stage 3A and Stage 3B: Continued Process Verification

includes the process design stage through commercial manufacturing. The data
collected through all three stages, Stage 1, process design; Stage 2, process quali-
fication; and Stage 3, continued process verification, is continually utilized. The
new guidance emphasized the Stage 1 and Stage 3 monitoring phase.

Benefits of Continued Process Verification Program

Implementation of Stage 3: continued process verification needs careful consid-

erations, one from regulatory expectation and the other how to make the program
beneficial for the operations. Continued process verification (CPV) or ongoing
process verification (OPV) [3] is applicable for drug substance and drug product
manufacturing. The incorporation of CPV/OPV is a major milestone in demon-
strating that manufacturing processes performed as expected and consistent.
Continued process verification is initiated subsequent to commercialization and
completion of Stage 2. It assures that the process remains in a state of control
during commercial manufacturing. The implementation of Stage 3 CPV justifies
to biopharmaceutical organizations as it frees up of production lines and enables
higher throughput of the manufacturer’s product portfolio. The program mini-
mizes the opportunities for process failures, one of the most important deterrents
in preventing from uninterrupted product supply. The third monitoring phase is
the continuation of quality by design approach adopted during product design
stage. Stage 3: continued process verification is an enabler as it allows quality
risk management by detecting the trends and implementing preventive measures
prior to failures. The implementation of Stage 3 CPV reduces cost of quality,
enhances product/process knowledge, and reduces regulatory compliance risks.
The supply chain benefits with continuous product supply and better manufactur-
ing planning as an outcome [4]. The CPV stage employs data and scientific meth-
ods for better decision-making (Fig. 7.1).
The FDA guidance (Guidance for Industry: Process Validation  – General
Principles and Practices dated Jan. 2011) does not require splitting Stage 3;

Fig. 7.1  Statistical process control chart

Continued Process Verification Stage 3A 81

however, a specific CPV stage (Stage 3A) involving a statistically relevant number
of batches to gather adequate trending data is highly recommended for new com-
mercially launched products where historical product data is not available. This
stage is designed to allow close monitoring of process parameters and quality attri-
butes while detecting the undesirable process variabilities and providing an oppor-
tunity to enhance the product control strategy (CS) . Additional sampling and testing
are typically at Stage 3A. The continued batch to batch monitoring at Stage 3B will
subsequently highlight any undesired trends.

Regulations Requiring CPV Program

Regulatory guidance outlines the expectations for understanding and controlling

sources of product variability throughout a product’s life cycle. The Stage 3 of the
life cycle starts following successful completion of Stage 2B (PPQ) activities.
The assurance gained at Stage 2 is continually monitored over Stage 3. The intent
of Stage 3 CPV or CPV/OPV is to provide continual assurance that a process
remains in a state of control during commercial manufacturing. It is an ongoing
program to collect and analyze process data in a timely manner should be estab-
lished. Analysis of information the collected can detect new sources of variation
that were not detected or observed during the initial Stage 2 activities. Therefore,
CPV is used to optimize the process and provide opportunities for continuous
improvement. Although not defined in the regulatory guidance’s, Stage 3 is dif-
ferentiated into two distinct phases: Stage 3A and Stage 3B.  The former is the
initial phase; Stage 3A is performed as soon as substantial knowledge of process
(data and batches) is gained. Stage 3A provides an opportunity to enhance the
product CS. A CS is designed to ensure that a product of required quality will be
produced consistently. The latter Stage 3B is a long-term phase of the commercial
life cycle of the product.
CPV/OPV provides assurance during routine production that the process remains
in a state of control. Being a regulatory (FDA, EMA, PIC/S) guidance recommenda-
tion [5], the data collection and statistical assessment provides opportunities for
continuous improvement activities prior to reaching failure mode. Regulators rec-
ommend that the manufacturer use quantitative, statistical methods whenever
appropriate and feasible. Scrutiny of intra- and interbatch variation is part of a com-
prehensive CPV program under Code of Federal Regulations (CFR) Title 21. CPV
is the third process stage after design and qualification.

Continued Process Verification Stage 3A

Stage 3A is the initial assessment post new product launch that utilizes a substan-
tial body of data for statistical evaluation to gain deeper product understanding.
The assessment utilizes data from all PV life cycle stages. Understanding of
82 7  Stage 3A and Stage 3B: Continued Process Verification

product variability is pivotal hence Stage 3A. The evaluation is a valuable resource

for product development and risk mitigation of similar products and processes.
Stage 3A assessment demonstrates the organizations compliance in establishing an
enhanced product CS and attaining a high level of product understanding and qual-
ity. It is the initial phase of the CPV program. Stage 3A is beneficial for new mol-
ecules, newly introduced processes, or where the processes may be complex and
sufficient data from Stage 2B was not available to determine statistical control
limits. The number of batches required on Stage 3A should be statistically signifi-
cant to provide sufficient data, understand variation in the process, and establish
statistical control limits for Stage 3B. The Stage 3A protocol requires a heightened
sampling and testing plans though there are regular commercial batches. As done
in Stage 2B, experience from similar products and processes can be leveraged at
this stage. The sampling and testing requirements are maintained at the same level
of Stage 2B in certain cases.
Upon completion of Stage 3A batches, the organization acquires sufficient body
of data for a higher level of statistical evaluation to gain product knowledge and
trend. The Stage 3A assessment utilizes data from the previous stages of process
validation: Stage 1, process design; Stage 2, process performance qualification;
and the Stage 3A. The CS are essentially developed based on estimates and process
capabilities developed during early stages of the product. The CS was appropriate
for the time of launch based on the amount of data available at the time. This is
when Stage 3A becomes relevant and important in gaining knowledge of the
scaled-­up commercial manufacturing used in further enhancement of the CS. The
stage allows for understanding the sources of analytical and process variability.
Since there is a predetermined number of batches analyzed at Stage 3A, it helps in
better understanding of a substantial shift. The assessment evaluates impact of
variability and its potential impact on the critical quality attributes. The QbD-based
product development, technology transfer, scale, equipment qualification, batch
manufacturing, and so on are used during Stage 3A assessment. The report is sup-
ported by statistical analysis and tools to identify continuous improvement correla-
tions and substantiate the findings. The Stage 3A protocol with predefined
requirements is typically approved along with the Stage 2B PPQ study report. A
Stage 3A study demonstrates the firms control and compliance in maintaining a
robust product CS to maintain product quality and understanding [6]. Stage 3A
systematically evaluates:
1. Material attributes
2. Process parameters
3. Quality characteristics
4. Drug release profiles
5. Enhance CS
6. 3B CPV monitoring criteria.
Continued Process Verification Stage 3A 83

Fig. 7.2  Inherent process variability

Stage 3A assessment is vital for new products in understanding product robust-

ness and managing variability. The conclusions made should provide sufficient
information to make a scientific and risk-based decision on product robustness and
product quality (Fig. 7.2).
There are assessment tools developed once there is substantial process and prod-
uct knowledge has been collected. Stage 3A assessment is a great resource for prod-
uct development and risk mitigation activities. The gained process and product
understanding can be applied for new similar process/product development.
The Stage 3A assessment starts with determining the number of batches required
for the assessment. Statistical tools are now available to determine the number of
batches required. The methodology of determining process and analytical variabil-
ity is applied at this stage. The quality metrics for the product and improvement
needs are determined. The Stage 3A is utilized to enhance the initially developer
CS. US FDA recognizes the importance of statistical process control (SPC) in
understanding and managing variability. Understanding the causes of variability
allows for control at the source. First step in estimating process variability is to
ensure that variability contributing factors are constant. Continuous improvement
strategies may be developed based on observed variability.
84 7  Stage 3A and Stage 3B: Continued Process Verification

Continued Process Verification Stage 3B

Stage 3B assures that during routine production the process remains in a state of
control.
A system or systems for detecting unplanned departures from the process as
designed is essential to accomplish this goal. Collection and evaluation of process
performance data will allow detection of process drift. The information collected
verifies that the quality attributes are being appropriately controlled throughout the
process. If properly carried out, these efforts can identify variability in the process
and/or signal potential process improvements (Fig. 7.3).
Ongoing monitoring of the process is required and the Stage 3A continued moni-
toring report will document the details of the Stage 3B monitoring stage. The Stage
3A Report will discuss the interbatch variability and include process capability and
performance (Ex. Cpk, Ppk). Additionally, the conclusion of the monitoring report
will determine the CPV Stage 3B.
SPC was initially developed by Walter Shewhart and gained popularity following
W. Edwards Deming implementation in automobile industry [7]. SPC trend limits,
coupled with control chart rules (e.g., Western Electric or Nelson Rules), alert to
potential non-random events or deviations. There are a multitude of SPC charting
rules that may be useful to identify potentially statistically anomalous events. These
include, but are not limited to (Table 7.1).

Fig. 7.3  Batch trend summary – thickness, hardness

Continued Process Verification Stage 3B 85

Table 7.1  Control chart rules

Rule Description Possible concern
Rule 1 One point more than three standard deviation from Indicates a statistically
mean anomalous event
Rule 2 Nine sequential points on the same side of the mean Potential prolonged bias
Rule 3 Six sequential points continually decreasing or A potential trend
increasing
Rule 4 Fourteen sequential points alternate in direction Potential multiple underlying
processes

Triggering one of these rules indicates with reasonable statistical confidence

that something may have changed within the process that may have an impact on
the product robustness and control. To ensure that the manufacturing processes
continue to remain in a validated state after the PPQ completed process will con-
tinue to meet current validation requirements, monitoring (Stage 3B) is required.
The information is reviewed and used to assess the need for continuous improve-
ment. Legacy products are placed in Stage 3B since the products have undergone
multiple annual product review [8] which is also a mechanism to periodically
determine gradual variation from the validated state due to the cumulative effects
of changes (Fig. 7.4).
Stage 3B verification stage is performed by technical operations or quality
departments. Any instances of product data appearing to trend adversely will be
evaluated. Interpretation criteria are developed and documented for each product
based on statistical analysis of historical product data. All data will be reviewed and
reported.
Signals should trigger a response reaction based on risks. If properly carried out,
CPV efforts can identify variability in the process and/or signal potential process
improvements. A process is likely to encounter sources of variation. Statistical sig-
nals need not be classified as deviations and investigated immediately. A controlled
manufacturing process is expected to see “process shift” signals. It has to be under-
stood that not all signals are created equally. The reaction strategy should depend on
the influence on patient impact CQA’s.

Use of Product/Process Data

Information captured during the life cycle include elements such as detailed manu-
facturing processing stages, equipment used, and process parameters. A well-­
maintained product history, including change control summaries, validation statuses,
investigations, complaints, field alerts, and stability data, lends itself well to devel-
oping annual product quality review report. Electronic systems and integrating typi-
cal pharmaceutical document, content, and workflow management systems such as
Laboratory Information Management System (LIMS), Enterprise Resource Planning
(ERP), and Quality Management System (QMS) are essential to managing the
86 7  Stage 3A and Stage 3B: Continued Process Verification

Fig. 7.4  Decision tree for Stage 3B

process validation life cycle stages and ensuring knowledge and data gained is uti-
lized. Such data must be accessible, gathered, interfaced, and delivered to continu-
ally support all life cycle stages. Product and process knowledge about all process
validation life cycle stages must be captured, organized, managed, stored, and
shared. It must also remain easily accessible to promote data-driven, science-, and
risk-based decision-making. Available, reliable data that can be evaluated statisti-
cally at any time ensures that each stage of the life cycle is in control. This enhances
both regulatory compliance and product/process confidence, and improves product
understanding. The greatest benefits of a well-implemented life cycle Knowledge
Management program include reduction in product-remediation costs, lower cost of
quality, and, above all, consistent delivery of quality products to the patient (Fig. 7.5).

ICH Guidance’s Working in Tandem

Effective continuous improvement and uninterrupted drug product supply require

a systematic product life cycle management approach. The life cycle-related ICH
guidances works in tandem to achieve the desired outcomes that regulators
ICH Guidance’s Working in Tandem 87

Feedback Mechanism
Int Search & Query Notification
IP Spec er
fac
Mfg stage and Results e
batch info
ERP (SAP) Interface

Interface Trending

QMS

e c
rfa
te
Stats, Risk
In

Documents
FP and Micro Assessment
Spec + Results
Holistic View
LIMS

Fig. 7.5  Continued process verification system

expect [7]. Harmonized life cycle management approach promotes innovation

and continual industry improvement while strengthening quality assurance and
improving essential drug products’ supply to patients. The approaches outlined
in ICH quality guidances Q8(R2): Pharmaceutical Development, Q9: Quality
Risk Management, Q10: Pharmaceutical Quality System and Q11: Development
and Manufacture of Drug Substances provides an opportunity for science- and
risk-based approach. This is for decision-making throughout the product life
cycle stages. ICH Q12 guidance addresses the identified technical and regulatory
gaps for practical implementation to help realize past guidance. The guidance is
intended to enable more flexible regulatory approaches for post approval once
implementing the life cycle guidance. Risk-based approaches regarding inspec-
tional scrutiny, use of advanced technologies, and articulation of a clearer role of
conformance batches in the product life cycle are part of the approach. Applying
knowledge throughout the product life cycle is a key element.
ICH Q10 adoption through product life cycle facilitates innovation and con-
tinual improvement and strengthens the link between pharmaceutical develop-
ment and manufacturing activities. The elements of the guidance should be
applied in a manner that is appropriate and proportionate to each product life
cycle stage, recognizing the differences among, and the different goals of each
stage. The quality system elements and management responsibilities in this guide-
line are intended to encourage the use of science and risk-based approaches at
each stage, thereby promoting continual improvement across the entire product
life cycle. Applying knowledge and quality risk management will enable to imple-
ment ICH Q10 effectively and successfully. The life cycle stages in the guidance
include (Fig. 7.6):
88 7  Stage 3A and Stage 3B: Continued Process Verification

Fig. 7.6  Leveraging product, process knowledge

1. Pharmaceutical development: These activities’ goal is to design a product and its

manufacturing process to consistently deliver the intended performance and
meet patients and healthcare professionals’ needs, and regulatory authorities and
internal customers’ requirements. Approaches to pharmaceutical development
are described in ICH Q8.
2. Technology transfer: These activities are intended to transfer product and pro-
cess knowledge between development and manufacturing, and within or between
manufacturing sites, to achieve product realization
3. Commercial manufacturing: The goals include achieving product realization,
establishing, and maintaining a state of control and facilitating continual
improvement and
4. Product discontinuation: The aim here is to manage the product life cycle’s ter-
minal stage effectively.
Each stage is connected, as is application of ICH Q8 to Q11 throughout the life
cycle stages. An effective CPV monitoring program providing assurance of pro-
cesses and controls’ continued capability to produce commercial product of desired
quality and to identify areas for continual improvement is a requirement for both
ICH Q8 and Q10.
The application of existing data can eliminate the need for experiments, pre-
vented delays, reduced failure, and limited additional cost of material. The
­availability of data can reduce the need for production resources and ensure contin-
ued commercial supply of the product. The ability to retrieve essential information
through the life cycle KM system can negate the requirement for additional manu-
facturing floor trials and additional resources. As per US FDA process validation
guidance, it is not typically necessary to explore the entire operating range at a
commercial scale if assurance can be provided from credible experience with suf-
ficiently similar products and processes. The trending of quality attribute and pro-
cess parameter data is required to ensure compliance with US FDA process
validation guidance.
References 89

References

1. US FDA. Guideline on general principles of process validation. Rockville: FDA; 1987.

2. US FDA. 2011. https://www.fda.gov/downloads/drugs/guidances/ucm070336.pdf.
3. EMA.  Guideline on process validation for finished products  – information and data to be
provided in regulatory submissions. London: EMA; 2016.
4. Alsmeyer D, Pazhayattil A. A case for stage 3 continued process verification. Pharma Manuf. 2014.
https://www.pharmamanufacturing.com/articles/2014/stage3-continued-process-verification/.
5. Pazhayattil A. Integrating PV lifecycle approach to a global organization, PDA annual meeting.
2018.
6. Sayeed-Desta N, Pazhayattil AB, Collins J, Chen S, Ingram M, Spes J. Assessment methodol-
ogy for process validation lifecycle stage 3A. AAPS PharmSciTech. 2017;18:1881–6.
7. Best M, Neuhauser D. Walter A Shewhart, 1924, and the Hawthorne factory. Qual Saf Health
Care. 2006;15(2):142–3.
8. Pazhayattil A.  Annual product reviews: how to conduct an effective annual product quality
review. Pharma Manuf. 2012. https://www.pharmamanufacturing.com/articles/2012/018/.
Index

C I
Capability, 18, 19, 31, 34–35, 53, 63, 72, 73, International Conference on Harmonization
82, 84, 88 (ICH), 4, 29, 34, 38–40, 42, 45, 53,
Capsules, 9, 22–27, 32, 43 59, 75, 86–88
Concurrent, 5, 72–74
Continual improvement, 31, 34–35, 87, 88
Continued process verification, 1–3, 5, 69, 75, K
79–88 Knowledge management (KM), 1, 37–50, 86
Control strategy (CS), 3, 4, 30, 31, 34, 38, 39,
43, 46, 53, 58–59, 66–69, 81–83
Critical material attributes (CMAs), 5, 30, 31, L
33, 34, 38, 42–46, 48 Life cycle, 1–7, 37–50, 54, 58, 68, 75, 79, 81,
Critical process parameters (CPPs), 15, 19, 30, 86–88
31, 33, 34, 38, 43–45, 47, 48, 50,
53, 56, 58, 64, 68, 69, 75
Critical quality attributes (CQAs), 5, 29, 31, M
33, 34, 42–48, 53, 56–58, 68, 75, Manufacturing process, 2, 3, 5, 6, 9, 12–23,
82, 85 26–27, 29, 31, 33, 34, 53–55, 68,
70–74, 76, 77, 80, 85, 88

D
Design of experiments (DoE), 4, 31, 34, 45, P
48, 55, 56 Process design, 1–6, 29–35, 65, 68, 79, 82
Design space, 29, 34, 35, 43–50, 53, 59 Process performance qualification (PPQ), 2–6,
41, 42, 61, 68–76, 79, 81, 82, 85
Process validation, 1–7, 37–40, 64, 72, 73, 79,
E 80, 82, 86, 88
EMA, 81

Q
F Quality by design (QbD), 6, 29–35, 38, 53, 58,
FDA, 1, 5, 37, 54, 79–81, 83, 88 80, 82
Formulation, 3, 9–27, 31–34, 38, 41–43, 48, Quality target product profile (QTPP), 29, 31,
50, 54, 66, 74, 76, 77 32, 53

© American Association of Pharmaceutical Scientists 2018 91

A. B. Pazhayattil et al., Solid Oral Dose Process Validation, AAPS Introductions
in the Pharmaceutical Sciences, https://doi.org/10.1007/978-3-030-02472-7
92 Index

R Stage 2, 1, 2, 4–5, 37, 42, 54, 57, 61–82

Risk assessment, 4, 34, 37, 67–69, 71, 74, 77 Stage 3, 1, 2, 5, 37, 58, 75, 77, 79–88

S T
Scale-up, 41, 42, 50, 53–59, 68, 76 Tablets, 9–23, 25, 26, 29, 32, 33,
Solid dose, 9–27, 53, 54 54–58, 63
Stage 1, 1–4, 37–50, 53–59, 68, 70, 75, 80, 82 Technology transfer, 2, 42, 66–69, 82, 88