USP Technical Guide:

Control Strategies for

Continuous Manufacturing of
Solid Oral Dose Drug Products
USP Technical Guide

How to use this Technical Guide

This document is intended to serve as a helpful illustration

of the process of developing control strategies for solid
oral dose drug products. Although there are guidance
documents available [ICH 2023] for pharmaceutical continuous
manufacturing in general, and for specific process components
such as process analytical technologies, this document
presents a more detailed conceptual and practical discussion of
control strategy limited to solid oral products.

This document is intended for informational purposes only.

The document does not reflect the opinion of any USP Expert
Bodies on future revisions to official text of the USP–NF. The
recommendations herein are not intended to be binding in
any way, nor should they be considered the only acceptable
approach. Parties using this document are solely responsible
for making decisions regarding its suitability for use. USP
will not be responsible for the use or implementation of this
document, or any information contained herein. None of
the recommendations or other information in this document
constitute a legal opinion or advice, or an opinion or advice on
regulatory matters. Parties relying on the information in this
document bear independent responsibility for awareness of,
and compliance with, any applicable federal, state, or local
laws and requirements.

© 2023 The United States Pharmacopeial Convention, 12601 Twinbrook

Parkway, Rockville, MD 20852.

Help us continually improve and update this document. USP

welcomes your valuable feedback, email PCM@usp.org.

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 Control Strategies for Continuous Manufacturing of Solid Oral Dose Drug Products

Contents
4. PAT in the Development of Control Strategy 22
1. Introduction 4
4.1. Introduction: PAT-based and Parametric
1.1. Pharmaceutical Continuous
Quality Assessment 22
Manufacturing (PCM) 4
4.2. Spectroscopic PAT Tools 22
1.1.1. Continuous Manufacturing for Oral Solid
Dose Drug Products 4 4.2.1. Near-Infrared Spectroscopy 22

1.1.2. Continuous and Semi-continuous 4 4.2.2. Raman Spectroscopy 23

1.2. Regulatory Guidance and Requirements 5 4.3. Chemometrics 24

1.3. Control Strategy: Origins 5 4.3.1. Sampling and Data Quality 24

1.4. Key Terminology 6 4.3.2. Preprocessing 24

1.4.1. Quality by Design 6 4.3.3. Variable Selection 24

1.4.2. Quality Target Product Profile 7 4.3.4. Quantitative Predictive Modeling 25

1.4.3. Critical Quality Attributes 7 4.3.5. Model Optimization and Validation 25

1.4.4. Continuum Approach to CQA Classification 8 4.3.6. Model Maintenance and Lifecycle
Management 25
1.4.5. Critical Process Parameters 9

1.4.6. State of Control 9

5. Application to Oral Solid Dose, Drug
1.5. Control Strategy: Steps 9
Product Manufacturing 26

5.1. Solid Oral Dose CM Methods and their

2. Elements of Control Strategy: Part I 12 Specific Control Strategies 26

2.1. Material Attributes 13 5.1.1. Direct Compression (DC) 26

2.2. Process Monitoring and Control 15 5.1.2. Wet Granulation 26

2.2.1. Process and Unit Operation Modeling 15 5.1.3. Dry Granulation 27

2.2.2. Process Control Systems 16 5.2. Feeding and Blending Unit Operations 27

2.2.3. Operational Procedures 16 5.3. Example Control Strategy 28

2.2.4. Equipment and System Integration 17

6. Appendix 29
3. Elements of Control Strategy: Part II 18

3.1. Risk Assessment 18 7. References 31

3.2. Material Characterization 18

3.3. Experimental Design 19

3.4. PAT Development 20

3.5. Full-Line RTD, Performance, and Modeling 20

3.6. Out-of-specification Determination

and Diversion 20

3.7. Scale-up Considerations 20

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USP Technical Guide

1 Introduction
1.1. Pharmaceutical Continuous
Manufacturing (PCM)
As per the ICH Q13 guideline, a pharmaceutical process
is considered to be a continuous manufacturing (CM)
process if it involves a unit operation chain featuring a
“continuous feeding of input materials into, the transformation
of in-process materials within, and the concomitant removal
of output materials from it.” The guideline further states that
the process must have a minimum of two connected unit
operations featuring a flow of material from one operation
to the next. Hence, the manufacturing process for simple
solid oral dose drug products (e.g., tablets) could feature a
continuous feeding and mixing step for it to be considered a
CM process. Further downstream, there are process designs
that differentiate between various solid oral drug product
process lines (described in detail in Section II[b]) which may
also run in a continuous mode.
While CM has been a modality of choice for many
manufacturing industries such as fine chemicals, foods,
and oil and gas, its implementation in the pharmaceutical
industry is relatively new. Hence, several techniques and
practices are being adapted from other industries, and new
ones are being developed. Manufacturing and regulatory
experience from the past two decades, however, has resulted
in the development of certain best practices in solid oral
drug product manufacturing. This guide is limited to control
strategy considerations for CM of solid oral drug products.
1.1.1. Continuous Manufacturing for Oral Solid
Dose Drug Products
Oral solid dose traditional batch process development
has had the advantage of substantial product and process
understanding stemming from historical experience with
equipment such as blenders, granulators, roller compactors,
and tablet presses. This process knowledge allows for the
streamlining of experimentation needed to support the
manufacturing process control strategy. Three commonly used
approaches for oral solid dosage (OSD) drug products (DP) are:
• direct compression (one or more blending steps of the
drug substance [DS] and excipients followed directly by
tablet compression)
• dry granulation (compaction and milling of DS to improve
particulate properties prior to blending), or
• wet granulation (water or organic solvent is added to the
pre-blend of the DS and excipient[s] to agglomerate fine
particles into granules and improve particle properties)
Other less commonly used approaches include hot-melt
extrusion (HME) and direct encapsulation. However, CM for
oral solids introduces new equipment with new modes of
operation, new means of operating and controlling familiar
equipment, new risks, and new fundamental principles that
are unique to this method of manufacturing. Due to these
factors, enhanced development approaches (i.e., Quality by
Design [ICH 2009], use of process analytical technology (PAT)
[FDA 2004], or use of process models) have been proposed
for developing CM control strategies.
1.1.2. Continuous and Semi-continuous
A CM process in the pharmaceutical context does not
necessarily have to be “end-to-end”, nor is it expected that it will
always run continuously for weeks or months. Most processes
have a well-defined operating time range before they are
stopped for cleaning and other maintenance. Often processes
are run in one or two shifts per day. Not all unit operations have
to be run in a connected, continuous mode. Many successful
CM processes have unit operations such as pre-blending,
sieving, milling, or tablet coating that are run in batch mode.

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 Control Strategies for Continuous Manufacturing of Solid Oral Dose Drug Products

1.2. Regulatory Guidance and 1.3. Control Strategy: Origins

Requirements
Regulatory guidance specific to developing CM control
strategies has been provided through ICH Q13. In addition,
an ASTM standard guide, E2968-14 [E2968], defines key
concepts and principles for the development and operation
of continuous processing technologies for pharmaceutical
manufacturing. These guidances and standards align with
Quality by Design (QbD) principles and process design
concepts described in the FDA Process Validation guidance
[FDA 2011]. The concept of a “state of control”—a condition
that provides continued process performance and product
quality—is defined in ICH Q10 [ICH 2009]. The control
strategy includes elements to be monitored and parameter
settings to be adjusted when necessary to maintain the state
of control. If necessary, non-conforming material is identified
and diverted from the process.
The regulatory filing dossier for a CM process should be
in accordance with the ICH guidance of industry M4:
The CTD – Quality (ICH M4Q) [ICH 2002].
USP’s Quality Standards for Pharmaceutical Continuous
Manufacturing Expert Panel (2015-2020) noted [Matos 2018]:
• A CM process is subjected to the same requirements
regarding current good manufacturing practice (cGMP)
compliance as a batch process.
• Principles of risk management apply equally to batch and
CM processes.
As per the ICH Q8(R2) Guideline [ICH 2009], control strategy
is defined as “A planned set of controls, derived from current
product and process understanding that ensures process
performance and product quality. The controls can include
parameters and attributes related to drug substance and drug
product materials and components, facility and equipment
operating conditions, in-process controls, finished product
specifications, and the associated methods and frequency of
monitoring and control.”
The definition is valid for both batch and CM operations. It
is encouraged that control strategy be used during process
development and manufacturing and included in the regulatory
filing in the ICH M4 Common Technical Document (CTD) format.
It can be included within section 3.2.P.2 of this document,
referred to as the Pharmaceutical Development section.
An OSD DP consists of several components such as the
DS, one or more excipients, and other substances such as
lubricants, glidants, and stability enhancers. Figure 2 is an
illustration of this implementation of CM. This illustration
shows a single loss-in-weight feeder equipped with a refill
system, a horizontal continuous blender, a tablet compaction
machine, temporary tablet collection bin, and a continuous
coating machine. A process consisting of these steps
can be classified as a ‘direct compression’ process. Many
formulations require preliminary steps before tableting,
such as wet granulation (followed by drying and milling) or

• Pharmacopeial product specifications should be met Figure 1: Control Strategy is included in the Pharmaceutical
regardless of the mode of manufacture. Development section of the Common Technical Document

• Regulatory expectations for ensuring product quality as

well as reliable and predictive processing are the same
for batch and continuous manufacturing.

However, ICH Q13 provides additional requirements that are

CM-specific. Control strategy is included among these, with
the following specific components:

• Input material attributes

• Process monitoring and control
• System operation
• Material diversion and collection
• Real-time release testing (if implemented)
• Equipment and system integration
This document discusses these topics in detail.

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USP Technical Guide
dry granulation (followed by milling). As far as feasible, it is
preferable to use direct compression (DC) due to process
simplicity, lower cost, and fewer opportunities for quality
deviation. Given the available process understanding and
significant experience with DC, it is no longer considered an
emerging technology by the US FDA [FDA 2022].
1.4. Key Terminology
The control strategy, in simple terms, is a strategy that the
manufacturer deploys to ensure that the desired quality
attributes are achieved from the manufacturing process.
The control strategy must be clearly defined and reported
in the appropriate sections of the Common Technical
Document (CTD).
1.4.1. Quality by Design
ICH Q8(R2) defines QbD as:
“A systematic approach to development that
begins with predefined objectives and emphasizes
product and process understanding and process
control, based on sound science and quality risk
management.”
kg/hr
kg/hr
1
2 3
3 7
5
6
Development of the control strategy usually starts with
specification of the Quality Target Product Profile (QTPP),
which is the desired set of attributes of the product in
question. This forms a part of the “predefined objectives” of
QbD, as defined in ICH Q8(R2).
1.4.2. Quality Target Product Profile
In ICH Q8(R2), the QTPP is defined as:
“A prospective summary of the quality
characteristics of a drug product that ideally will be
achieved to ensure the desired quality, taking into
account safety and efficacy of the drug product.”
QTPP encompasses the attributes of the product that must
meet the claims on the label on the container in which
the product is sold. Examples of attributes in the QTPP
are dissolution (immediate release or sustained), dosage
strength, and mode of administration. Once the QTPP is
determined, the CQAs and associated critical process
Figure 2: A basic solid oral DP manufacturing line beginning
with loss-in-weight feeders and culminating in tablet
coating unit operation.
Basic Solid Oral DP Manufacturing Line
1 Feeders Refill System
2 Feeder
Mixer
4 Intermediate Hopper
5 Tablet Press
6 Tablet Coater
CM Batches
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 Control Strategies for Continuous Manufacturing of Solid Oral Dose Drug Products
parameters (CPPs) can be determined using quality risk
management (QRM) [ICH 2006] and scientific rationale.
This is where development of an effective control strategy
can begin.
Since the output material can become the input material
of the downstream unit operation, output quality attributes
become material attributes of the next input material. When
raw materials (DS and excipients) are first introduced into
the process, some material attributes are defined as critical
material attributes (CMAs) if they impact one or more
finished or intermediate product’s CQA(s). However, CMAs
are not officially defined in the ICH Guidelines. Attributes
are either sampled or measured directly with inline/online
instruments (i.e., PAT). Test results of attributes are assessed
against control limits (if used as part of feedback or feed
forward control loops to adjust process parameters) or
against acceptance limits (if used for rejection or diversion of
non-conforming products).
1.4.3. Critical Quality Attributes
ICH Q8(R2) defines a CQA as:
“A physical, chemical, biological or microbiological
property or characteristic that should be within an
appropriate limit, range, or distribution to ensure
the desired product quality.”
The ICH guidelines state that thorough risk assessments
must be carried out. The factors that contribute to risk
7
are those that affect product performance, along with the
severity of harm and the likelihood of occurrence. To identify
CQAs, one must list the quality attributes on the basis of
prior knowledge or experimentation, and one must consider
the severity of harm in terms of safety and efficacy that the
particular attribute can cause. How the CQAs link back to
the QTPP must also be clearly understood, and so should
the impact of any source of variation on the CQAs.
It is best to define the CQAs, the rationale for selecting
them, their acceptable limits (or the design space) and
ranges (high and low), and the protocols for their
measurement. As an example, content uniformity of the
dosage form can be a CQA while the product’s odor may
not be. The target profile must be stated, for example,
whether the content uniformity conforms to USP General
Chapter <905> Uniformity of Dosage Units.
During the manufacturing process, there are many process
parameters that could affect a product’s quality and its
performance. Some parameters have a pronounced effect
while others may have an insignificant impact (this is
assessed using the criticality analysis). The parameters that
significantly affect product performance can be considered
as the Critical Process Parameters (CPPs). These parameters
must be given special consideration when creating the
control strategy, and their mutual interplay and impact on
CQAs must be well understood.
In addition to the DP CQAs, a set of intermediate CQAs can
be identified. These are the CQAs of intermediate material
USP Technical Guide

during the manufacturing process. For example, if content strategy on those parameters and material attributes with the
uniformity is the DP CQA, the blend uniformity can be the greatest impact on quality.
intermediate CQA. In a CM process, the associated CPP can
be a mixer parameter such as impeller speed or flow rate.
1.4.5. Critical Process Parameters

1.4.4. Continuum Approach to CQA
Classification
A continuum approach may be adopted so that the “impact”
is interpreted in relative terms of significance and measurable
effects on CQAs.
The following is a proposed classification of criticality of
material attributes and process parameters:
• High impact: shift within parameter control limits that are
likely to cause CQA to go out of limits.
• Medium impact: shift within parameter control limits that
are likely to cause measurable shift in CQA but remains
within limits.
• Low impact: shift within parameter control limits that are
likely to cause minor, but measurable shift in CQA.
• No impact: shift of parameter creates no measurable shift
in CQA (or has no mechanistic relationship).
Applying this approach allows for a simpler way to categorize
criticality and also a way to appropriately focus the control
Process parameters are inputs to the unit operation; if
they impact one or more CQA(s), they are defined as
CPPs. Process parameters are predefined settings that are
determined either in advance or based on the output of a
control loop (feed forward or feedback). Even though fixed
settings may be predetermined, they may vary around a set
point within a proven acceptable range over time.
The ICH Q8 guidance only defines CPPs as relative to their
impact on CQAs. CMAs can be similarly defined relative to
DP CQAs. A binary approach to defining criticality (critical
or not critical) of parameters can be limiting since the ICH
guidance uses the imprecise terminology, “whose variability
has an impact.”
The Quality by Design approach to control strategy
development starts with the development of the QTPP, which
Figure 3: Relationship between CMAs, CPPs, and QTPP,
exemplified by a coated tablet product. PSD is particle
size distribution.

CPPs CPPs CPPs

Unit Operations 1 Unit Operations 2 Unit Operations “n”

Feeding Mixing Coating

Feed Rate Content Unit Coating Drug
Intermediate Operations Product
CMAs Uniformity Thickness
Uniformity CQAs Chain CQA
Shear Coating Quality
Uniformity
Assured
Color
Product

CPPs
Examples of CMAs Drug Product CQAs
f Particle Size f Bulk & tapped f Potency
f PSD density f Efficacy
f Cohesion f Electrostatic f Bioavailability
f Flowability affinity

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 Control Strategies for Continuous Manufacturing of Solid Oral Dose Drug Products

includes elements describing how the quality of the product
is achieved. Examples of QTPP attributes for OSD include
appearance, mode of administration, drug release (immediate
or extended), dosage strength, degradation pathways, stability,
and primary packaging requirements. Additionally, the QTPP
includes the first descriptions of CQAs. In general, most
CQAs will be included as testing attributes on the finished
product’s specification, but some CQAs may be tested as in-
process intermediates. CQAs are derived from general drug
requirements (safety, identity, strength, purity, and quality)
and specific dosage form requirements (dissolution, content
uniformity, microbial requirements). For the purposes of
this control strategy development exercise, the focus is on
quality attributes (impacting product quality); there are also
non-quality or performance attributes such as yield, cost,
throughput, and processing time that may need to be taken
into consideration during the control strategy definition.
Initially, a manufacturing scheme is chosen to produce the
OSD DP, either via direct compression, dry granulation, or
wet granulation. Each unit operation of the process has
input materials with defined material attributes, process
parameters, and output material with defined quality
attributes; see Figure 3.
to be negligible or controllable, resulting in no or
minimal impact on product quality. Larger changes
in process variables and/or quality attributes may
happen when the CM process is in a transient state,
such as during start-up, shut down, changes from
one operating condition to another, and significant
disturbances (e.g., equipment failure or sudden
change of raw material attributes).”
1.5. Control Strategy Steps
While the decision on when to start process development
can be taken with practical feasibility in mind, several
companies have reported starting it in parallel to the clinical
development of the product. The following are the important
considerations for designing a control strategy for a process
such as the one shown in Figure 2:
I. Equipment design, configuration, and integration in
the CM equipment train: Specific attention must be
given towards harmonizing the individual equipment
inputs and outputs and identifying risk spots such as
locations of build-up or fouling.

The CQAs can be expressed as dependent on (a function

II.
of) all CMAs and CPPs (Figure 3). While the CMAs and CPPs
are relevant during manufacturing, the resulting CQAs are
relevant for the product performance. The final outcomes,
safety and efficacy, are ultimately relevant to the patient.
1.4.6. State of Control
USP’s Quality Standards for Pharmaceutical Continuous
Manufacturing Expert Panel (2015-2020) noted that
homogeneity, process parameters, and quality attributes are
described as a function of time in CM as opposed to batch
[Matos 2018]. The panel further elaborated on the state of
control as:
“A state of control does not imply the process is
at steady state. Continuous unit operations can
be designed to operate at a steady state, but in
practice, a CM process does not run at a steady-
state condition, but rather at a condition in which
a set of critical process parameters and/or quality
attributes are kept within a specified range of
target values (state of control). Deviations from
III.
these target values triggered by disturbances do
generally occur during the normal operation, but
they can be detected and are often small enough
Material characterization and compatibility checks:
The formulation (qualitatively and quantitatively) should
be designed keeping in mind the commercial equipment
train constraints [particularly the loss-in-weight
feeders (LIWFs) performance]. The excipients and drug
substance(s) must be characterized in terms of density
ranges and particle size distribution specifications.
These attributes are usually proven to be critical
towards one or several DP CQA(s) as they are often
demonstrated to impact blend and content uniformity,
as well as dissolution rate. The material characterization
is conducted using industry-standard in-process control
(IPC) equipment as well as with testing on LIWFs (either
at smaller scale or directly at the commercial scale).
Based on the DP quantitative formulation and the
process throughput range, the process designer will
have to demonstrate that the LIWFs can deliver every
raw material at the required throughput range. Several
specific conditions should be tested (startup, shutdown,
LIWF hopper refill, change in line throughput, impact of
increased runtime, etc).
Residence Time Distribution (RTD) model
implementation: Process dynamics must be understood
to track the material and to support the development of
sampling and diversion strategies.

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USP Technical Guide
Even if the RTD can be defined based on in-silico
modeling, confirmatory trials at commercial scale
are still needed. As these trials are performed at the
beginning of the CM process establishment, a tracer is
generally used for the RTD definition. It could be either
a visually detectable colored tracer (e.g., Fe2O3) or a
chemical tracer easily quantified in samples drawn.
Based on the RTD model, the material diversion strategy
can be set up at this stage. As the material tracking is
provided, the diversion of potentially non-compliant
material is enabled. Calculations can be performed to
determine the quantity of wet granules, dry granules,
uncoated or coated tablets to be discarded at each
diversion point, depending on the line throughput. It
is recommended to be conservative while doing these
“diverting” calculations to ensure that all the material
maintained in the equipment train meets the desired
specifications (in-spec).
IV. Risk Analysis: Manufacturing process risk analysis
(MPRA) is conducted either in parallel with, or after
the RTD tests. The outcome of this exercise is the
identification of potential CPPs (pCPPs), and potential
CMAs (pCMAs) based on their magnitude of impact on
DP performance (DP CQAs). This MPRA step is a paper
exercise which creates a foundation for the final control
strategy. The confirmation of the criticality (or lack
thereof) of the identified pCPPs and pCMAs must be
demonstrated via the Design of Experiments (DoEs).
The DoEs can be conducted before or after the PAT
models implementation and validation. Depending
on the status of (and level of experience with) the PAT
models, the responses used for model creation could
either come solely from sampling and characterization,
or partially from them (and partially from the PAT
models). The MPRA combined with the DoEs (screening
and optimization) will lead to the final list of CPPs and
CMAs. A control strategy is mandatory to ensure the
DP CQAs will always be compliant during the lifecycle
of the manufacturing process.
V. PAT implementation: Establishment of PAT model(s) is
required to run a PAT-enabled CM process. Experiments
for this purpose can start after the characteristics to be
measured are defined, PAT probes selected, and their
locations determined.
a. Initially the measurements are done statically, i.e.,
on fixed samples. The samples are manually taken
from experiments covering a range of parameters
10
(e.g., content, moisture, PSD, coating thickness)
and measurements are taken under varying
conditions (e.g., range of temperature, flow-rate
disturbances) and compared to a reference. Special
attention is given to the whole signal chain and
process: speed of measurement/data acquisition,
speed of conveying the data from the probe to the
Supervisory Control and Data Acquisition (SCADA)
system, data processing speed (transforming the
signal into values) and machine response speed
(for example, opening and closing of a diverting
valve) ensuring that the non-compliant material in
eliminated from the equipment train.
b. Once the models are defined statically, the second
step is to verify them in dynamic conditions
applying the same mindset. In this step, the
granules, blends, uncoated tablets and coated
tablets (compliant or not) will be generated by
running the CM line under different parametric
settings. The results generated by the PAT and the
reference method on specific collected samples are
compared. Ultimately, the diverted material (due to
the PAT measurement leading to an opening of the
diverting valve) will have to be analyzed with the
reference method and its non-compliance will have
to be verified. The same treatment is applied to the
“good” material maintained in the CM train right
after the closing of the diverting valve. Identification
of the sample to be drawn will be only possible
because of the RTD models generated earlier.
VI. Equipment Qualification: Once the list of CPPs and
CMAs is available and the PAT models established, it is
of primary importance to understand the relevant input
factors that affect the process performance. These inputs
are identified thanks to the models (outputs from the
optimization DoE[s]) via a sensitivity analysis. A sensitivity
analysis assesses how variability in the model inputs
contributes to variations in model outputs.
As a simple example, the dissolution rate of tablets has
been identified either by simulations or by output from
the DoE(s) to be a function of water flow rate introduced
during wet granulation, milling speed, compression force
and compression speed. After carrying out the sensitivity
analysis (based on trials conducted on the line), the
model error will be quantified and the contribution
(weight) of each CPP on the DP CQA (dissolution rate)
will be precisely calculated.
 Control Strategies for Continuous Manufacturing of Solid Oral Dose Drug Products

VII. Verification trials: At this stage, the verification trials
on the commercial line can be carried out since the
CPPs and CMAs have been identified, and the control
strategy is in place with the support of the IPCs, PAT
sensors and control loops. These can include:
a. Design space verification runs (runs at the “edges”
of the design space)
b. Test of the minimum and maximum throughput on
the line
c. Disturbance tests (e.g., filling of hoppers,
vibrations from the high-speed tableting machine),
tests of diverting valves operation, checks for
fouling of the probes (defining the need for line
shutdown to clean the probes), clogging of the
filters, etc.
VIII. The batch size range (or setpoint) will have to be
defined taking into account the previous conclusions
but also other factors like:
i. Supply chain constraints (e.g., launch schedule,
country-specific regulatory considerations,
future forecasts)
ii. Economic constraints, such as the resources
needed to assemble, disassemble, and clean
the line.
The flow chart in Figure 4 demonstrates a stepwise process
for OSD DP manufacturing. The stages that contribute to the
development of the control strategy are indicated.

Figure 4: Typical CM solid oral dose manufacturing process stages with specific steps that contribute to the establishment of the
control strategy.

Define initial formulation, establish

1
QTPP, production range

Identify, install, and test equipment,

2
instrumentation
Control
Strategy
3 Characterize material attributes

Define design space and normal

4
operating ranges

Design of experiments: establish

5
CQA, process control strategies CPPs

Production; Data collection CPPs

6 Process monitoring: PAT, modeling
OOS detection & diversion CQAs
CPPs
Real-time release
CPP is critical process parameters,
Continuous process validation QTTP OOS is out of specification.

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USP Technical Guide

2 Elements of Control
Strategy: Part 1

A control strategy for solid oral dose CM should include [ICH 2023] assessment of input material attributes, process
monitoring and control, operational procedures, and equipment and system integration aspects. These are described in detail
in this section.

Elements of a CM Control Strategy

Control
Strategy

Process Equipment
Material Monitoring Operational Operation &
Attributes & Control Procedures System
(PMC) Integration

Figure 5: Elements of a CM control strategy

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 Control Strategies for Continuous Manufacturing of Solid Oral Dose Drug Products

2.1. Material Attributes
Continuous processes can be more susceptible than batch
processes to failure due to certain material attributes
such as adhesion to equipment and electrostatic charge
accumulation. For example, powders sticking to the outlet
of loss-in-weight feeders can result in uneven flow rate
and accumulation of ingredients which drop into the
feeder as an agglomerate. Not only does this destabilize
the formulation on an ongoing basis but it can also cause
spikes of potent active material in the flow stream with
catastrophic implications for quality.

Such issues can be avoided by careful selection of

Figure 6: A schematic example of a direct compression equipment such as feeders with agitators, different screw
manufacturing train and associated potential failure designs, use of flow enhancers, and periodic equipment
modes as well as material properties impacting them and cleaning. Issues can also be prevented by developing a
respective methods for their characterization. deep understanding of unit operations, gained through

•
•

•
•
•

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USP Technical Guide

Unit Operation Failure Mode Material Property Characterization Technique

f Tapped density
Flow rate set point
f Density f Bulk density
divergence
Feeding f Permeability

f Cohesion f Shear Cell

Flow rate variability
f Adhesion f Electrostatics measurement

f Surface energy f Inverse gas chromatography

Agglomerate f Particle size

Milling f Droplet shape analysis
cohesion distribution

f Laser diffraction

f Surface energy f Inverse gas chromatography

Poor mixing/ f Particle size

f Droplet shape analysis
segregation distribution

f Laser diffraction
Blending
Choking, jamming,
— ­­ —
discontinuous flow

f Inverse gas chromatography

f Surface energy
Dry coating
or Contact angle
f Droplet shape analysis

f Inverse gas chromatography

f Surface energy
Dry coating
or Contact angle
f Droplet analysis

f Bonding
Failure to comply
f Plastic f Fitting compaction model
breaking force
Tableting
f Elastic

f Bonding
Failure to comply
f Plastic f Fitting compaction model
dissolution
f Elastic

Table 2: Examples of potential failure modes, respective

material properties, and characterization techniques for the
manufacturing line depicted in Figure 6.

14
 Control Strategies for Continuous Manufacturing of Solid Oral Dose Drug Products

well-planned experimental campaigns. Prior determination
of normal operating range and design space of each unit
operation is encouraged. Other unit operations also have
materials-related failure modes, and a thorough risk analysis
must be performed and included in the control strategy.
Figure 6 depicts common failure modes of a simple direct
compression equipment train. Input materials in a typical
OSD DP process include:
• DS or the active pharmaceutical ingredient (API)
in powdered form
• Excipients
• Lubricants and/or glidants
• Binder
• Water
• Coating components
2.2. Process Monitoring and Control
Process monitoring and control can be achieved using a
combination of tools such as:
• Spectroscopic PAT instruments (e.g., near infrared,
Raman)
• Process measurements (e.g., feed rate, mass flow rate,
compression force)
• Models (e.g., residence time distribution, process
models)
• Soft sensors
Section VI: PAT in the Development of Control Strategy
describes these tools in more detail. The aim of using these
tools is to achieve and maintain the process in a state of
control. This is facilitated by real-time data collection and
processing followed by control decisions being made
(Figure 7).

2.2.1. Process and Unit Operations Modeling

Unlike batch processes, continuous processes are

dynamic. Changes to operating conditions, whether
Figure 7: PAT, soft sensors, and models facilitate real-time data planned (adjustment to a parameter, start up, shutdown)
collection, thereby helping maintain a state of control which or unplanned (unexpected change to material properties
can eventually lead to continued process verification (CPV). or equipment performance), can propagate from one unit

Elements of Process Monitoring and Control

Process Analytical
Technologies (PAT)
State of Control

Real-time data Continuous Process

Soft Sensors
collection Verification (CPV)

Models

15
USP Technical Guide
operation to the next and disrupt the state of control.
One approach to understanding process dynamics is
the concept of residence time distribution (RTD). RTD
characterizes the time available for material transport
and transformation, and it is specific to the process,
composition/formulation, material properties, equipment
design, and configuration [E2968]. RTD is the degree
of back mixing in that it ranges from plug flow (RTD
approaches zero) to fully back mixed. It determines the
quantity of an ingredient of interest (e.g., API) in the output
material for the process (important for material traceability)
and determines when a change to the input material will
impact the output material (important for process control
and sampling). Process dynamics directly impact the use
of online monitoring and control (PAT). Understanding
RTD is critical in the placement of instruments (PAT tools)
and how they can respond to disturbances in real time for
adjustments and/or diversion strategies.
2.2.2. Process Control Systems
In a dynamic process, material attributes, quality attributes,
process parameters, and equipment conditions will not
remain static, and therefore a mechanism of control may be
needed. Categories of control strategies [E2968] include:
• Feedback control: This entails measuring the attributes
at the exit of a process and comparing them to a target
value or range. A model is used to adjust parameter
settings to bring the measured attributes back to
16
target/range. Example: Measuring assay at the output of a
blender in order to adjust the feed rate of DS at the inlet.
• Feed forward control: This entails measuring attributes
at the inlet of a process and using a model to determine
the necessary set point for the process. Example:
Measuring the DS prior to a blender and adjusting the
addition rate to target 100% in the blend.
• Multivariate model-based control (also referred to
as parametric control): Attributes that were measured
previously during model development are correlated
with process parameters. The process parameters are
monitored and constrained to ensure that predicted
attribute values remain within acceptable limits.
Attributes may be monitored to compare them to model
predictions. Example: Feed rate and drying temperature
for a continuous dryer are correlated to achieve a target
moisture level, which is then monitored at the exit and
compared to model predictions.
Both feedback control and feed forward control rely on the
response time of measurement instruments and a clear
understanding of the RTD model for every unit operation.
Otherwise, control responses to disturbances occur too late
to be effective. The reliability of the instruments (such as
build up and calibration drift) must be considered. Although
advanced control approaches such as feedback or feed
forward control have been recommended by regulatory
agencies, their implementation can be complex and should
not be the default approach to control strategies.
2.2.3. Operational Procedures
Operational procedures include considerations such as:
sequence of events during start-up, use of surge tanks or
intermediate bulk containers (IBCs) to maintain line rate (if
any), material transfer procedures (pneumatic, belt conveyed,
etc.) and the potential impact of these choices on quality, on
how acceptance or rejection decisions are made, etc.
CM start-up and shut-down processes are transient, and
unless an achieved state of control has been demonstrated,
the product cannot be considered acceptable. Therefore, the
control strategy should include a description of the procedure
for starting up the production line and information on which
signals and calculations are used to conclude the steady state
has been achieved, including how the product is diverted until
then. Similarly, a cut-off point must be specified before the
line shutdown begins. Also, the fate of the material in the line
while this process (startup/shutdown) is on must be described.
 Control Strategies for Continuous Manufacturing of Solid Oral Dose Drug Products

In many situations, material must be held up at one point
for a certain duration before the next unit operation is ready
to accept it. This can occur when unit operations require
more time to process material than others, or the product
itself requires some time (e.g., tablets needing a relaxation
period between compression and coating operations). The
control strategy must describe the procedure, the duration
of hold-up in an intermediate bulk container, and the mode
of transfer of such material.
Finally, if during normal processing, the control system
triggers an alarm that requires material to be temporarily
diverted out, the complete sequence of events and
procedures must be listed in the control strategy. For
example, in a direct compression process, a feeder control
system triggers an alarm indicating that a big chunk of API
is exiting the feeder and entering the next unit operation
(mixing). The process must have been characterized a priori
to understand the residence time distribution of the API
through the mixer and into the tablet press. Data from the
in-line sensor (which could be installed in the feed frame of
the tablet press or in a transfer chute after the mixer) must
be analyzed to inform the control system, and a decision to
divert or not divert should be made. This is an example of
feed-forward control.
2.2.4. Equipment and Systems Integration
Finally, the ICH Q13 guideline states that those aspects
of the equipment design that are shown to be critical to
the material quality and its control should be described
and justified. For example, the blade configuration in a
continuous mixer can be changed so they always face
forward, or they can be set to be a mix of forward and
backward facing. During the unit-operation characterization
stage, the amount of back-mixing and material hold-up in
the blender is determined for different blade configurations
at given impeller speeds. The mixer RTD is hence known.
If the blade configuration is changed, it can impact the
amount of time the materials have available to mix and by
extension, the degree of shear they experience. During
mixing of the lubricant, for example, the amount of shear
is an important factor. Over-lubricated blends can lead to
failures in dissolution performance testing. For this reason,
any such design changes must be justified.

Developing a Control Strategy

DP
Ishikawa (Fishbone) CQAs
Diagram

Risk Analysis

Variables ranked, sorted

Control
Strategy

DoE (Design of Experiments) Enhanced Process

and Design Space Understanding

Figure 8: An approach for developing a control strategy that keeps the desired quality attributes as the central focus during
process design.

17
USP Technical Guide
Elements of Control
3 Strategy: Part II
An effective control strategy describes all relevant material
attributes that can impact product quality and also
demonstrates how the manufacturer will control them.
Furthermore, it identifies the procedures to be used for
in-process controls. PAT is commonly used to assess process
performance against predetermined metrics. Mechanistic and
process models, as well as soft sensors, can also be used to
support real-time decision making. If used, these form a part
of the control strategy and should be validated and reported in
the appropriate section. The manufacturing equipment must
be qualified to show it is able to perform as expected within
the desired line rate (flow rate). A unique feature of CM is that
decisions regarding product acceptance/rejection can be
made in real time, and any out-of-specification (OOS) material
or product can be rejected using a diversion mechanism built
into the manufacturing line.
3.1. Risk Assessment
Once a list of process parameters and attributes has been
created for each unit operation, the next step is to apply
first principles and existing process understanding to
make an initial assessment of the process risks to CQAs. A
Failure Mode and Effects Analysis (FMEA) is a common risk
assessment tool but may be difficult to score when used in
early process development. An alternative, simple risk matrix
is shown in Figure 9.
This matrix is applied at the unit operation level, first to
score the relative impact of that unit operation on final and
intermediate CQAs. Note that the intermediate CQAs listed
are also potential in-process controls. Where high or medium
impact is shown, it is highly likely that unit operation has
CPPs and/or CMAs.
Once the higher-impact unit operations are identified,
a parameter (and material attribute) risk assessment is
performed on that unit operation. For each factor, the
18
relative impact is estimated (using historical process knowledge
and understanding) for relevant CQAs. The relative, expected
control level is also considered (e.g., if a parameter is fixed,
it has no variability to impact quality, and if a parameter is
tightly controlled, its impact may be relatively low).
Process parameters and material attributes having high and
medium impact are likely to impact CQAs and, therefore,
must be included with process experimentation (DoEs)
when a range is desired for these factors. The DoEs are
designed to determine the actual magnitude of effect on
one or more CQAs. Consequently, at the conclusion of DoEs,
the risk assessments are revisited and re-scored based on
the additional process knowledge achieved. If high-impact
parameters and material attributes remain, then these
unit operations are considered for more rigorous control
strategies including in-process control using PAT.
3.2. Material Characterization
CM depends on the consistent gravimetric feeding of both
the DS and the excipients. Material characterization and
particle engineering for properties may be required. Powder
build-up, hopper bridging, surface adhesion, agglomeration,
and dusting are all potential problems that can interfere with
consistent powder flow. Since multiple batches of material
may be added to the same feeder, batch-to-batch variability
must be minimized. Once a particular excipient has been
developed to have optimal flow for a CM process, it may be
used across multiple products without further development.
The accuracy of gravimetric feeding is evaluated in feeding
trials. Although feeders are available in a variety of flow rates,
low-flow-rate feeding remains a challenge for low potency
DSs and low-proportion excipients (such as magnesium
stearate and silicon dioxide). Strategies such as pre-mixing of
some components or proportional feeding (linking feeders
in a master/slave control scheme) may be required. Refilling,
 Control Strategies for Continuous Manufacturing of Solid Oral Dose Drug Products

Figure 9: Example of simple risk matrix for CM of OSD: How unit operations impact intermediate and final CQAs.

Unit Operation
CQAs
Wet
LIW Feeder Drying LIW Feeder Blending Compression
Granulation

Appearance No Low No No Low Medium

Assay High High No Medium Medium No

Content Uniformity No Low No Medium High Medium

Dissolution No High No No Low Low

Impurities No Medium Medium No No No

Water Content No Medium High No No No

Intermediate CQAs (In-Process Controls)

Blend Uniformity No Medium Low Medium High No

Water Content No High Medium Low Low Low

Weight Check No No No No No High

Hardness No No No No Low High

Risk Of Impact, Small Risk

High = Risk Of OOS Medium = Low =
But In Spec Of Impact

No Potential
No = LIW = Loss-In-Weight
Impact

perturbations, noise, and vibration can all impact feeding
accuracy and are included as part of these studies.
3.3. Experimental Design
Initial feasibility studies usually begin with a direct
compression process due to its simplicity and cost-
effectiveness, but if direct compression is not possible,
dry or wet granulation unit operations are used.
First, engineering/placebo studies are typically done with
the objective of evaluating the parameter ranges of unit
operations. In early studies, it is acceptable to substitute a
suitable placebo to save the cost of the DS. As operating
ranges are refined, the DS is added to the formulation so
that RTD models can be developed for each unit operation.
However, a tracer may be used instead of the DS for RTD
studies. Tracer characterization and rationale are critical.
When selecting a tracer, the critical physical attributes should
be as comparable to the DS characteristics as possible.
Excipients should also be included in model development.
The next step is the application of DoEs to define design spaces.
Initial screening designs may use a placebo where possible.

19
USP Technical Guide

Factorial studies will finalize the design spaces and confirm • Medium: Can affect product quality, but there are
that DP CQAs are met. Once the uncoated tablet properties other engineering controls available to mitigate any
have been achieved, a coating process DoE is performed, if redundancies due to false prediction.
required. Unlike batch processing, different DoE conditions
can be run in succession after allowing for conditions • High: The sole control/assurance of product quality.
to stabilize per the RTD model. This allows for more DoE
Low- and medium-impact models are the most common
conditions and more samples to be tested than is done
types in control strategies. Where the impact is high to
during batch process development.
medium, validation of the model will likely be necessary.

3.4. PAT Development

PAT instrument and control development will proceed in
parallel with later DoE studies. Measurements of identity,
blend uniformity, content uniformity, loss on drying, and
particle size distribution are commonly done using online PAT
instruments. However, not all unit operations may require PAT
if parametric controls maintain low variability of the attribute.
Typically, as process understanding increases, the use of PAT
tools decreases, allowing for a robust control strategy that
is not overburdensome for data collection and reporting. A
risk assessment is appropriate to determine whether PAT is
needed for the control of the unit operation.
3.5. Full-Line RTD, Performance,
and Modeling
3.6. Out-of-specification Determination
and Diversion
Most CM manufacturing trains deploy a diversion system
to direct any material deemed to be OOS to scrap
or for further analysis. As described in Section 1.5, a
comprehensive analysis of the process dynamics will lead to
an understanding of how a disturbance propagates through
the line. For example, to describe how a disturbance in the
mass flow rate of an ingredient, often starting from a feeder,
would propagate through the system and affect one or more
DP CQAs. Material traceability along the manufacturing
line is required to divert any non-conforming product. In
simple words, the control system must know precisely, and
at all times, “what” material is “where” and “when” in the
integrated line.

Overall process control software to coordinate multiple unit

operations will be needed and optimized during full-line 3.7. Scale-up Considerations
performance runs. It is not uncommon for the development
For batch processing, development is done on a smaller
and optimization of the control software to take significant
scale than the expected commercial scale will require. This
time during process development. During these runs, the
allows for performing multiple development experiments
full-line RTD model is verified and the diversion strategy for
while using smaller quantities of expensive materials such
non-conforming materials is finalized.
as the DS. Afterwards, however, a series of scale-up runs
RTD models may be simulated in silico through a digital twin is needed to ensure that the small-scale process control
but are typically developed experimentally using spiking strategy can be translated to the larger commercial scale.
or tracer studies. Consequently, the RTD models cannot CM has three approaches to scale up:
anticipate unexpected disturbances and non-conformities
1. Development uses the same scale equipment
(e.g., poor material flow, vibration, or product build up). More
as commercial, but the run-time is increased for
commonly, a PAT instrument is needed to not only detect
commercial manufacturing.
and respond to these disturbances, but also to provide a
redundant control to the RTD model. 2. Development uses the same scale equipment as
commercial, but the mass flow rate is increased for
When using process models, their impact on product quality
commercial manufacturing.
can be categorized as follows:
3. Development uses smaller-scale equipment than
• Low: Information only, which does not impact process or
commercial, and a scale-up transfer is required for
product quality strategy.
commercial manufacturing.

20
 Control Strategies for Continuous Manufacturing of Solid Oral Dose Drug Products
Approach #1 provides the shortest development time and
lowest cost, but also requires an investment and installation
commitment to equipment sized at the same scale as
the eventual commercial line. Approach #2 has a distinct
disadvantage, since changing the mass flow rate through
the equipment impacts the RTD for the process steps,
which in turn requires new modeling and control strategy
development. Approach #3 has a similar disadvantage to #2
since the control strategy will not transfer directly to larger-
scale equipment.
21
A suggested hybrid approach for a new product is to begin
with smaller-scale equipment, but to use this only for
process feasibility and early development studies. Many
CM equipment suppliers have development facilities for
this express purpose. For the later process design, the
R&D equipment should be scaled to match the eventual
commercial line. This is to ensure that the commercial
line has the same mass flow rate and that scale-up can be
achieved by a longer run-time. This turnkey approach should
reduce the cost of transfer to the commercial line.
USP Technical Guide

PAT in the Development

4 of Control Strategy

4.1. Introduction: PAT and Quality 4.2. Spectroscopic PAT Tools

Assessment
An OSD CM process may be designed to facilitate the use of
process analytical technologies (PAT) such as near-infrared
spectroscopy (NIRS) and Raman spectroscopy. PAT is an
umbrella term whose meaning can differ from company to
company. In OSD DS applications, a common interpretation
of PAT is the application of analytical tools to learn deeply
about the process in order to devise best practices that lead
to the desired CQAs. A broader interpretation of PAT includes
techniques such as statistical process control and modeling
[Clegg 2020].
A CM process, by design, facilitates in-process monitoring
and collection of large amounts of data. The data can be
used to develop models during the development stage,
which can be helpful during the commercial manufacturing
stage.
In OSD DS processes, common locations for installing
spectroscopic probes are between feeder and blender,
after blender, or in the feed-frame of a tablet press. Some
modern tablet press equipment allows analyzing every tablet
immediately after compression. Common measurements
in such processes include flow rate and its variability, blend
composition and homogeneity, particle size and distribution,
impeller torque in the continuous blender, tablet press main
compression force, etc.
In some special processes, especially semi-continuous
ones, it may be possible to eliminate spectroscopic PAT
measurements altogether in the production runs after using
them extensively to build representative models. Soft-sensor
and gravimetric controls can be used as surrogates for
spectroscopic PAT, thereby saving resources [Medendorp,
Shapally, Vrieze and Tolton 2022].
4.2.1. Near-Infrared Spectroscopy
The advent of modern spectroscopy technology can be
traced back to the development and utilization of NIR
spectroscopy. The NIR region (780-2500 nm) of a spectrum
is characterized by the absorption bands from overlapping
overtones and combinations of the fundamental vibrations
of functional groups containing hydrogen atoms. The low
absorptivity of NIR light enables direct analysis of samples
without prior preparation, as well as measurements
involving scattering effects of diffuse transmittance
or diffuse reflectance.
In CM, NIR is a commonly employed PAT for monitoring
various stages of the process in real time and providing
valuable information about the quality and consistency
of the final product. NIR has several key advantages over
traditional analytical techniques, including its ability to
analyze the sample noninvasively in real time, its potential
for faster and more cost-effective analysis, and its ability
to perform multiple analyses simultaneously. These
advantages have led to the successful application of NIR in
the continuous monitoring of various key quality attributes.
For example, NIR can be particularly useful in the continuous
blending and granulation processes for predicting blend
homogeneity, particle size distribution, and moisture
content, which are all important parameters that influence
intermediate flowability and compressibility.
In the context of PAT methods, soft sensors combining NIR
with other process parameters can also be used to predict
an attribute such as dissolution using tablet weight, main
compression force, and NIR-predicted API content. In
addition, the integration of NIR spectroscopy into existing

22
 Control Strategies for Continuous Manufacturing of Solid Oral Dose Drug Products
process control systems has been shown to provide real-time
feedback on the manufacturing process, leading to improved
process control and increased efficiency. It is important to
note that the implementation of NIR spectroscopy in CM
requires the careful consideration of several factors. First,
one must select NIR spectroscopic instrumentation that
is suitable and appropriate for the specific manufacturing
process. Second, robust and validated analytical methods
must be developed to ensure accurate and reliable results.
Finally, a formal lifecycle management plan must be in
place so that the equipment and models are monitored
and maintained proactively to incorporate new sources of
variation and ensure continued performance and accuracy.
4.2.2. Raman Spectroscopy
Raman spectroscopy is another widely used PAT tool in CM,
probing the molecular vibrations in a sample and providing
detailed information about its chemical composition and
structure. The basic principle of Raman involves inelastic
scattering of photons by a molecule interacting with the
monochromatic incident light. In this process, only a small
23
fraction of the scattered light will undergo an energy change
(corresponding to the vibrational energy levels of the
molecule) that determines the size of the wavelength shift as
well as the number of shift occurrences.
As a complementary method to NIR, Raman spectra feature
sharp, well-resolved bands over approximately 50-4000
cm-1, making it suitable for the analysis of crystalline
compounds and polymorphs. In addition, the spectrum of
water is extremely weak, which in some scenarios can be a
desired characteristic, in that it allows direct measurement
of complex mixtures with limited interference from sample
moisture content. One of the biggest and most frequent
challenges associated with Raman, however, is the presence
of fluorescence background when collecting quality Raman
spectra for certain compounds (e.g., microcrystalline
cellulose or MCC). Fluorescence can occur when the
excitation wavelength used to generate Raman signal
overlaps with the absorption spectrum of the sample. This
can cause some molecules to be excited to higher energy
states, leading to fluorescence emission rather than Raman
scattering. To mitigate the impact of fluorescence, several
strategies can be employed: light source wavelength
USP Technical Guide
optimization, sample preparation, instrument configuration,
and appropriate data analysis methods.
In CM, Raman spectroscopy enables real-time process
monitoring and control with rapid, non-destructive analysis
of the chemical and physical properties of raw materials,
intermediate products, and finished products, providing
critical information for process optimization and quality
assurance. Some of the key learnings when Raman
spectroscopy is used as a PAT tool include blend uniformity,
amorphous content, powder flowability, and tablet quality
(e.g., API content, hardness, and disintegration time). It
must be noted that some of these attributes are not directly
measured by Raman spectroscopy alone, but it contributes
to the measurement process. The aforementioned factors for
NIR implementation, such as instrument selection, analytical
method development, and maintenance, also apply to Raman
spectroscopy for accurate and reliable measurements
throughout its lifecycle.
4.3. Chemometrics
4.3.1. Sampling and Data Quality
When developing a calibration model for PATs, it is of utmost
importance to ensure that the data are accurate and relevant.
The old adage “garbage in, garbage out” holds well when
it comes to chemometric modeling. The total amount of
variation in the dataset consists of explainable variation
that potentially can be modeled and random variation or
noise that cannot be captured. A successful application
of chemometrics in PAT depends on several factors such
as sample representation, quality of the measurement
system, and the model structure. To gather representative
data, samples should be selected across the entire range
of expected concentration variation in the process and
should include in the mixture all possible components
to be tested in the future. In addition, the calibration set
should be large enough to statistically determine the
mathematical relationship between spectral variables and
concentrations. When preparing samples, the process
should be standardized to ensure that all samples are treated
consistently, and the actual process being measured is
mimicked accurately.
Another consideration involves the inherent heterogeneity of
sampling that depends on where in the process, the samples
are collected. Prior to data collection, instrumentation
elements such as the spectrometer, optics/probes, and
spectral analysis software should be determined based on
the applications. To ensure repeatable and reproducible
24
measurements, the NIR or Raman instrument should be
calibrated regularly using reference standards that are
traceable to recognized standards. Other aspects of
acquisition parameters, sampling interface, sample size,
and modes of measurement (e.g., at-line, in-line, and on-
line) should also be considered. Moreover, the reference
analytical procedure is the “gold standard” when developing
quantitative models and thus should be performed on
the same samples that are used for spectral acquisition
whenever possible.
4.3.2. Preprocessing
The goal of preprocessing is to eliminate or reduce variability
that is irrelevant to the property of interest and thereby
represent the data better for modeling purposes. When
implementing Raman or NIR, the complex, high-dimensional
spectral data are often affected by various factors such
as the quality of the instrument, properties of the sample,
and manufacturing conditions. To obtain reliable, accurate
spectral data, appropriate preprocessing methods should be
applied to improve signal-to-noise ratio and mitigate artifacts
and baseline variations. In the manufacturing of oral solid
DPs, variations in powder physical properties such as particle
size, packing density, or surface morphology can introduce
unwanted light-scattering effects manifested in the additive,
multiplicative, or wavelength-dependent spectral data.
In addition, as mentioned in the preceding section, a
stronger fluorescence signal can overshadow Raman
scattering by creating a broad band, which will benefit from
data pretreatment to amplify Raman peaks while eliminating
fluorescence background. The most widely adopted
preprocessing methods in spectroscopy are mean-centering,
baseline correction, standard normal variate (SNV),
multiplicative scattering correction (MSC), and derivatives.
Other approaches such as extended multiplicative signal
correction (EMSC) and generalized least-squares (GLS)
weighting are becoming popular.
4.3.3. Variable Selection
Variable selection is another important aspect of
chemometric modeling when implementing NIR or Raman
spectroscopy as PAT. Careful selection of the spectral
variables most relevant to chemical composition or
physical properties can simplify the model and reduce the
noise, leading to more accurate, robust, and interpretable
prediction results. The choice of the variable selection
approach depends on the nature of the data, the complexity
 Control Strategies for Continuous Manufacturing of Solid Oral Dose Drug Products
of the system, and the desired model performance. Based
on the fitted partial least squares (PLS) regression model, for
example, loading weights and regression coefficients can be
used as a measure of association between each variable and
the response. Moreover, variable importance in projection
(VIP) scores are used to assess the importance of each
predictor variable in the PLS model, which takes into account
both the contribution of the variable to the model and its
ability to explain the variation in the response variable.
Selectivity ratio is another measure defined as the ratio
between the explained variance of each variable and
the residual variance. Genetic algorithm (GA) is a search
algorithm that mimics the process of natural selection and
genetics to find an optimal solution to a problem. In the
context of PLS variable selection, GA works by iteratively
selecting a subset of predictor variables, evaluating the
performance of the PLS model using only those variables,
and then selecting the best-performing subset for the next
iteration. This process continues until a stopping criterion is
met or the algorithm converges to a solution.
In addition, interval PLS (iPLS) is a variable selection method
that aims to identify subsets of predictor variables that are
highly correlated with the response variable across a range
of intervals. In iPLS, the predictor variables are divided into
intervals based on their values, and PLS models are fitted
separately for each interval. The variables that have the
highest correlation with the response variable across all
intervals are selected for inclusion in the final model.
4.3.4. Quantitative Predictive Modeling
The quantitative models commonly used in PAT
implementation include multiple linear regression (MLR),
principal component regression (PCR), and partial least
squares regression (PLS). MLR models the linear relationship
between a dependent variable and one or more independent
variables. PCR combines principal component analysis
(PCA) and MLR to develop calibration models. PCA is used to
reduce the dimensionality of the spectral data and then the
principal components are used as input variables to predict
25
the properties of interest. PLS identifies the latent variables
that maximize the covariance between X and Y datasets.
In comparison to MLR, PLS can handle noisy and high-
dimensional data as well as multicollinearity, and it improves
predictive performance.
4.3.5. Model Optimization and Validation
Determining the optimum number of latent variables in PLS
involves finding the number of components that provide the
best trade-off between model complexity and prediction
accuracy. Cross-validation is a widely used technique for
determining the model dimensionality and evaluating model
predictive performance. It is recommended to use an
independent test set to estimate the prediction error, which
is less biased than the error obtained from the training set.
This helps to ensure that the PLS model is not overfitting
to the training set and can be applied to new data with
reasonable accuracy.
4.3 .6. Model Maintenance and Lifecycle
Management
Chemometric models require maintenance and lifecycle
management for continued accuracy and reliability over
time. One of the most important aspects is the quality of the
data used to develop the model. Data should be monitored
regularly and assessed for outliers, missing values, and
other quality issues. Data cleaning procedures should be
established to address any issues that are identified. In
addition, models should be routinely monitored to ensure
that they continue to perform accurately and reliably. Models
may need to be retrained or updated with appropriate
frequency to reflect changes in the process or product being
monitored. Lastly, documentation and version control are
important to ensure that models can be understood and
maintained easily by other users and that different versions
of the model can be tracked and compared throughout the
lifecycle.
USP Technical Guide
Application to Oral
5 Solid Dose, Drug
Product Manufacturing
5.1. Solid Oral Dose CM Methods and
their Specific Control Strategies
5.1.1. Direct Compression (DC)
A typical OSD DC process consists of the following
components:
• A facility to store, pre-condition, and deliver the input
materials to the first unit operation in the process, which
is feeding.
• A number of loss-in-weight gravimetric feeders so that
each ingredient can be accurately fed to the next unit
operation. It is typical to have separate feeders for APIs,
excipients, lubricant, etc. They have a predetermined
set-point to maintain the desired ratios of ingredients in
the formulation.
• Blending unit operation that typically features a
horizontal or vertical continuous blender. A common
design for the blender is an impeller housed in a
cylindrical shell. The impeller has blades mounted along
its length and as it rotates along its axis, powders are
fluidized, mixed, and conveyed by the blade action.
• Tableting unit operation involving a rotary tablet press.
The output from the feeder typically passes through a
transfer chute or hopper into the feed-frame of the tablet
press, wherein rotating paddles disperse the powder into
dies on a rotating turret to be punched into tablets.
• Tablet coating operation using a continuous or traditional
batch-mode pan, or a Wurster coating equipment.
The direct compression process (see Figure 2) involves
feeders, blender(s), optional mills, and compression and/or
coating equipment. It is called “direct” compression because
26
there is no intermediate major unit operation between
blending and tableting.
In all modes of OSD CM discussed here, the following will be
common:
• There is a need to characterize and control input material
properties.
• One must monitor the effects of feeder refill and material
property variations on feed uniformity.
• There is a need to characterize blender performance.
• It is important to consider the feeder-blender
combination and their combined performance.
• Factors related to tableting operation need to be
considered.
5.1.2. Wet Granulation
A CM line with wet granulation involves feeders, blender(s),
optional mills, continuous wet granulator, continuous dryer and
tableting equipment. The wet granulation step can be high or
low shear, depending on the process requirements, and it is a
major unit operation between blending and tableting.
In high-shear continuous wet granulation, added factors will
include binder properties and quantity, rate and amount of
shear imparted, and resulting granule size and uniformity.
In low-shear continuous wet granulation, a process featuring
twin screw granulators is low shear, wherein the shear
may not be a significant factor affecting the intermediate
CQAs. Other parameters mentioned under high-shear wet
granulation will potentially remain relevant in this case. In
some cases, heating is involved, so temperature is another
key parameter.
 Control Strategies for Continuous Manufacturing of Solid Oral Dose Drug Products
5.1.3. Dry Granulation
In this scenario, the compression imparted by rollers will be
a significant factor. Parameters such as roll gap, roll speed
and the feed rate will determine the properties of the rolled
material as it progresses to the next unit operation, which
typically is milling.
5.2. Feeding and Blending Unit
Operations
The equipment train is selected based on the desired
production rate and it includes a loss-in-weight feeder for
each component (e.g., excipients, lubricants), which is
tuned to maintain the desired ratio corresponding to the
formulation. Loss-in-weight feeders are equipped with a
load cell that measures the weight of material inside the
feeder at a high frequency and records it via an onboard
computer. As the material is fed into the process, the weight
inside the feeder goes down. The feeder control system
adjusts the feeder screw speed accordingly to maintain the
desired set-point in feed rate. This is typically the first point
of process monitoring and control. The sensor acts as a non-
spectroscopic PAT tool.
27
Process designers carry out experiments using individual unit
operation equipment such as feeders and blenders. These
experiments help designers understand the performance
across the design space, which could include the expected
material property and process parameter ranges. It is
intuitive to carry out experiments with a feeder-blender
combination, as some feed rate irregularity coming in from
the feeders can be mitigated by the back-mixing action
of the blender. From a risk assessment perspective and to
determine process robustness, it is important to understand
whether this is such a case, and if it is, then what range of
disturbance can be mitigated. Some key material properties
in these unit operations are material density, particle size,
and particle distribution, cohesion, and electrostatic affinity.
The process-related factors and parameters include feeder
refill frequency and quantity of material input, variability
between batches of input material, processing rate, blender
impeller speed, fill level, blender design, etc.
It is critical that both the feeding and blending unit
operations are well understood and controlled to have
an OSD DP line operating under a state of control.
Table 1: Feeding-Mixing Unit
Operation and Key Parameters
Material Process
Property-Related Parameter-Related
Powder density Feeder refill frequency
Particle size Refill quantity
Particle size Vibrations or other physical
distribution disturbances
Cohesion Processing rate
Electrostatic affinity Blender impeller speed
Blender fill level
Blender design (vertical,
horizontal, tilt, weir, etc.)
USP Technical Guide

5.3. Example Control Strategy

Direct Compression

Process Parameters
Potential Impact Of
Process Step
Equipment Parameters Range Related Dp Cqas
Target Designation
Used Studied Studied

Drug Flow Rate 1 –

Feeder Flow Rate Critical Uniformity of Dosage
Feeding Substance Flow Rate 2
Model(s) (kg/hr) or Not Units (CQA)
PSD (μm) (kg/hr)

(Brand and
Model) Impeller
rpm1-rpm2
Horizontal/ Speed
Vertical/
X kg/h – Content Uniformity
Blending Y/N
Y kg/h (CQA)
Blade Design Forward
Tilted
Continuous
Mixer Blender Tilt X°

Main
Compression kN Range Friability
Force Based on
(Brand and
DoE and
Compression Model) Tablet
Design API Dosage (CQA)
Press Turret Speed/
rpm Range Space
Dwell Time
Disintegration Time

Tablet Load
Rate
(Brand and
Model) Rotation Coating Thickness
Coating
Continuous Speed and Uniformity
Coater
Air
Temperature

28
 Control Strategies for Continuous Manufacturing of Solid Oral Dose Drug Products

6 Appendix
USP Standards impact Continuous Manufacturing
Relevant General Chapters (Required, below <1000>)

Public
Input Continuous standard
Materials Manufacturing for the product in
Properties Process the market

<429> Light Diffraction Measurement of <429> Light Diffraction Measurement of <905> Uniformity of Dosage Units
Particle Size Particle Size
<711> Dissolution
<430> Particle Size Analysis by Dynamic <430> Particle Size Analysis by Dynamic
Light Scattering Light Scattering Official Product Monographs
<432> Determination of Zeta Potential <696> Characterization of Crystalline Solids
by Electrophoretic Light Scattering by Microcalorimetry and Solution Calorimetry
<467> Residual Solvents <699> Density of Solids
<616> Bulk Density and Tapped Density <776> Optical Microscopy
of Powders <811> Powder Fineness
<695> Crystallinity <846> Specific Surface Area
<699> Density of Solids <856> Near-infrared Spectroscopy
<731> Loss on Drying <858> Raman Spectroscopy
<776> Optical Microscopy <891> Thermal Analysis
<786> Particle Size Distribution Estimation by <921> Water Determination
Analytical Sieving
<941> Characterization of Crystalline and
<811> Powder Fineness Partially Crystalline Solids by X-Ray Powder
<846> Specific Surface Area Diffraction (XRPD)
<856> Near-infrared Spectroscopy
<858> Raman Spectroscopy
<891> Thermal Analysis
<921> Water Determination
<941> Characterization of Crystalline and
Partially Crystalline Solids by X-Ray Powder
Diffraction (XRPD)

29
USP Technical Guide

USP Standards impact Continuous Manufacturing

Relevant General Chapters (Required, above <1000>)

Public
Input Continuous standard
Materials Manufacturing for the product in
Properties Process the market

<1059> Excipient Performance <1039> Chemometrics <1010> Analytical Data-Interpretation

<1063> Shear Cell Methodology for Powder
Flow Testing
<1856> Near-Infrared Spectroscopy—Theory
and Practice
<1858> Raman Spectroscopy—Theory and
Practice
<1174> Powder Flow
<1195> Significant Change Guide for Bulk
Pharmaceutical Excipients
<1197> Good Distribution Practices for Bulk
Pharmaceutical Excipients
<1776> Image Analysis of Pharmaceutical
Systems
<1058> Analytical Instrument Qualification and Treatment
<1062> Tablet Compression Characterization <1029> Good Documentation Guidelines
<1174> Powder Flow
<1039> Chemometrics
<1216> Tablet Friability & <1217> Tablet
<1079> Good Storage and Distribution
Breaking Force
Practices for Drug Products
<1241> Water Solid Interactions in
Pharmaceutical Systems Sampling Procedures
<1243> Wettability of Pharmaceutical <1099> Limit on Number of Large Deviations
Systems When Assessing Content Uniformity in
<1244> Electrostatic Properties of Large Samples
Pharmaceutical Systems <1220> Analytical Procedure Lifecycle
<1245> Fitting Compaction Model
<1856> Near-Infrared Spectroscopy—Theory
(Compactor simulator) Characterization
and Practice
<1430> Analytical Methodologies Based on
Scattering Phenomena – General <1858> Raman Spectroscopy—Theory
and Practice
<1711> Oral Dosage Forms – Performance
Tests
<1776> Image Analysis of Pharmaceutical
Systems
<1856> Near-Infrared Spectroscopy—Theory
and Practice
<1858> Raman Spectroscopy—Theory
and Practice

30
 Control Strategies for Continuous Manufacturing of Solid Oral Dose Drug Products

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