ASTM E2968-23

This international standard was developed in accordance with internationally recognized principles on standardization established in the Decision on Principles for the
Development of International Standards, Guides and Recommendations issued by the World Trade Organization Technical Barriers to Trade (TBT) Committee.
Designation: E2968 − 23
Standard Guide for
Application of Continuous Manufacturing (CM) in the
Pharmaceutical Industry
This standard is issued under the fixed designation E2968; the number immediately following the designation indicates the year of
original adoption or, in the case of revision, the year of last revision. A number in parentheses indicates the year of last reapproval. A
superscript epsilon (´) indicates an editorial change since the last revision or reapproval.
1. Scope 2. Referenced Documents
1.1 This guide introduces key concepts and principles to 2.1 ASTM Standards:
assist in the appropriate selection, development and operation E2363 Terminology Relating to Manufacturing of Pharma-
of CM technologies for the manufacture of pharmaceutical ceutical and Biopharmaceutical Products in the Pharma-
products. Athough selected concepts covered here can be ceutical and Biopharmaceutical Industry
applied to biopharmaceutical CM (BioCM), the focus of this E2475 Guide for Process Understanding Related to Pharma-
guide is on non-biopharmaceutical applications. ceutical Manufacture and Control
E2537 Guide for Application of Continuous Process Verifi-
1.2 Particular consideration is given to the development and
cation to Pharmaceutical and Biopharmaceutical Manu-
application of the appropriate scientific understanding and
facturing
engineering principles that differentiate CM from traditional
E2629 Guide for Verification of Process Analytical Technol-
batch manufacturing.
ogy (PAT) Enabled Control Systems
1.3 Most of the underlying concepts and principles (for
E2898 Guide for Risk-Based Validation of Analytical Meth-
example, process dynamics and process control) outlined in
ods for PAT Applications
this guide can be applied to both Drug Substance (DS) and
2.2 Regulatory Guidance and Other Documents:
Drug Product (DP) processes. However, it should be recog-
21 CFR 210.3 Current Good Manufacturing Practice in
nized that in Drug Substance production the emphasis may be
Manufacturing, Processing, Packing or Holding of Drugs,
more on chemical behavior and dynamics in a fluid phase
General Definitions
whereas for solid drug product manufacture there may be a
EMA Guideline on process validation for finished products
greater emphasis on the physical behavior and dynamics in a
information and data to be provided in regulatory submis-
solid/powder format.
sions
1.4 This guide is also intended to apply in both the devel-
EU Guidelines for Good Manufacturing Practice for Medici-
opment of new processes, or the redesign of existing ones.
nal Products for Human and Veterinary Use, Annex
15: Qualification and Validation
1.5 All values are stated in SI units. No other units of
FDA Guidance for Industry PAT A Framework for Innova-
measurement are included in this standard.
tive Pharmaceutical Development, Manufacturing, and
1.6 This standard does not purport to address all of the
Quality Assurance (2004)
safety concerns, if any, associated with its use. It is the
FDA Guidance for Industry Process Validation: General
responsibility of the user of this standard to establish appro-
Principles and Practices (2011)
priate safety, health, and environmental practices and deter-
ICH Harmonized Tripartite Guideline, Continuous Manufac-
mine the applicability of regulatory limitations prior to use.
turing of Drug Substances and Drug Products, Q13 (Step
1.7 This international standard was developed in accor-
2b version, dated 29 July 2021)
dance with internationally recognized principles on standard-
ICH Harmonized Tripartite Guideline, Pharmaceutical
ization established in the Decision on Principles for the
Development of International Standards, Guides and Recom-
mendations issued by the World Trade Organization Technical
For referenced ASTM standards, visit the ASTM website, www.astm.org, or
Barriers to Trade (TBT) Committee.
contact ASTM Customer Service at service@astm.org. For Annual Book of ASTM
Standards volume information, refer to the standard’s Document Summary page on
This guide is under the jurisdiction of ASTM Committee E55 on Manufacture the ASTM website.
of Pharmaceutical and Biopharmaceutical Products and is the direct responsibility of Available from Food and Drug Administration (FDA), 10903 New Hampshire
Subcommittee E55.11 on Process Design. Ave., Silver Spring, MD 20993-0002, http://www.fda.gov.
Current edition approved Jan. 1, 2023. Published February 2023. Originally Available from International Council for Harmonisation of Technical Require-
approved in 2014. Last previous edition approved in 2014 as E2968 – 14. DOI: ments for Pharmaceuticals for Human Use (ICH), ICH Secretariat, Route de
10.1520/E2968-23. Pré-Bois, 20, P.O Box 1894, 1215 Geneva, Switzerland, https://www.ich.org.
Copyright © ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959. United States
E2968 − 23
Quality System, Q10 (Step 4 version, dated 4 June 2008) certain time, or containing a certain lot of a starting material),
and subjected to a disposition decision.
3. Terminology (4) A process consisting of a series of interconnected unit
operations or transformations can be considered to be continu-
3.1 Definitions:
ous even if it contains transformations of defined quantities of
3.1.1 For general definitions, refer to Terminology E2363
material which might be considered to be composed of a
and Guides E2537 and E2475.
sequence of individual discrete events.
3.2 Definitions of Terms Specific to This Standard:
(5) During periods of startup, shutdown or processing of
3.2.1 back mixed process—a process with a residence time
small quantities of material, or both (for example, for
distribution (RTD) that is significant compared to the mean
development/experimental or clinical studies), it is possible
residence time. A process where the deviation of a material’s
that not all unit operations within a continuous production line
residence time distribution from its mean residence time is
will be in normal or steady state conditions at the same time.
large enough to indicate significant mixing of materials intro-
For example: the first unit operation could already be shut
duced at a single point into the process at different times.
down while the material is processed further in subsequent unit
3.2.1.1 Discussion—For example, in a fully back mixed
operations. This condition should not automatically invalidate
process, quantities of material will be mixed into a single
the definition of the process as representative of normal
homogeneous condition such that a rapid step change in the
continuous operation; however, care must be taken to under-
properties of inlet material will not result in an equivalent step
stand the impact of this mode of operation on product quality.
change in the properties of the output material but will be
3.2.3 critical process parameter (CPP)—a process param-
reflected in a more gradual change. The rate of this change will
eter whose variability has a significant impact on a CQA and
depend on the material properties, equipment characteristics,
therefore should be monitored or controlled to ensure the
residence volume, and the residence time distribution/degree of
process produces the desired quality (ICH Q8 (R2)).
mixing. A fully back mixed process may be considered and
3.2.4 critical quality attribute (CQA)—a physical, chemical,
modeled as one or more continuously stirred tank reactors
biological, or microbiological property or characteristic that
(CSTR) connected in series.
should be within an appropriate limit, range, or distribution to
3.2.2 continuous manufacturing (CM)——a process where,
ensure the desired product quality (ICH Q8 (R2)).
during normal operation, raw materials are continuously fed
into the system at the same time as product is continuously
3.2.5 dynamic or adaptive process control system—an au-
removed from the system. In the context of this guide,
tomated control system that utilizes process and control models
continuous manufacturing is considered to be a series of 2 or
and the use of dynamic critical process parameters (CPP) (see
more continuous, or quasi continuous, transformation steps or
Guide E2629 - 11, section 4.2 for detail description) to deliver
unit operations which are integrated into a CM line which may
required product quality. Depending on the dynamics of the
be part of a complete CM plant.
process the corrections may be applied immediately as a step
3.2.2.1 Discussion—The term continuous process may be
change or as a time dependent function (for example, a ramp or
used to refer to a single continuous process step or unit exponential function). Such real time control systems may
operation where the output may not be a finished product. A
include, for example:
single continuous process step or unit operation is not consid-
3.2.6 feedback control—a control strategy which is intended
ered to be representative of CM as considered by this guide as
to eliminate drift or deviation in a specific product attribute
continuous processes are often used as unit operations within
away from the target (setpoint) by means of:
batch (or bin to bin) production.
(1) Measuring the attributes of material leaving a process
(1) In a CM process, the degree of transformation of any
operation,
specific quantity of material from an initial condition into the
(2) Comparing the measured values with target (setpoint)
subsequent condition is a function of the process parameters
values for the attributes, and
applied and either:
(3) Using a process model or real-time tuning (that is,
(a) The position of the material as it flows through the
reaction to action) in order to calculate revised setpoint values
process,
for the relevant process conditions.
(b) The duration that the material has been within the
3.2.7 feed forward control—a control strategy which mea-
process, or
sures either: (1) specific critical attributes of materials as they
(c) A combination of both (a) and (b).
enter a specific process, or (2) other upstream factors (for
(2) A CM process transforms a pre-defined quantity of
example, flow rates, temperature, etc.), and uses this informa-
material into a pre-defined physical quantity of product which
tion in combination with an appropriate process model to
is then subjected to a disposition decision. The amount of
adjust the setpoint of the process conditions in order to reduce
expected final product produced is predefined by the amount of
the impact of the upstream change on the quality of the
starting material but can be divided into separate lots in a
material leaving the process step.
flexible way based on principles of science and risk.
(3) Alternatively, CM may be operated with a ‘flexible’ 3.2.8 multivariate model based control—measurements of
run-time, in which quantities of product are defined during the one or more product attributes and process conditions are used
operation of the process in a flexible way, based on principles in a model of the process to determine the process conditions
of science and risk (for example, as any entity produced in a required to achieve the desired product quality.
E2968 − 23
3.2.9 normal operation—behavior of the process which can 3.2.18 state of control—a condition in which the set of
be expected or predicted, or both, based on an understanding of controls consistently provides assurance of continued process
the process. Unforced variability in the process or product performance and product quality (ICH Q10).
which can be expected, predicted and characterized statistically 3.2.18.1 Discussion—In CM, the state of control constitutes
or predictable variability which is forced by an external the manufacture of material with acceptable quality whilst the
stimulation, or both, may be considered as normal operation. process variance stays within previously determined ranges, as
well as the rejection of identified non-conforming material.
3.2.10 plug flow process—a process where the residence
State of control should not be confused with just the periods in
time distribution (RTD) has zero variability and is equal to the
which the system is producing acceptable material, and atypi-
mean residence time.
cal process variance should trigger out of trend investigation.
3.2.10.1 Discussion—For example, in an idealized plug
3.2.19 steady state—consistent operation over a period of
flow process, a step change of the quantity, quality, or identity
time where all relevant process parameters and product quali-
of the input materials is, after a defined time, directly and
ties are not subject to significant unforced variation.
equally reflected by a step change in the output.
3.2.19.1 Discussion—Running at a steady state, by itself,
3.2.11 process control setpoint—a process control setpoint
does not directly imply that the defined targets are correct with
is a specific target value for a process parameter or product
respect to achieving acceptable product quality. Steady state
attribute which is used by a dynamic control system. The
implies only that the process is not subject to significant
dynamic process control system will determine what corrective
variance with respect to time. Achieving or maintaining ac-
control action to apply in order to try to bring the specific
ceptable product quality may require an adjustment of target
parameter or attribute closer to the setpoint value.
values and hence a transition between two steady state condi-
tions.
3.2.11.1 Discussion—A setpoint may be specified together
with upper and lower target values such that corrective control 3.2.20 transient conditions—conditions where the process is
action may be reduced once the value is within the target range.
disturbed from steady state or is in transition between one
A target range specified by upper and lower target values only steady state condition to another (that is, the process conditions
has no explicit specified setpoint value and hence corrective
or product quality are not in steady state or quasi-steady state).
process control action is often suspended once the parameter or
Transients may be due to either external disturbances or
attribute is within the target range.
intentional changes in the selected operating conditions.
3.2.12 process disturbance—an un-requested and un-
3.2.21 under process control—behavior of the process when
controlled change in a measured or unmeasured parameter
it responds in a predictable way to the actions of the control
which has the effect of changing the process conditions or
system and is able to achieve and maintain operation at a
product quality (that is, a short-term transient condition).
specific process control setpoint or setpoints.
3.2.13 process time constant—a measure of the rate at
4. Significance and Use
which the process can change from steady state operation at
4.1 Although some CM is used in the pharmaceutical
one condition to steady state operation at another condition.
industry (for example, purified water production), and some
3.2.14 quasi-steady state—conditions where some indi-
processes are inherently continuous individual unit operations
vidual process parameters are consistently varying in time but
(such as dry granulation and compression), these operations are
with a set pattern of variation (for example, compression force
generally operated in isolation and do not deliver the potential
in a tablet press) such that the process is in a state of control.
benefits of an integrated CM operation. The FDA Guidance for
In this guide, quasi-steady state conditions are considered
Industry PAT document specifically identifies that the introduc-
equivalent to steady state conditions.
tion of continuous processing (now redefined as CM) may be
3.2.15 recipe-based process control system—an automated
one of the outcomes from the adoption of a science-based
control system which maintains specific process parameters at
approach to process design.
pre-specified fixed values (that is, according to a predetermined
4.2 This guide does not:
recipe) without adjustment of process parameters based on
4.2.1 Suggest that CM is suitable for the manufacture of all
either measurement and feedback of product quality attributes
pharmaceutical products.
or measurement and feed-forward of input material quality
4.2.2 Provide guidance on issues related to the safe opera-
attributes or upstream conditions.
tion of a CM process or continuous processing equipment. It is
3.2.16 residence time—the time that process material is in a
the responsibility of the user of this standard to establish
specific process environment/vessel/unit operation.
appropriate health and safety practices and determine the
3.2.17 residence time distribution (RTD)—a measure of the applicability of regulatory limitations prior to use.
4.2.3 Recommend particular designs or operating regimes
range of residence times experienced by material passing
through a specific process environment/vessel/unit operation. for CM.
3.2.17.1 Discussion—RTD is impacted by the flow rate of a
4.3 Appendix X1 includes a table comparing the character-
material. Therefore, if flow rates are changed (for example, due
istics of continuous and discrete or batch processes.
to process or material changes), the RTD will likely change and
5. Process Design in Continuous Manufacturing
impact development studies and subsequent commercial manu-
facturing. 5.1 Principles:
E2968 − 23
5.1.1 The design of a CM process requires the same good 5.2.3 The potential effects on product quality of various
process design and engineering practices (for example compli- time constants of the process and the equipment (for example,
ance to ICH Q8 (R2), Q9, Q10, Q11 or Q13) that may be used effects of thermal mass), especially during start up and tran-
in batch process. sient conditions, should be considered.
5.1.2 However, the design of the CM process may require 5.2.4 An understanding and subsequent verification of the
various time constants of the process is specifically important
the consideration of additional factors which are not as
in determining the expected behavior of the process during
important in a batch process.
start up and shutdown and hence the impact on quality
5.1.3 Hence when designing a CM process, consideration
decisions regarding the disposition of material manufactured
should be given to the process conditions experienced by the
during this period.
materials as they flow through the system, for example:
5.2.5 Consideration should be given to the use of monitor-
5.1.3.1 The flow rate, or range of flow rates, through the
ing systems which ensure that the required product attributes
process (that is, the target plant production rate).
are achieved before the process is allowed to proceed to the
5.1.3.2 The balance between the process and buffer capaci-
next unit operation.
ties of the elements of the system to ensure that the desired
5.2.6 In addition to the time needed to monitor and analyze
process conditions and overall line flow rates under the
in process material attributes, considerations should be made
required operating regimes can be achieved, for example:
for time to identify non-conforming material and to trigger
(1) How the capacity of a tablet press is balanced with the
systems to segregate this material.
feed rate of an upstream powder preparation system,
(2) How the drying capacity of a dryer is balanced with the
5.3 Residence Time, Residence Time Distribution, and the
liquid addition rate of a granulation system, and
Degree of Back Mixing:
(3) Ability to manage heat balance in endo- or exo-thermic
5.3.1 In order to characterize a continuous process the
reaction operations.
process residence time and residence time distribution, which
5.1.3.3 The instantaneous/peak flow rate at locations in the is a function of the internal mixing, must be understood and
system where material flow may be discrete. quantified during both start up and normal operation as well as
during process disturbance and shutdown conditions (that is,
5.1.3.4 The flow pattern of the materials in the system (for
until product is no longer collected).
example, plug flow versus back mixed).
5.3.2 The flow of product within the system and in particu-
5.1.3.5 The process conditions required in order to achieve
lar the degree of back mixing may be characterized using
a specific transformation.
parameters such as RTD, or from appropriate process dynamics
5.1.3.6 The process time constants, reaction rates, average,
models (for example, n CSTRs in series or axial dispersion).
maximum and minimum residence times required to achieve a
These can be estimated by an appropriate combination of:
specific process objective.
5.3.2.1 Process modeling,
5.1.3.7 The relationship between material properties, pro-
5.3.2.2 Characterization tests using specific markers/tracers,
cess conditions and equipment design required to achieve a
and
reliable flow of materials.
5.3.2.3 Online/inline process measurement of appropriate
5.1.3.8 The analysis of the mass and energy balance for the
product attributes.
system using process and chemical engineering principles, for
5.3.3 Two extremes of mixing are commonly identified as
example:
“plug flow” or “fully back mixed,” but most processes will
(1) Capacity of physical transfer systems, and
have some attributes of both, and hence are referred to as
(2) Capacity of heating systems.
having a ‘degree of back mixing.’
5.1.3.9 Implementation of appropriate monitoring tools.
5.3.4 An estimation of the RTD within the process enables
5.2 Process Time Constants:
an understanding of the following:
5.2.1 The time available for a given process transformation 5.3.4.1 Which output material contains which input
is determined by the residence time of the material in a specific material,
process environment, that is, how quickly material in the 5.3.4.2 Which process conditions have had an impact on a
process will proceed from initial conditions to final conditions.
specific quantity of output material,
5.3.4.3 How minor and transient changes in feed or process
5.2.2 As the material flows through the system, rate limiting
elements within the process must be considered to ensure that, conditions will impact output product attributes, and
for a given flow rate, the required process end point or product 5.3.4.4 The degree of intermixing with adjacent material
attribute can be achieved within the time available, for ex- during the transition through the process equipment.
ample: 5.3.5 Process understanding and risk analysis should be
used to demonstrate that both product quality and the ability to
5.2.2.1 A powdered binder may take a given time to react
identify specified quantities of material at specified locations
with water in order to become an effective binder. This time
within the process is not adversely impacted by the degree of
may be temperature dependent, and hence, if a powdered
back mixing under:
binder is to be used, it is important that the relationship
between time, temperature and binder hydration is fully under- 5.3.5.1 Initial startup conditions;
stood in order to achieve effective use of the binder as the 5.3.5.2 Normal operating conditions, where the process is in
product flows through the process. a state of control;
E2968 − 23
Discussion—Normal operation in a state of control does not (2) Suitability for manufacture of variable quantities of
necessarily imply steady state, but does imply the process product at stable operating conditions for clinical trials sup-
variance is typical (within trend). plies.
5.3.5.3 Disturbances and abnormal operating conditions; 6.1.1.2 Considerations for increasing process capacity from
and development to commercial production:
(1) Scale up of run length or duration,
5.3.5.4 Shutdown conditions.
(2) Scale out by addition of parallel processing lines,
5.3.6 In particular, an understanding and quantification of
(3) Increase in production rate,
the residence time distribution may be used to determine which
(4) Increase in size of equipment, and
material may have been affected by a deviation in process
(5) Scale-up effects on critical process parameters.
conditions and hence the specific identity of any product within
6.1.1.3 For stable manufacturing operations over the target
the scope of any investigation or disposition decision.
run length, consider:
5.4 Product Transport and Material Properties:
(1) Ability of the system to produce consistent product
5.4.1 A CM process may consist of a number of unit
over the intended duration of the operation,
operations (a single step in the process intended to transform a
(2) Mechanisms of failure and degradation of performance
material from one condition to another, for example, powder to
together with robust methods of detection,
granule, wet to dry) linked together by elements which
(3) Degree of redundancy in equipment and sensors re-
transport materials between sequential unit operations.
quired to assure continuous stable operation, and
5.4.2 Careful consideration should be given to the design of (4) Necessity and frequency for operator intervention in
transport and flow control elements within a continuous system
order to maintain normal operation.
in order to ensure that materials will flow in a predictable way
6.1.1.4 In addition, sites conducting CM, particularly those
without adverse impact on product quality (for example,
that have not previously operated CM, should consider:
segregation, sedimentation, and phase separation during trans-
(1) Training of development, manufacturing and quality
port).
assurance personnel, both existing and new hires, in the
5.4.3 Transporting and controlling the flow rate of cohesive
theoretical and practical aspects of continuous processing, and
powders may be a specific problem in this respect. Hence, the (2) Impact of continuous operation on facilities, staff and
handling and flow properties of materials to be processed
systems (for example, extended shift working patterns, devia-
should be determined as early as possible within the develop- tion management).
ment of the product such that the process equipment may be
This list is not intended to be exhaustive, but points to major
designed appropriately.
aspects of the pharmaceutical quality system, noted in ICH
5.4.4 Characterization of materials using laboratory tech- Q10.
niques on small samples may give good early indication of
6.2 Operating States:
potential problems but where there are concerns about material
6.2.1 The operation of a CM system must be considered
properties it is recommended that testing of representative
over the whole life cycle of the product (that is, development,
equipment and representative materials is carried out under
validation, clinical trial supply, technology transfer, commer-
representative process conditions as early as possible.
cial manufacturing, and product discontinuation) for which it is
5.4.5 Transport processes may also cause some degree of
intended to be used.
transformation (for example, segregation or attrition of pow-
6.2.2 Risk analysis techniques, practical tests, or modeling
ders) and therefore careful consideration should be given to
tools, or any appropriate combination of these, should be
ensure:
employed to ensure that all potential impacts on product
5.4.5.1 Effects are identified and understood,
quality are understood and appropriately managed over all
5.4.5.2 Steps are taken to minimize such effects during plant
potential operating states, for example:
design, and
6.2.2.1 Equipment start-up (for example, initialization and
5.4.5.3 Controls are put in place to manage or mitigate such
warm up ready for processing);
effects over the entire range of operating conditions.
6.2.2.2 Process start-up (introduction of feed materials to
start processing and reaching state of control, that is, the
6. Operation of Continuous Manufacturing Systems
process to manufacturing material of acceptable quality and
with typical process variance);
6.1 Operational Considerations:
6.2.2.3 Normal, steady state, and in specification operation
6.1.1 In order to successfully introduce continuous
(that is, verified to deliver material which is suitable to be
processing, due consideration should first be given to the
released);
overall operation and support of the system during the lifecycle
6.2.2.4 Transient operation during rate or product specifica-
of the plant and product, for example:
tion changes;
6.1.1.1 Considerations for process and product development
6.2.2.5 Replenishment of feedstock materials; and consid-
based on business needs:
ering the impact of any variability in raw materials;
(1) Flexibility of the system to produce small quantities of
material under different operating conditions during develop- 6.2.2.6 Process pause or hold (for example, as a result of
ment of product and process understanding, and alarm conditions);
E2968 − 23
6.2.2.7 Process shutdown (including extracting product that (2) Changes in clearances due to wear.
meets specification); 6.3.4 The maximum length of time over which the process
6.2.2.8 Emptying of equipment of any residual material that is run may be determined by monitoring specific product
does not or would not meet specification; attributes or process parameters rather than by validating a
6.2.2.9 Cleaning/ product/ grade changeover; single fixed length of run time.
6.2.2.10 Controlled safe status (software-controlled safe 6.3.5 Where one unit operation within a process line is
status (SSS), hardware-controlled safe status (HSS)); and determined to be disproportionally vulnerable to degradation in
6.2.2.11 Mechanically shut down and out of service. performance or lack of robustness then strategies to maximize
the potential run time in order to avoid the need to stop the
In some defined circumstances, manufacturers of drug sub-
overall process should be considered, for example:
stance or drug product, or both, may reprocess, or continue to
process material held under quarantine, provided the require- 6.3.5.1 Rapid change over of individual items of equipment,
and
ments for rework/reclaim of the production material are
defined in a written procedure and the rework/reclaim is
6.3.5.2 Redundancy, parallelization, or duplication of criti-
approved by the quality authority, and when other appropriate
cal equipment elements (for example, filters, pumps, tubing,
considerations are met, that is, is part of system design (for critical instruments).
example, impact on system dynamics/residence time
6.4 Requirement for Operator Intervention:
distribution, batch/material traceability, strategy for material
6.4.1 Generally, CM should be expected to operate with the
diversion, etc. are established).
minimum practical level of operator intervention.
6.3 Process Robustness:
6.4.2 Processes should be developed so as to not require
6.3.1 CM may pose challenges due to behaviors of both
operator intervention. Due to the time-scale of material move-
equipment and material which occur gradually over a long
ment and attribute monitoring, automated actions are prefer-
period and which therefore may not be easily observed during
able and advantageous.
either batch processing or short test runs of continuous
6.4.3 When operator intervention is required to maintain
systems.
stable process operation, the frequency should be minimized or
6.3.2 Suitable risk analysis, practical tests and modeling
process redesign considered.
techniques should be considered in order to determine and
6.4.4 Unplanned operator intervention should be considered
evaluate potential challenges in maintaining stable process
as a potential source of uncontrolled variability. Continued
conditions during the operation of CM over the full length of
unplanned intervention may indicate a lack of process robust-
the required production run, and any sampling or data review
ness or uncontrolled or unmanaged variability in process
as part of this risk analysis and on-going risk management
conditions or material properties.
should be done in consideration of the on-going process
6.4.5 Continuous improvement tools (for example, real time
dynamics.
statistical process control) should be used during operation in
6.3.3 Consideration should be given to:
order to identify the causes of any unplanned operator inter-
6.3.3.1 The potential for undesirable buildup of material due
vention and appropriate actions should be taken to ensure that
to physical and chemical processes, for example:
any impact on product quality is fully understood and that the
(1) Equipment surfaces (for example, impact on heat trans-
root cause of the need for intervention is eliminated and
fer);
monitored to ensure the adequacy of the correction.
(2) Ducts and pipes (for example, impact on flow patterns);
(3) Instruments and probes (for example, impact on
7. Product Quality Control for Continuous
accuracy, etc.);
Manufacturing
(4) Filters (for example, impact on flow and pressure of
7.1 CM provides several potential opportunities to improve
fluids);
control of product quality and to increase flexibility of manu-
(5) By-products with different or undesirable
facturing.
characteristics, or both; and
(6) Crystallization and encrustation.
7.2 Batch Definition for Continuous Manufacturing:
6.3.3.2 Changes in raw material behavior between batches/
7.2.1 The designation of batch size is proposed and justified
sources/suppliers which may not be covered within existing
by the manufacturer, considering the control strategy and risk
quality control requirements, for example:
to the patient. The definition of a batch has regulatory
(1) Flow properties,
implications, particularly with respect to GMPs, product
(2) Electrostatic properties, and
recalls, and other regulatory decisions. Current GMP regula-
(3) Safety properties.
tions describe a ‘batch’ as a specific quantity of drug or other
6.3.3.3 Impact of environmental changes on raw material material that is intended to have uniform character and quality
and product, for example:
within specified limits and is produced according to a single
(1) Temperature, and manufacturing order during the same cycle of manufacture.
(2) Relative humidity (RH).
The batch size can be defined based on the production period,
6.3.3.4 Changes in plant and equipment characteristics over quantity of material processed, quantity of material produced
time and with prolonged uninterrupted use, for example: or production variation (for example, different lots of incoming
(1) Changes in surface finish, and raw material).
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7.2.2 In a CM process, the amount of material in a batch for (6) This high impact model should be supported by a
release could be defined as: verification approach that may include extensive side-by-side
testing of the model and reference method for commercial
7.2.2.1 All of the material discharged from the process
between two specific times (irrespective of the amount of batches until a full range of variability is experienced. Robust
material produced). correlation is essential for these models, and subsequently
lifecycle verifications should occur.
7.2.2.2 A specific quantity of material produced (irrespec-
tive of the time taken).
7.3.2.2 Level 2: Quality assurance via operation within an
7.2.2.3 All of the material produced between two specific
established design space verified by in-process material testing
process events (for example, specific process conditions).
and confirmatory end product testing.
7.2.2.4 All of the material that is intended to contain a
(1) The product and process understanding obtained
specific lot or quantity of a specified input material.
through the establishment of a multivariate design space
facilitates the identification of potential sources of raw material
7.3 Control Strategy:
and process variability that can impact product quality.
7.3.1 A comprehensive control strategy for CM may include
(2) Understanding the impact that variability from these
additional elements such as input material control, in-process
sources has on in-process materials, downstream processing,
attribute measurement, material diversion, etc. in order to
and drug product quality provides an opportunity to shift
ensure the process stays in a state of control. Control strategy
controls upstream and to reduce the reliance on end-product
implementations can be categorized into three levels.
testing.
7.3.2 The dynamic nature of continuous manufacturing
(3) Product quality may be assured by a combination of
systems promotes the adoption of dynamic process control,
operating within an established design space verified using in
although a hybrid approach combining the different levels of
process testing (on-line, at-line or predictions of material
control is viable for some CM process designs.
attributes from process models) and confirmed by end product
7.3.2.1 Level 1: Quality assurance via application of dy-
testing.
namic or adaptive process control system.
7.3.2.3 Level 3: Quality assurance via operation within
(1) CM provides a potential opportunity to use a dynamic
validated and constrained material attributes and process pa-
or adaptive process control system to monitor and control the
rameters and release supported by in-process and end product
quality attributes of materials in real-time.
testing.
(2) In dynamic or adaptive process control, system process
(1) Quality assurance via operation control relies on tightly
parameters are monitored and may be adjusted in response to
constrained material attributes and process parameters.
disturbances to ensure that the quality attributes consistently
(2) The risk of releasing poor quality product is mitigated
conform to the established acceptance criteria. Timely moni-
toring of in process material attributes with process analytical through extensive and statistically adequate in-process and
end-product testing, at a frequency appropriate for the process
technology (PAT) (using on-line, at-line or predictions of
material attributes from process models) can be used to adjust dynamics (intermixing) and process variability. Timely mea-
surement of in process material attributes is necessary.
the process.
(3) The successful application of a dynamic or adaptive (3) There may be limited understanding on how raw
material and process variability affects product quality. Vari-
process control system requires a high degree of product and
process understanding as the design of an engineering control ability of raw material attributes (some of which may be poorly
system entails expressing the dynamic relationships among characterized or understood, or both) and the risk of potential
process parameters, raw material and product attributes in a transient process disturbances makes operating a CM process
quantitative and predictive manner. within very tightly constrained process parameter limits poten-
(4) The ability of a dynamic or adaptive process control tially challenging, with potential for a high occurrence of out of
system to compensate for variation in the raw material attri- specification material requiring segregation / diversion in real
butes or external disturbances to the process conditions signifi- time.
cantly reduces the risk of producing out of specification (4) In order to justify this level of control strategy, the
material and hence the requirement for routine segregation /
process must be demonstrated to be appropriately stable and
diversion of out-of-specification is also reduced.
capable of delivering a consistent output (for example by the
(5) Statistical monitoring tools, for example, univariate or
introduction of large back mixed buffers), and may generally
multivariate statistical process control, may be used to demon-
not be viable without considerable process history.
strate that the dynamic or adaptive process control system is
7.4 Quality Decisions:
ensuring that the process is operating in a state of control where
7.4.1 Decisions on the quality of product manufactured by a
there is a very low probability of out of specification material
CM system should be guided by a clear understanding of the
being produced. Successful implementation of a dynamic or
state of the control of the system.
adaptive process control system can support a real-time release
strategy. 7.4.2 State of Control:
7.4.2.1 State of control is a condition in which a set of
controls consistently provides assurance of continued process
performance and product quality. A CM process operating
“Modernizing Pharmaceutical Manufacturing: From Batch to Continuous
Production,” Journal of Pharmaceutical Innovation, Vol 10, Issue 3, Sept 2015. within a state of control helps to ensure that product with the
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desired quality is being manufactured consistently and verified (3) While a Level 3 control strategy may be feasible for a
by real time monitoring of the control variables, to control the well-mixed, segregation-resistant continuous manufacturing
system, it may be unlikely to be operationally feasible for a
CQAs.
continuous process with low back-mixing or for high-risk
7.4.2.2 A state of control could differ from “steady state”
formulations (that is, low drug content products).
where all the parameters and material attributes associated with
7.4.3 Control Decisions:
the process do not vary with time. Criteria for the establish-
ment of a state of control depend upon the control strategy 7.4.3.1 CM systems may be designed such that a portion of
in-process material or final product that does not meet quality
employed. Likewise, a state of control does not mean accept-
requirements is rejected to quarantine or waste.
able material is always being collected. Start up and shut down
periods are an expected and controlled part of the process 7.4.3.2 As a consequence, it is possible that not all of the
performance. While material is not collected during these materials that were originally fed into the process, as part of the
periods, they take place within a state of control. Likewise, the original single manufacturing order, will be in the finished
product intended for release to the market.
identification and diversion of non-conforming material can
also occur within a state of control as the process is designed
7.4.3.3 In the scenario where the diversion/separation of
to perform this action. material which does not meet quality requirements is employed
as part of the product quality control strategy, then this must be
7.4.2.3 State of Control for a Level 1 control strategy:
carefully assessed and may need to be justified to the appro-
(1) In a Level 1 control strategy, process parameters are
priate regulatory authority.
designated as a manipulated variable or a controlled variable.
7.4.3.4 Diversion/acceptance criteria must be suitable to
In process and end-product quality attributes are controlled
ensure compliance of the entirety of the material collected as
variables.
acceptable which is subject to the release decision (“good
(2) Manipulated variables are automatically varied in re-
material”) to the applicable specifications.
sponse to disturbances to maintain the controlled variables at
7.4.3.5 Real time diversion/rejection of material which does
their set-points or within the target range.
not meet acceptance criteria must be justified by proper
(3) Variations in these parameters within established ranges
demonstration that the diversion/rejection decisions are based
would not necessarily represent a departure from a state of
on reliable data and proper understanding of process dynamics.
control. A state of control is then established and maintained by
7.4.3.6 Excessive rejection of material may indicate that the
real-time monitoring of the controlled variables.
underlying process is not robust or is not operating normally, or
(4) The active process control system for integrated pro-
both, and should initiate a manufacturing investigation.
cesses should be able to appropriately respond to disturbances
originating within a unit operation or disturbances propagating
7.4.3.7 Appropriate process engineering, modeling, testing
from upstream unit operations. and risk assessment may be required in order to ensure that the
principles behind the following elements are well understood:
7.4.2.4 State of Control for a Level 2 control strategy:
(1) How unique identities will be assigned to quantities o
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