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Modernizing Pharmaceutical Manufacturing: from Batch to Continuous

Production

Article  in  Journal of Pharmaceutical Innovation · March 2015

DOI: 10.1007/s12247-015-9215-8

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J Pharm Innov
DOI 10.1007/s12247-015-9215-8

REVIEW ARTICLE

Modernizing Pharmaceutical Manufacturing: from Batch

to Continuous Production
Sau L. Lee & Thomas F. O’Connor & Xiaochuan Yang & Celia N. Cruz &
Sharmista Chatterjee & Rapti D. Madurawe & Christine M. V. Moore &
Lawrence X. Yu & Janet Woodcock

# Springer Science+Business Media New York (outside the USA) 2015

Abstract The Food and Drug Administration (FDA) regu- efficient, agile, flexible pharmaceutical sector that reliably pro-
lates pharmaceutical drug products to ensure a continuous duces high-quality drugs without extensive regulatory oversight
supply of high-quality drugs in the USA. Continuous process- [1]. The pharmaceutical manufacturing sector is in transition,
ing has a great deal of potential to address issues of agility, but overall processes, which are largely batch in nature, remain
flexibility, cost, and robustness in the development of phar- relatively inefficient and less understood as compared with those
maceutical manufacturing processes. Over the past decade, in other chemical process industries [2].
there have been significant advancements in science and The lack of agility, flexibility, and robustness in the phar-
engineering to support the implementation of continuous maceutical manufacturing sector poses a potential public
pharmaceutical manufacturing. These investments along health threat as failures within manufacturing facilities that
with the adoption of the quality-by-design (QbD) paradigm result in poor product quality can lead to drug shortages [3].
for pharmaceutical development and the advancement of pro- Drug shortages are a critical health care issue, affecting indi-
cess analytical technology (PAT) for designing, analyzing, and vidual patients across the USA. Recognizing that shortages
controlling manufacturing have progressed the scientific and commonly begin with a supply disruption related to product
regulatory readiness for continuous manufacturing. The FDA or facility quality, FDA is focusing on encouraging and sus-
supports the implementation of continuous manufacturing taining advancements in pharmaceutical manufacturing.
using science- and risk-based approaches. Continuous manufacturing is one such innovation that has a
great deal of potential to improve agility, flexibility, and robust-
Keywords Continuous processing . Quality by design . ness in the manufacture of pharmaceuticals. This article sum-
Process analytical technology . Control strategy . Traceability marizes the potential advantages of continuous manufacturing
for pharmaceutical products and highlights some unique qual-
ity aspects for consideration and how they may be addressed.
Introduction

The Food and Drug Administration (FDA) regulates pharma-

ceutical drug products to ensure a continuous supply of high Definitions of Batch and Continuous Manufacturing
quality drugs in the USA. In regulating the pharmaceutical
manufacturing sector, the vision for FDA’s Pharmaceutical General definitions of batch and continuous process are de-
Quality for the 21st Century Initiative is to promote a maximally scribed below [4].

(1) Batch process. The raw material(s) is charged into the

S. L. Lee : T. F. O’Connor : X. Yang : C. N. Cruz : S. Chatterjee : system at the beginning of the process, and the product is
R. D. Madurawe : C. M. V. Moore : L. X. Yu (*) : J. Woodcock discharged all at once sometimes later. No ingredients
Office of Pharmaceutical Quality, Center for Drug Evaluation and
cross the system boundaries between the time the raw
Research, Food and Drug Administration, 10903 New Hampshire
Avenue, Silver Spring, MD 20993, USA material(s) is charged and the time the product is
e-mail: [email protected] discharged (Fig. 1a).
 J Pharm Innov

Fig. 1 A simple depiction of two types of manufacturing. a Batch manufacturing: material(s) and the product are simultaneously charged
manufacturing: the material(s) is charged before the start of processing and discharged from the process, respectively
and the product is discharged at the end of processing. b Continuous

(2) Continuous process. The material(s) and product are to mitigate the impact of raw material and process variability
continuously charged into and discharged from the sys- on the quality of finished products.
tem, respectively, throughout the duration of the process Batch manufacturing is traditionally utilized for the produc-
(Fig. 1b). tion of pharmaceutical products. In this type of process, mate-
rials from one step are usually tested off-line as per the in-
The above definitions can be applied to individual unit process controls and stored before they are sent to the next
operations or an entire manufacturing process consisting of a processing step. If the in-process material does not meet quality
series of unit operations. A pharmaceutical manufacturing expectations, it may be discarded or, under certain circum-
process often consists of a combination of batch and continu- stances, reprocessed prior to moving to the next process step [6].
ous unit operations [5]. As such, there are situations where In continuous manufacturing, materials produced during
certain unit operations can be considered Bcontinuous^ each process step are sent directly and continuously to the next
(e.g., tablet press or roller compaction) while the step for further processing. Each processing step needs to
manufacturing process as a whole can be considered reliably produce an intermediate material or product with ac-
Bbatch.^ These situations are outside the scope of this ceptable characteristics. Extending processing time of partic-
article. Figure 2 depicts an example of the future vision ular unit operation(s) (e.g., synthesis, crystallization, blending
for continuous pharmaceutical manufacturing in where drying, etc.) to achieve the desired quality may not be possible
(1) individual continuous unit operations are connected for continuous manufacturing as it may create disruption for
to form an integrated manufacturing process, (2) process downstream unit operations. Continuous manufacturing, com-
analytical technology (PAT) systems are utilized to pro- pared to batch manufacturing, thus often involves a higher
vide real-time data for process monitoring and control, level of process design to ensure adequate process control
and (3) engineering process control systems are implemented and product quality.
J Pharm Innov

Fig. 2 A conceptual fully

integrated continuous
manufacturing process. A typical
batch manufacturing process for
tablets is also presented for
comparison

Development and Manufacturing Opportunities Under a continuous operating mode, hold times between steps
can be eliminated. This is a significant advantage for APIs or
Compared to traditional batch manufacturing, continuous intermediates that can degrade over time or are sensitive to
manufacturing provides several potential opportunities to im- environmental conditions, directly improving the overall drug
prove control of product quality and to increase flexibility of product quality. Furthermore, the small scale of continuous
manufacturing. Examples are provided below. manufacturing can decrease the safety hazards associated with
The pharmaceutical industry currently has a limited ability highly energetic or hazardous materials and potentially allow
to rapidly increase production in the face of drug shortages or for more flexibility in the use of non-specialized manufacturing
other emergencies such as pandemics. Bringing up a new facilities [8].
facility or manufacturing line in response to such emergencies Continuous manufacturing is strongly aligned with the
may take up to several months or years. Continuous FDA’s support of the quality-by-design (QbD) paradigm for
manufacturing can potentially permit increasing production pharmaceutical development. QbD is a systematic scientific
volume without the current bottlenecks related to scale-up, and risk-based approach to pharmaceutical development. This
providing more response capacity. Scale-up options, such as approach advises companies to demonstrate product and pro-
operating the process for longer periods of time, utilizing par- cess understanding and to use this understanding to implement
allel processing lines, or increasing the flow rate through the effective quality control strategies to achieve a predefined ob-
process, can be built into the process design and verification. jective. The ICH Q8(R2) (Pharmaceutical Development); ICH
Additionally, due to the small volume of materials needed to Q9 (Quality Risk Management); ICH Q10 (Pharmaceutical
run continuous manufacturing systems, it may be possible to Quality System); the ICH Q1WG on Q8, Q9, Q10, and
design and optimize a continuous system on commercial scale Question and Answers; the ICH Q8/Q9/Q10 Points to
equipment, thus eliminating scale-up [5, 7]. Eliminating scale- Consider document; and the ICH Q11 (Development and
up bottlenecks in the path to market may increase the agility to Manufacture of Drug Substances) documents have been is-
facilitate rapid clinical development of breakthrough drugs. sued and provide high-level guidelines with respect to the
Due to economic factors, supply chains for many active scope and definition of QbD as it applies to the pharmaceutical
pharmaceutical ingredients (APIs) and final drug products span industry [9–14]. Development of a robust process relies on
several countries and contain multiple supply vulnerabilities. utilizing the acquired product and process understanding to
Under current batch manufacturing process steps, intermediates identify sources of variation to product quality and to design
may not be immediately processed. Instead, they are stored in appropriate control strategies to address these risk areas.
containers and shipped around the world to the next Continuous manufacturing provides an opportunity to utilize
manufacturing facility. Continuous manufacturing provides ad- this enhanced product and process understanding to adopt
vantages to shorten supply chains. Continuous manufacturing advanced manufacturing controls to produce uniformly high-
allows the production at various scales with a given process, quality products with reduced waste resulting from the gener-
which may facilitate regional or in-country manufacturing. ation of out-of-specification material [2].
 J Pharm Innov

Continuous unit operations are generally more efficient Table 1 Features and potential benefits of continuous manufacturing
than their batch counterparts and offer much higher through- Features of continuous Benefits
put per unit volume and per unit time, thereby often greatly manufacturing
reducing the size of the processing equipment. The
manufacturing footprint is further reduced because the mate- Small equipment and Efficient, high throughput per unit volume
space required and per unit time
rial flows from one processing step to the next and does not Reduced safety hazards
need isolated suites or dedicated modules. For this reason, a Short supply chains No storage/shipping costs for intermediates
substantial reduction in both capital and operating expenses Fast response to market shortage
for a continuous process can be achieved [15]. Furthermore, Less degradation for sensitive intermediates
continuous processing can decrease the amount of potentially All key characteristics Lower batch-to-batch variations
expensive API required for process development studies, should be roughly Simple to develop process monitoring
constant at any time systems and control strategies
greatly reducing the materials cost of process development
Possible eliminations of some downstream
and optimization efforts. However, initial investment is re- corrective steps
quired for the construction of facilities and the generation of Non-stop continuous Reduction of number of operators on site
process knowledge required for continuous manufacturing. transport of materials Increased operator safety
The current inventory of available batch manufacturing facil- from unit to unit (no
batch handling)
ities can be an economic barrier for the adoption of continuous
Continuous flow Easy scale-up, such as a longer running time
manufacturing [16]. Therefore, potential candidates for adop- production Potential for reaction telescoping
tion of continuous manufacturing at present are likely new Facilitation of new synthetic routes (e.g.,
therapeutic entities or approved drugs with a very large market microwave, photochemistry, ultra-high
or low temperature)
requiring the new or expansion of existing manufacturing
Safe operation of highly exothermic reactions
facilities.
Continuous manufacturing may facilitate the streamlining
of the manufacturing process through the removal of correc-
tive or work-up unit operations. One potential example is re- understanding the impact of process dynamics on quality in-
action telescoping (collapsing of a multistep process into a cluding process startups and shutdowns, and designing appro-
smaller number of steps or unit operations). Traditional batch priate measurement systems for process monitoring and con-
reactions normally include several reaction steps with isola- trol [5, 20]. Fundamentally, the design, control, and optimiza-
tion and purification work-up operations in between each re- tion of continuous manufacturing facilities require a systems
action step. The post-reaction work-up steps can be highly approach [21]. Regulators and industry will need to continue
time consuming and generate large volumes of waste. To to develop knowledge and experience with such systems-
avoid this lengthy process, telescoping could be an ideal alter- based methods to support a broader implementation of con-
native and well suited for continuous flow chemistry [17]. tinuous pharmaceutical manufacturing.
Other examples include (1) the potential to eliminate down-
stream corrective drug product unit operations, such as sizing
steps (e.g., granulation, milling) due to better control of the Quality Considerations for Continuous Manufacturing
particle size distribution during crystallization and (2) reduc-
tion in the segregation risk from continuous blending [18, 19]. Process Understanding
Continuous manufacturing may also facilitate the adoption of
emerging processing technologies which are well suited for Design of experiments (DOE) has become a common tool to
continuous operations [20]. Examples of the potential advan- increase process understanding for the process ranges of inter-
tages of continuous manufacturing for the development and est. The fast response of a continuous process to changes in
operation of pharmaceutical processes are presented in process parameters allows for gathering a large amount of
Table 1. experimental information in a short time from smaller quanti-
Challenges do exist in the implementation of continuous ties of product. Moreover, continuous processing, compared
manufacturing. In continuous manufacturing, materials con- with batch processing, offers a greater opportunity to develop
tinuously flow between unit operations and product is formed and better utilize process models to gain process knowledge,
continuously over a long period of time. Considerations since their governing equations generally can be simplified.
unique to continuous production should be evaluated when Predictive process models can be used as a simulation tool to
developing a control strategy for a continuous process as the supplement experiments throughout process development and
process, product, or environmental conditions could potential- thus enhance process understanding. For example, process
ly vary over time. These considerations, for example, include modeling can be utilized to perform sensitivity analysis to
accounting for material attributes that affect flowability, identify the key interactions or relationships among process
J Pharm Innov

parameters and material or product attributes in support of a In a continuous process, it is important to link material
quality risk assessment. In addition, predictive process models traceability to the definition of a batch. If continued state of
can be used to develop and assess control strategies for con- control operation (see below for its definition) is demonstrat-
tinuous processes [22–24]. ed, it could be possible to designate large quantities of product
For continuous manufacturing, understanding the dynam- to be of uniform quality, even though different batches of raw
ics of how a material flows through the process is critical with materials and/or different processing conditions may have
respect to material traceability (the ability to preserve and been utilized during the production run. Within this frame-
access the identity and attributes of the material throughout work, a batch can be defined based on the production time
the process). Such an understanding of process dynamics can period, quantity of material processed, equipment run time
be obtained by characterization of residence time distribution capability, or production variation (e.g., different lots of in-
(RTD) through a tracer experiment and/or process modeling coming raw material). The batch definition for continuous
[25–27]. The RTD is a probability distribution that describes manufacturing is therefore closely linked to the design of the
the amount of time a mass or fluid element remains in a pro- control strategy for the process, which should be constructed
cess. The RTD curve can be utilized to predict the propagation to ensure uniform quality within a batch.
of material or disturbances through the system or, in a retro-
spective analysis, to determine when the ingredients in a given Control Strategy
product unit were fed to the manufacturing system. The RTD
is dependent upon several factors such as processing time, The control strategy for a continuous process should be de-
equipment parameters, and material properties. One option signed to control the quality of the product in response to
to describe the material traveling through the system is to potential variations in the process, equipment conditions, in-
define a traceability resource unit (TRU) [28]. A TRU can coming raw materials, or environmental factors over time.
be specified as a segment of material that flows through the Control strategy implementations generally can be catego-
process together and can then serve as a unique identifier from rized into three levels described below.
a process history perspective to achieve traceability through- Level-1 control utilizes an active process control system to
out the integrated continuous process. Material traceability monitor the quality attributes of materials in real-time. Process
has implications on control strategy described below. parameters are automatically adjusted in response to distur-
If the manufacturing process is integrated with the packag- bances to ensure that the quality attributes consistently con-
ing process, unique package identifiers (e.g., serial codes, form to the established acceptance criteria. This level of con-
timestamps, etc.) can further link product supply chain trace- trol represents a high degree of product and process under-
ability to process traceability (e.g., TRU). In this manner, a standing as the design of an engineering control system entails
packaged product for marketing can be traced from raw ma- expressing the dynamic relationships among process parame-
terials to processing conditions and all the way to the distri- ters, raw material, and product attributes in a quantitative and
bution to the end customer. predictive manner. The risk of producing out-of-specification
product is lowered through the implementation of adaptive
engineering controls which can enable a real-time release
Batch Definition for Continuous Processes strategy.
Level-2 control consists of pharmaceutical control with
The definition of a batch has regulatory implications, particu- appropriate end-product testing and flexible raw material at-
larly with respect to current good manufacturing practices tributes and process parameters within the established design
(cGMPs), product recalls, and other regulatory decisions. space (the multidimensional combination and interaction of
Current cGMP regulations describe a Bbatch^ as a specific input variables (e.g., material attributes) and process parame-
quantity of drug or other material that is intended to have ters that have been demonstrated to provide assurance of qual-
uniform character and quality within specified limits and is ity) [30]. The product and process understanding obtained
produced according to a single manufacturing order during through the establishment of a multivariate design space facil-
the same cycle of manufacture [29]. Furthermore, for contin- itates the identification of potential sources of raw material
uous processing, a Blot^ is defined synonymous to Bbatch^ (or and process variability that can impact product quality.
specific identified portion of a batch) and is a specific identi- Understanding the impact that variability from these sources
fied amount produced in a unit of time or quantity in a manner has on in-process materials, downstream processing, and drug
that assure its having uniform character and quality within product quality provides an opportunity to shift controls up-
specified limits. Note that the regulatory definition of Bbatch^ stream and to reduce the reliance on end-product testing [9].
is related to an amount of material and not the mode of man- Level-3 control relies on tightly constrained material attri-
ufacture. Consequently, it is possible for a continuous butes and process parameters. There may be limited under-
manufacturing process to generate batches. standing on how raw material and process variability affects
 J Pharm Innov

product quality. The risk of releasing poor-quality product is unlikely to be operationally feasible for a continuous process
lowered through extensive end-product testing. Level-3 con- with low back-mixing or for high-risk formulations (i.e., low
trol is generally not feasible for many continuous manufactur- drug content products). Although a high degree of back-
ing process designs, in part because of the risk of potential mixing may promote process robustness, it may represent a
transient process disturbances. The characteristic mixing pat- physical limitation to material traceability [33]. Thus, integrat-
terns of many continuous manufacturing systems promote the ed continuous manufacturing systems naturally lead to the
adoption of level-1 control, although a hybrid approach comb- development of a pharmaceutical control (level 2) or engineer-
ing the different levels of control is viable for some continuous ing control (level 1) strategy to ensure that quality product is
manufacturing process designs [31]. being consistently manufactured.

State of Control Diversion of Non-conforming Material

State of control is a condition in which a set of controls con- The ability to isolate and reject material that is out of specifi-
sistently provides assurance of continued process performance cation if the process is no longer in a state of control is one of
and product quality [11]. A continuous process operating un- the key aspects of a continuous manufacturing control strate-
der a state of control helps to ensure that product with the gy. During planned startup and shutdown, there may be pe-
desired quality is being consistently manufactured. A state riods of time when the in-process material or product does not
of control could differ from Bsteady state^ where all the pa- meet the target quality attributes. During these periods, proce-
rameters and material attributes associated with the process do dures to isolate the non-conforming material should be initi-
not vary with time. Criteria for the establishment of a state of ated. In addition, during normal operation, although the con-
control depend upon the control strategy employed. tinuous process will typically maintain a state of control, there
For a level-1 control strategy, process parameters are des- may be temporary process disturbances or upsets over the
ignated as a manipulated variable or a controlled variable. course of a production run. If the disturbance cannot be miti-
Quality attributes of in-process materials may also be candi- gated by the process, it is important to remove the impacted
dates for a controlled variable. Manipulated variables are au- material. The extent of material to be isolated and rejected
tomatically varied in response to disturbances to maintain the depends on the duration, frequency, and severity of the distur-
controlled variables at their set points or within the target bance and the mixing patterns of the system.
range. Variations in these parameters would not necessarily Diverting a portion of the in-process material or product
represent a departure from a state of control. A state of control relies on the capability to detect and isolate out-of-
is then established by real-time monitoring the controlled var- specification material at some point in the process. Physical
iables. The active process control system for integrated pro- separation of non-conforming material can occur immediately
cesses should be able to appropriately respond to both fast at the point of the detected failure or downstream if justified
(within a unit operation) and slow (propagating from upstream by knowledge of the residence time distribution to trace the
unit operations) disturbances [24, 32]. non-conforming material through the process to the diversion
If a level-2 control strategy is utilized, raw material attri- point. As the impacted material travels downstream through
butes and process parameters may vary within the established the process, back-mixing may occur and disperse the impacted
design space without impacting the desired product quality. A material to adjacent material. From a material traceability per-
state of control can be established by real-time monitoring of spective, this means that the impacted material as well as
the raw material attributes and process parameters to ensure adjacent (prior and subsequent) material portions should be
that they remain within the established design space. At this tracked and isolated as necessary. Predictive models, includ-
level of control, end-product testing or surrogate models are ing but not necessarily limited to RTD models, can be ex-
primarily utilized for a confirmatory purpose. tremely useful for determining the amount of adjacent material
When the process parameters reach and can be maintained that requires diversion.
very closely to their target values in conjunction with tight Establishing a priori criteria for product collection, product
control of raw material attributes, a level-3 state of control is rejection, rejection of an entire batch, and indicating how or
achieved. As mentioned above in level-3 control, the relation- who makes those decisions is important for continuous
ships among raw material and process variability and product manufacturing process from a quality management perspec-
quality might not be well characterized and understood. For tive, given that disposition decisions may need to be made in
this reason, process monitoring needs to be supplemented real time. The establishment of adequate process monitoring
with end-product testing at an appropriate frequency to ensure criteria (e.g., alarms, adjust limits, and isolation limits) can
that the process is being maintained in a state of control. While prevent ad hoc decisions and helps to ensure the desired qual-
a level-3 control strategy may be feasible for a well-mixed, ity and consistency of a final product. Consideration of the
segregation-resistant continuous manufacturing system, it is disposition strategy of product obtained when process is not
J Pharm Innov

under control (e.g., during startup, shutdown, and process up- [9]. A supervisory control and data acquisition (SCADA) sys-
sets) is also an important component to assure quality during tem can be implemented that incorporates measurements of
the manufacturing run. process parameters, incoming raw material, and in-process
material attributes, as well as final product quality attributes
Implementation of Process Analytical Technology with a model of the process dynamics to reconcile the data in
order to support RTRT [32, 41]. Due to a high frequency of
PAT is a system for designing, analyzing, and controlling data collection, statistical methods for large sample sizes can
manufacturing through timely measurements (i.e., during pro- be applied to increase the confidence level that the batch con-
cessing) of quality attributes of raw and in-process materials forms to the desired quality [42]. RTRT batch calculations
and process conditions, with the goal of ensuring final product should consider the observed variance in critical quality attri-
quality [34]. Due to the absence of isolated intermediates and butes over the production run to account for intra batch vari-
the typically faster process dynamics for a continuous process ability. A risk analysis aids in consideration of PAT failure,
that may necessitate more frequent measurements, real-time and procedures can be developed in order to establish contin-
monitoring of process parameters and quality attributes of in- gencies for process monitoring and batch release. The proce-
process materials typically constitutes an essential component dures could include end-product testing or utilizing surrogate
of a control strategy for the establishment of a state of control. measurements to ensure that the product maintains an accept-
In addition to supporting the validation and control of the able level of quality [5].
manufacture process, PAT tools and principles can be used In addition to naturally lending itself to RTRT, the increase
to gain process understanding. Multivariate models are often in the amount of process and quality data collected during a
used for extracting process knowledge (e.g., blend uniformity) continuous production facilitates the adoption of multivariate
from the data provided by process analyzers (e.g., spectro- process monitoring approaches. Multivariate statistical pro-
scopic measurements). Consensus standards are available for cess control (MSPC) is a process monitoring approach used
building, validating, and maintaining such multivariate to determine whether the variability in the process is stable
models [35–37]. over time [43]. It can be used to detect abnormal events in the
The sampling interface for continuous manufacturing sys- process that may lead to adverse consequences (e.g., out-of-
tems can be challenging. Industrial experience indicates that specification product, equipment malfunction, or process safe-
poor measurement performance is often attributable to sam- ty incident) if not mitigated and provide diagnostic informa-
pling system issues rather than the process analyzer itself [38]. tion of which process variables may be responsible for the
On-line and in-line measurements may reduce but do not nec- event. Taking advantage of the fact that process variables are
essarily eliminate sampling errors [39]. Thus, sampling con- often correlated, MSPC simplifies process monitoring by re-
siderations should be assessed. For example, the location of ducing the number of control charts being tracked without
the sensor should be evaluated to achieve representative sam- losing information. MSPC may also enhance the detection
pling and minimizing the effect of the probe on the process. of abnormal process operations by identifying changes in the
Powders and dispersions limit the penetration depth of spec- relationships among process parameters and quality attributes
troscopic techniques. This may increase the importance of the [43] that may be difficult to detect using solely univariate
sample probe location [40], size of the sampling spot, intensity process monitoring approaches [44].
of the incident signal, etc. The sample size for the measure-
ment should be representative of a unit dose and consider
factors such as flow rate, penetration depth, and the number Conclusions
of scans. It is important to utilize the knowledge of the process
dynamics (e.g., RTD) for determining the adequate sampling Continuous pharmaceutical manufacturing offers potential
frequency for PAT measurements. The measurement frequen- flexibility, quality, and economic advantages over batch pro-
cy implemented should provide sufficient resolution for the cessing, both in process development and manufacturing for
detection of a pulse of variability from a process disturbance. the pharmaceutical sector. Over the past decade, there have
The utilization of PAT tools can be applied to measuring been significant advancements in science and engineering to
surrogates for the quality attributes of a final product, some of support the implementation of continuous pharmaceutical
which may have already been incorporated into the control manufacturing. These investments along with the adoption
strategy for process monitoring and control. For this reason, of the QbD paradigm for pharmaceutical development and
continuous manufacturing naturally lends itself to real-time the advancement of PAT for designing, analyzing, and con-
release testing (RTRT), which is the ability to evaluate and trolling manufacturing have progressed the scientific and reg-
ensure the quality of in-process materials and/or final product ulatory readiness for continuous manufacturing. Building on
based on process data that typically include a valid combina- this progress, research efforts should continue in several key
tion of measured raw material attributes and process controls areas including the development of integrated process models
 J Pharm Innov

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