Review Article

Adaptations of Pharma 4.0 from Industry 4.0

S. Hemanth Kumar*, Divya Talasila, M. P. Gowrav, H. V. Gangadharappa

ABSTRACT

Pharma 4.0 conceptualizes extremely systematic automated processes, which could be batch, continuous, or a hybrid of these,
operated by an integrated manufacturing control strategy. Quality by design and process analytical technology principles
are used to strengthen the hypothesis of Pharma 4.0. These provide the potential for robust, efficient, and quickproduction.
Industry 4.0 is employed in medical technology, health-care facilities, and biopharmaceutical manufacturing. Digital
transformation plays a major role. Pharma 4.0 provides better instruments to enforce product safety and supply chain security.
This review explains the impact of data analytics technology, digitization, industry 4.0, artificial intelligence, digital twins,
and continuous manufacturing and their impact on Pharma 4.0.

KEY WORDS: Artificial intelligence, Digital twins, Digitization, Pharma 4.0, Process analytical technology, Quality by
design

INTRODUCTION process robustness and improves quality, productivity,

and profit.[3] It makes pharmaceutical production safer
Pharma 4.0 is an integrated manufacturing control and more efficient.
strategy, and it is a holistic operating model for
Pharma companies. It is the next step toward PHARMA 4.0 OPERATING
smart manufacturing, and it is based on Industry
4.0, which was first introduced by the Germans.
MODEL
Pharma 4.0 is the digitalized operations model of a From moving Industry 4.0 to Pharma 4.0 ISPE’s
pharmaceutical organization that consists of trends Pharma 4.0, SIG has developed an operating
such as big data, interconnectivity, collaborative model.[4,5] It is a combination of digitalization and ICH
robotics, artificial intelligence (AI), and distributed Q10.[6] The operating model combines submission-
cloud-based architectures.[1] International Society based and manufacturing control strategies to create
for Pharmaceutical Engineering’s (ISPE) introduced a pharmaceutical quality system and covers the
Pharma 4.0 to pharmaceutical manufacturing and in complete product life cycle; the quality management
2017 ISPE Pharma 4.0 Special interest group (SIG) process is based on ICH Q10. When both ICH Q10
was formed to come out with a working model for and Pharma 4.0 elements and enablers are combined,
implementing Pharma 4.0 concepts. It is a new they form a complete product lifecycle.[1]
industrial revolution and deals with automation,
digitization, paperless document, data integrity, and Industry4.0 + ICH Guidelines = Pharma 4.0
risk-based approach. Digitization is an important Operating Model
component, it creates a new level of transparency as ICH Q10 consists of PQS elements such as corrective
it enables quick decision-making and provides in- action and preventive action, change management,
line and in-time control over operations and quality,[2] management review, and enablers such as knowledge
by employing advanced data analytics it increases and Quality Risk Management. The operating model is
based on digital maturity and data integrity by design.
Access this article online These are upgraded in the ICH Q10 PQS model. The
Website: jprsolutions.info ISSN: 0975-7619
control strategy was explained in this model across the
finished product lifecycle in which the manufacturing

Department of Pharmaceutics (Pharmaceutical Quality Assurance), JSS College of Pharmacy, JSS Academy of Higher
Education and Research, Mysuru, Karnataka, India

*Corresponding author: Mr. S. Hemanth Kumar, Department of Pharmaceutics (Pharmaceutical Quality Assurance),
JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru - 570 015, Karnataka, India.
Phone: +91-9343582337. E-mail: [email protected]

Received on: 17-10-2019; Revised on: 21-11-2019; Accepted on: 10-12-2019

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 S. Hemanth Kumar, et al.

and submission control strategy is composed. ICH as preventive maintenance, environmental monitoring,
Q10 defines critical quality attributes (CQAs), critical automation, continuous process verification, mass
process parameters (CPPs), and critical material serialization, real-time-release, and the batch release
attributes as key elements of product and design. should have integration with IT systems.
ICH Q12 identifies these parameters as established
conditions. These parameters are monitored by Organization and processes
product quality and process performance systems to Organization refers to both the company’s internal
detect out of trend and out of specification. Knowledge organization and value network. It collaborates
management of all sub-organizations and integration internally and externally. The holistic control strategy
of IT systems leads to a holistic process and enables is the key element for lifecycle management in
data integrity of all big data and analytical approaches pharmaceutical processes. To ensure high product
for decision-making. Pharma 4.0 includes PQS quality, CQAs and CPPs are monitored in continued
elements and enablers. These have a huge impact on and ongoing process verification. To design the
complete product lifecycle management and quality. step-by-step approach and ensure the integrity and
performance of holistic control strategy, cross-
PQS elements functional communities are established.
It includes:
• Resources: Workforce 4.0, digitalization, available, Culture
and qualified It covers the value system within the company
• Information System: Holistic value network, and describes the collaboration. By implementing
integration, and traceability automation technologies, paperless execution came to
• Organization and Processes: Holistic control existence. This requires a culture of the collaboration
strategy, and lifecycle management of all systems such as production process, technology,
• Culture: Communication and decision-making. and quality. The collaborative value chain contains
three elements – design, execution, and realization
PQS enablers where tech transfers, innovation, and maintenance
It includes digital maturity and data integrity by together form a holistic control strategy.
design.
PHARMA 4.0 ENABLERS
Pharma 4.0 Elements
Digital Maturity
Resources
The four divisions of an operating model are common
It includes human resources, equipment and machinery, to all stages of the industry, but the implementation
materials, tools, and the final product. The efficiency differs. Pharma specific model is developed that
of mass production is increased as smart equipment allows organizations to assess holistic control
adapts to multiple configurations. Process analytical capabilities, future capabilities, and operated within
technology (PAT) monitors KPPs and communicate the parameters. An organization should provide data
through digital infrastructure. Reference Architectural visibility, data transparency, predictive capacity, and
Model Industry 4.0 (RAMI4.0) cube explains the adaptability to move toward Pharma 4.0. The latest
product-quality and process performance system. The technologies such as paperless execution systems,
integration layer acts as a task-based interface between virtual and augmented reality, collaborative robotics,
humans and machines. Traceability and visibility 3D printing, and blockchain can authorize resources if
of information are enabled by communication and all the four divisions are equally implemented.
information layers that are sent to the manufacturer
for predictive maintenance through AI. Each layer Data Integrity by Design
communicates with the entire value chain network Data integrity plays a key role in Pharma 4.0, data are
throughout the company. This increases the quality transparent, and it travels in horizontal and vertical
and availability of products. directions and poses new challenges. The performance
product lifecycle depends on structural capabilities. If
Information systems IT should implement in an organization, there should
It is based on economic criteria by both people and be defined processes and data flow. Data integrity
communication technology. The computerized systems is all about data quality, the data lifecycle, and
are integrated throughout the value chain network. This ALCOA+ principles. It requires well-defined, robust,
includes data interfaces, PAT technologies are applied repeatable processes, risk management principles, and
to continuous process verification to support process critical thinking. For example, excipients used in the
automation, and real-time release testing (RTRT) is company should have one name and one reference
established by predictive process controls. Areas such number across the company to mix-ups and errors.

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IMPACT OF INDUSTRY 4.0 ON programming. This allows for increasing the quality
and machine setup times.
PHARMA 4.0
Industry 4.0 is defined as the technical integrating Horizontal and vertical system integration
of cyberphysical systems (CPS) into manufacture Using computer systems, clients, vendors, and
and organization, as well as the implementation of manufacturers are connected, thereby provides highly
internet of things (IoT) and services in industrial automated value chains.
operation. In general, Industry 4.0 deals with computer
integrated manufacturing (CIM), whereas industry 4.0 IIoT
consists IOT where the machines and people associate The devices and sensors are connected with centralized
and transmit each other. It is the digitalization of controllers, which allow us to communicate and
production.[7] It applies machine learning and industrial interact with one another and analyze data to predict
IOT (IIoT). Manufacturing processes are improved failures, which result in rapid, flexible, and efficient
by employing data and analytics and maintains manufacturing processes to high quality with low
internal, autonomous, communication within the costs and enables real-time responses.
factory. The data are transferred between the types
of equipment, and it analyzes the data periodically to Cybersecurity
control different processes.[8] It is dependent on CPS, The systems and production lines are fully
IoT, cognitive computing, and cloud computing. It interconnected with one another should be protected
accelerates production while reducing faults and errors from cybersecurity threats such as hacking, industrial
and has improvements in distribution and supply copyright, personal data, and privacy.
chain management (SCM). In CPS, operations are
monitored, coordinated, controlled, and integrated by Cloud
computing. The human thought process is simulated The industry adopts cloud solutions powered by
in a computerized model using cognitive computing, blockchain and other technologies. These challenge
whereas IT systems and cloud offer to solve problems data storage, data integrity, privacy, and protection.
without human assistance and aids in decision making. The information is coupled with analytics and
SCM in Pharma plays a crucial role. From country integrated with the end consumer information and
to country, the product standards, environment and feedback, which allows good quality and effective
temperature, packaging, and labeling requirements products. The cloud technologies gather the data from
vary. Technologies such as cloud computing, all over the production systems and store it.
blockchain, radio frequency identification (RFID)
tags, electronic records, cognitive computing, and Additive manufacturing
CPS are used to track and trace continuously. Through 3-D printing is the latest technology, which prototype
electronic batch record systems (EBRS) the graphic and produce customized products in small batches. Raw
user interface captures the data automatically, exchange materials, stocks, and transport distance are reduced.
of batch information, batch production management,
report generation and accuracy of operators. In Augmented reality
addition EBRS will provide central storage of data to
These support a variety of services and send
maintain data security and integrity. AI and Pharma
information directly to mobile devices. It gives real-
digitalization play a crucial role in Pharma 4.0.[9] Nine
time information to workers to enhance decision-
technologies form the building blocks of Industry 4.0
making and work processes.[10]
they are discussed below:

Big Data and Analytics AI

Real-time decision making is supported by collecting It is an emerging technology used in Industry 4.0. In
and evaluating data from different sources such as regulatory perceptive AI creates difficult questions
manufacturing equipment and customer management because many algorithms are used for product
systems (mass data analysis). manufacturing, then the validation of the product
becomes difficult. AI affects the industry, so the Pharma
Autonomous Robots industry must focus on it, and the changes should be
Robots have a wide range of capabilities; they interact managed.[11] Pharmaceutical companies and health-
with humans and improves performance. care organizations adopt AI for early drug discovery,
clinical trial optimization, and business intelligence. In
Simulation delivering novel drugs to market, AI is assisted in clinical
In-plant operations, the real world is reproduced in a development and go-to-market activities. In operational
virtual mode to perform tests and minimize machine tasks, AI manages external innovation projects, clinical

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trials, and risk assessment. Innovations such as predictive a prominent role in medication efficacy and decreases
analytics, and big data analytics create a digital plant. the risk factors. Pharma digitalization transformation
This improves production processes. Using AI new drivers are health-care market challengers, complex
drugs are designed. Pharma companies must build market regulations, and increasing operational
internal digital capabilities to continuously monitor challenges.
the risks.[12] Big Pharma adopts AI to encourage drug
discovery. Drug target identification, validation, target- Health-care Market Challengers
based and phenotypic drug and polypharmacology It includes as follows:
discovery, drug repurposing programs, biomarkers • Innovations and competition of the Pharma business
development, and biomedical, clinical, and patient data • Expanding price pressure generated by the
are included.[13] AI-powered digital twins used to predict strengthening price regulations in the market and
and detect deviations. By running potential simulations patent expiries of major blockbuster medicines
and using data, the design and development of drugs • Demand for enrich data on the prescription potency
take place, which leads to manufacturing drugs. In and patient standard of life
digital twin technology, advanced sensor data are used; • New business models and ecosystems are
it creates digital representations of existing assets. challenging the current way of business.
However, by implementing the standards and emerging
technologies such as AI and digital twins, the industry Complex Market Regulations
can find a way to move effectively into this new arena It includes as follows:
of manufacturing.[14] • Distinctive and speed changing global regulating in
drug manufacturing and supply chain conformation
PHARMA DIGITALIZATION are exacting infrastructure changes over ongoing
There are two reasons for adopting digitization. First, fitness and abilities
the information in a variety of formats can be collected • USFDA’s perception for the 21 st -century
and processed with the same efficiency. Second, pharmaceutical quality manufacturing requires
the smart factory is achieved where the operations effective, acute, and flexible production that
are carried with minimal manual intervention, high faithfully generates high-quality drugs.
reliability, and flexibility. The automated workflow,
Increasing Operational Challenges
synchronization of assets, tracking, and scheduling
increases yield and quality and reduces the cost.[15] In It includes as follows:
this digitalized concept, machines collect process and • Pharma companies are facing increasing challenges
product data and communicate with other machines in production flexibility, competent resources, time-
through IIoT. AI plays a key role in the industry and no to-market, and operational costs
human intervention, so the chances of errors are less.[16] • Global production is highly distributed and non-
Equipment, raw materials, and finished products are standardized
transported through collaborative robots, autonomous • A value network is very complex, with lot of
mobile robots. Robotics eliminates repetitive and manual partners and suppliers
activities and improves safety and control. Pfizer and • Information paradox: There is a lot of it, but not
Sanofi are beginning a digital transformation.[11] Pharma accessible or usable.[17]
digitalization facilitates health-care transformation.
Transformation drivers include health-care market Benefits of Digitization
challenges, complex regulatory requirements, and • Process control is assured continuously
increasing operational challenges. By adopting • Used to quickly detect any deviations
digitalization, the health-care transformation leads to • Due to automatic monitoring, there is continuous
evolving new therapies and increased patient-centric data which is validated against regulatory guidelines
care.[17] In wearable technology, wearable devices are • Man-hours are decreased by generating annual
used which are continuously monitored by health-care reports automatically.[19]
facilities. It provides a continuous data stream which
decreases risk levels and helps the drug companies for In digitalization, digitalization ecosystem plays a
better understanding of the medical conditions. The significant role. Pharma IoT and Pharma Industrial
quality of life increases and expenditure decreases. In Internet are the two digital ecosystems in Pharma
personalized care, 3D printers are used for personalized digitalization. It elucidates the product lifecycle and
treatment. Spritam levetiracetam is the first product product supply network.
produced using 3D printers. IoT and cyber systems
play a prominent role.[18] Now Pharma companies are Pharma IoT
adopting new technologies and innovations to improve IoT influences quality control, supply chain
medicine development and health care. The data play traceability, and overall supply chain efficiency. The

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digitalization of Pharma products and processes with Patient access

acute connected medical devices and IT services and Wearable devices chip in a pill, smart pill with dose
patient care are conceptualized in Pharma IoT. It is serialization, drug usage tracking, and medication
market for utilizing; analyzing the Pharma products compliance.
and deals with patient care data.[17] IoT is based on
smart devices such as “Organ in a Chip” this allows Advantages of IoT
us to run real-life diagnostics. The output from these • It increases manufacturing efficiency and operational
devices is clubbed with Big Data analytics, thereby efficiency in the warehouse
increases R&D productivity. IoT helps Pharma • It maintains desired storage conditions
companies by saving costs, improved quality, better • It ensures product integrity and traceability across
compliance adherence, and lesser time to market. the supply chain
“Chip in a Pill” is an ingestible pill on the consumption • It optimizes inventory costs and maintains drug
sensor that gets activated. Stomach fluids powders quality during transit.[20]
sensors. Sensor communicates health status using
body’s physiological response system. The wearable Pharma industrial internet
device captures the physiological response from the The digitalization evolution of product supply
sensor and sends information to smart devices. The infrastructures from manufacturing to dispensing
smart devices are synced with the cloud ecosystem. the medicines to patients is conceptualized. It
These IoT drive improvements are making operations manufactures and supplies to market.
more efficient and robust.
• Infrastructures and capabilities
Internal Systems • Implementation of intelligence in manufacturing
Drug efficacy data and health information received • Execution of software in packaging control
are sent to R&D. The data can be fed to the analytics • Implementation of integration supply chain
engine, and results are used in pharmacovigilance to • Exploit back-end IT cloud-based services
identify adverse events. (XAAS) that use the data from the product supply
[Figure 1].[17]
External Environments
Health statistics are directly shared with health-care Digitization and Automation in QC Lab
professionals. Hence, this information is used to Digitization and automation ensure better quality
control drug dosage and intensity levels. and compliance by decreasing manual errors and
variability, allows faster, and effective resolution of
Regulatory Submissions problems. As Pharma labs incorporate digital and
Regulatory bodies receive the data directly; this can automation technologies, there is a drastic change.
be helpful in clinical trials and post-drug launch. The manufacturing line is connected with high
Using these smart devices, it decreases time-to-market accuracy digital sensors. The evolution of Pharma
drugs, errors are detected, and regulatory compliance labs – digitally-enabled labs, automated labs, and
is improved. Personalized medicines are prescribed by distributed quality control.
HCPs from the wearable devices data 4, it improves
drug efficacy and decreases treatment period. Digitally Enabled Labs
Digitally enabled labs are 100% available nowadays,
IoT Application Across Pharma Value Chain
80% of paperless operations are achieved, and 90% of
These are applied in various stages they are drug testing is done in labs. Technologies such as automated
discovery and development: Organ chip devices to run data transcription between equipment and systems,
real-life diagnostics, wearable devices with sensors advanced data analytics for real-time data insights, and
for real-time health reporting, sensors, and devices are optimized schedules are used. The labs are transitioned
used to monitor clinical sites, subjects, and real-time from manual data to automatic data transcription
monitoring. between equipment and General Laboratory
Information Management System (GLIMS). To track
Manufacturing and supply chain trends and to prevent out-of-specification, real-time
Auto-ID with AIDC is used for smart serialization. data analytics and process verification are used.
Report parameters, smart warehousing, and routing, Digital tools like smart glasses are employed they
predictive maintenance of equipment are captured create a digital twin of the lab to identify impacts
using RFID and sensors. before making changes. In production operations,
these eliminate 80% of manual documentation work
Sales and marketing and increase personnel, equipment, and material
It includes drug interaction checker. utilization. These employ smart glasses, advanced

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Figure 1: Pharma digitalization

analytics-enabled lab planning and schedule, digital AG’s Innovation Factory, which manufactures
management, GLIMS interface, advanced analytics sterile containers
problem solving, and real-time trending. • Siemens AG’s electronics plant in Amberg produces
printed circuit boards are the digital company
Automated Labs • Piston filling machines for liquid pharmaceuticals
To perform all tasks advanced automation technologies such as cough syrup are manufactured by Bosch.
are used and predictive maintenance technologies are This machine is a part of the digital network
used to plan for infrequent tasks which lead to decrease • ESCAD Medical GmbH entered Industry 4.0.
downtime and reduce costs. 70–80% is available, This company specializes in endoscopy. It adopted
60–80% testing is done in labs, and 20–40% twisting a storage system called endoSTORE® which
on the shop floor. It employs automated compendia improves endoscope processing. Endoscopes are
testing, automated settle plate handling, robotic registered with barcodes; this prevents disinfected
process automation, automatic sample preparation, endoscope to reach near patients.[7]
and processing.
PHARMA 4.0 APPLIED
Distributed Quality Control
TO PHARMACEUTICAL
In the production line, routine product testing
occurs, enables RTRT. AI capabilities are adopted
MANUFACTURING
for equipment and robots. The adoption of PAT Pharma 4.0 is the future of pharmaceutical
and RTRT is slow because of regulatory filing manufacturing. The advent of the internet changed
and approvals. In the future, operations should every industry. In Pharma 4.0, there is a huge demand
collaborate with R&D to improve quality control for for personalized products and it creates the increased
new products and manufacturing sites. Distributed pressure on R&D for the production of new drugs.
quality control can enable 0-20% testing in labs Pharma 4.0 creates a single virtual network that
and 80-100% online real-time testing. Automated connects human data and machines. Using IoT and big
transcription of testing and product-quality-relevant data analytics, it gathers real-time data. Quality and
process data is used, artificial-intelligence-enabled productivity are improved due to interconnectivity
equipment and robotic technologies are used. 50– and automation. The manufacturing process is real-
60% is available. In future Pharma manufacturing time monitored to identify any error that may occur in
line instantaneous microbial detection of water the future. In manufacturing, Pharma 4.0 transformed
and air, parametric real-time release, automated AI from batch to continuous process because it is a
and machine learning are enabled for process and lengthy and time-consuming process. To overcome
product parameter control.[21] this continuous process is developed. This is a flexible
and precise process where there is no need to stop
Advantages of Industry 4.0 in-between the process during manufacturing. Fully
• It increases profits integrated components are adopted in an assembly
• It is applied in the medical device sector. For line where the materials are supplied; there is no
example, it becomes an integral part of Aesculap shut down of equipment and no human error. Many

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companies switched to a continuous process to catch • Advanced process controls are used to enhance
up with Pharma 4.0. For example, cystic fibrosis the quality and effectiveness of products. Robotic
drug is manufactured using a continuous process. and integrated manufacturing control is essential
Meeting the requirements of GMP in Pharma for a continuous manufacturing system. Real-time
4.0 is a big challenge. Pharma 4.0 enables smart data are consigned to control the system by PAT.
manufacturing with the help of integrated systems Instead of fed-batch reactors perfusion technology
and software. The gap between manufacturing and used.
automation is bridged by various technologies such
as AI, big data, and cloud computing. For example, Nowaday’s, Pharma companies support
in manufacturing process sensors are fitted in every modernization. These technologies provide
component, these sensors predict any failure or risks. the capability for robust, effective, and quick
The quality is relayed on real-time data exchange. For manufacturing.[11] Pharma 4.0 allows the industry
publishing and submissions, organizations rely on with smart tools, which leads to drug safety. IIoT
electronic submission experts. Cloud-based systems impacts pharmaceutical manufacturing technologies
are highly used. For example, in the life sciences, to improve the efficiency of complex manufacturing
GxP-critical information is managed. The data are operations. The Pharma companies adopt digital
stored in electronic format and located in the cloud. technologies to improve the process efficiencies,
Storing the data in the cloud gives the manufacturers increase profits, and decrease efforts. Pharma
to access the data directly.[22] Digitalization and companies face several challenges in regulatory
automation play a prominent role in the manufacturing standards, so it is mandatory for companies to
of pharmaceuticals. CIM and computer-aided implement digital technologies. By digitization,
manufacturing were included in product development product quality is enhanced, process efficiency is
and manufacturing activities. Intelligent, virtual, improved, decrease cycle times, scrap and rework,
and internet controlled manufacturing is advanced and reduce downtime. During manufacturing, all the
manufacturing.[23] There are four evolutionary stages information and data regarding machines, materials,
of manufacturing. They are operators should be recorded. Real-time reporting and
IIoT play a prominent role in continuous monitoring
• First stage – Mechanization, water power, and steam of equipment, personnel, and assembles the requisite
power data. By Supervisory Control and Data Acquisition
• Second stage – Mass production, assembly line, and or Manufacturing Execution Systems or Distributed
electricity Control Systems, the equipment is connected and
• Third stage – Computer and automation controlled. By enabling informed decisions through
• Fourth stage – Cybersystems.[19] data connectivity, the effectiveness of processes is
improved. By full automation of plant, it enables
Based on autonomous, computerized processes,
faster time-to-market for products.[25] In Pharma 4.0,
Pharma 4.0 deals with digitalization and automation of
continuous manufacturing and continuous process
the manufacturing world. To sustain the internal, self-
verification play a major role. These two processes
governing, communication within the factory machine
are highly digitalized to produce a robust process.
learning and IoT involved. Data are transferred and
monitored continuously. For example, apart from the
Pharma industry semiconductor industry implements CONTINUOUS
Industry 4.0.[24] Intelligent networks were created MANUFACTURING
by connecting machines and systems. For example,
machines predict failures and trigger maintenance Industry 4.0 technologies are executed by the Pharma
process autonomously. Decentralized intelligence industry. The batch manufacturing process is used,
creates independent process management, which but it is a lengthy process, and in each step, the
represents a new aspect of the manufacturing process. product is stopped and tested for quality. Sometimes
EMI, cloud computing big data analytics, CPS, machine the product is stored in the container and kept under
to machine communication, and automation concepts hold times to complete the manufacturing process.
are explored. IT department plays an important This leads to an increase in the chance of defects and
role; it ensures necessary connections are made and errors. FDA delivered a blog entry in 2016, states
maintained. Communication technologies like CPS that it is promoting manufactures to metamorphosis
will detect the defects and production failures early and from batch to continuous production. Nowadays,
increase productivity, quality. It should avoid problems; manufacturing of personalizing medicine is coming
otherwise, it leads to expensive production outages.[19] into existence. In continuous manufacturing, the
process is done in the same installation without
• Digitalization is employed in the pharmaceutical interruption, hold time between different stairs is
manufacturing process. Various PAT and eliminated, and the assembly line consists of fully

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Figure 2: Continuous manufacturing versus batch manufacturing

Table 1: Examples of pharmaceutical industries Quality attributes

adopted continuous manufacturing Incoming materials, in-process materials, and finished
Johnson and In 2016, FDA approved the Janssen drug products are monitored.[19]
Johnson’s unit to transit to continuous production[26]
Vertex In July 2015, continuous the manufacturing PHARMA 4.O TECHNOLOGIES
process is used for producing cystic fibrosis
drugs[27] AND APPLICATIONS
Eli Lilly Formulated a compound for Phases I and II
clinical trials in Eli Lilly’s Ireland site by Industry 4.0 has an immense influence on Pharma 4.0,
adopting continuous production[28] where industries move from automated process control
GSK In 2014, commenced an upper providence (APC) with reactive reporting to a true predictive
continuous pilot plant[29] analytics capability across the supply chain. APC tells
Pfizer Unlocked a recent tablet production, what has gone wrong, whereas Pharma 4.0 predicts
continuous manufacturing plant in Freiburg what will go wrong, and how to handle and avoid it.
in May 2017. Due to regulatory orders,
Both of these synchronize digital and physical value
manufacturing was stopped[30]
streams of product planning, production and assembly,
quality assurance, packaging, and logistics. By adopting
integrated components in which materials are fed. It Pharma 4.0, the industries go beyond automation and
saves time and abolishes human error [Figure 2 and using machine learning; IoT improves productivity,
Table 1].[24] ensures regulatory compliance and drug safety, reduces
unplanned downtime, and identifies complex business
CONTINUOUS PROCESS KPIs.[31] Advanced process controls such as smart
VERIFICATION equipment and PAT are used in process modeling.
For example, smart equipment improves process
CPV is adopted by all pharmaceutical companies, in control and efficiency by reducing waste in biopharma
every stage of the product development, the data are manufacturing. For example, the smart mixer is utilized
captured, analyzed, and reported continuously and for buffer solutions it estimates pH continuously and
validated to ensure that they are within the parameters. using acid and base pumps automatic titration is done.
By digitization, CPV can be achieved using four ways. This saves time compared to manual titration. In real-
time, PAT measures CQAs and employed in upstream
Analytics bioprocessing, it takes time to employ in downstream
Statistical process control and statistical methods are and manufacturing. Mass spectrometry employs multi-
used to collect data, and these procedures are used to attribute methods as PAT. The data are collected by
compute and estimate the process stability and process sensors and PAT. This data are used to analyze what is
capability. happening in the process and if any changes are given
it will identify what impact the changes will happen
Risk-based Real-time Approach in a process. Using simulation algorithms, the process
It verifies all CQAs and control strategy requirements optimized. By enabling these processes, we gain greater
of process materials. knowledge of the process before performing the actual
process.[16] The areas that can benefit the Pharma
In-line, On-line, or At-line Controls industries with high predictability, interconnectivity,
Process performance and product quality are supervised. and automation are listed below:

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Regulatory Compliance and Traceability goes beyond traditional modeling. A  generic digital
FDA compliance through visibility into the factory, representation of an asset type was created. Multiple
production lines, processes and machines, and track attributes of an asset are captured by twins from
and trace solutions through barcodes, it increases sensor data, and this data are used for the detection
revenue and market growth. of problems. Digital twins are used to estimating
accurately the continuation and interruption; plans
Minimize Unplanned Downtime for process enhancements, and develop substitute
With smart predictive maintenance, capital asset plans in case of disruption without terminating
management, it increases revenue and decrease in the manufacturing process.[11] By employing this
cost. technology, new problems are identified and
analyzed. From patient care to production, radical
Monitor and Predict Complex Business KPIs transformation is established in many areas of the
pharmaceutical industry.[18] For example, digital
KPI metrics, predictive analytics, and big data, it
transformation is engaged in Sanofi to simulate the
increases revenue.
biopharma production process. The digital plants
Eliminate Manual Processes have digital twins, which are connected directly to
sensors. A real-time view of plant operation is given
Automated actions based on predictive and reactive
to managers by circulating the data to these digital
alerts. It reduces costs.
twins. By analyzing this data potential, deviation
With Pharma 4.0, the companies can not only rely on real- recognized and rectified. Using process control
time updates but also real-time production monitoring strategies, yield is improved and by optimizing
with predictive ability to identify faults and failures maintenance activities, downtime is reduced, which
before they occur. When there is a fault in the production ultimately increases the overall output.
line, there is no need to throw out entire batches. If the
Advantages
shop floor is in sync with ERP, it can track any upcoming
equipment service requests and inventory requirements. • Intense asset
It provides real-time updates, auto inventory adjustments, • Operation robustiousness
automated testing results, shop floor and ERP in • Root-cause analysis is used to reduce cost
synch, no manual updates, and real-time production • Risks can be diminished proactively.
manufacturing. For example, the manufacturing line Data Analytics, Drug Development, and Discovery
of tablets is fully automated and connected to IoT and
Machine learning algorithms. The line has captured the Pharma companies employ advanced analytics
data through sensors and generates service requests at across the research and development, development,
regulatory and safety, manufacturing and supply chain,
various checkpoints. By predictive analysis of finished
market access, commercial, medical, and enabling
tablets, machine breakdown, the company can reduce
functions.[32] Digital analytics provides the relationship
the man-hours.[31] Pharma 4.0 adopts new technologies
between raw material variability and process
for ensuring product quality and patients safety.
performance during manufacturing.[12] Pharmaceutical
Technologies such as robotic process automation, digital
companies can use data analytics in the following ways
twins, data analytics, drug development, and discovery
to advance drug discovery and development, optimize
play a key role.[18] These things accelerate the growth
and enhance the efficacy of clinical trials, target
of digital transformation. These reduce risks and ensure
specific patient populations, improve safety and risk
quality through real-time analytics.[12]
management, and improve insight into marketing and
Robotic Process Automation sales performance.[33] From incoming raw materials to
the finished product, a single outlook is provided. It
It is also known smart manufacturing or APC which
shows all the critical parameters and reports any issues
consists of IoT, machine learning, data analytics that affect the product under manufacture. A green or
by AI, computing, cloud technologies, etc., some red dashboard is used where operators can rapidly
companies like Pfizer are shifting toward “connected check which parameters require observation so they
manufacturing plants” that makes data visible and can prevent errors and improve the manufacturing,
available. Collaborative robots augmented reality and and finally, it leads to increase product quality and
paperless operations in their manufacturing site are profitability.[19]
employed by Sanofi. Merck connects “smart factories”
for responsive and adaptive manufacturing.[18] CONCLUSION
Digital Twins Pharma has typically been a disinclined industry;
Digital twins provide real-time data about the regulators encourage stimulating it into the
condition of a process of equipment.[12] Digital twin Pharma 4.0 approach. Pharma 4.0 helps industries

Drug Invention Today | Vol 14 • Issue 3 • 2020 413

 S. Hemanth Kumar, et al.

to maximize productivity. By implementing the 13. Available from: https://www.innovareacademics.in/journals/

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Source of support: Nil; Conflicts of interest: None Declared
2019 Dec 05].

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