CONTINUOUS MANUFACTURING IN

BIOLOGICS ADOPTION AND

REGULATORY ENGAGEMENT

Dr. Ana Silvia Nita

Dir. RA CMC Biologics Development
MSD, Switzerland

CASSS conference 17th – 19th Oct 2022, Brugge

❑ MANUFACTURING INNOVATION IN PHARMACEUTICAL INDUSTRY

❑ CONTINUOUS MANUFACTURING VERSUS BATCH PRODUCTION

❑ REGULATORY GUIDANCE IN CONTINUOUS MANUFACTURING

❑ REGULATORY ADVOCACY - HEALTH AUTHORITY INTERACTIONS

❑ CONTINUOUS MANUFACTURING - SHAPPING THE FUTURE

Proprietary

MANUFACTURING INNOVATION
IN PHARMACEUTICAL INDUSTRY
Industrial processes can be classified based on the process’
output as:

❑ Batch processes

Batch process refers to a process consisting of a sequence of one

or more steps that are performed in a defined order. A defined
quantity of the product is produced at the end of the sequence
which is repeated in order to produce another product batch.

❑ Continuous processes

Continuous manufacturing (CM) integrates traditional step-wise

manufacturing processes into a single system based on modern
process monitoring and controls. In a CM process, product is made
over time, so a drug manufacturer can easily control the amount of
product being made to meet demand.

These efficient, integrated continuous systems also require smaller

footprints to operate.
3
 MANUFACTURING INNOVATION
IN PHARMACEUTICAL INDUSTRY

• Integrating Novel Technological Approaches

➢ Using established techniques in a new or innovative
way
➢ Applying production methods in a new domain where
there are no defined best practices or experience

• New Manufacturing Technologies currently in

progress:
➢ Portable manufacturing units to respond to
production on demand (POD’s)
➢ End-to end continuous manufacturing processing
➢ Additive manufacturing (e.g. 3D printing)
 WHAT IS CONTINUOUS MANUFACTURING ?

❑ Continuous production is a flow production method use to manufacture, produce, or process materials
without interruption.

❑ End-to-end Continuous Manufacturing (according to

FDA), is a fully integrated process in which raw materials
or chemical intermediates are continuously fed into and
transformed within the system (under continuous control
and monitoring) and finished drug products are
continuously removed from the system.
❑ Drug substance and drug product process steps are fully
integrated into a single continuous system; testing and
control are built into the system.
❑ The hybrid approach is a combination of batch and
continuous processing steps. The pharmaceutical industry
is increasingly adopting hybrid systems as it combines the
advantages of batch and continuous processes.
Possible continuous processing manufacturing domains
 BATCH PROCESS VERSUS CONTINUOUS PROCESS

❑ CM constitutes a direct translation of the unit operations

contained on the process flow diagram.
❑ CM is based on the application of engineering solutions to
create continuous flow and unit operation linkages, while
conserving the underlying intent of the unit operations
themselves as characteristic of fed-batch process.
❑ CM of API manufacturing is more complicated due to longer
residence time, higher quantity and diversity of unit
operations, and complexity of distinguished key molecules.
❑ Protein expression from either a fed-batch or continuous
perfusion bioreactor utilizes the same cellular machinery in a
conserved cell line.
 BATCH PROCESS VERSUS CONTINUOUS PROCESS
Batch Process Continuous Process

Definition Process that involves a sequence of steps The flow of a single unit of product between every step of the process without
followed in a specific order. any break in time, substance or extend.
Coordination Scheduling is done to maintain the timing Each machine performs a certain processing function and they operate in a
between move to earth. steady state.

Quantities produced A whole unit of products is produced. Large quantities of products are obtained, greater ability to scale up

Process (cap)ability Can be adapted to different products Limited possibility to reconfigure the units operation
Lower flexibility to accommodate different products per manufacturing line
(minimize validation issues and the risk for contamination)

Cost of equipment Low equipment cost High equipment cost

Controlling Batch process can be controlled very easily Control batch process requires sophisticated, highly automated control systems
Batch release when testing is finalized and Real time batch release
confirmed

Shut Down times Often Rare

Workforce Small workforce is needed Continuous process is generally available in fully automated plants. If not, large
workforce will be necessary.
 CHALLENGES IN DEVELOPING CONTINUOUS
MANUFACTURING IN BIOLOGICS
PRACTICAL CHALLENGES
• Raw material properties and variability
• Impurities and removal (degradation products accumulated
over time)
• Viral safety and bioburden
• Material traceability
• Cell line stability and life span during a long fermentation
process

• Product knowledge and structural/functional relationship

• Process, analytical control and control strategy, real time testing
• Design space and potential interactions between steps
• Evaluation of manufacturing changes and impact on product
quality
 CONTINUOUS MANUFACTURING PROGRESS

Medicine Products using continuous manufacturing process, approved on the market are
Small Molecules, solid oral dose drug products.

Drug Pharma company Indication FDA EMA PMDA

Japan
Daurismo Pfizer Acute Myeolocytic X
Leukemia
Orkambi Vertex Pharmaceuticals Cystic Fibrosis X X
Prezista Johnson&Johnson HIV X X
Symdeco/ Vertex Pharmaceuticals Cystic Fibrosis X X
Symkevi
Trikafta Vertex Pharmaceuticals Cystic Fibrosis X

Verzenio Elli Lilly Metastatic Breast X X

Cancer
 REGULATORY LANDSCAPE
➢ In addition to technical challenges, there are also regulatory challenges,
especially for implementation of CM in Biologics.

Current CM guidance:
ICH Q8-12: Product and process understanding and process control (ICH Q8)
Quality risk management (ICH Q9)
Quality systems (ICH Q10)
Development and manufacture of DS/ Quality by design (ICH Q11)
Lifecycle approach to process control/validation (ICH Q12)
Continuous Manufacturing of DS and DP covered by ICH Q13 – available
CM is consistent with EMA/FDA quality by design (QbD) guidance.
There is still limited experience on HA side with CM on Biologics.

➢ Industry and regulators need to collaborate and embrace innovation to

advance and facilitate the implementation of CM in Biologics.
 CURRENT REGULATORY LANDSCAPE
Variation Description Type (EU)

B.I.1.2 c) The change refers to a biological/immunological substance or use of a II (major)

Change in manufacturing process of an API different chemically derived substance in the manufacture of a
biological/immunological substance, which may have a significant
impact on the quality, safety and efficacy of the medicinal product and is
not related to a protocol
B.I.a.3 c) The change requires assessment of the comparability of a biological/ II (major)
Change in batch size (including batch size ranges) of active immunological active substance
substance or intermediate used in the manufacturing process of
the active substance

B.I.b.2 d) Substantial change to or replacement of a II (major)

Change in test procedure for active substance or starting biological/immunological/immunochemical test method or a method
material/reagent/intermediate used in the manufacturing using a biological reagent for a biological active substance
process of the active substance
B.II.b.3 c) The product is a biological/immunological medicinal product and the II (major)
Change in the manufacturing process of the finished product, change requires an assessment of comparability
including an intermediate used in the manufacture of the
finished product

B.II.b.4 c) The change requires assessment of the comparability of a II (major)

Change in the batch size (including batch size ranges) of the biological/immunological medicinal product or the change in batch size r
finished product requires a new bioequivalence study
 REGULATORY LANDSCAPE

❑ The science exists to enable continuous manufacturing of

pharmaceuticals. Specific scientific considerations related to
sampling frequency for continuous manufacturing
❑ FDA/EMA support the implementation of continuous
manufacturing using a science and risk-based approach.
Recommend and supports early and frequent discussion with
Agency before implementation
❑ North America is likely to be a faster adopter of continuous
manufacturing. It is expected to hold dominance in the global
market. Support from regulatory bodies, openness of leading
pharmaceutical companies toward the latest technologies, and the
mounting pressure on pharmaceutical companies to reduce
operational costs will fuel the demand for continuous
manufacturing in North America.
 CONTINUOUS MANUFACTURING-
REGULATORY ENGAGEMENT
❑ Interactions with different health authorities
❑ Interactions with other industry representatives to identify and discuss common challenges, seek alignment
on industry position on CM implementation strategy

• Prepare for new

EU manufacturing
(ETT) Pharma technologies
FDA Strategy
• Support innovation

• Q office, ITF
(IMTC) • EFPIA
EMA
PMDA • GMDP Insp. WG
• QWP/BWP

• ICH (EMA view)

MHRA • PIC/S
Globally
• Different HA’s
engagement
 CONTINUOUS MANUFACTURING-
SHAPING THE FUTURE

❑ To facilitate adoption and ensure global consistency:

-new regulatory guidelines and policies are needed to
support the future state of ILM (in line monitoring)/RTR (real
time release)
-facilitate submissions for new and existing products.
Regulatory agencies need to be involved throughout the process
to prevent issues resulting from missing or inconsistent
guidelines.

❑ Regulatory agencies are supportive to innovative

technologies, but are not globally harmonized, requirements
may differ significantly, therefore, global implementation is
still a challenge, complicating supply chains.
 CONTINUOUS MANUFACTURING-
SHAPING THE FUTURE

Significant engagement efforts between industry

and regulators are ongoing and focus on:
❑ How to ensure suitable and effective
regulations and guidance to facilitate faster
implementation of new technologies and allow
faster patient access to breakthrough therapies?

❑ How to facilitate the implementation of CM

as a post approval submission for marketed
products and allow the option to use two
manufacturing processes under one license
for a product, especially when global
harmonization is still a challenge?
 CONTINUOUS MANUFACTURING-
SHAPING THE FUTURE

❑ Drugs in various pharmaceutical dosage forms using CM

technology would likely be approved in the coming years

❑ Regulatory harmonization can be achieved through a large

adoption of ICH Guidelines, as a main reference, by health
authorities to provide:
-better clarity to the manufacturers on the regulatory requirements
for global implementation
-confidence to invest and overcome challenges using a new
technology by pharma companies

❑ Implementation of ICH Q13 should limit significantly the

hurdles of CM implementation
 CONTINUOUS MANUFACTURING
SHAPING THE FUTURE

❑ Commercial implementation is on the way. Pharma industry

and regulators work together to support CM technology,
engage in active discussions, building experience and
facilitate implementation.

❑ Current regulations and guidance are supportive, nevertheless

there are still challenges and specific technical aspects to be
considered, therefore, early and active engagement with
authorities is crucial in successful approval.

❑ CM prepares pharma industry for the future, using novel

and flexible technologies to adapt, to meet therapeutic needs
(e.g. personalized medicines), market changes and demand,
and minimize the risks and costs.