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Batch Vs Continuous
Batch Vs Continuous
PROCESSING
Many new product processes have and are being fit into existing facilities and their
available batch equipment leading to processing inefficiencies and increased costs,
especially as product titers improve.
REASONS FOR BATCH PROCESSING OF
SMALL MOLECULE PHARMA PRODUCTS
Unfortunately, the pharmaceutical industry generally has been hesitant to introduce innovative systems into
the manufacturing sector for a number of reasons. One reason often cited is regulatory uncertainty, which
may result from the perception that our existing regulatory system is rigid and unfavorable to the
introduction of innovative systems. For example, many manufacturing procedures are treated as being
frozen and many process changes are managed through regulatory submissions. In addition, other scientific
and technical issues have been raised as possible reasons for this hesitancy. Nonetheless, industry's
hesitancy to broadly embrace innovation in pharmaceutical manufacturing is undesirable from a public
health perspective. Efficient pharmaceutical manufacturing is a critical part of an effective U.S. health care
system. The health of our citizens (and animals in their care) depends on the availability of safe, effective, and
affordable medicines.
Pharmaceuticals continue to have an increasingly prominent role in health care. Therefore pharmaceutical
manufacturing will need to employ innovation, cutting edge scientific and engineering knowledge, along
with the best principles of quality management to respond to the challenges of new discoveries (e.g., novel
drugs and nanotechnology) and ways of doing business (e.g., individualized therapy, genetically tailored
treatment). Regulatory policies must also rise to the challenge.
U.S. Department of Health and Human Services Food and Drug Administration Center for Drug
Evaluation and Research (CDER) Center for Veterinary Medicine (CVM) Office of Regulatory
Affairs (ORA) Pharmaceutical CGMPs September 2004
IMPLEMENTING CONTINUOUS VS. BATCH
MANUFACTURING
Process and Business Driving Forces
Manufacturability
∗ Batch production of complex, less‐stable proteins is often impossible, for instance decreases in
MAb product quality over the course of fed‐batch culture is known to occur preventing batch
production.
∗ One of the big benefits to continuous manufacturing is eliminating a fixed batch size, allowing one
to make as little or as much as needed.
∗ Continuous manufacturing product lead times (Raw materials procurement to distribution of
finished product) are typically significantly less than for batch which can substantially reduce
inventory carrying costs.
∗ Improved safety based on processing smaller quantities of hazardous materials and operating at a
safe steady state point rather than cycling through changes of state in batch processing.
Some Physiochemical Factors that Influence
Change from Batch to Continuous: Small
Molecule
∗ Unit Operation Cycle Times
∗ Reaction Kinetics
∗ Drying Rates
∗ Separability of Constituents
∗ Ease of aqueous/organic layer seperation
∗ Robustness of Intermediate and Product
∗ Effect of Temperature
∗ Effect of agitation
Some Physiochemical Factors that Influence
Change from Batch to Continuous: Biologics
∗ Cell Culture
∗ Cell stability and robustness,
∗ Excretion of product from cell
∗ Production/removal of toxins during cell growth
∗ Product stability
∗ Ability to grow at a steady state
∗ Cell cycles
∗ Chromatography
∗ Bind and Elute (IEX and affinity chromatography) is inherently
a batch process
∗ Robustness of Intermediate and Product
∗ Effect of temperature, pH and agitation
Unit Operations – Batch Processes
OPERATION HOW ACCOMPLISHED MONITORING
Cell
Retention
Device
Overview of Perfusion Culture
∗ Continuous addition of fresh media
(nutrient feed)
∗ Continuous removal of waste products
(harvest)
∗ Animal cells retained at high
concentration
∗ Separation by Size Exclusion (TFF, ATF,
spin-filtration)
∗ Separation by Particle Mass
(sedimentation, hydrocyclones,
centrifugation, acoustic resonance)
∗ Types of Perfusion
∗ Heterogeneous perfusion
microcarriers
∗ Homogeneous perfusion
Cells in suspension
Perfusion Engineering Challenges
∗ Particle Imaging
∗ Particle Vision Measurement (PVM)
∗ Acoustics
∗ Fluorescence
APPLICATIONS FOR PAT TECHNOLOGIES
PAT TECHNOLOGY
FBRM Nalas Engineering Services,
∗ Documentation of manufacturing
21 CFR 211.188 Batch product and control records shall be prepared for each batch of
drug product produced and shall include complete information relating to the
production and control of each batch
∗ Recall situation
21 CFR 211.150(b): Distribution procedures shall include […] a system by which the
distribution of each lot of drug product can be readily determined to facilitate its recall
if necessary
From C. Moore, FDA, 13SEP2011
∗ SPINID
∗ Chemtrix
∗ Uniqsis
∗ Access Flow
∗ Proteaf
∗ Micronit Microfluidics
∗ ConsiGma™
∗ Fluitec
∗ Lonza
ATF Case Study
Idea
Innovator Manufacturer 2
Vendor
Startup
Engineering Manufacturer 3
Firm(s)
Other
Vendors
Manufacturer
Manufacturer
Process Manufacturer 4
Development PRODUCTION
ACKOWLEDGEMENTS