PHOTO COURTESY OF ROGER LUNDBLAD (PICTURED).
When I officiated at high school (US) football, I learned a lot from the experience. Contrary to popular opinion, there are rule books referees study. However, although the rule book is modest in size, the case book for interpretations is large. This brings me to the topic of generic or follow-on biologicals and biosimilar products for which there will be rules, and the interpretations will be many. Continuing with the US football analogy, the approval of a generic biological, be it a follow-on or a biosimilar, will be a little like pass interference: considered a foul that should be penalized by company A, but a good play by company B.
Say company A, which has a profitable product coming off patent protection, wishes to protect its end zone from company B, which is in the red zone and moving. Conventional drugs which can be modestly changed to improve performance and secure additional patent protection. But modification of a protein to secure the same intellec...
IBC’s 16th annual Bioassay Conference is the meeting for learning about developing, qualifying, validating, and maintaining important biological assays. Come and discover the newest techniques for streamlining development and validation using easy-to-understand statistical approaches. Hear how other assay developers are accelerating their development plans and meeting aggressive timelines. Learn about use of the newest technology and regulatory trends to develop the right assay, at the right time, in the quickest possible way. After attending this conference, you will catapult your assay development efforts to a higher and more successful heights.
This is the only forum that focuses solely on biological assays. Take advantage of this unique opportunity to discuss nitty gritty practical approaches with your colleagues and explore best practices that can be applied right away.
Highlights
What’s Different?
Preconference Workshop
Working Session:
“Practical Approaches to Establishing Parallelism for Your Pot...
Downstream Processing
Product:
SciPure 300 GMP production platform
Applications:
Tangential-flow filtration (TFF)
Features:
Revolutionary purification platform automates, documents, and analyzes any TFF application needed in a GMP environment. The user-friendly interface is built on the familiar Windows XP operating system and .NET framework; administrative users have easy access to and control over all process parameters, users, permissions, and recipes. The system logs all program variables and automatically maintains optimal TFF conditions through continuous data acquisition and precision control loops.
Contact SciLog
www.scilog.com
Sterilization
Product:
No. 970 500 °F (∼260 °C) electrically heated, class 100 cleanroom oven
Applications:
Sterilization, depyrogenation, curing, and drying
Features:
The unit measures 33-in. wide × 42-in. deep × 66-in. tall and is heated by 30-kW Incoloysheathed tubular elements. A 2,400 cfm, threehorsepower recirculating blower provides horizontal airflow to the ...
Acceptance criteria
Numerical limits, ranges, or other suitable measures for acceptance of results from analytical procedures that a drug substance, drug product, or materials at other stages of their manufacture should meet (
1
).
Numerical limits, ranges, process signatures, or other suitable measures that are necessary for making a decision to accept or reject the result of a process, in-process variable, a product, or any other convenient subgroups of manufactured units (
2
).
Numerical limits, ranges, or other suitable measures for acceptance of test results (
3
).
Accuracy
The accuracy of an analytical procedure expresses the closeness of agreement between the value that is accepted either as a conventional true value or an accepted reference value and the value found (
4
).
Active pharmaceutical ingredient (API) See
drug substance
.
Analytical procedure
Refers to the way of performing an analysis. It should describe, in detail, the steps necessary to perform each analytical test. This may inclu...
Long-term hopes for stem cells to cure various diseases are nourished by the latest developments in stem cell research. First clinical studies have begun (Thera Vitae, Israel: congestive heart insufficiency), and patents have been filed (Stem Cell Therapeutics, Canada: combined regulation for the production of neural cells). Clinical use depends on technological requirements for a reproducible cultivation and controlled differentiation of cells in sufficient numbers, so more and more researchers are focusing on the scale-up of stem cell production. For instance, Susanne Terstegge at the University of Bonn in Germany has studied cultivation conditions on cell growth and differentiation in vitro (
1
). First results indicate the importance of shear forces and oxygen supply, both of which are discussed here.
PRODUCT FOCUS:
Cell therapies
PROCESS FOCUS:
Production
WHO SHOULD READ:
PRODUCT AND PROCESS DEVELOPMENT, R&D
KEYWORDS:
Bioreactors, process optimization, cell culture, stem cells, process control
LE...
The use of cellular physiology to make target molecules has been practiced for centuries, with early examples being the production of wine and beer through yeast fermentation. Single (e.g., bacteria and yeast) and multicellular (plant or animal) organisms can be harnessed to produce otherwise chemically complex, low-yield, or chemically uncharacterized materials. These include “lock-and-key” receptor complexes with perfect stereochemical specificity, large-scale protein scaffolds, or antibiotics. One example is penicillin, with a sensitive β-lactam ring structure at its core (
1
). Mass-production of penicillin began several years before its first synthesis was even published (
2
).
PRODUCT FOCUS:
Biologics
PROCESS FOCUS:
Production
WHO SHOULD READ:
QA/QC and process development
KEYWORDS:
PAT, spectroscopy, cell culture, batch processing
LEVEL:
INTERMEDIATE
In the 20th century, designer biological synthesis entered the age of mass production. The first large-scale manufacture of penicillin succeeded ...
Today, there is much discussion regarding the promise of improved insight into bioprocess industry processes. Look to the pages of industry publications such as this one, and you’ll see that industry leaders in process measurement and control have begun to discuss openly the potential for simulating and modeling bioprocesses.
“Important opportunities such as the application of mass spectrometers, dissolved carbon dioxide probes, and inferential measurements of metabolic processes have come to fruition today opening the door to more advanced process analysis and control technologies,” says Greg McMillan with Emerson Process Management.
However, speak to such professionals for any length of time, and you’ll learn that unlike processes associated with petroleum manufacturing, for example, which have been modeled for nearly 40 years, biotechnology involves living processes, which are much more challenging to predict. But if the industry is going to improve its process reliability and product quality while red...
A polysaccharide is a complex glycan with at least 10 monosaccharide units. It can be formed by the multiples of the same monosaccharide (a homopolysaccharide) or by two or more monosaccharides combined (heteropolysaccharide). Two homopolysaccharides can have completely different conformations — and thus properties — based on the position and type of glycosidic linkages in the structure (Figure 9). Polyglucose ranges from cellulose — β(
1
,
2
,
3
,
4
) glucan, with its zig-zag chains regularly superimposed to each other and bound tightly by hundreds of hydrogen bonds to form strong fibrils that confer structural strength to standing trees — to flexible α(
1
,
2
,
3
,
4
,
5
,
6
)-glucans with twirling structure and high solubility, which are typically used by plant seeds as a nutrient during early development.
PRODUCT FOCUS:
Glycoproteins
PROCESS FOCUS:
Analytical
WHO SHOULD READ:
QA/QC, product development, process development, and analytical personnel
KEYWORDS:
GLYCANS, CARBOHYDRATES, OLIGOSACCHARIDE...
Broadley-James Corporation, Emerson Process Management, and the University of Texas at Austin are working together to examine and quantify the potential for faster optimization of batch operating points, process design, and cycle times. We’re also looking for more reproducible and predictable batch endpoints.
The objective of this effort is to show that the impact of PAT can be maximized through the integration of dynamic simulation and multivariate analytics in a laboratory-optimized control system during product development.
Data from bench-top and pilot-plant cell culture runs are being used to create multivariate analytic and high-fidelity, first-principle cell culture models to prototype process changes. The tools that are being used could provide significant improvement in process development and process control by laying a foundation for real-time release capabilities as defined by the PAT guidelines (
1
). Potential benefits include a more automated, seamless, and effective commercialization proce...
+2Bioassays are required for a variety of purposes in the development and production of biopharmaceuticals including drug candidate selection, product releases, product stability assessment, and comparability to support proposed process changes. However, because of their complexity and susceptibility to many variables, bioassays often prove problematic and difficult to develop. Timely development of suitable assay systems represents a major investment on the part of the biopharmaceutical industry — but late development often results in even more costly clinical holds.
PRODUCT FOCUS:
All biologics
PROCESS FOCUS:
Product testing
WHO SHOULD READ:
ANALYTICAL, PRODUCT DEVELOPMENT, QA/QC, regulatory affairs, formulations
KEYWORDS:
bioassays, immunoassays, functional assays
LEVEL:
BASIC
Recent and ongoing advances in biology and technology provide the possibility of new types of assay systems and readouts. Some offer significant logistical and scientific advantages so that, in addition to being investigated f...
A rich cup of coffee is what comes to mind for many people when you mention the word
robust
. For biotechnologists it is often a comfortable term, generally referring to the overall strength or ruggedness of a
manufacturing process
. However, the origin of the robustness concept for manufacturing is found in the field of robust design, which has for decades been a rigorous discipline with its own metrics, algorithms, and mathematical tools. Lately it has experienced a renewed interest in further development of its formal approaches, mathematical modeling, and applications. Applications of robust design exist in many specialized disciplines from economics to engineering (including bioprocess engineering), with each emphasizing different elements of the concept.
Process Robustness
For bioprocessing professionals, an appropriate definition of
process robustness
is provided in ICH Q8: “ability of a process to tolerate variability of materials and changes of the process and equipment without negative impac...
The introduction of therapeutic monoclonal antibodies (MAbs) has greatly revolutionized therapies for several cancer immune disorders (
1
,
2
,
3
,
4
,
5
). Benefits to patients have been substantial, translating into both increased life expectancy and improved quality of life. Currently, twenty-one therapeutic MAbs are registered for marketing in the United States, with the introduction of several more expected in the coming years (
6
,
7
,
8
,
9
,
10
,
11
).
PRODUCT FOCUS:
MONOCLONAL ANTIBODIES
PROCESS FOCUS:
Technology transfer (production) and analytical methods development
WHO SHOULD READ:
PRODUCTION AND PROCESS DEVELOPMENT, MANUFACTURING
KEYWORDS:
IGF-1R, EXPRESSION, TECH TRANSFER, CELL-LINE CULTIVATION, SIZE-EXCLUSION CHROMATOGRAPHY, ISOELECTRIC FOCUSING, MATRIX-ASSISTED LASER DESORPTION/IONIZATION TIME-OF-FLIGHT MASS SPECTROMETRY, ELECTROSPRAY IONIZATION MASS SPECTROMETRY
LEVEL:
INTERMEDIATE
Some cancer cells over-express growth factor receptors on their surface, which when activated signal c...
+15 The level or intensity of product and process understanding that can or should be achieved beyond the acceptable minimum level promises to be the scope of a continuing debate among biotech industry and its regulators. In practice, the path of increased understanding may follow a series of incremental steps toward the
desired state
(Figure 1) after a product launch. Realistically that is expected to occur when the level of product and process understanding has reached or slightly exceeded the minimum regulatory acceptable level. Development of such understanding beyond information collected from product and process characterization studies (see the appendices online) during development can come from using a
process analytical technology
(PAT) approach for process monitoring or using newer scientific approaches such as
systems biology.
Continual or Continuous Improvement
Some authors prefer the term
continual improvement
over
continuous improvement
.
Although both are similar, they may invoke diffe...
Risk is inversely proportional to one’s distance from a problem. For regulators, it seems straightforward to control biopharmaceutical and medical device risk. For pharmaceutical, biotechnology, and medical device executives, however, risk is hardly so clearly defined; it extends, grows, twists, and compounds through a chain of suppliers, consultants, and business partners. So when regulatory officials claim that compliance accountability cannot be delegated, biopharmaceutical and medical device companies are left holding the bag.
Years ago, as a C-level executive for a combination medical device company, I consistently wished for some way to entrust compliance accountability to those suppliers and outsourced vendors conducting the work, whether computer validation or contract manufacturing. Although blanket contract terminology (“company X will comply with regulations Y”) can be inserted into any agreement, a supplier or vendor will not be the one in the news due to a regulatory investigation nor be the ...
Elements of the biopharmaceutical industry’s new operating paradigm have inevitably created an immediate need to condense, interpret, and relate their implications to existing regulatory and industry practices. This also provides us with an opportunity to look at them in a broader context and in relationship to one another. Such a perspective may open up new directions in discussion on how design and control aspects of biopharmaceutical manufacturing are likely to evolve. These are exciting times for scientists, engineers, statisticians, quality professionals, and regulators alike because contributions from each are needed to establish new practices that will deliver on the intentions and expectations of these new initiatives.
In Chapters 2 and 3, we explore in a harmonized context the fundamental concepts of
quality by design
(QbD) (
1
,
2
),
process analytical technology
(PAT) (
3
),
quality risk management
(QRM) (
4
) and pharmaceutical quality (
5
,–
6
) initiatives, as well as the emerging fie...
Currently the biopharmaceutical industry is transitioning to a new business model of production efficiency through implementing operational excellence (Op Ex). Borrowing from such principles as “lean manufacturing” and
“Six Sigma”
(6σ), and incorporating
quality by design
(QbD) (
1
), Op Ex is being applied through the implementation of such advanced enabling concepts and technologies as
quality risk management
(QRM) (
2
),
process analytical technology
(PAT) (
3
), and
systems biology
(SB) (
4
).
Some people see a conflict here: This paradigm shift is occurring amid ever-increasing product development costs, looming biogenerics and biosimiliars, and shortened
product life-cycles
. On the contrary, however, those very burdens contribute to the industry’s increasing need for innovation and efficiency, whether that be in product and process development (including control strategies), manufacturing, or quality assurance. And that is precisely what the FDA intended to address with its guidances on ...
Counterfeit products are no longer restricted to Gucci purses and Rolex watches. The pharmaceutical business has seen an alarming rise in the number of counterfeit products entering traditional distribution and supply chains. As a result, consumers can unknowingly purchase counterfeit pharmaceuticals from their local pharmacy and receive little or no therapeutic benefit, or worse, die as a result of ingesting counterfeit products.
Pharmaceuticals are subject to counterfeiting in a number of ways. A counterfeit product may contain no active ingredient or a wrong one, or it might even contain random mixtures of harmful toxic substances or components (
1
). All types and brands of drugs have been counterfeited. Copied drugs are manufactured to look like branded products to trade off the product integrity, safety, and efficacy of the original brand.
Branded Drugs Are Particularly Vulnerable:
Although counterfeits have infiltrated all aspects of the pharmaceutical industry, brand-name drugs are especially vul...
