Michael Pohlscheidt, Eric Fallon, David Chang, Dan Stark, Frank Trach
Since the early 1980s, biotechnology products have shaped the pharmaceutical industry. A large number of monoclonal antibodies and therapeutic proteins have been approved and are anticipated to be a major growth driver for the industry in upcoming years [1-6]. Mammalian cells are the expression systems of choice due to their ability to properly fold and modify these complex protein therapeutics [7-10]. Tremendous advances in process development throughout the last decade have resulted in significantly increased manufacturing scales, product
titers, and recovery yields thereby satisfying increasing market demand for existing and new products. Manufacturing scales up to 25 m3 operated
in batch, repeated batch, or fed batch mode followed by a sequence of chromatography, filtration, and concentration steps represent state-of-theart
technology [11, 12] – a typical antibody production process is shown in Shukla and Thömmes 2010 [13].
Jilla Boulas, Delphine Decker, Valerie Pimpaneau, Florence Philippoz
Clinical trials testing the Benefit/Risk ratio of Investigational Medicinal Products (IMPs) in the European Union/European Economic Area (EU/EEA) are governed currently by Directive 2001/20/EC [1], defining the requirements for the conduct of clinical trials in the EU. The Directive became effective in 2004 and its implementation in the different EU Member States (MS) occurred by transposition into the national laws of each MS. Approval of clinical trials is under the responsibility of individual MS and involves a thorough evaluation of the products used in the clinical study. The implementation of the Directive has, however, led to different requirements amongst the Competent Authorities (CAs) and Ethics Committees (ECs) of each concerned MS.
Small biotech companies’ historically
bundled stability testing with product
manufactures and leave stability storage and testing at the contract
manufacturer sites. Often the manufacturing sites do not have the
full analytical testing capability, so some tests (e.g. bioassay, peptide
mapping) were subcontracted to a third party. In the extreme case,
samples pulled from stability were sent to several testing labs to
complete the full battery of tests for a single stability point ultimately
extended timelines.
Claude Ammann
Pharmaceutical manufacturers are accountable for delivering medicinal products with the right quality attributes to patients. Control of storage and transport conditions is one key element in achieving this goal. It is not unusual for the storage to experience uncontrolled situations where temperature deviates from the specified values and for the transport to not follow the forecasted routes and scheduled plans. For temperature sensitive products, one possible consequence may be temperature excursions outside the specified range. What are the right tools to help make the right decision?
Ghulam A. Shabir, Ph.D.
There is a growing awareness that an improvement in the quality of
pharmaceutical products and services is a vital factor in the battle to
maintain sales and remain commercially viable in the fast-growing
and changing market. In many markets, quality competition is at least as
important as price competition and this trend is bound to continue. With
the prospects of more stringent product liability legislation and the threat
of heavy financial penalties for products and services which fail to meet
safety, good manufacturing compliance (GMP) or functional requirements,
profitable trading will depend on sound Quality Assurance best practices.
Material resources are becoming scarce and most expensive, and it is
therefore economically desirable to minimize losses on scrap products by
more effective quality control.
Thomas M. Eckrich, Ph.D.
Many years ago I heard a QA executive say, “The only difference between
two batches of a validated process should be their dates of manufacture.”
The underlying message here is that the manufacturing process should
be so well designed, so well understood and so well described that it
is obvious when anything is wrong. The complexity of pharmaceutical
active ingredient (API) processes allows opportunity for great variability.
John Lepore, Ph.D., Kevin D. Seibert, Ph.D., Timothy Watson, Ph.D., Susan Wollowitz, Ph.D.
As many pharmaceutical companies begin to leverage the principles
outlined by the Quality by Design initiatives described by the US Food and
Drug Administration in the Guidances for Industry [1-4], the way in which
firms generate supporting data, and ensure long term process robustness is
rapidly evolving. Developing a process control strategy from an enhanced
development approach [1] involves a greater degree of understanding of
the impact of a particular synthetic route or formulation process to both
material attributes (i.e., raw materials) as well as process parameters in both
a univariate as well as multivariate sense. Building enhanced knowledge,
assessing risks intrinsic to a process, and presenting information in a clear
and logical fashion are vital to demonstrating control and understanding
of a process to a regulatory agency. These remain key deliverables and
responsibilities for the asset owners.
The shortage of Venture Capital investment to support early phase clinical development programs over the past few years has resulted in fewer early phase clinical development projects entering Phase I. CMOs like Almac had to quickly react to this fast-changing market or face dramatic consequences. Over the past few years, Almac’s API business has continued to grow at a double digit pace, +15% last year, and forecasted to be +17% in 2013.
Christopher L. Burcham, Ph.D., Daniel J. Jarmer, Ph.D.
The demands for increasing control of drug substance physical properties
in the pharmaceutical industry have evolved considerably in the past
decade. Regulatory agencies must be assured that a continuous supply of
drug substance can be delivered to the patient, and that the drug substance
attributes (e.g., physical properties, chemical purity) used in clinical trials is
equivalent to the attributes in the commercial dosage form. Increasing cost
pressure, decreasing development time, and increasing speed to the market
are driving larger companies to leverage CMOs to achieve delivery timelines
for clinical supplies.
Scott A. May, Ph.D., Martin D. Johnson, Ph.D.
20th century English journalist Malcolm Muggeridge once said, “All new news
is old news happening to new people.” This quote seems oddly appropriate
when considering the recent interest in continuous processing within
the pharmaceutical industry. Continuous processing technologies have
revolutionized the auto, food, electronics and commodity chemical industries
just to name a few. Why then has the pharmaceutical industry resisted
continuous processing in favor of traditional batch infrastructure for so
many years?
Growth for us is about increasing capacity and capabilities. Having
capacity available is incredibly important to us at Xcelience. Capacity
is synonymous with speed. If we can’t fit a project in, that project’s
time to market could be delayed.
James R. Bruno
As we entered the 21st century, there was a host of new technologies on
the horizon that could significantly change the way we do things in the
pharmaceutical industry. The FDA clearly recognized the need to innovate.
This, however, could require that we do things differently. The FDA agreed
and wanted to ensure they were not in the way of innovation, which could
significantly improve the overall economics of delivering new medicines
to the general population. At the 2010 AAPS Annual Meeting, Christine
Moore, Deputy Director for Science and Policy for CDER Office of New
Drug Assessment, commented that the Agency saw definite economic and
quality advantages to continuous manufacturing and that the science exists
[1]. Furthermore she said that there are “no regulatory hurdles” for industry
to implement continuous practices.