Sulaf Assi, Ph.D., David Osselton, Bethany Wallis
Novel psychoactive substances have been increasing over the last
decade with more than 450 derivatives available on the market. The
issue with novel psychoactive substances is much more complicated
than their effects/side effects. Hence, these substances often contain
mixtures of pharmacologically active/inactive impurities which
interfere with their effects.
Crystal Booth, MM
Understanding container closure integrity systems, reviewing past
observations, and following the regulations and guidance documents
are excellent ways to establish a compliant container closure integrity
assay. This article describes recent changes to the United States
Pharmacopeia (USP) <1207>, guidance documents, regulatory
observations, common container closure methods, and provides
recommendations on developing and validating a compliant container
closure integrity test.
Hilary A. Chan, Lynn Johnson
Regulatory expectations for microbial control in non-sterile manufacturing
remain largely undefined, which is in contrast to well-defined
expectations that exist for sterile manufacturing. This deficit is particularly
evident for so-called “near-sterile” processes which demand
particularly low levels of bioburden, effectively blurring the line between
sterile and non-sterile processes. This article aims to affirm the
importance of clearly outlining the strategy, rationale, requirements
and measures of contamination control programs for these complex
near-sterile systems, highlighting continuous improvement using a
lifecycle management approach.
Dr. Danny K. Chou, PharmD, PhD, Dr. Mitra Mosharraf, PharmD, PhD, Dr. Rajiv Nayar, PhD, Dr. Michael F. Drenski, PhD
Therapeutic proteins are challenging to develop and manufacture because their marginal stability makes them prone to denaturation and aggregation during purification, storage, distribution, and administration.
Emil W. Ciurczak, Ph.D.
It wasn’t all that long ago that Raman spectroscopy was an expensive,
lab-based research tool. It was largely used for structural information
and identification of materials in mixtures. One problem had been the
LASERs used, mostly in the visible wavelength range, caused a lot of
fluorescence interference with the “pure” Raman signal. In fact, my first
introduction, in the early 1970’s, was less than impressive. One of the
professors at Rutgers (Newark) was working with highly constrained
inorganic compounds. When the full energy of the LASER struck the
sample the resulting explosion even powdered the cuvette.
Michael G. Clark, PhD
In an increasingly competitive landscape for the launch of new
biopharmaceutical products, there are significant efforts within the
industry to reduce the time-to-market, in an attempt to secure market
share and maximize the duration of market exclusivity. In addition, the
FDA has introduced the breakthrough therapy designation to expedite
program timelines for treatments that target serious diseases. Since
the first breakthrough therapy approval in 2012, an additional 144
programs have received this designation through the end of the 2016
fiscal year.1
The increased emphasis on shortened program timelines
can result in Chemistry, Manufacturing and Controls (CMC) activities
moving to the critical path for enabling product launch. Among
the key CMC activities that could be rate-limiting is manufacturing
process characterization. This article reviews strategies to increase the
rate and quality of process characterization, with an emphasis on the
manufacturing of antibodies and related protein therapeutics.
A. Kielt, I. Nir, J. Seely, G. Inman
UV Spectrophotometry has traditionally been a simpler and less
time and labor consuming method for analyzing dissolution testing
samples. However, as soon as a product contained more than one
active pharmaceutical ingredient (API), analysis with UV was no longer
considered an option. This is because both species often absorb over
the same spectral region, causing deviations from Beer-Lambert Law.
This linear relation between absorbance and the absorbing species is
the basis for calculating concentration values based on the measured
absorbance at a specific wavelength. In these cases, separation
techniques such as HPLC become the de facto analysis methods.
Shaukat Ali, Technical Service Manager,
BASF: Drug delivery has been a hot topic for
many years and continues to face many challenges.
These challenges have become more
pronounced because of the increased number
of poorly soluble new chemical entities
(NCEs), and the industry’s ability to develop
appropriate technologies to enhance their
bioavailability. The impact of this bioavailability
challenge has been the launch of fewer
marketed drugs. The other challenges stem
from effective “controlled” delivery of highly
soluble drugs over an extended period of
time to avoid dose dumping and/or any side
effects. Moving forward, addressing the issues
related to effective delivery of poorly
soluble drugs and highly soluble drugs will
continue to be a focus in the industry.
What should U.S. based pharmaceutical companies
consider when seeking to commercialize their
combination products in Europe?
It should be understood that the term “combination product” can
be subject to misinterpretations in Europe. Unlike in the U.S., where
the FDA clearly defines what a combination product is in 21 CFR
3.2(e), Europe has no such clear definition. The term is applied when
referring to products having both a device and a drug element. In
Europe, such combinations are regulated as either a medical device
or a medicinal product, with the regulatory route being determined
by the principle mode of action of the product.
Doug Rea
Viral clearance studies are a necessary
component of any regulatory submission
for clinical trials or commercial product
approval for all biopharmaceutical products.
These studies are performed to evaluate
the capability of the purification process
to remove or inactivate viruses that could
potentially contaminate the starting material.
They are complex studies that require
substantial financial and personnel resources,
as well as specialized scientific expertise
to perform. As such, viral clearance studies
are often performed at a qualified contract
testing laboratory rather than in-house. When
multiple parties are involved in this process,
clear communication and a comprehensive
understanding of the approach and timeline
is critical.
Mo Jiang, Richard D. Braatz
Continuous manufacturing has received increased attention as a way to
increase product quality and reduce costs and risk. This article provides
an introduction to continuous manufacturing, the selection of control
strategies for each critical quality attribute, and the effective use of
modular plant-wide simulation. The main concepts are illustrated for a
small-molecule pharmaceutical pilot plant and a bench-scale biologic
drug manufacturing platform, each with total manufacturing times
less than 50 hours. Additional challenges associated with biologic
drugs are discussed. Aided with in-line process analytical technology,
plant-wide automated control was designed and implemented to
satisfy specifications on the critical quality attributes.
Johannes Kiefer, Ph.D.
Raman spectroscopy is a very versatile analytical tool that finds
numerous applications in the pharmaceutical industry, for example,
in the structural analysis of pharmaceuticals or as a means of process
analytical technology. Besides the signal-to-background level, the
spectral resolution is a key parameter determining the quality of a
Raman spectrum. The spectral resolution is commonly referred to as
the smallest difference in wavelength ?? that can be distinguished
at a given wavelength ?. In other words, if there are two signal peaks
close to each other in a spectrum, the spectral resolution determines
whether they can be identified as individual spectral features or
appear as a single band.
The controversy pertaining to low recovery of
purified endotoxin (CSE) and natural endotoxin
(NOE) now dominate BET discussions. Does this
recovery problem impact the work in your setting,
and have you lost confidence in an LAL reagent
being able to detect endotoxin in a pharmaceutical
contamination event?
Ulrich Reichert, PhD
The International Conference on Harmonization
(ICH) finalized the ICH Q3D Guideline
for Elemental Impurities1
in December
2014. Regulators are now implementing the
requirements worldwide. The U.S. Federal
Drug Administration2
and the European
Medicines Agency3
both adopted a start
date of June 2016 for new drug products
and December 2017 for authorized drug
products. Health Canada has announced
that applications submitted after December
31, 2016 must include a risk assessment for
elemental impurities. Japanese regulators
will begin implementing the guideline for
new drug products in April 2017.
Fernando J. Muzzio, Ph.D., Savitha Panikar
Pharmaceutical tablets are the most widely used dosage forms of
oral drug delivery,1
accounting for nearly 80% of all dosage forms
administered.2
Ideally, a “good” tablet should have good physical and
chemical stability, high purity, an acceptable dissolution profile and
good manufacturability. There are known knowledge gaps in the
current tablet manufacturing processes, particularly regarding the
relationship between material properties of ingredients, processing
conditions, and resulting product attributes. A better understanding
of tablet microstructure is essential in bridging this gap to enable
the design of tablets with ideal properties for every formulation.
Understanding the microstructure of a tablet requires knowing the
spatial distribution of the different ingredients and void space, which
is usually referred to as “chemical imaging”.
Robert Sedlock
Compression tooling and tablet press manufacturers
are faced with ongoing challenges
in the tablet manufacturing environments.
Providing support in all aspects of the tablet
compression process should be expected from
your tooling and tablet press partner. These
services should include: press operator training,
maintenance/calibration services, quick delivery
of replacement parts, tooling, tablet design and
powder formulation support
Catherine Casey, MSc, Karl Rogler, Xhorxhi Gjoka, René Gantier, PhD, Engin Ayturk, PhD
Continuous bioprocessing initiatives have accelerated in recent years.
The transition from batch to continuous bioprocessing offers numerous
advantages, including process time savings and lower capital costs
due to smaller equipment, tanks, and tubing sizes.
Rodolfo J. Romañach, Kim H. Esbensen
This feature presents a brief of the principles of the Theory of Sampling
(TOS) and these help to develop more effective spectroscopic
calibration models.1
TOS shows that sampling is both a science and a
practice building on a set of principles developed over the last 60 years,
starting in the mining industry but since then accepted in many other
process industries, indeed broadly within science, technology and
industry.2
As such TOS is also an asset for spectroscopic measurements
and in Process Analytical Technology (PAT).3
Many opportunities
exist for improving Quality Control by including these principles in
pharmaceutical manufacturing.4
There is now a concerted effort for
widespread application of the TOS and the 8th World Congress on
Sampling and Blending is being organized for this purpose.
Ratul Saha, PhD, Jeffrey Horsch, Paula Peacos, Sandra L. Lyons
In the pharmaceutical industry, the generation and collection of data
is key to ensuring product quality and patient safety. As such, the
integrity of this data is paramount. “Data integrity”, for the purposes
of this discussion, is defined as the degree of accuracy, completeness
and consistency of generated and collected data.
The highest level
of integrity must be maintained in all aspects of data generation,
compilation and storage. Some of the most egregious data integrity
issues encountered concern the intentional falsification of data.
However, data integrity may be adversely impacted by unintentional
actions as well.
Kanyaphat Bunchongprasert, Pulkit Khatri, Jun Shao
Macromolecule drugs such as protein drugs have become a very
important part of clinical treatments. There have been several hundred
macromolecule drugs approved for clinical use. But mainly due to their
low permeability through various absorption membranes, almost all of
the macromolecule drugs are administered by injections with very few
exceptions.
Thermo Fisher being a leader in the industry offers cell
culture media, feed supplements, process development support
for cell culture process. Proven HyPerforma Single Use Bioreactors,
Mixers, Storage and Transport solutions across upstream and
downstream processes are core technologies offered by Thermo
Fisher. Chromatography Capture Select resins for capturing, Poros
resin platform for ion exchange and polishing steps and PCR/qPCR
based analytical technologies from Thermo Fisher are integral part
of most of the current molecules under development.
This application note reports the development of two rapidly reacting
fluorescent dyes (Teal™ and Turquoise™ dyes) for N-glycan analysis. The
dyes also eliminate the use of toxic sodium cyanoborohydride from the
labeling chemistry.
Friedrich von Wintzingerode
Since first reported by Chen and Vinther in 2013 (Chen and Vinther,
2013), the phenomenon known as low endotoxin recovery (LER)
has been broadly observed in certain matrices commonly used for
biologic formulations and certain therapeutic proteins. LER is defined
as loss of detectable endotoxin activity over time using compendial
LAL assays (Bacterial Endotoxin Test = BET per USP <85>/EP 2.6.14./
JP 4.01) when undiluted products are spiked with known amount of
endotoxin standards.
Tony Wang, Vicky Wang, Gregg Schorner, Myra Coufal
Raw material variability can impact lifecycle of a biopharmaceutical
manufacturing process as it could dictate operational and business
strategy chosen to mitigate raw material associated risks. Differences
from lot-to-lot could affect growth and productivity, create purification
problems that could lead to operation issues and even delay or prevent
product release. Understanding the source and degree of impact of
raw material variability prior to use in the manufacturing process could
prevent deleterious events from unfolding. It is possible to monitor lot-
to-lot variability of incoming materials by creating multivariate models
using Raman spectra.