Elemental Impurities
Transcript of Elemental Impurities
Advancing Development & Manufacturing
MARCH 2015 VOLUME 27 NUMBER 3
LYOPHILIZATION
Cycle Optimization for BiologicsPEER-REVIEWED
Real-Time Imaging for Particle Characterization
FORMULATION
Semi-Solid Dosage Forms
ElementalImpuritiesA closer look at the new ICH Q3D guidelines
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Cover: Rafe Swan/Getty ImagesArt direction: Dan Ward
March 2015
Features
COVER STORY
12 Implementation of ICH Q3D Elemental Impurities
Guideline: Challenges and Opportunities
Assessing risk factors is key to
implementing the new ICH Q3D guidelines.
LYOPHILIZATION
24 Lyophilization Cycle Optimization
of Cell-Derived Products
Viscosity and aggregation after product
reconstitution must be carefully managed.
FORMULATION
38 Semi-Solid Dosage Forms
While the skin offers an alternative route of
administration for local and systemic drug delivery,
developing semi-solid dosage forms can be a challenge.
PharmTech.com
Column and Regulars
6 Editor’s Comment
Lifting the Veil on Drug Pricing
8 European Regulatory Watch
Europe Strives for a More Efficient
Generic-Drug Approval Framework
29 API Synthesis & Manufacturing
Minimizing Risk during HPAPI Manufacture
41 Troubleshooting
Removing Aggregates in Monoclonal Antibody Purification
44 Product/Service Profiles
50 Ask the Expert
Managing Supplier Data Collection
50 Ad Index
Peer-Reviewed32 Monitoring Fluid-Bed Granulation and
Milling Processes In-Line with Real-Time Imaging
This study examines the efficacy of a particle
characterizing technology to capture particle images
under dynamic conditions and to calculate particle
size distribution data both in-line and at-line during
fluid-bed granulation and milling.
32 3824 12
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EDITOR’S COMMENT
Lifting the Veil on Drug Pricing
Every now and then,
you will hear about
the rising costs of R&D,
which in turn, translate
into high prices for
new drugs entering the
market. Of course, with
the blockbuster model
becoming obsolete and
the pharmaceutical industry shifting focus
to personalized medicines, one can only
expect drug prices to hit the roof.
Cost is always a controversial matter that
sparks questions regarding affordability and
sustainability. Now if you’ve ever wondered
how drugmakers come up with a price
tag for their product, there is a possibility
that the veil may be lifted. The United
States could be leading the way in a push
for greater transparency in drug pricing
as assembly member and San Francisco
democrat David Chiu introduced a new
bill (AB 463) requiring pharmaceutical
companies to disclose information on how
they set the price tags for new drugs (1). If
this law is passed, the manufacturer of any
course of treatment costing $10,000 or more
per year must report the production costs
for the drug, which include R&D costs paid
by the manufacturer or by grants; clinical
trial and other regulatory costs; financial
assistance offered to patients through
various programmes; manufacturing costs;
acquisitions costs such as licensing fees
or the purchase of patents; total spend
on marketing and advertising; and profits
attributed to the drug.
A recent report by the Tufts Centre for
the Study of Drug Development estimates
that, on average, it costs $2.6 billion to
bring a drug to market (2). Whether or not
it is a myth or fact, this figure has caused
disputes with critics accusing the industry
of using R&D cost as an excuse to mark up
drug prices. Perhaps the new transparency
act on drug pricing will clear up some of the
confusion and serve as an eye opener as
to why our medicines cost so much. And
it would be interesting to see if Europe will
follow suit.
References1. AB 463 Pharmaceutical Cost Transparency
Act of 2015, http://leginfo.legislature.ca.gov/faces/billNavClient.xhtml?bill_id=201520160AB463, accessed 2 Mar. 2015.
2. Tufts CSDD, Cost to Develop and Win Marketing Approval for a New Drug is $2.6 Billion, Press Release, 18 Nov. 2015.
Adeline Siew, PhD
Editor of Pharmaceutical Technology Europe
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8 Pharmaceutical Technology Europe MARCH 2015 PharmTech.com
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The European Union’s decentralized procedure (DCP) for drug
approval is regarded outside Europe as an effective system
for cross-border collaboration in the authorization of medicines,
such that it is being used as a model for a number of new global
initiatives in the harmonization of pharmaceutical regulatory
standards. Yet within the EU, both industry and regulators now
acknowledge that deficiencies with the procedure need to be
tackled before they start to undermine its benefits.
“The DCP has been a very successful procedure,” Stella
Koukaki, managing partner and scientific affairs director at
PharOS Ltd., a Greek-based developer of generic medicines,
told the annual regulatory and scientific affairs conference of
the European Generic Medicines Association (EGA) in London
in January 2015 (1). “But it is time to take the DCP to the next
stage [of its evolution] so that it is able to face a very
challenging environment,” she added.
Room for improvement
The EGA used the meeting as a platform to reveal publicly, for
the first time, a series of its own proposals for making the
procedure more efficient. Generic and hybrid medicines now
account for more than 90% of the activities of the DCP, which
is currently used by the 28 member states of the EU and three
non-EU European countries—Norway, Iceland, and
Liechtenstein. A key objective of the EGA is to make the
handling of information on the manufacturing processes for
generic drugs quicker and less cumbersome. Some of the
regulators from the 60 national and regional medicines
authorities from 27 countries attending the conference also
outlined their suggestions for improving the DCP, although
their ideas were not so radical as the EGA’s.
“It’s time to ask ourselves whether we are efficient enough,”
said Xavier De Cuyper, chief executive of the Belgian Federal
Agency for Medicines and Health Products (FAMHP), speaking
on behalf of the management board of the Heads of Medicines
Agencies (HMA) in Europe. “We can do better, especially in the
way we interact with other medicines agencies both inside
and outside Europe,” he said.
De Cuyper was referring in particular to the operations of
the European Medicines Regulatory Network (EMRN), which
includes 44 national competent authorities in medicines
control in the 31 countries involved in the DCP. It also
embraces the EU’s centralized procedure (CP) for
pharmaceuticals approval run by the European Medicines
Agency (EMA). “I am convinced that if we continually set higher
standards, we can improve how our network currently
operates,” De Cuyper continued.
The DCP was introduced 10 years ago to streamline a
system of multistate mutual recognition under which an
authorization of a medicine in one state could be automatically
accepted by other EU states. It was drawn up to help
companies wanting to market the same drug in only a limited
number of states rather than in all EU countries for which the
centralized procedure had been devised.
Under the decentralized procedure, a marketing application
for an individual medicine is assessed by a reference member
state (RMS). This evaluation is submitted to the other countries,
called concerned member states (CMSs), where the applicant
wants to market its drug. Disagreements about the RMS
evaluation among CMSs are normally resolved by the
Co-ordination Group for Mutual Recognition and Decentralized
Procedures—human (CMDh) that is responsible for the smooth
running of the DCP.
Speeding up generic-drug approvals
The DCP is seen to have been operating so well that it is
influencing the ways new international initiatives, such as the
International Coalition of Medicines Regulatory Authorities
(ICMRA) and the International Generic Drug Regulators Pilot
(IGDRP), are being organized. With the IGDRP, which aims to
provide a foundation for faster authorization across the world
on safe, effective, and high-quality generic-drug products, a
pilot information sharing system is based on that used in the
DCP. As part of the pilot, details of assessments of products
carried out by RMS countries are, with the agreement of the
companies applying for authorization, being sent to the states
participating in the IGDRP.
The pilot, which was due to be completed in 2014, is likely to
be extended for another two years to 2016 with the assessment
A key objective of the EGA is to make the handling of information on the
manufacturing processes for generic drugs quicker and less cumbersome.
Europe Strives for a More Efficient
Generic-Drug Approval FrameworkProposals to make the decentralized procedure more efficient were discussed at the January 2015 EGA conference.
Sean Milmo
is a freelance writer based in Essex,
UK, [email protected].
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10 Pharmaceutical Technology Europe MARCH 2015 PharmTech.com
of generic medicines under the EU’s centralized procedure also
being included in the information sharing component of the
project. EMA agreed in January 2015 to share its CP
assessments in real time with regulatory agencies in the IGDRP.
“We should be proud of what we are doing in Europe in the
regulation of medicines,” commented Peter Bachmann, CMDh
chair and head of the European and international affairs
co-ordination group of the German Federal Institute for Drugs
and Medical Devices (BfArM) at the EGA conference (2). “One of
Europe’s strengths is the existence of a (cross-border) legal
framework. Also, after years of experience, we trust each other.”
“People inside Europe are thinking the CP and DCP are still
not working as well as they should be,” Bachmann added.
“It is always more difficult [to appreciate how well they are
working] when you are inside the box.”
In the eyes of the EGA, the shortcomings of the DCP now
need urgent attention to ensure that it operates efficiently and
reliably for generic-medicine producers. From the industry’s
viewpoint, there were two important prerequisites for a
successful authorization procedure.
“One absolute need is flexibility and we need a lot of it,”
said Caroline Kleinjan, chair of the EGA’s regulatory and
scientific committee and head of the European regulatory
competence centre of Sandoz, part of Novartis (3). “Our
association has many different types of companies with
difference needs—small and big ones and companies
developing medicines for licensing.”
“Another big need is speed,” Kleinjan continued. “Timelines
need to be as short as possible and as transparent and
predictable as possible.” Among the flaws pinpointed by the
EGA in the current DCP are delays in the granting of marketing
authorizations (MA) and approvals of process and other post-
authorization variations. Some applications for marketing
authorizations can take more than three years to be accepted
so that the MA is often too late to be used, according to the
association. These lengthy hold-ups are frequently caused by
duplication of examinations of dossiers and CMS
prevarications when evaluating RMS assessments.
Four types of DCP
The EGA has suggested the creation of four DCP types that will
help to deal with the present needs of generic medicine
producers. They would assist companies wanting to take quick
advantages of new manufacturing processes and to respond
rapidly to changes in market conditions within groups of
countries, according to Kleinjan.
A major change should be the introduction of what the EGA
called a “backbone” decentralized procedure, with similar
characteristics to the CP, with one application undergoing a
core assessment and approval by a rapporteur and
co-rapporteur, with the approval being confirmed by the
CMDh. The holder of this marketing authorization would be
able to choose in which state it wanted further approvals “in
any number and at any point of time within five years,”
Kleinjan told the meeting.
A “basket” DCP, another EGA proposal, would also comprise
one application containing all potential strengths, supply
arrangements, and pack sizes. “The MAH would be able
to choose the desired elements in each of the involved
member states,” Kleinjan said.
Another suggested change would be the introduction of a
“mini” DCP that would be applied to a minority of states when
the majority of countries have approved a product. It would
provide “almost immediate access” to these other states.
Finally, the EGA has put forward the idea of a DCP under
which several applications for a medicine could be assessed
under a work-sharing arrangement by different RMSs to make
better use of assessment resources in agencies.
“What we want to do with these proposals is start a dialogue
with regulators,” Kleinjan told Pharmaceutical Technology
Europe. “The response at the meeting from regulators was
very promising—much more so than we expected. One
national agency has said it will hold a special meeting to
discuss them while another has already come up with its own
alternative proposals.”
In addition, the association is pressing for a simplification of
data requirements in application dossiers, such as, for
example, details of GMP certification being dealt with
separately. The mandatory inclusion of some GMP information
in dossiers is seen as being a barrier to the fast approval of
post-authorization variations.
Reorganization of the DCP, however, will not be easy. Even if
eventually the regulators and industry reach agreement on a
modified, more efficiency procedure, it is likely to require
amendments to existing EU legislation that will have to be
approved by the European Parliament and EU governments. It
could, therefore, be a lengthy process.
References
1. S. Koukaki, “10 years’ Experience with the DCP—Does
DCP Need Refreshing,” presentation at the 14th EGA
Regulatory and Scientific Affairs Conference (London, 2015).
2. P. Bachmann, “Opportunities and Challenges of
Globalization,”presentation at the 14th EGA Regulatory and
Scientific Affairs Conference (London, 2015).
3. C.Kleinjan, “’Dream DCP’—The EGA’s Proposal for Improve-
ments,” presentation at the 14th EGA Regulatory and Scientific
Affairs Conference (London, 2015). PTE
The EGA has suggested the creation of four DCP
types that will help to deal with the present needs
of generic medicine producers.
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*Andrew Teasdale is a principal scientist at AstraZeneca, [email protected]; Cyrille
C. Chéry is a senior scientist, analytical sciences for biologicals, UCB Pharma SA; Graham Cook, PhD,
is a senior director, Pfizer Global Quality Intelligence and Compendial Affairs; John Glennon is a stability
laboratory team leader, GlaxoSmithKline; Laurence Harris and Carlos W. Lee are both associate
research fellows, analytical research and development, pharmatherapeutics pharmaceutical sciences, Pfizer,
Inc.; Nancy Lewen is a senior principal scientist, Bristol-Myers Squibb; Phil Nethercote is analytical
director, product quality, global functions at GlaxoSmithKline; Samuel Powell is a scientist, analytical
research and development, pharmatherapeutics pharmaceutical sciences, Pfizer, Inc.; Helmut Rockstroh
is head, pharmacopoeial affairs office, F. Hoffmann-La Roche Ltd.; Laura Rutter is SM manager, analytical
services at GlaxoSmithKline; Lance Smallshaw is worldwide analytical expert for biologics and strategies,
corporate analytical sciences, UCB; Sarah Thompson is an associate principal scientist and Vicki
Woodward is a technical services manager, both at AstraZeneca; Katherine Ulman is vice chair of
science and regulatory policy for IPEC-Americas and a global regulatory compliance manager at Dow Corning.
*To whom all correspondence should be addressed.
Implementation ofICH Q3D ElementalImpurities Guideline: Challenges and OpportunitiesAssessing risk factors is key to
implementing the new ICH Q3D guidelines.
New guidelines relating to
elemental impurities from
the International Conference on
Harmonization (ICH), Q3D Guideline
for Elemental Impurities (1) have
presented the pharmaceutical
industry with new challenges.
These challenges include the
complexity of introducing new
analytical technology—specifically
inductively coupled plasma (ICP)-
based techniques replacing the
wet chemical ‘heavy metals’ limit
test—along with new and specific
limits for individual elements.
Perhaps the most significant
challenges, however, are related
to the practical implementation of
the guideline.
ICH Q3D advocates the use
of a risk-based approach to
assessing the potential presence
of elemental impurities in drug
products. While such assessments
are common within other aspects
of pharmaceutical development,
application to elemental impurity
assessment presents new
challenges. Specific challenges
include determining how to
assess or quantify the risks
associated with factors such as
water, container-closure systems,
and excipients. Defining where
in the assessment process data
may be required and identifying
where risks can be determined
to be negligible through a
thorough scientific theoretical
risk assessment also present
significant questions. This article
seeks to review these questions by
looking at the various risk factors
and, where possible, weighting the
risk factors based on appropriate
and relevant considerations to
establish an effective framework
for the systematic assessment of
risk and final control strategy.
Introduction of ICH Q3DThe introduction of ICH Q3D
(1) is one of the most complex
changes in regulations pertaining
to impurities seen by the
pharmaceutical industry. While the
guideline is ultimately intended to
focus on final drug product quality,
the actual risk assessment will
touch all facets of the manufacture
of a drug product. The guideline
12 Pharmaceutical Technology Europe March 2015 PharmTech.com
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Elemental Impurities
introduces toxicologically relevant
permitted daily exposure (PDE) limits
to individual elements replacing non-
specific 19th century wet chemical
‘heavy metal’ limit tests. ICH Q3D
advocates the use of a risk-based
approach to assessing the potential
for presence of elemental impurities
in drug products. The process of
executing and documenting the risk
assessment is a major challenge,
primarily as a result of a limited global
understanding about how to assess
or quantify the risk associated with
factors such as water, container-
closure systems, and excipients.
Defining where in the assessment
process data may be required and
identifying where risks can be
determined to be negligible through
a thorough scientific theoretical risk
assessment also present a significant
challenge. Where the risk assessment
identifies the need for testing, the
level of the PDEs for the element(s) of
concern may also require the broader
introduction of new, more sensitive,
and specific analytical technology,
adding further to the complexity.
This article specifically seeks to
examine relevant risk factors and,
where possible, the weighting of
these risks based on appropriate
and relevant considerations. It also
seeks to specifically define where in
the assessment process data may be
required as well as seeking to identify
where risks can be determined to be
negligible simply through a thorough
scientific theoretical risk assessment.
The general principles outlined in
this article are believed to address
most scenarios or product types;
however, ultimately any drug-product
manufacturer needs to consider
potential sources of elemental
impurities appropriate for their
specific product.
Risk assessmentThe evaluation of the potential risk
posed by elemental impurities within
a formulated drug product requires a
holistic approach taking into account
all potential sources of elemental
impurities. Figure 1 illustrates
potential sources that should be
considered in such an evaluation.
Drug substance As presented in Figure 1, the drug
substance is a key component that
can contribute elemental impurities to
the finished drug product. The risk of
inclusion of elemental impurities from
a drug substance, therefore, needs
to be considered when conducting a
drug product risk assessment. Control
of the elemental impurity content
of a drug substance can be assured
through a thorough understanding
of the manufacturing process
including equipment selection,
equipment qualification, GMP
processes, packaging components,
and the selection and application of
appropriate control strategies.
A principal responsibility for any
drug-substance manufacturer is
to develop a strategy to ensure
effective control of the levels of
elemental impurities in the finished
drug substance. An approach
based on assessing and controlling
potential sources of elemental
impurities, coupled with focused,
limited testing, is preferable to
exhaustive testing on the finished
drug substance. A scientific, risk-
based approach combined with
knowledge and control of the key
sources of elemental impurities in
the drug-substance manufacturing
process such as catalysts, provides
an efficient and comprehensive
elemental impurity control strategy
for finished drug substances.
Figure 2 shows potential sources
of elemental impurities in the drug
substance manufacturing process.
Of the sources highlighted, the
Figure 1: Sources of elemental impurities in finished drug products.
Figure 2: Primary sources of elemental impurities in drug substances (DS).
Drugsubstance
Manufacturingequipment
Utilities(e.g., water)
Containerclosure system
Elementalimpurities indrug product
Excipients
Elementalimpurities
in DS
Primarycontainer
closure
Metalcatalysts
Manufacturingequipment
Processingaids
Inorganicreagents
Organicmaterials
Water
Solvents
All
figu
res
are
co
urt
esy
of
the a
uth
ors
.
14 Pharmaceutical Technology Europe March 2015 PharmTech.com
ES582502_PTE0315_014.pgs 03.10.2015 22:55 ADV blackyellowmagentacyan
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Elemental Impurities
greatest risk comes from intentionally
added metals (e.g., metal catalysts
used in the process). Manufacturing
equipment, processing aids, inorganic
reagents, water, solvents, and other
organic materials are less likely
to serve as major contributors of
elemental impurities in the finished
drug substance, but do require
consideration.
Metal catalysts. Metal catalysts,
such as palladium and platinum, are
often used in the drug-substance
manufacturing process and can
therefore be present at low levels
in the finished drug substance. The
synthetic route should be reviewed
for intentionally added metals, and
data from purging studies, including
any supportive testing of appropriate
isolated intermediates, should be
used in the design of an appropriate
control strategy.
The ability to remove the catalyst
(purge capacity) will be influenced
by catalyst loading and the nature of
the catalyst used in the process (i.e.,
homogeneous vs. heterogeneous
catalysts). Heterogeneous catalysts,
such as palladium on carbon, are often
easily removed from reaction mixtures
by filtration, and therefore, the risk of
carryover of elemental impurities into
the drug substance is typically low.
Even in cases where metal catalysts
are used in the final stages of the
process, good historical data and/
or understanding of carry-over may
permit reduced testing schemes.
Biotech products do not normally
rely on the use of catalysts. As ICH
Q3D points out, typical purification
schemes in biotech drug substance
manufacturing are well capable of
clearing any elements introduced
either intentionally or inadvertently
“to negligible levels.” The principles
outlined previously may nonetheless
be relevant in some specific cases
(e.g., chemically modified biotech
drug substances).
When considering the other
potential sources highlighted in
Figure 2, it is recommended to
focus primarily on the manufacturing
steps that occur after the formation
of the final intermediate. Washes,
crystallizations, phase separations,
chromatography, distillations, and
processing aids/scavengers aid in
purging of elemental impurities and,
therefore, reduce the risk of carryover
into the finished drug substance from
stages earlier in the upstream process.
Areas for further consideration include
manufacturing equipment, processing
aids/inorganic reagents, solvents,
water, and packaging.
Manufacturing equipment. In
general, GMPs, including equipment
compatibility assessment and
qualification, are sufficient to ensure
that significant levels of elemental
impurities are not leached from
manufacturing equipment into
the drug substance. Hastelloy,
stainless steel, and glass are the
most commonly used materials of
construction for drug substance
manufacturing equipment, due to their
superior chemical resistance. Nickel,
cobalt, vanadium, molybdenum,
chromium, and copper are key
elements in some Hastelloy and
stainless-steel alloys. Under extreme/
corrosive reaction conditions, such
as high temperature and low/high
pH, these elements could have the
potential to leach from manufacturing
equipment. In such cases, it may be
necessary to supplement standard
GMP equipment compatibility
assessments with specific
studies to assess the elemental
impurity-leaching propensity from
manufacturing equipment due to
corrosive reaction conditions.
Other potential sources include
high-energy processes such as
milling/micronization equipment.
These are also generally considered
to be low risk, but should be
addressed via appropriate GMP
including cleaning records and visual
inspection. Particle size reduction
is discussed in the Drug Product
Manufacture section.
Processing aids/inorganic
reagents. Processing aids such as
charcoal, silica, celite, and darco, and
inorganic reagents such as sodium
chloride, magnesium sulfate, and
sodium sulfate, are often used in drug-
substance manufacturing processes
and may be used in significant
quantities. Depending on their specific
composition, inorganic reagents
should be considered within the risk
assessment, especially when ICH Q3D
elements are integral to the formula.
The levels used should also be
considered as some reagents may be
employed in higher relative amounts
(i.e., in stoichometric amounts). In
such instances not only the elements
(intentionally) present in the reagents,
but also reagent purity (or lack thereof)
need to be taken into account.
In general, the use of such reagents
presents a low risk. In studies
conducted within the organizations
associated with this article, there
is little evidence to support such
materials being a significant risk.
Therefore, the risk assessment should
primarily focus on processing aids
and inorganic reagents used late in
the drug substance manufacturing
process, and/or where aggressive
reaction conditions exist (e.g.,
extreme pH/high temperatures for
prolonged times).
Solvents. Most solvents used in
the manufacture of drug substances,
particularly those listed in ICH Q3C,
Impurities: Guideline for residual
Solvents (2) Class 3, are unlikely to
contribute elemental impurities to the
finished drug substance. The majority
of solvents are purified by distillation
and few involve the direct use of
metal catalysts in their manufacture;
hence, they are considered a low risk
source of elemental impurities. In the
event that solvents have not been
purified by distillation, especially if a
catalyst in used in their manufacture,
further evaluation in the risk
assessment should be considered.
Water. Refer to the environmental
factors discussion is the Drug Product
Manufacture section.
Packaging. Packaging is discussed
in the section Container-Closure
Systems (CSS) as a Potential Source
of Elemental Impurities in Finished
Drug Product.
Evaluation option limits. It
must be recognized that, from a
compliance perspective, the limits
for elemental impurities in ICH Q3D
One of the greatest challenges to performing an elemental impurity risk assessment for a drug product is to understand the potential contribution of elemental impurities from excipients.
16 Pharmaceutical Technology Europe March 2015 PharmTech.com
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Elemental Impurities
apply only to the drug product. To
ensure effective control of the level
of elemental impurities in the drug
substance a number of options are
available:
• The ICH Q3D option 1 concentration
limits assume a maximum daily
drug product intake of 10 g/day.
Drug substances that meet option
1 concentration limits can be used
at any dose in the drug product.
• ICH Q3D option 2 concentration
limits are calculated specifically
based on the actual daily drug
product intake (and composition)
and may provide higher
concentration limits than option
1 (if the maximum daily intake of
drug product is < 10g).
The acceptable level of elemental
impurities in a drug substance may be
defined and agreed upon in a suitable
quality agreement between the drug
substance manufacturer and the drug
product manufacturer.
Conclusion for drug substancesWhile drug substance manufacturing
often involves a complex series of
processes, some simple scientific
principles can be applied to ensure
that elemental impurity levels in the
final drug substance are controlled
to appropriate levels. The application
of a risk-based control strategy,
involving an understanding of the
manufacturing process and key
sources of elemental impurities,
appropriate equipment selection/
qualification, adoption of suitable
GMP processes/procedures, and
the selection and application of
appropriate control options will
typically result in the manufacture
of drug substances with elemental
impurity levels well below ICH Q3D
option 1/option 2 concentration
limits. This overall low risk status
is supported by the emerging
dataset from ICP–optical emission
spectrometry (OES) and ICP–mass
spectrometry (MS) screening of a
wide range of drug substances plus
the significant body of historical
heavy-metals test data.
Excipients One of the greatest challenges to
performing an elemental impurity
risk assessment for a drug product
is to understand the potential
contribution of elemental impurities
from excipients. Elemental impurities
of concern for excipients would
typically be:
• Class 1 and Class 2a elements
potentially present at trace
levels in the excipient based on
environmental factors
• Intentionally added catalysts or
reagents for synthetic excipients
• Class 3 elements from excipients
that are targeted for a specific route
of administration (e.g., inhaled).
Unlike drug substances, there may
be less information available from
excipient vendors with respect to
the manufacturing equipment and
processes used (e.g., any high energy
steps, corrosive reagents, or added
catalysts), which may potentially
introduce elemental impurities.
While many vendors will supply, on
request, a compliance statement
with the European Medicines Agency
(EMA) metal catalyst guideline (3), the
elemental impurity testing reported
on the certificate of analysis is
typically based on a non-specific, wet
chemistry heavy-metals limit test
with the result reported as less than
the specification value in parts per
million. When considering the risk of
elemental impurities potentially being
introduced into the drug product via
excipients at levels greater than the
PDE, the following points should be
considered:
• Source of the excipient (mined,
plant, animal, synthetic, etc.)
• Excipient level in the formulation
(wt. %) (4)
• Drug-product daily dose.
Source of the excipient. The origin
of an excipient can have a significant
impact on the degree of risk
associated with elemental impurities.
Figure 3 provides a useful guide.
Mined excipients may exhibit a
natural variation depending on the
location of the mine and the natural
geology. The potential levels of
elemental impurities from mined
excipients may be more variable and
therefore pose a higher risk than
synthetic excipients manufactured
using metal reagents and/or catalyst
where the levels are less variable as a
result of well-defined manufacturing
processes and controls.
Excipients harvested from plants
also pose a potential risk as a result
of their uptake of metals from their
environment. Synthetic excipients
that are manufactured without
the use of metal catalysts and/or
reagents present the lowest risk of
introducing elemental impurities to
the drug product.
Proportion of formulation. An
essential consideration in determining
the risk contribution for elemental
impurities from an excipient is the
proportion of the excipient used in
the formulation. The risk contribution
from a mined excipient used as a filler
or diluent (typically >20 wt. % of the
blend), for example, will be greater
than the risk contribution of a mined
excipient used in a tablet film coat
(typically <5 wt. %).
Generally, low-weight percentage
components that are not mined
are regarded as low risk; however,
the daily product dosing and route
of administration also need to be
considered.
Dose/route of administration.
Dose and dosing regimens should
also be considered. A low, orally
administered, daily dose clearly
presents a lower risk than an inhaled
Figure 3: Potential sources of elemental impurities in excipients.
Elementalimpurities in
excipients
Mined(e.g., talc)
Synthesized with metal catalyst(e.g., mannitol)
Plant Origin(e.g., cellulose derivatives)
Animal origin(e.g., lactose & gelatin)
Synthesized without metal catalyst(e.g., colloidal SiO
2)
Increasing
potential risk of
contributing
elemental
impurities
18 Pharmaceutical Technology Europe March 2015 PharmTech.com
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Elemental Impurities
product as shown by the lower PDE
limits for inhalation vs. oral found in
Table A.2.1 of the ICH Q3D guideline (1).
Conclusion for excipientsThe above principles can be used as
part of an excipient risk assessment
and are a useful guide in the absence
of data. In addition, manufacturers
should consider the principles for
controlling elemental impurity
generation from manufacturing
equipment, as described in the
Manufacturing Equipment section for
drug substances.
With the pending removal of United
States Pharmacopeia (USP) <231>
from the United States Pharmacopeial
Convention, however, uncertainty
exists as to whether excipient
manufacturers and vendors will test
for elemental impurity concentrations
and, if so, for what elements, to what
levels, and using what procedures/
equipment.
It must be recognized that, from a
compliance perspective, the limits for
elemental impurities in ICH Q3D only
apply to the drug product. Excipient
manufacturers may, however, be
requested to assist in assuring
compliance through awareness of the
level of elemental impurities within
the excipient itself. In addition, the
same general principles of evaluation
options for drug substances
described previously apply to
excipients.
In some instances, it may be
appropriate to define and agree on
the acceptable level of elemental
impurities in an excipient through a
suitable quality agreement between
the excipient manufacturer and the
drug product manufacturer.
Ultimately, it is the responsibility
of pharmaceutical manufacturers to
demonstrate, via risk assessment
and/or data, that the drug product
is compliant with ICH Q3D. To this
end, the development of a common
database for excipient elemental
impurity profiles will be a useful
activity to support risk assessments.
The International Pharmaceutical
Excipients Council of the Americas
(IPEC-Americas) and FDA have
performed an exercise examining
elemental impurity levels from
multiple excipients, which is planned
for publication. This information
indicates that the vast majority of
excipients (analyzed by ICP–MS)
contain elemental impurities at levels
unlikely to cause concerns at typical
usage levels in oral solid dosage forms.
Drug product manufactureThe drug-product risk assessment
needs to consider the potential
elemental impurity contribution
from the drug product
manufacturing equipment/process.
Manufacturing for solid products
encompasses a large variety of
processes, such as solid mixing
(blending), granulation, tableting
(compression), coating, and
particle size reduction. For liquid
product manufacture, dissolution
or suspension of solid excipients
and drug substance is often carried
out in metallic equipment. In
contemporary cGMP facilities, the
likelihood of additional contribution
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Elemental Impurities
of elemental impurities is negligible.
However, there is a theoretical risk
associated with Class 2A metals such
as vanadium, nickel, etc., because
these elements are commonly
found in manufacturing equipment;
for example, 316L stainless steel
contains approximately 10% w/w
nickel. Therefore, understanding the
drug product equipment in terms
of materials of construction will be
a key factor in completing the risk
assessment. The risk assessment
should focus on any steps involving
high kinetic energy (solids) or
corrosive liquids that may facilitate
the transfer of elements from the
equipment into the product.
A consideration of typical drug
product manufacturing steps and
conditions is provided in Table I.
Manufacture of liquid dosage
forms. Processing a liquid product
containing a drug substance,
excipients, and solvent (typically
water-based buffer) in metallic
vessels can potentially facilitate the
transfer of elements into the liquid
drug product, particularly at high/low
pH. An assessment of material
compatibility should be completed,
taking into account factors such as
ionic content, pH, temperature,
hyrdophilicity/hydrophobicity,
terminal sterilization conditions, and
contact time. Testing should only be
required if this assessment identifies
a substantive risk.
Conclusion for drug product manufactureIn general, the risk for elemental
impurity contribution due to processing
of solid drug product components
in cGMP facilities is low, as stated
explicitly in ICH Q3D. Although much
equipment used to process drug
product is metallic (e.g., stainless steel
vessel), the majority of the processes
used in drug product manufacture
can be discounted as a source of risk.
Even areas highlighted as needing
consideration (Table I) are expected to
only result in controls outside routine
cGMP in extreme cases.
Environmental factors As part of the holistic risk assessment
of elemental impurities described in
ICH Q3D, there is a need to consider
the potential contribution resulting
from environmental factors such as
water and air.
Table I: cGMP controls for selected operating conditions in drug product manufacture.
Unit operationKinetic
energy
Aggressive
conditions
Recommended routine
cGMP controlsRemarks
Mixing/ granulation
Low Dry = no NAe.g., Low equipment rotation/translation
speed
High (Shear) Wet = yes
Periodic visual inspection of
the equipment for abrasion
and/or corrosion.
Although the likelihood of a potential
elemental impurity contribution is increased
when moving from low shear mixing to high
shear mixing, the overall risk of a significant
elemental impurity
contribution remains low.
Tableting High NAPeriodic visual inspection, as
above.
Normal wear on dyes/punches is unlikely to
release any appreciable amount of elemental
impurities into the product.
Encapsulation High NAPeriodic visual inspection as
above.–
(Liquid) filling, lyophilization
LowProduct
specific
For aggressive, e.g.,high pH
conditions, regular visual
inspection of the equipment
for corrosion.
Effect of actual corrosion, as with tablet punch
erosion, unlikely to result in
substantive release of elemental impurities at
levels of concern into the product.
Coating Low LowCovered by routine cGMPs,
e.g., for maintenance, cleaning.–
Particle size reduction
High Very high
Despite the high energy it is
not expected that the particle
size reduction process will lead
to the need for routine drug
product testing requirements
for elemental impurities
associated with the materials
of construction of the mill. In
the vast majority of cases,
routine cGMP will be sufficient.
Although the possibility of metal transfer
during this process is high due to abrasion,
the risk of levels approaching the limits defined
in ICH Q3D is extremely low. Such a risk may be
evaluated through a mathematical
assessment, evaluating the theoretical
maximum level of metal possibly transferred
during the process, comparing this to the
permitted limits. Practical evaluation through
comparison of the elemental impurity profile
of the ingoing material to that of the outgoing
material may also be performed. Such an
assessment may also take into consideration
historical knowledge of similar processes and
substances. Such approaches may be used to
determine if further controls other than cGMP
are required.
20 Pharmaceutical Technology Europe March 2015 PharmTech.com
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Elemental Impurities
Water. Water used in the manufacture of both drug
substances and formulated drug products is a potential
source of elemental impurities. The level of risk, however,
may be strongly related to the quality of water. This risk
was examined in detail in a USP stimuli article on water
for pharmaceutical use (5). The following position was
articulated:
• The source water used in drug product manufacturing
must meet the World Health Organization (WHO)
standard for drinking water. When this source water
is further purified in a contemporary plant to generate
purified water (PW) and/or water-for-injection (WFI), the
elemental impurity levels should be below acceptable
concentrations allowed for drug roducts using option 1
control strategy defined in ICH Q3D.
• As part of standard GMP, water quality should be routinely
monitored and the purification system and storage of the
water should not re-introduce elemental impurities.
Based on this position, the risk of elevated elemental
impurity levels within aqueous-based formulations—even
large-volume parenterals—is considered negligible. The
risk associated with the use of water in the manufacture
of the drug substance can also be effectively eliminated
through the appropriate use of WHO-standard potable
water combined with the use of USP purified water for
the final stage in the manufacture of the drug substance,
including its isolation.
Air. Air is not likely to present a substantive risk;
furthermore, air quality can also be managed through
proper GMPs via use of HEPA filtered air, etc. No specific
assessment is therefore generally required.
Container-closure systems as a potential source of elemental impurities in finished drug productOne of the potential sources of elemental impurities is
product packaging, often referred to as container-closure
system (CCS). In determining the risk posed by the CCS,
there are a number of factors that need to be taken into
consideration including:
• Nature of formulation—mechanism for contamination
• Level of metals present in the CCS
• Nature of risk: safety vs. quality risk
• Duration of storage (liquids).
In terms of the type of formulation, it is inconceivable that
substantive or even trace-level contamination would occur
where physical contact is limited to solid-to-solid contact.
This is entirely consistent with the FDA Guidance for
Industry, container closure Systems for Packaging human
Drugs & Biologics (6), which in relation to extractables and
leachables considers solid-to-solid contact of low risk. It
is, therefore, reasonable to conclude that any assessment
of risk associated with CCSs should be limited to those
associated with either liquid or semi-solid formulations.
The second aspect of any risk assessment of the CCS
involves an understanding of the potential levels of metals
present within the material concerned. A major review
of materials in manufacturing and packaging systems as
sources of elemental impurities in packaged drug products
was published in 2013 (7). The publication summarized
literature data for a number of common packaging
materials, including levels of elemental impurities within
the component material (determined by digestion), as well
as elemental impurities extracted from the component
materials. The data, while fragmentary, are nevertheless
comprehensive, and several key conclusions were drawn.
While certain materials were found to contain elemental
impurities, the presence of the elemental impurity was
Figure 4: Illustration of risk factors associated with packaging.
Limited solubility in
drug product
Limited interaction, buthigh metal content in
packaging
Good solubility in drug
product
Intimate contact, but low
metal content in packaging
Metal solubility in product
Meta
l co
nte
nt
in p
ack
ag
ing
Highest risk
High concentration of
metals in packagingHigh degree of interaction
between packaging and
drug product
Lowest risk
Low concentration of
metals in packagingLimited interaction
between drug product and
packaging
Elemental
impurities
from
packaging
Pharmaceutical Technology Europe March 2015 21
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Elemental Impurities
predominantly associated with
deliberate use of metal catalysts,
for example the use of antimony in
the manufacture of polyethylene
terephthalate (PET). In the case of PET,
levels of antimony of approximately
50 ppm are typical (full digestion).
Focusing particularly on those
elements of high concern (Class 1 and
Class 2), only fragmentary data exist
to suggest even trace levels present
within the component material, for
example cadmium and lead levels up
to 100 ppm were reported in polyvinyl
chloride. Even when low levels of
elemental impurities are present in the
material itself, the effective ‘availability’
of the elemental impurity needs to be
considered. What is consistently clear
from the extraction data presented
is that extracted elemental impurity
levels (under relevant conditions)
are a minute fraction of the total
elemental impurity levels present in
the component materials, typically
<0.1% of that observed following
digestion. Therefore, even when trace
levels of certain elements are found in
the component material, the available
elemental impurity concentration may
represent an extremely low safety risk
(Figure 4).
There may, however, be potential
quality-related risks. Such risk
may result from potential metal-
catalyzed degradation of the product
in question. While the interaction
between packaging material and solid
dosage forms is negligible (ICH Q3D),
this may not always be the case for
non-solid drug products. Reported
examples include iron (8), nickel (9),
and tungsten oxide. In the case of
tungsten, this related to leaching from
the syringe barrel, causing protein
aggregation (10). As a consequence,
many biopharmaceuticals include
ethylenediaminetetraacetic acid to
“mop up” metals. Assessments of
such risks should be addressed on a
case-by-case basis.
Evaluations should thus focus on
liquid and semi-solid formulations.
Detailed leachable studies should only
be required where there is a lack of
elemental impurity extractives data for
the packaging components in question.
Analytical testingAnalytical testing for elemental
impurities is clearly an important
aspect of the assessment of elemental
impurities. It is not, however, within
the scope of ICH Q3D. The guideline
states that “Pharmacopoeial
procedures or suitable validated
alternative procedures for determining
levels of elemental impurities should
be used, where feasible.”
USP has developed General
Chapter <233> “Elemental
Impurities—Procedures” (11), and
the European Pharmacopoeia (Ph.
Eur.) has recently published general
chapter 2.4.20 “Determination of
Metal Catalyst or Metal Reagent
Residues” covering analytical testing
(12). USP <233> describes two
specific procedures for the evaluation
of the levels of metal impurities.
Importantly, it also describes criteria
Figure 5: Elemental impurity control strategy.
Yes
Yes
Yes
Yes
Yes
Is source of EIknown?
Has a risk beenidentifed?
Document:
Existing controls are adequate
and/or
rationale for not requiring EI testing
Justifcation for
higher PDE
Higher PDE
justifed?
Open discussions with
regulatory bodies
Defned control strategy
Risk assessment
Replace source
of EI?
Change control:
Justifcation for
replacement
Establish appropriate limit
for EI in the product
Identify source of
elemental impurity
Identify how EI level
will be controlled
Use engineering controls
Choose suitable
approach
Use specifcation
Monitor EI level with testing
Is the control
successful?
Is the control
successful?
Justifcation for
engineering controls
Justifcation for
periodic controls
Yes No
No
No
NoNo
No No
22 Pharmaceutical Technology Europe March 2015 PharmTech.com
ES582517_PTE0315_022.pgs 03.10.2015 22:55 ADV blackyellowmagentacyan
Elemental Impurities
for the use of alternative procedures. Thus,
a flexible approach may be adopted in
terms of the analytical procedure, provided
the method concerned meets the required
acceptance criteria.
Control strategyA drug-product risk assessment can use
prior knowledge of the input materials to
demonstrate that the risk of significant
elemental impurity levels is low across
multiple batches. When the risk
assessment concludes that elemental
impurities are below 30% PDE, it should be
acceptable to rely on the quality system to
maintain the control of the process and the
existing use of standard cGMPs as a control
strategy of the drug product, without
requiring any additional element-specific
testing on each batch of product.
Other factors to consider could include:
• Security of external supply chain along
with a quality history (e.g., audit history,
levels of complaints, recalls, etc.) for
each vendor
• Control of vendor elemental impurity
specifications and elemental impurity
reporting on ingredient certificates of
analysis
• Security of internal supply chain.
It is anticipated that a properly executed
and documented elemental impurity
risk assessment for the majority of drug
products may justify the use of standard
cGMP as being a sufficient control strategy
to ensure levels of elemental impurities
meet the levels defined in ICH Q3D, without
the need for additional testing.
Where the drug product elemental
impurity risk assessment identifies the
need for additional elemental impurity
control, it is crucial to first understand
the potential source of the elemental
impurity(s). Once the source is known,
appropriate controls, in addition to cGMP,
can be applied. The flow chart in Figure 5
can be followed to help determine when
additional controls are required and what
those controls may look like.
Lifecycle managementProduct and/or process changes have
the potential to change the elemental
impurity content of the final drug product.
Therefore, their impact on the overall risk
assessment, including established controls
should be evaluated. Such changes could
include, but are not limited to, changes in
synthetic routes, excipient suppliers, raw
materials, processes, equipment, container
closure systems, or facilities. All changes
are subject to internal change management
process ICH Q10 Pharmaceutical Quality
System (13) and, if needed, appropriate
regional regulatory requirements.
ConclusionThe implementation of the ICH Q3D guideline
can be adequately achieved through
using an appropriate risk-based process
combined with existing GMP standards. A
risk assessment should be performed to
identify any elemental impurities that may
potentially be present at significant levels
in the drug product. Such an assessment is
then used to define an appropriate control
strategy. ICH Q3D allows the option that the
scope and extent of quality control testing
may be reduced, or even eliminated provided
there is adequate control. In many cases,
this can be successfully achieved through
the use of appropriate GMP controls both in
terms of input materials and manufacturing
processes, limiting testing to those areas
clearly identified as a substantive risk.
AcknowledgementsThe authors would like to thank Patrick
Drumm, Mark Schweitzer, and Darragh
Norton of Novartis, who also contributed to
the article.
References1. ICH, Q3D Guideline for Elemental Impurities
(2014).
2. ICH, Q3C Impurities: Guideline for residual
Solvents (2011).
3. EMEA, Guideline on the Specification Limits for
residues of Metal catalysts or Metal reagents,
EMEA/CHMP/SWP/4446/2000 (2008).
4. IPEC Americas, PDE Calculator, http://
ipecamericas.org/content/pde-calculator,
accessed 17 Feb. 2015.
5. T.S.A. Bevilacqua, “Stimuli to the
Revision Process: Elemental Impurities in
Pharmaceutical Waters,” Pharmacopoeial
Forum 39 (1) (2013).
6. FDA, Guidance for Industry: container
closure Systems for Packaging human Drugs
and Biologics (Rockville, MD, May 1999).
7. D. Jenke et al., PDa J Pharm Sci and Tech, 67,
354-375 (2013).
8. I. Beck-Speier et al., Particle and Fibre
Toxicology, 6, 34-36 (2009).
9. M. Schmidt et al., Nature Immunology, 11,
814-820 (2010).
10. J. Bee et al., J Pharm Sci, 98, 3290-3301, (2009).
11. USP General Chapter <233> ”Elemental
Impurities–Procedures” http://www.usp.org/
sites/default/files/usp_pdf/EN/USPNF/key-
issues/2013-12-27_233_pf40-2.pdf.
12. Ph.Eur. General Chapter 2.4.20, EDQM,
Strasbourg, France).
13. ICH, Q10 Pharmaceutical Quality System
(2008). PTE
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Pharmaceutical Technology Europe March 2015 23
ES582518_PTE0315_023.pgs 03.10.2015 22:55 ADV blackyellowmagentacyan
Fe
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The ability of a biological formulation to maintain its physical,
chemical, and therapeutic properties is often put to the test during
transportation and storage. Because many cell-derived therapeutics
are administered by infusion or injection, lyophilization is a common
method used to keep the product viable. There are, however, many
factors that can influence the behaviour of a drug within a batch of
vials, and issues with maintaining biological activity and stability during
formulation. This article provides an overview of the factors that can
influence protein behaviour during lyophilization of a pharmaceutical
product and the ways in which manufacturers can reduce processing
costs and timelines.
Special considerations for cell-derived productsBecause proteins are prone to chemical and physical degradation,
aggregation events and potency loss of the product are common
challenges associated with the lyophilization of biologics. “While
lyophilization is done to achieve long-term stability, the process
itself can be quite destabilizing for the molecule,” says Mathew
Cherian, PhD, director and senior fellow, pharmaceutical development
Randi Hernandez
While the optimization of a lyophilization cycle for a biologic relies
on a well-characterized formulation, viscosity and aggregation after
product reconstitution must also be carefully managed.
Lyophilization Cycle Optimization ofCell-Derived Products
at Hospira. “Finding the optimal
cryoprotectant levels; the optimal
rate and extent of freezing; the
optimal pressure during primary and
secondary drying; and measuring
the extent of primary and secondary
drying” are crucial to ensuring a
good-quality final product. Changes
to the product, such as freezing,
concentration and pH shifts,
decreasing temperatures, and
desorption can cause irreversible
denaturation, adds Edward H.
Trappler, president of Lyophilization
Technology.
Protein stress. Although primary
freezing is believed to cause the
most stress to a biologic product,
degradation and the formation
of aggregates can occur at any
stage in the lyophilization process.
According to Martin Gonzalez, senior
group leader, One-2-One R&D at
Hospira, primary freezing can cause
pH shifts, super-concentration
of protein species, and exclusion
of solvents, which can result in
problems in protein thermodynamic
stability. This instability can cause
protein unfolding, denaturation,
or aggregation. Specifically, says
Cherian, the formation of a solid-
liquid interface due to the advancing
freezing front can generate
aggregates.
Dehydration stresses during
drying can also cause problems.
An emerging theory is that drying
increases surface area, and as a
result, the protein molecules on
the surface of the dried solute (i.e.,
those that are under mechanical
stress within the solid matrix) are
at a “greater risk for aggregation
or other negative consequences
upon reconstitution,” notes Jim
Searles, PhD, technical fellow,
global manufacturing science and
technology, Hospira. Proteins in
dried products, therefore, are not
as protected by the amorphous
environment of the inner matrix.
According to Kevin Ward, PhD,
director of R&D, Biopharma
Technology, the risks of protein
instability can be minimized by
“intelligent formulation design
and the use of excipients with
specific cryo- and lyo-protective
qualities.” Searles of Hospira points
24 Pharmaceutical Technology Europe March 2015 PharmTech.com
ES582466_PTE0315_024.pgs 03.10.2015 22:53 ADV blackyellowmagentacyan
Fundamentals of Spray-Dried Dispersion TechnologyLIVE WEBCAST: Thursday, March 19, 2015 at 11:00 am ET/ 8:00 am PT
Register for free at www.pharmtech.com/spray
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n Product development group leaders
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often translates to rapid absorption and improved bioavailability.
Amorphous solid dispersions are typically prepared by using hot-
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on the fundamentals of formulating and processing of spray-dried
dispersions, including stability assessment, in-vitro performance,
and downstream manufacturability. In this webinar, experts will discuss:
n Key parameters that indicate amorphous dispersions and
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n How the spray drying process can be scaled from tens of
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n Best practices for formulation screening and evaluation of stability,
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n Methodologies and tools for spray drying process development
and scale-up through clinical supply and commercial
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Key Learning Objectives:
n Develop an appreciation of key factors leading to the use of spray-
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a division of Capsugel
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Moderator
RITA PETERS
Editorial Director
Pharm Tech
ES582690_PTE0315_025_FP.pgs 03.11.2015 02:36 ADV blackyellowmagentacyan
Lyophilization
out that the “addition of a surfactant to
the formulation can mitigate interfacial
damage, and emerging science is showing
that post-drying, super-Tg [glass-transition
temperature] annealing can allow structural
relaxations in the lyophilized matrix that
result in stability improvements.”
To ensure optimal storage conditions
and preservation of structure for a freeze-
dried biologic, molecular mobility must be
minimized and suitable excipients selected,
according to Trappler. A sound formulation
is the first step, and then the formulation
must be protected from temperature
cycling, light, and oxygen. Vials should
be stored upright, packed with vibration-
absorbent secondary packaging, and
handled with care during shipping, notes
Cherian.
Other concerns lie in the post-
reconstitution risks that exist with
biologics. “Aside from the all-important
retention of activity, as clinical demand
for high-concentration formulations (>
100 mg/mL) continues, the formulation
scientist must be cognizant of increased
aggregation propensity as well as managing
viscosity after reconstitution,” says John
G. Augustine, PhD, principal development
scientist, analytical and formulation
development at CMC Biologics.
The most important step to control
instability during storage is to carry out
thorough preformulation work as early
as possible during the drug-development
process. This information can help inform
the downstream processing cycle, aid
future purification efforts, and help ensure
that the proper excipients to minimize
degradation and aggregation have been
selected, says Augustine.
Scale-up: Moving from the laboratory to a commercial facilityOne of the common mistakes in
lyophilization scale-up is to assume
that a laboratory-scale freeze dryer
containing a few hundred vials behaves
the same way as a production-scale freeze
dryer containing thousands of vials (1).
Commercial equipment capabilities can
vary widely depending on their design
specifications and their age. Equipment
differences and batch uniformity under new
temperature profiles must be considered
during processing when switching from lab
lyophilization experiments to commercial
lyophilization systems, says Trappler.
Equipment differences can create drying
rate differences and variations in the final
water content in the products. “Industrial
freeze dryers have larger chambers with
larger shelf dimensions,” says Ward. “This
leads to a reduction in radiative heating and
often an increase in intra-shelf temperature
profiles.”
As a result, sublimation rate capability of
the production equipment should be carefully
tested, note representatives from Hospira.
Product quality testing on at least one full
shelf of vials should be done on products
sampled from the edge as well as the interior
of the shelf on the drying unit, they note.
Additionally, vial handling, washing, and
depyrogenation characteristic of full-scale
manufacturing can weaken glass, making
vials susceptible to potential vial breakage.
Cost-saving effortsShortened lyophilization times.
Shortening lyophilization times is
economical and reduces cost-per-unit.
“Reducing the cycle time reduces the
energy costs per run, and also increases
the potential throughput of a facility by
maximizing the number of runs that can
be processed in a similar timeframe,”
comments Ward.
Oftentimes, altering the design space
can facilitate shorter drying times and help
with product output. This type of process
alteration, however, should occur while the
product is still in the lab, observes Hospira’s
Gonzalez. “It’s better to achieve cycle time
reduction before going into full commercial
operation, perhaps by spending a little bit
more time developing a robust cycle that
yields more in the long run,” he says.
The design space influences shelf
temperature, chamber pressure, and hold
time for each step of the lyophilization
cycle, notes Mark Nachtigall, PhD,
scientist, global manufacturing science
and technology, Hospira. The ideal
design space—one that will generate
optimal primary drying times—will allow
a product to remain as warm as possible
without collapsing. A shorter drying time
will also rely on the sublimation rate
capability of the lyophilizer, says Nachtigall.
To ensure optimal storage conditions and preservation of structure for a freeze-dried biologic, molecular mobility must be minimized and suitable excipients selected.
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26 Pharmaceutical Technology Europe March 2015 PharmTech.com
ES582475_PTE0315_026.pgs 03.10.2015 22:53 ADV blackyellowmagentacyan
Lyophilization
“Experimental exploration of these
parameters in combination with
statistical evaluation of the effects
of changes in the parameters will
help determine the optimal process
conditions,” he says.
According to Ward, the single
biggest influence on drying time
is the critical temperature of the
formulation itself. As a result,
designing a formulation with a high
critical temperature is the best way
to obtain better lyophilization cycle
times. Ping Ma, PhD, senior group
leader, global pharmaceutical R&D at
Hospira, however, says that increasing
shelf temperature would be the most
efficient way to reduce cycle time.
Robert Stoner, associate research
scientist, Global Pharmaceutical R&D
at Hospira agrees, saying, “Designing
cycles that run at warmer shelf
temperatures and higher pressures
reduces equipment stress with
greater facility/utilities savings.”
Another option would be to
lyophilize a more concentrated
solution (i.e., increasing API
concentration to reduce the amount
of solvent), because less water to
sublimate is correlated with shorter
lyophilization cycle times, note Stoner
and Ma. Manufacturers can also
reduce lyophilization cycle time by
reducing freezing hold time, says Ma.
Related cost-saving measures.
Other ways to create shorter
lyophilization cycle times include
increasing the vial size. Using taller
vials will allow more vials to fit into the
lyophilization chamber per batch, notes
Stoner. This method, however, may
have to be coupled with longer drying
times, as there would be smaller shelf
contact area and taller lyophilization
cakes. Lastly, reformulating with fewer
excipients can reduce cost as well,
suggests Gonzalez.
Influences on drying timeForm and function. The physical
properties set during the freezing
phase can influence drying time
greatly, says Nachtigall. These
properties include the size of the
crystals in the matrix and crystal form
of the frozen product. In general,
slower cooling produces larger, better
networked crystals, says Ward, and
the larger pores and more “open
structure” that is produced present
less of an impedance to vapor
migration during drying. Primary
drying and sublimation is accelerated
with larger crystal sizes. Ward warns,
however, that control is needed to
balance safety and efficacy, as some
biologic products are sensitive to slow
cooling. Additionally, total process
time may be adversely affected
because of larger crystal sizes, notes
Trappler. Larger crystals represent
a reduction in the surface area and
a decreased desorption rate, which
could mean the product would require
longer secondary drying times.
A primary drying rate can be
significantly influenced by an
additional annealing step, which
can improve the appearance and
homogeneity of the cake of the final
drug product and ameliorate the non-
uniform nature of freezing and drying.
A post-freezing annealing process has
been shown to increase the rate of
primary drying (1). “This is because
annealing eliminates the smallest ice
crystals through Ostwald ripening,”
asserts Nachtigall. “These ice crystals
leave channels as they dry that water
vapor lower in the cake will travel
through; larger channels equal less
resistance, and therefore, faster
drying times.” Crystal forms matter
as well, and annealing can promote
crystallization for those products
predispositioned to crystallize, he
adds. “A crystalline product matrix
typically has a higher collapse
temperature than an amorphous
one,” which allows for higher drying
temperatures, and subsequently,
faster drying times.
Controlled nucleation. While
obtaining larger ice crystals and a
reduced surface area through the
use of controlled nucleation has been
shown to improve reconstitution
times and reduce the primary drying
time for concentrated proteins
and antibodies, there is still some
uncertainty as to whether controlled
nucleation is truly a benefit to
biologics, according to Trappler. He
says, “Preliminary data show there
is no detrimental effect in the initial
critical quality attributes (CQA) of
the protein preparation,” but that
the “complete impact on CQA can
only be confirmed from the results
of long-term stability tests.” Even
though controlled nucleation offers
some process benefits, investigators
may be able to better control for
differences in freezing and drying
with better glass vial “bottom
geometry,” says Trappler. “Even
with controlled nucleation, there are
differences in ice crystal growth as
well as consistency during drying due
to vial bottom contour.”
With controlled ice nucleation-
formed cakes, the rate of sublimation
is greater than in cakes formed as
a result of uncontrolled freezing.
“From a clinical standpoint, for highly
concentrated protein formulations,
a reduction in reconstitution times
can be observed in cakes produced
under controlled nucleation,” says
Augustine.
Regardless of what methods
are used to control for differences
in freezing behaviour and prevent
non-uniform drying of batches of
biologics, there will always be some
variation in product heterogeneity,
says Ward. These differences can be
due to differences in temperature
control across a shelf or variations
in vapor flow across a chamber, he
points out.
Know your characters. Process
engineering for lyophilization relies
on adequate characterization
of a formulation. To figure out
the parameters for adequate
solidification and the threshold
temperature required to maintain
product structure, a suite of tests and
preformulation tests, such as studies
of solubility, pH effect, stability
in solution, and low-temperature
analysis should be conducted, says
Trappler. “Use of freeze-drying
microscopy—an insightful method—
coupled with low-temperature
differential scanning calorimetry and
electrokinetic or electrical resistance
measurement” is essential to the
The single biggest influence on drying time is the critical temperature of the formulation itself.
Pharmaceutical Technology Europe March 2015 27
ES582467_PTE0315_027.pgs 03.10.2015 22:53 ADV blackyellowmagentacyan
Lyophilization
formulation characterization process, he adds. Ward echoes
these sentiments, saying that freeze-drying microscopy is the
only method for determining collapse temperature, and thermal
analysis can identify glass transitions and other events such as
eutectic melting and crystallization. “Without this information,”
he says, “cycle development is very much a trial-and-error
process.”
Hospira’s Ma points out that characterization tools “enable
[drug developers] to better understand each composition
and its physicochemical interactions in formulation,
optimize formulation process parameters, evaluate overall
risk assessment, and establish in-process and final release
specifications” for each formulation.
Future focus: Intelligent formulation designQuality by design (QbD) is built into a well-characterized
formulation. Thus, a product in development must be tested
for collapse temperatures, sensitivity to freezing rates, and
stability against excess moisture, among other factors, says
Gonzalez. “For lyophilization, this [the QbD approach] usually
means the designation of freezing rates, temperatures,
pressures, and hold times as critical process parameters,”
he says. “With so many parameters, one must fully leverage
process understanding to decide which combinations of these
to test in laboratory runs. It is also important to make use
of process analytical technology, such as instruments that
indicate completion of primary and secondary drying.”
Advances in protein characterization methods may allow
greater assessment and insight in the development of
formulations and processes for biologicals, says Trappler.
He lists light scattering, size-exclusion high-performance
liquid chromatography, dynamic light scattering, right-angle
light scattering, infrared, and nuclear magnetic resonance as
important analytical tools of the trade.
For biologics, the development of standard platform
technologies may help companies optimize formulations
and processing procedures. Companies are now developing
such platforms for evaluating molecules with a risk-based
approach, says Lisa Cherry, senior group leader, global
pharmaceutical R&D at Hospira. Molecule formulation
development and manufacturability are increasingly being
driven by prior knowledge gleaned from similar molecules. “For
formulation development of lyophilized biologics, there are
relatively few combinations of excipients in currently licensed
products,” notes Cherry. Starting within this formulation
design space will offer a high probability of success, she says.
“While formulations are being screened, one should use a
conservative (and therefore long) lyophilization cycle, which
can then be optimized once the final formulation candidate(s)
are selected.”
Reference1. B.S. Chang and S.Y. Patro, “Freeze-drying Process Development for
Protein Pharmaceuticals,” in Lyophilization of Biopharmaceuticals,
H.R. Constantino and M.J. Pikal, Eds. (2004), pp. 113-138. PTE
The development of standard platform technologies may help companies optimize formulations and processing procedures.
Frankfurt am Main · 15 – 19 June 2015
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➢ 3,800 Exhibitors from 50 Countries
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www.achema.de
ES582476_PTE0315_028.pgs 03.10.2015 22:54 ADV blackyellowmagentacyan
API SyntheSIS & MAnufActurIngM
ich
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an
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ag
es
The market for formulated drugs based on highly
potent active pharmaceutical ingredients
(HPAPIs) is growing at a rapid pace, largely due
to the development of highly targeted therapies
based on antibody-drug conjugates, which can
include cytotoxic small-molecule components. The
manufacture of this expanding field of HPAPIs is
challenging and requires specific know-how, facilities,
equipment, and procedures designed to mitigate
the risk associated with producing and handling
potent compounds. Standards and technologies
are continually changing, and HPAPI manufacturers
must remain vigilant and prepared to adopt and
implement the latest designs, equipment, training,
and procedures to reduce the risks posed by HPAPIs.
Dealing with uncertaintyAlthough many challenges exist for high-containment
API manufacturing, the variability and uncertainty
associated with each compound present the greatest
risks, according to Waldo Mossi, general manager
of Helsinn Advanced Synthesis. “The importance of
occupational exposure limits (OELs) is widely neglected
in discovery research and early development,” he
states. He explains that many companies use a one-
size-fits-all approach to handling and managing the
containment of bulk drug substances. Each individual
process, however, offers different challenges, and
no two new chemical entities (NCEs) are alike. The
situation is aggravated by the lack of universally
accepted definitions for various compound types,
such as highly active, highly potent, and cytotoxic
agents, which can lead to confusion between sponsor
companies and custom-manufacturing organizations
(CMOs), according to Mossi.
To manage the variation and address the
uncertainty associated with new substances,
Helsinn continues to strive for design of toxicology
testing and safety evaluation from the early stages
of process development. The company also uses
a comprehensive, science-based OEL evaluation
approach from the start of an HPAPI project, and
works with experienced industrial hygienists to assign
initially conservative OELs to each potent compound
that will enter its facility. “Since a certain level of
risk will always exist when working with HPAPIs, it
is important to foster a strong company culture of
excellence in protecting employees, products, and
the environment. Our comprehensive approach to
process and compound evaluation helps to clearly
define the needs and objectives in handling each
process step,” Mossi observes.
Fortunately, as an HPAPI project proceeds through
the development lifecycle and into clinical trials, the
understanding of the risks associated with the potent
compound increases and risk mitigation generally
becomes less difficult, according to Patrick Klipstine,
director of SAFC’s Madison, WI site. “During the
development process, SAFC pursues ongoing internal
evaluations and works with third parties to bolster
this process. As the definition of potency becomes
better defined during the development cycle, our
process engineers and environmental, health, and
safety (EHS) representatives can make appropriate
modifications to the manufacturing engineering
controls,” he notes.
Manufacturing and process continuity are also
crucial during scale up to ensure that risks are
minimized, according to Mossi. “Laboratories and
small-scale GMP equipment should be designed so
that they are aligned with the large-scale equipment
used for commercial production in order to ease the
transition and reduce uncertainty and risk during
scale up,” he says. At Helsinn, the risk associated
with scale up is reduced through facility design and
investigated during early design-of-experiment (DOE)
analyses.
More than chemistryIn any chemical manufacturing plant, the protection
of operators is a top priority. In facilities producing
HPAPIs, providing operator protection is absolutely
critical and the top priority, according to Klipstine,
which means that appropriate engineering controls
are in place and personal protective equipment is
available. In addition, every unit operation must be
considered with regard to both the chemistry and
potential occupational exposure. “Chemical
processing steps are evaluated on their merits with
regard to sound chemical process hazard criteria, and
Protecting workers, patients, and the environment requires advanced technologies.
Minimizing Risk during HPAPI Manufacture
cynthia A. challener, PhD,
is a contributing editor to
Pharmaceutical Technology.
Pharmaceutical Technology Europe March 2015 29
ES582374_PTE0315_029.pgs 03.10.2015 22:27 ADV blackyellowmagentacyan
API Synthesis & Manufacturing
30 Pharmaceutical Technology Europe March 2015 Pharmtech.com
considerations for personal protective equipment when handling cytotoxic drugs
Cytotoxic drugs are widely used in the healthcare industry. However,
whilst effective in treating diseases, the toxicity of these drugs can
present a significant health risk to the manufacturers, pharmacists,
and other healthcare professionals who handle them. Occupational
exposure can occur in many ways; staff are at most risk when
preparing the cytotoxic drugs. The greatest hazards arise through
the formation of dusts (e.g., in the event of defective injection vials
containing dry solids), liquids (e.g., on transfer and dispensing of
the dissolved substance), aerosol formation (e.g., when dissolving
the dry solids), or when containers containing cytostatics are
inadvertently dropped. Once exposed, a wide range of potential side
effects could occur, including abdominal pain, vomiting, and allergic
reactions. To mitigate the risk of exposure, it is vital that companies
involved in the manufacturing and handling of cytotoxic drugs
ensure that staff are given the highest possible levels of protection.
Cytotoxic drugs are hazardous substances as defined by the
Control of Substances Hazardous to Health Regulations 2002
(COSHH) [www.hse.gov.uk/healthservices/safe-use-cytotoxic-drugs.
htm]. Under COSHH regulations, employers must assess the risks
from handling cytotoxic drugs for employees and take suitable
precautions to protect them. This includes carrying out a full risk
assessment that will identify any potential hazards, define who may
be harmed and how, as well as flag up if existing precautions are
adequate or whether more could be done. Risk assessments should
continue to be carried out periodically to ensure that the protective
measures are still suitable.
controlling exposure It is important that all possibilities of removing the hazard
altogether are exhausted before considering ways of limiting staff
exposure. The following hazard-control hierarchy can be used as
a guide to good practice:
• Eliminate—remove the risk altogether if possible.
• Substitute—find a safer substitute (e.g., a less toxic material or a
different working method).
• Safeguard—put technical solutions in place that protects the
worker (e.g., mechanical ventilation, machinery guards, and
remote controls).
• Warn and educate—implement worker training and install
suitable alarm and warning systems.
It is the responsibility of management to implement safe working
methods and to reassess procedures in response to changing
conditions such as the emergence of new hazards. However,
employees must also be trained and educated to accept responsibility
for identifying risk situations and for taking the necessary safety
precautions. This includes a responsibility for using the personal
protective equipment (PPE) provided in the correct manner and being
aware of its use, its limitations, and its correct disposal.
choosing the optimum PPe PPE is the final line of defence when it comes to protecting
personnel from toxic substances. PPE, whilst primarily intended
to prevent the body from coming into contact with hazardous
chemicals and dusts, also plays a vital part in protecting the
manufacturing process from human contamination, including hair,
shedding skin, and clothing fibres. As such, it is a crucial safety
measure that cannot be compromised. The following factors should
be considered when choosing coveralls and protective garments.
Protection from particle intrusion. Barrier efficiency against
migrating particles, such as those from clothing or human skin,
is a crucial performance feature when working with cytostatics.
When determining the level of protection from particle intrusion,
it is important to look at the Type 5 test results. The Type 5 test
specifies the minimum requirements for chemical protective
clothing resistant to penetration by airborne solid particles. To test
particle intrusion, the Type 5 test method uses sodium chloride
particles at 0.6 micron sizes suspended in a fine spray in a test
chamber. The 9-minute test (3 minutes standing, 3 minutes walking,
and 3 minutes squatting) is repeated on 10 suits. To pass the test,
eight out of the 10 suits tested must have on average less than 15%
inward leakage into the suits. This means that coveralls that have
passed the Type 5 test offer a certain level of protection against
fine particulates. It is important to choose a coverall that offers
the lowest level of inward leakage for the best possible protection
when working with cytostatic drugs.
Material. While most coveralls look similar, the material used
makes a difference in determining the end protection level. There
are three common types of material: microporous film (MPF),
spun bond–melt blown–spun bond (SMS) and Tyvek (DuPont),
which is a synthetic material made out of flashspun high-density
polyethylene fibres. When tested against BS 6909, these materials
perform differently. MPF (sometimes known as LMPF) is made
using a spunbond polypropylene and a film of polyethylene. Due
to the structure of the material, it is not breathable and has a
high particle shed count. SMS is a breathable material but has
poor liquid repellency. Due to the short fibres in the material, it
sheds fibres quickly and is, therefore, unsuitable for cleanroom
environments. Tyvek, manufactured only by DuPont, is made up
of ultrafine endless high-density polyethylene fibres using specific
spinning and bonding technology. Because of the endless fibres, it
has a low particle shed count.
comfort. Whilst protecting both the worker and the process
is crucial, a further, important issue is having coveralls that are
comfortable. If workers are comfortable, they are more willing
to wear the protective garments and protection is, therefore,
heightened. The garments should ideally be designed to be durable
enough to allow for a range of movement and flexibility, without
compromising safety through ripped seams. At the same time, the
fabric should offer sufficiently high levels of permeability to both air
and water vapour to allow it to “breathe.”
The German Apothekenbetriebsordnung (ApBetrO, regulation on
the operation of pharmacies), which has been in force since June
2012, has also set out specific hygiene conditions for working with
cytostatics. According to the regulation, protective clothing must
also comply with the following requirements:
• Liquid-tight at arms and front
• Long sleeves
• Closed at the front
• Tight seal at cuffs
• Low-linting
• Barrier against pure and dilute cytostatics as well as fine particles
• Smooth surface (prevents particles from adhering to the surface)
• Optional: comfortable to wear, antistatic treatment, sterilizable.
Ian Samson, DuPont consultant for the EMEa and russia
regions, www.chemicalprotection.dupont.co.uk.
ES582366_PTE0315_030.pgs 03.10.2015 22:26 ADV blackyellowmagenta
API Synthesis & Manufacturing
then each process is developed to
allow for the safest execution of the
process within the identified
equipment train, taking into
consideration compatibility with
materials of construction, thermal
output, gas evolution, waste stream
management, etc.,” Klipstine notes.
With these considerations taken into
account, SAFC then applies
engineering controls for containment
to mitigate the risk for occupational
exposure. Specifically, the company
has adopted a risk-minimization
strategy that is systematically
constant, but allows for different
outcomes depending on the
chemistry and potency of each API.
“Each opportunity that turns into
a project goes through a defined risk
assessment process, with experts
in our process development, EHS,
and process engineering groups
closely collaborating to provide a
robust process from both a chemical
engineering and process engineering
standpoint. One of SAFC’s first
principles is that all processing of
powders and liquids are conducted
in closed systems that have been
verified to be effective for the
prevention of occupational exposure.
Second tier to these systems are
robust training programs that have
been designed for specific unit
operations,” he adds.
Helsinn also emphasizes the use
of fully closed systems and isolation
to avoid or mitigate areas of greatest
risk. The company fosters the
approach of contained chemistry,
which means that equipment for each
individual process (e.g., balances,
rotary dryers, pressure filter dryers,
and slurry vessels) is installed inside
an isolator that has been qualified
for occupational exposure levels
down to nanogram levels according
to the International Society for
Pharmaceutical Engineering’s
(ISPE) Standardized Measurement
of Equipment Particulate
Airborne Concentration (SMEPAC)
methodology. The use of such an
approach, according to Mossi, was
made possible by a clean atmosphere
design supported by accurate general
ventilation using double-pass, high-
efficiency particulate arrestance
(HEPA) filtration.
It should also be noted, according
to Mossi, that in addition to variable
chemistry, operational risk depends
greatly on several factors, including
the company culture, personnel
training, proper operational
execution, and the design and
engineering of the facility. In general,
the greatest challenges are typically
associated with operations such
as sampling, loading/unloading
of the reactor, and transfer of the
material. “Powder handling presents
the highest probability for potential
worker exposure, and it is important
to carefully study optimal methods for
minimizing and, wherever possible,
removing powder handling operations
from an HPAPI process,” he states.
At Helsinn, if powder handling is
necessary, effective and consistent
safeguards are factored in with
redundancies to mitigate the risk
even further.
SAFC handles both liquid and
powder HPAPIs under a defined set
of unit operations to minimize the
potential for occupational exposure.
“By using one common system
defined appropriately for scale to
ensure containment, our chemists
can be assured that the processes
they are executing are appropriately
identified for the defined potency,”
Klipstine explains. To reduce risk, all
large-scale isolation of powders is
conducted in jacketed filter dryers
where solids can be filtered and dried
without the necessity for discharge
from the drying unit operation.
Once dry, the HPAPI is discharged
using glove-box containment
techniques directly into predefined
drug-substance packaging using ILC
Dover continuous liner technologies,
according to Klipstine. As a best
practice, Helsinn investigates each
manufacturing process step for
hazard and safety together with the
aid of an outside industry expert as
part of its DOE analysis.
cross-contamination preventionOf significace to HPAPI producers
is having a thorough understanding
of the cleaning procedures required
to meet allowable carryover limits
for multipurpose equipment,
according to Klipstine. “Controlling
cross-over contamination mitigates
any potential risk to patients,” he
asserts. Mossi agrees that safety
cleaning verification at each stage of
a manufacturing process and GMP
cleaning validation is crucial. SAFC’s
philosophy is to apply a continuous
improvement mentality so that its
systems will exceed current industry
standards. Even so, one challenge the
company faces regularly as a CMO
with a multipurpose facility relates
to servicing customers ranging from
virtual biotechnology firms to large
pharmaceutical manufacturers that
have a wide range of expectations
regarding handling and cleaning
verification.
constant evolutionAnother challenge for CMOs that
offer HPAPI manufacturing services
is the continual evolution of industry
standards and technologies.
“Companies that want to participate
in this market must adopt these
newer technologies,” Klipstine
asserts. SAFC, for example, had to
transition to more robust analytical
technologies with improved
sensitivity and detection levels
that allow for the determination of
potential API carryover at part-per-
billion levels.
On the other hand, as the industry
continues to mature, consultants and
innovative equipment manufacturers
can help design state-of-the-art
engineering controls to better
suit specific facility containment
requirements, according to Mossi.
He notes that Helsinn’s recent facility
expansion was custom-designed
to support workflow, ergonomics,
and safety, while containing several
unit operations within only a few
isolators. Pte
In addition to variable chemistry, operational risk depends greatly on several factors, including the company culture, personnel training, proper operational execution, and the design and engineering of the facility.
Pharmaceutical Technology Europe March 2015 31
ES582369_PTE0315_031.pgs 03.10.2015 22:26 ADV blackyellowmagenta
32 Pharmaceutical Technology Europe March 2015 PharmTech.com
PEER-REVIEWED
I. Jones is founder and CEO of Innopharma Labs, jonesi@
innopharmalabs.com; Matti-Antero Okkonen is research team
leader, VTT Research Centre of Finland; A. Greene is senior
lecturer, School of Chemical and Pharmaceutical Sciences,
Dublin Institute of Technology, Kevin Street, Dublin 2, Ireland; and
P.J. Cullen is senior lecturer, School of Chemical Engineering,
UNSW Australia, Sydney NSW 2052 Australia.
Submitted: Feb. 18, 2014. Accepted: May 2, 2014.
Monitoring Fluid-Bed
Granulation and Milling Processes
In-Line with Real-Time ImagingI. Jones, Matti-Antero Okkonen, A. Greene, and P.J. Cullen
The pharmaceutical manufacturing platforms of
fluid-bed granulation and milling are widely used
to modify particle size. However, the adoption of
process analytical technology to monitor and control
these processes is difficult because of their dynamic
nature. This study examines the efficacy of a particle
characterizing technology to capture particle images
under dynamic conditions and to calculate particle
size distribution data both in-line and at-line during
fluid-bed granulation and milling.
Granulation methods are used in the pharmaceutical
sector to enlarge and densify small powder particles
into larger ones, typically to improve powder flow so that
the material can be processed effectively and efficiently
into solid dosage forms. In addition, granulation methods
are important for “locking in” the API within the formulation,
thereby reducing the risk of segregation. Granulated material
is attained by direct size enlargement of primary particles or
size reduction from dry compacted material (1).
Granule properties play a pivotal role in the f inal
performance of the tablet; for example, granule size can affect
the flowability and hence the average tablet weight and weight
variation. The effect of granule size and size distribution on
final blend properties and tablet characteristics is dependent
on formulation ingredients, their concentration, and the type
of granulating equipment and processing conditions employed.
Granulation and sizing of granulation are therefore critical unit
operations in the manufacture of oral solid dosage forms (2).
Granulation methods can be divided into two types—wet
methods, which use some form of liquid to bind particles
together, and dry methods, which do not use liquid (1).
The objectives of this study were to assess the ability to
measure particle size distributions under static (offline) and
Figure 1: Image of Eyecon particle characterizer
on a Glatt fluidized-bed granulator.S
UN
NY
/D
IGIT
AL
VIS
ION
/GE
TT
Y I
MA
GE
S
CITATION: When referring to this article, please cite it as I. Jones et
al., “Monitoring Fluid-Bed Granulation and Milling Processes In-Line
with Real-Time Imaging,” Pharmaceutical Technology 39 (3) 2015.
ES582408_PTE0315_032.pgs 03.10.2015 22:28 ADV blackyellowmagentacyan
Pharmaceutical Technology Europe March 2015 33
Real-Time Imaging
dynamic (on-line) conditions for milled and fluidized particles
as well as to determine the following:
• A correlation with known particle size ranges for certified
ceramic spheroids for at-line benchtop analysis
• Acquisition of high resolution images during a dynamic
manufacturing environment
• The tracking of a fluidized bed process within a fluid-
bed granulator and the ability to monitor the wetting,
agglomeration, and drying phases of granulation
• A correlation between mesh size reductions and particle
size distribution for polyvinylpyrrolidone (PVP) during cone
milling.
Materials and methods
For the off-line analysis, aluminium oxide (Al2O
3) ceramic
microspheres (Brace GMBH) of size ranges 212–250 µm,
500–560 µm and 900–1120 µm were tested to determine
the precision of the instrument. For in-line evaluation within
0.05
0.045
0.04
0.035
0.03
0.025
0.02
0.015
0.01
0.005
0
0.004
0.0035
0.003
0.0025
0.002
0.0015
0.001
0.0005
0
0.012
0.01
0.008
0.006
0.004
0.002
0
2000
1800
1600
1400
1200
1000
800
600
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0
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100
80
60
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20
0
0
0
0 200 400 600 800 1000 1200 1400 1600
100 200 300 400 500 600 700 800 900 1000
50 100 150 200 250 300 400 500
Eyecon Data
Normal Distribution ofSpecifcation
Eyecon DataNormal Distribution ofSpecifcation
Eyecon Data
Normal Distribution ofSpecifcation
Al2O
3 sintered spheres 212µm and 250µm
(a)
(b)
(c)
Al2O
3 sintered spheres 500µm and 560µm
Chart Al2O
3 sintered spheres 900µm and 1120µm
350 450
Figure 2: Particle size distribution and images of Al2O
3-sintered spheres, (a) 212 µm–250 µm, (b) 500 µm–560 µm,
(c) 900 µm–1120 µm.
AL
L F
IGU
RE
S A
RE
CO
UR
TE
SY
OF
TH
E A
UT
HO
RS
.
ES582393_PTE0315_033.pgs 03.10.2015 22:27 ADV blackyellowmagentacyan
34 Pharmaceutical Technology Europe March 2015 PharmTech.com
Real-Time Imaging
a fluidized-bed chamber, a
placebo of microcrystalline
cellulose (Avicel) and lactose
was granulated. Four granu-
lation experiments were car-
ried out in a laboratory scale
f luid-bed granulator (Glatt,
model GPCG15). The formu-
lation comprised of 33.33%
Avicel 101 (BASF), 66.66% lac-
tose 200 (Meggle). The spray
solution comprised of water
and 5.5% PVP 90 (supplier
BASF) with an addition rate
of 220 g/min using a Watson
Marlow 505S peristaltic pump.
Measurements were taken in
real-time and the granulate
growth per batch was evalu-
ated. For the in-line evaluation
of the rotary milling process,
granulate that was processed
by twin-screw granulation and
fluid-bed drying was meas-
ured during rotary milling.
During this study, granules
of PVP (Kollidon 30, supplier
BASF) were milled through
mesh sizes of 2000, 1575, 1397,
and 991 µm.
The imaging technology (the
Eyecon particle characterizer)
employed in this study is
based on high-speed machine
vision. It enables the capture
of both size and shape of
par t icles between 50 and
3000 microns. A continuous
i m a g e s e q u e n c e o f t h e
particles is captured using
il lumination pulses with a
length of one microsecond
for freezing the movement of
particles that are moving at
a speed up to several meters
per second. The illumination
is arranged according to the
p r inc ip le o f photomet r ic
stereo for capturing the 3-D
features of the particles in
addit ion to a regular 2-D
image. The particle size is
calculated from the images
u s i n g t h e 2 - D a n d 3 - D
information, applying novel
image ana l y s i s metho ds
145
140
135
130
125
120
115
110
(a)
(b)
(c)
480
460
440
420
400
380
360
340
320
300
175
170
165
160
155
150
145
140
135
130
Batch 1
Batch 2
Batch 3
Batch 4
Batch 1
Batch 2
Batch 3
Batch 4
Batch 1
Batch 2
Batch 3
Batch 4
End point
1 5 9 13 17 21 25 29 33 37 41 45 49 53 57 61 65 69 73 77 81 85 89 93 97
Part
icle
siz
e (
µm
)Pa
rtic
le s
ize (
µm
)Pa
rtic
le s
ize (
µm
)
Measurement points
1 5 9 13 17 21 25 29 33 37 41 45 49 53 57 61 65 69 73 77 81 85 89 93 97
Measurement points
1 5 9 13 17 21 25 29 33 37 41 45 49 53 57 61 65 69 73 77 81 85 89 93 97
Measurement points
D10 granule size for four repeat batches
D90 granule size for four repeat batches
Mean granule size for four repeat batches
Figure 3: Particle size results from fluid-bed granulation platform. Green
bars indicate the commencement phase of granulation, completion phase of
granulation, and the end point of granulation.
ES582392_PTE0315_034.pgs 03.10.2015 22:27 ADV blackyellowmagentacyan
Pharma Supply Chain Security:Are You in Control?
Who Should Attend:
n Chemist, Scientist, Researcher
n Vice President, Director, Manager,
and Group Leader for Research,
Development, Discovery, Quality
n Vice President, Director, Manager,
Buyer of Purchasing, Sourcing,
Supply, Outsourcing
Sponsored by Presented by
Register for free at www.pharmtech.com/security
EVENT OVERVIEW:
Recent regulations, including the U.S. Drug Supply Chain
Security Act, the FDA Safety and Innovation Act and the EU’s
Falsifed Medicines Directive, require that drug manufacturers
have more control than ever over their supply chains and
the quality and safety of APIs, and contractors that make
them. New requirements require a change in thinking,
from the broadest supply chain management concepts, to
the most granular, including audits, quality agreements and
maintaining supplier records.
Control assumes close communication and awareness, from
the time a supplier or services provider is selected. n Can you ensure compliance and prevent legal
liability?
n How strong are your auditing and communication
practices?
n How closely do you monitor practice and
performance?
n How efective are your legal agreements?
In this webcast, an expert on pharma and biopharma
supply chain management and security will look at new
regulations and enforcement, and what it means for you and
your business.
You Will Learn:
n The major factors that can compromise your chemical
ingredient supply chain.n What you can do to minimize these risks.
n How to identify and select a reliable and trustworthy
supply chain partner.
BONUS
CONTENT:
Attend to receivea FREE executive
summary of the webcast
For questions,
contact Sara Barschdorf at
Presenter
HEDLEY REES Managing ConsultantPharmafow Ltd
Moderator
AGNES SHANLEYSenior EditorPharm Technology
ON-DEMAND WEBCAST (Originally aired 25 February, 2015)
ES582718_PTE0315_035_FP.pgs 03.11.2015 02:37 ADV blackyellowmagentacyan
36 Pharmaceutical Technology Europe March 2015 PharmTech.com
Real-Time Imaging
and direct geometrical measurement. As the approach is
based on direct measurement instead of indirect, such
as laser diffraction, there is no need for material based
calibration. In addition, the method is non-contact and
can be applied, for example, behind a view glass on a
granulator without physical modification of the process
equipment. Direct imaging technologies may be considered
more accurate methods of measurement compared with
laser and sieve analysis techniques because of the two
dimensional method of measurement. These advantages
of non-product contact and more accurate size estimation
for in-line measurement are considered beneficial to the
pharmaceutical development
and manufacturing sector
where reduct ion of cross
cont aminat ion r i sks and
accuracy of measurement are
paramount. Figure 1 provides
an example of an integrated
technology on a Glatt fluidized
bed granulator.
Results and discussion
Summar y of data f rom
benchtop, fluidized bed and
milling platforms
Experiment 1: Benchtop
evaluation. Figures 2a, b,
and c show the size distri-
butions from Al2O
3-sintered
spheres plotted against their
certified size ranges. The red
line indicates a normal distri-
bution of the sample based
on defined lower and upper
range specif ications to 3σ.
Representative images for
each distribution are also pre-
sented. During experiment 1,
the at-line benchtop analysis
using certified Al2O
3-sintered
spheres of known size distri-
butions indicates a signif i-
cant level of accuracy of the
imaging technology. Figures
2a, b, and c indicate that a
minimum of 91% of spheres
were calculated as being
within the pre-defined sup-
plier certified specifications.
The number of Al2O
3-sintered
spheres measured were 4572
(212 µm–250 µm), 440 (500
µm–560 µm), and 314 (900
µm–1120 µm). Because of
the tight certif ied distribu-
tion range for these samples, it was deemed that a low
sample population was acceptable. A larger data set may be
required if greater variability is present within the sample set,
for example, when evaluating granulates or milled materials.
Experiment 2: Fluidized bed evaluation. Figures 3a, b,
and c show the D10 and D90 (i.e., the diameters at which
10% and 90% of the samples mass is comprised of smaller
particles and mean particle distributions during fluid-bed
granulation trials. All fluid-bed granulation trials were circa
40 minutes in duration. Graphs illustrating the D10, D90,
and mean indicate the wetting, agglomeration, and drying
phases that are typical of a fluid-bed granulation process.
120010008006004002000
(a)
(b)
(c)
(d)
00:00 00:17 00:35 00:52 01:09 01:26 01:44 02:01
dia
mete
r (µ
)d
iam
ete
r (µ
)d
iam
ete
r (µ
)d
iam
ete
r (µ
)
120010008006004002000
120010008006004002000
Time
00:00 00:17 00:35 00:52 01:09 01:26 01:44 02:01
Time
00:00 00:17 00:35 00:52 01:09 01:26 01:44 02:01
Time
120010008006004002000
00:00 00:17 00:35 00:52 01:09 01:26 01:44 02:01
Time
D90 Run 1 2000 µm mesh
D90 Run 2 1575 µm mesh
D90 Run 3 1397 µm mesh
D90 Run 4 991 µm mesh
Figure 4: A summary of results from rotary milling platform. D10 and D90 are the
diameters at which 10% and 90% of the samples mass is comprised of smaller particles.
ES582413_PTE0315_036.pgs 03.10.2015 22:28 ADV blackyellowmagentacyan
Pharmaceutical Technology Europe March 2015 37
Real-Time Imaging
Other D values (D25, D50, and D75) were also tracked
and similar profiles were identified. During the process,
the technology successfully captured images, measured
granulate size, and tracked a typical fluid-bed granulation
process. The granulate size for all four batches reflected the
typical granulate growth profile for a fluid-bed granulation
process, including the wetting, agglomeration, and drying
phases. The granulation growth trajectory (3) and end points
(as illustrated in Figure 3a) could be monitored with this
data. The variability between batches 1 and 4 versus 2 and
3 is most likely linked to variability in humidity levels during
the trials as the dew point was not a controlled parameter
and all other parameters remained fixed. These changes
were confirmed through off line sieve analysis.
It can be seen from the particle size data illustrated in
Figures 3a–3c that the dried granulate is of a smaller size
compared to wet granulates earlier in the agglomeration
process. This observation is to be expected when
considering the removal of moisture and granule-granule
attrition during the fluidized bed drying phase. All of the
information presented in Figures 3a–3c could be used to
develop, model, and control fluid-bed granulation processes.
Experiment 3: Rotary cone milling evaluation. Figures
4a, b, c, and d show the results achieved with the imaging
technology during a rotary cone milling evaluation. The
technology was capable of detecting the reduction in particle
size of the milled material as the mesh size was reduced
from 2000 µm to 991 µm as measured with D90 values. A
positive correlation (weighted R2 = 0.8696) was calculated.
The reduction in particle size was also evident in the
images that were captured during each milling run. A
sample of images are included in Figures 4a–4d. There
is a visible reduction of larger
particles as the mesh size was
reduced.
It can be seen in Figure 5
that the level of particle size
variability reduces with the
reduction in mesh sizes. Run
1 with a mesh size of 2000 µm
mesh generated a D90 particle
size range from 385 µm to
1196 µm (standard deviation
= 199 µm). Run 4 with a mesh
size of 991 µm generated a
D90 particle size range from
427 µm to 707 µm (standard
deviation = 69 µm).
T h e s a m p l e s i z e w a s
c o n s i d e r a b l e w i t h o v e r
46,000 particles measured
during each run, which was
between 90 and 120 seconds
in duration. The number of
particles analyzed will vary
depending on the speed of
material flow, the volume of material transferred to the
interface window for analysis, and the particle size range
being analyzed. The density, hardness, and moisture content
of particles were also considered during the development
of the integration device to ensure a repeatable and
representative sample for analysis.
Conclusion
The imaging technology (the Eyecon particle characterizer)
successfully captured images and subsequently calculated
particle size distributions for the sample materials in a rapid
and accurate manner. As expected, there will be a degree
of modification required as part of integration on new
equipment types to ensure a representative and consistent
sample presentation—which is critical to enabling accurate
sample measurement. It can be concluded that the Eyecon
particle characterizer can be successfully integrated within
typical pharmaceutical fluid-bed granulators and milling
environments in addition to accurately measuring samples
in an at-line benchtop set-up.
References
1. D.M. Parikh, Chapter 1 “Introduction,” in handbook of Pharmaceutical
Granulation Technology, pp. 1–3 (Tailor and Francis Group, 2005).
2. G. Singh Rekhi and R. Sidwell, Chapter 17 “Sizing of Granulation,” in
handbook of Pharmaceutical Granulation Technology (Tailor and Francis
Group, 2005).
3. J. Huang and M. Moshgbar, “Platform Technologies for Manufacturing
Process Optimization through Integration of PAT and Control System,”
www.intellicentic.com/wp-content/uploads/2014/08/Platform-
technologies-for-manufacturing-process-optimization-through-
integration.pdf, accessed 18 Dec. 2014. PTE
900
800
700
600
500
400
300
200
100
0
900 1400 1900
mean
median
D10
D50
D90
Part
icu
le s
ize (
µm
)
MESH size (µm)
Figure 5: An evaluation of correlation for mesh size versus size parameters. Bars
represent standard errors.
ES582411_PTE0315_037.pgs 03.10.2015 22:28 ADV blackyellowmagentacyan
Yu
ji S
aka
i/G
ett
y Im
ag
es
Matthias Springfelter, senior formulation scientist at Recipharm
Pharmaceutical Development AB, Solna, Sweden, spoke to
Pharmaceutical Technology Europe about the advantages and the key
considerations in developing topical formulations.
AdvantagesPTE: What advantages do topical formulations offer compared to
other dosage forms?
Springfelter: Perhaps the most obvious advantage is that topical
formulations allow for local treatment of a number of dermatological
conditions with very little systemic exposure. A high drug load can be
applied on the actual site where the drug is required, with a reduced
risk of unwanted side effects. Topical products are easy for the
patient to apply, and the moisturizing effect of topical formulations,
such as creams and ointments, may also be beneficial for several skin
conditions.
Transdermal delivery systems offer an alternative route for systemic
administration of various drugs with the benefit of a reduced risk of
loss of potency or unwanted variability due to first-pass metabolism.
Transdermal delivery systems can be designed to offer prolonged
and controlled-release absorption of certain drugs, which can be
convenient for pain relief drugs, nicotine, and hormone products.
Drug absorptionPTE: Can you tell us more about the mechanisms of drug absorption
across the skin barrier and how they affect the development of topical
drug products?
Springfelter: The human skin functions as an efficient barrier
against the outside environment. Achieving sufficient drug absorption
can, therefore, prove challenging for many molecules. For a drug
to reach its target site or to be absorbed into the blood stream, a
sufficient amount has to pass through the outer part of the epidermis,
the stratum corneum, and the epidermis. Even though there are
some passages, such as the hair follicles, sweat glands, and active
transportation mechanisms, the most important mechanism for drug
A Q&A by
Adeline Siew, PhD
absorption is by passive diffusion. The
rate of diffusion will, to a large extent,
depend on the properties of the drug
molecule itself. However, formulators
can use a number of methods to
optimize drug absorption.
In general, small-sized and
relatively lipophilic molecules are
most likely to be readily absorbed
through the skin, and this aspect
must be considered when selecting
a drug candidate. Sometimes,
it is possible to modify the drug
properties or alternatively, choose a
pro-drug that is delivered in inactive
form and that better matches
these criteria. The choice of vehicle
depends on the properties of the
drug substance, such as the solubility
profile and partition coefficient, so
that the chemical potential of the
drug is maximized. The permeability
of the skin is also an important
factor—the penetration rate could
be increased by an increase in skin
hydration, for example, by choosing
an occlusive vehicle or patch. A
number of penetration enhancers
that increase the absorption of a
drug by temporarily increasing the
permeability of the skin have been
evaluated, but there are limitations
because of skin irritation or toxicity
concerns.
PTE: What are the main
components of a topical formulation?
Springfelter: The components
of a topical product will depend on
the type of formulation. It could be
as simple as an active ingredient
dissolved in a solvent with suitable
additives such as pH-buffers,
co-solvent, and preservatives to
achieve adequate solubility and
stability for the formulation. In a
topical gel, viscosity modifiers such as
cellulose-based or synthetic polymers
are added to achieve the desired
rheological properties. Ointments
are semi-solid preparations of a drug
substance dissolved or dispersed
in a semi-solid ointment base made
of paraffin or other hydrocarbons.
Emulsions are somewhat more
complex because they consist of
two liquid phases, one of which is
dispersed within the other, usually oil
droplets dispersed in water. A number
of excipients are often necessary to
achieve a physically and chemically
stable emulsion. Water and one or
Semi-Solid Dosage FormsWhile the skin offers an alternative route of administration for local and
systemic drug delivery, developing semi-solid dosage forms can be a challenge.
38 Pharmaceutical Technology Europe March 2015 PharmTech.com
ES582367_PTE0315_038.pgs 03.10.2015 22:27 ADV blackyellowmagentacyan
Applying Water Activityto Pharmaceutical Products
Who Should Attend:
n Directors, group leaders, and managers
of quality, QA/QC, and compliance
n Directors, group leaders, and managers
of development
n Directors, group leaders, and managers
of manufacturing/production
n Scientists
Sponsored by Presented by
Register for free at www.pharmtech.com/water
EVENT OVERVIEW:
An understanding of water activity—or the measure
of the free water in a substance—is crucial to the
development of pharmaceutical products to achieve
optimal stability, shelf life, and physical properties. Water
activity measurement also is a useful quality and safety
measurement tool to assess the potential for microbial
growth in pharmaceutical products.
In this 60-minute educational webcast, two experts on
water activity applications in pharmaceutical product
development will explain the basics of water activity and
the role it plays in pharmaceutical products, compendial
and regulatory requirements for water-activity
determination, and practical applications of water activity
to assess chemical stability, microbial content, physical
properties, and other pharmaceutical characteristics.
Key Learning Objectives:
n Learn how water activity is defned and regulatory
implications
n Understand how water activity measurement can be
used to assess the stability and physical properties of
pharmaceutical products
n Review applications for water activity in
pharmaceutical products
For questions,
contact Sara Barschdorf at
Presenters
Tony Cundell, PhDConsulting Microbiologist
Linda K. SkowronskySenior Development MicrobiologistGlaxoSmithKline Consumer Healthcare
Moderator
Rita PetersEditorial DirectorPharmaceutical Technology
LIVE WEBCAST: Wednesday, March 25, 2015 at 11:00 am EDT
ES582696_PTE0315_039_FP.pgs 03.11.2015 02:36 ADV blackyellowmagentacyan
Formulation
more organic compounds, such as
mineral or vegetable oils, make up
the two liquid phases, and one or
more emulsifying agents will be
needed to keep the phases apart.
The stability of the emulsion can be
further improved by the addition of
polymers to increase the viscosity
of the water phase. Additional
excipients such as pH-buffers,
antioxidants, and preservatives are
usually added as well.
Considerations in formulation developmentPTE: What are the key considerations
when designing a formulation for
topical drug delivery?
Springfelter: First of all, the
choice of formulation must be made
based on the disease or condition
to be treated, the type of skin upon
which it is to be applied, and the
properties of the drug substance.
After that, one has to ensure that
sufficient amount of the drug
reaches its site of action, whether it
is on the skin layer, or systemically.
The drug absorption may have to be
optimized, for example by adjusting
the vehicle or adding penetration
enhancers. It is also important
to ensure that skin irritation and
toxicity are minimized.
As always in formulation
development, the physicochemical
properties of the drug product must
be well controlled. The stability of
the active ingredients and other
functional excipients, such as
preservatives or antioxidants, will
have to be monitored.
Phase changes, such as
separation or bleeding, must
be prevented in emulsions and
ointments. The microbial quality
control of the drug product needs
to be considered, especially in
water-rich formulations; in this
case, it is often necessary to add
preservatives. The viscosity and
rheological behaviour should
be adjusted to fit the type of
application and the overall cosmetic
properties should be acceptable.
Vehicle selectionPTE: Can you elaborate more on
the selection of a vehicle for topical
formulations and how drug properties
will affect the choice of a vehicle?
Springfelter: The selection of a
vehicle for a topical formulation is
based on several factors, ranging
from stability and compatibility,
the type of disease and skin to be
applied on, to biopharmaceutical
considerations.
In general, the lipophilic type of
vehicles, such as ointments and
emulsions, are preferred for conditions
that involve dry skin. Ointment
vehicles are commonly used as they
provide a moisturizing effect on dry
and flaky skin due to their occlusive
properties. In addition, the increase in
hydration of the skin can also improve
the absorption of the drug. Ointments
are also less irritating to sensitive skin
than water-based formulations, but
they have a greasy feel that patients
tend to dislike.
Emulsion-type vehicles, such as oil-
in-water creams, are often preferred
for their improved cosmetic properties
because they are easy to apply and
are less viscous and greasy. Achieving
a stable emulsion, however, can prove
to be challenging in some cases.
Liquid vehicles such as solutions or
gels are convenient for application on
hairy skin areas such as the scalp and
are sometimes preferred in dermal
conditions for which a drying effect is
desired. For transdermal applications,
a suitable patch or other device would
have to be evaluated together with the
formulation.
Testing drug release and drug absorption PTE: How do you test drug release
and drug absorption?
Springfelter: A number of
methods are available for the
evaluation of the drug release and
absorption of dermal and transdermal
products. There is, however, no gold
standard, and the method used will
vary from case to case.
Some in-vitro methods are
particularly useful for early studies
and screening purposes. For
transdermal patches, the paddle-
over-disc method described in the
United States Pharmacopeia and
the European Pharmacopoeia is
a reliable test to determine the
in-vitro dissolution rate. For semi-
solids, no compendial methods
are available, but the diffusion cell
systems, such as Franz or In-Line
cells, are widely used and may
be fitted with various artificial or
animal skin membranes, or even
excised human skin. Diffusion
cell systems can provide useful
information and guidance, for
example, when choosing the vehicle
for a topical product, but as always,
caution should be taken when
extrapolating into more complex
in-vivo conditions. New in-vitro
models and methods are also being
developed, and are becoming more
useful in the characterization of
topical products. In-vivo studies
in different species of animals are
often performed, but as animal skin
differs from human skin, results
should be extrapolated with caution.
PTE: As the pharmaceutical
landscape becomes increasingly
competitive, drug developers are
now focusing more on patient
centricity and formulation for specific
populations. In your opinion, what
is the future outlook for semi-solid
drug products and do you expect
demand for this type of dosage form
to increase?
Springfelter: We have seen
increased interest in semi-solid
products in recent years and there
may be several reasons for this
trend. Where, several years ago, the
focus was on blockbuster products,
today there is a move toward more
niche applications. As demand for
personalized products increases,
topical administration is gaining
popularity. Another key driver is the
increasing interest in new products
that use existing drug substances.
New topical formulations using drugs
that were previously administered
in another dosage form can offer
significant benefits, not only
therapeutic benefits, but financial
ones, as they reduce development
cost and risk. PTE
The choice of formulation must be made based on the disease or condition to be treated, the type of skin upon which it is to be applied, and the properties of the drug substance.
40 Pharmaceutical Technology Europe March 2015 PharmTech.com
ES582372_PTE0315_040.pgs 03.10.2015 22:27 ADV blackyellowmagentacyan
TROUBLESHOOTINGD
AN
le
AP
/ge
tt
y i
MA
ge
s
William Evans
is technical service
specialist at Tosoh
Bioscience, 800.366.4875,
Several chromatographic resins are available for downstream purification.
Removing Aggregates in Monoclonal Antibody Purification
Monoclonal antibodies (mAbs) are a successful
class of therapeutic products used increasingly
in the past 15–20 years, but the manufacture of safe
and effective mAb drug products provides many
challenges to downstream molecule purification.
One of these challenges is the tendency of
mAb molecules to aggregate during processing.
Aggregates in the final drug product are undesirable
for two major reasons. First, aggregates may cause
a decrease in product efficacy due to lowering the
effective concentration of the drug product. Second,
aggregates increase the risk of an immunogenic
response in patients, including anaphylaxis. For
these reasons, the removal of aggregates is a focus
of downstream processing. The mAb purification
procedure must effectively reduce aggregate
concentration in the drug product, and processes
are usually optimized to target an aggregate
concentration of less than 1% for the final mAb drug
product. Additionally, processes must be optimized
to prevent the additional aggregation of the drug
molecule during processing.
Aggregate removal Removal of aggregates, especially soluble aggregates,
presents a challenge due to the physical and chemical
similarity of the aggregates to the drug product itself,
which is usually a monomer. Chromatography steps
can effectively remove aggregates, and typically,
one or more chromatography steps in a process will
be optimized for aggregate removal. The need for
aggregate removal, however, must be balanced by the
productivity of the process, the step yield, and the
overall purity of the product through the removal of
host-cell proteins and other contaminants.
For mAb products, nearly all processes begin with
an initial Protein A affinity chromatography step to
remove the bulk of impurities present in the clarified
harvest. This initial step provides a product that is
typically >90% pure and the subsequent processing
steps focus on the removal of the remaining
minor impurities. Due to the chemical similarity of
aggregates to the monomer molecule, however,
Protein A chromatography does not effectively
remove aggregates already present in the feedstock.
Additionally, Protein A elution conditions must be
optimized to prevent the further aggregation of
molecules due to denaturation at the acidic pHs
typically used. Finally, Protein A eluate is usually
maintained at a low pH for 30–60 minutes as a viral
inactivation measure. This hold has the potential to
exacerbate aggregate formation.
Secondary purification steps are often used
to remove aggregates following Protein A
chromatography and low pH treatment. Because
aggregate molecules are, chemically, multiples
of the monomer, aggregate molecules will have
proportionately greater surface charge or surface
hydrophobicity. Ion (anion or cation) exchange and
hydrophobic interaction chromatography modes may
be employed to take advantage of this increased
charge and hydrophobicity of the aggregates to
separate them from the monomer molecule. Figure
1 shows the strategy for aggregate removal with
ion exchange (IEX), hydrophobic interaction (HIC),
and mixed-mode chromatography. IEX methods
will separate based on molecule charge, while HIC
methods separate based on hydrophobicity. Mixed-
mode methods separate based on both charge and
hydrophobicity. Merits of the various chromatography
modes are discussed as follows.
Ion-exchange chromatographyCation-exchange chromatography. In cation exchange
chromatography (CEX), a positively-charged molecule
is adsorbed by the column resin and then displaced
with a high concentration of a positively-charged ion
such as Na+. As they require a positively-charged
molecule, CEX steps are performed at a pH below the
isoelectric point of the target molecule; for mAbs, this
is often in the range of 7.5–9. To determine elution
conditions during process development, separations
of aggregate-containing product may be done in
which material is bound at low conductivity and
eluted with a conductivity (salt) gradient (Figure 2) at
a constant pH.
The strength of the binding of the mAb to a CEX
resin is determined by the pH and the type of CEX
Pharmaceutical Technology Europe March 2015 41
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Troubleshooting
ligand used. Alteration of the pH will
affect the charge of the molecule and
increase or decrease the binding to a
given resin. The chemical properties of
the ligand will also affect the binding
affinity of the molecule. For instance,
carboxylic-type (CM) resins often
show a stronger binding then sulfonic
acid-type, thus requiring a higher
solution conductivity to cause elution.
For this reason, the CM-type resins
may be said to be “salt-tolerant”.
During process development, it is
common to screen multiple resins
at various pH points to optimize
the resolution between monomer
and aggregate peaks. In the final
processes, elution conditions are set
to collect primarily monomer. Species
that bind more weakly than the mAb
are washed off the column prior to
elution, while those that bind more
strongly, including aggregates, remain
bound and are cleaned off prior to
the processing of the next batch.
Theoretically, it is also possible to
adjust solution conductivity to allow
the monomer to flow through and the
aggregate to be retained, although this
method is not typically employed.
Anion exchange
chromatography. Anion exchange
(AEX) chromatography may also be
employed to remove aggregates.
Often, anion exchange is employed
in mAb processes in a product
flow-through mode to remove DNA
and some viruses that are highly
negatively charged at neutral pHs.
Salt-tolerant anion exchange resins,
though, may be used in bind-and-
elute mode, because significant
antibody binding can be achieved at
neutral to slightly-basic pHs. In this
mode, the salt-tolerant AEX resin
would be used in a manner similar to
CEX described previously.
Hydrophobic interaction chromatographyHIC may be used in much the
same manner as IEX to remove
aggregates. In this case, the
aggregates will show increased
surface hydrophobicity relative to
the monomer. HIC steps present
more variables for optimization
during process development, as the
hydrophobicity of the protein, the
type and concentration of salt in the
feedstock, and the hydrophobicity
of the resin come into play. Protein
hydrophobicity may be modulated by
change in pH to increase or decrease
the net charge of the molecule.
Different types of salts may be
used to modulate the strength of
the hydrophobic interaction of the
mAb with the resin. Different resin
ligands will also have varying levels of
hydrophobicity. For instance, a butyl
ligand will be more hydrophobic than
a phenyl ligand, which will, in turn,
be more hydrophobic than an ether
ligand.
Usually, HIC is performed in bind-
and-elute mode. The product is
bound under high-salt conditions
to strengthen hydrophobic effect
with the resin. To determine
elution conditions, a reverse-salt
gradient is then used to elute the
protein (Figure 3). Analogous to
cation exchange, the aggregate will
remain bound following monomer
elution due to greater surface
hydrophobicity. During process
development, various salt/resin
combinations may be screened
to provide the greatest aggregate
removal. Use of HIC in bind-and-
elute mode, however, provides
additional challenges, especially at a
manufacturing scale. The HIC eluate
may contain substantial amounts of
salt, which then must be removed
by diafiltration, or reduced in
concentration by the dilution of the
eluate prior to further processing.
This has led to the development of
low-salt or salt-free flow-through
HIC steps in some processes. For
these, a highly hydrophobic ligand
(such as hexyl) is used, and the
hydrophobicity of the mAb molecule
is modulated by pH change to allow
the monomer to flow through the
column, while aggregate and other
contaminants remain bound.
Other chromatographic modesMixed-mode chromatography.
Mixed chromatographic modes
allow separation based on both
charge and hydrophobicity in a single
step. Mixed-mode chromatography
(MMC) can provide a different
Figure 1: Strategies for aggregate removal with ion exchange (IEX), mixed-mode, and hydrophobic interaction (HIC) chromatography; mAb is monoclonal antibody.
Figure 2: Aggregate gradient elution profile with cation exchange chromatography (CEX).
Figure 3: Aggregate gradient elution profile with hydrophobic interaction (HIC) chromatography.
Hydrophobicity
HIC
IEX
mAb
monomer
dimer
trimer
tetramer
Mixed-Mode
Bound
Eluted
Bound
Eluted
BoundEluted
Charge
Volume
Aggregate
Monomer
Salt c
oncentr
atio
n
UV
Ab
sorb
an
ce
Volume
Aggregate
Monomer
Salt concentration
UV
Ab
sorb
an
ce
All f
igu
re
s A
re
co
ur
te
sy
of t
he
Au
th
or
.
During process development, it is common to screen multiple resins at various pH points to optimize the resolution between monomer and aggregate peaks.
42 Pharmaceutical Technology Europe March 2015 PharmTech.com
ES582375_PTE0315_042.pgs 03.10.2015 22:27 ADV blackyellowmagentacyan
Troubleshooting
selectivity than either IEX or HIC
alone. One drawback of mixed-mode
chromatography, however, is that
because of the increased binding
due to hydrophobic interactions, a
higher salt concentration is usually
needed to elute molecules bound
to an MMC resin than a simple IEX;
in effect, mixed-mode resins may
be employed as highly salt-tolerant
IEX resins (Figure 4). An alternate
strategy for separation by MMC
is to use both a conductivity and
pH change for elution; this may
provide the needed selectivity for
separation, as well as reducing the
salt concentration of the eluate.
Optimum elution conditions may
be determined by using combined
salt and pH gradients for elution, as
shown in Figure 5.
Why not size exclusion? A
special mention should be given
to size-exclusion chromatography
(SEC) for the purposes of aggregate
removal. As aggregates would
be proportionally sized relative
to the monomer (e.g., a dimer
would occupy twice the volume
of the monomer), molecule size
should provide a basis to separate
out aggregates. In analytical
chromatography (HPLC, UHPLC),
SEC is often used to determine the
amount of aggregate in a sample,
as monomer will be more highly
retained due to pore access, and
elute later than aggregates (Figure
6). For purification, however, it is
difficult to conduct SEC on the scale
necessary to perform industrial mAb
manufacture, and, therefore, it is not
used in practice. SEC is useful though
on a laboratory scale, especially as
a final purification step for material
that must be very pure (e.g., for
crystallography).
ConclusionThe removal of aggregates present in
a mAb purification process presents
a challenge to process development.
However, several chromatographic
tools are available to reduce the
concentration of aggregates to maintain
drug product efficacy and safety. Ion
exchange, HIC, and MMC may be used
for aggregate removal. PTE
Figure 4: Comparison of elution pro-files for S-type cation exchange chro-matography (CEX), CM-type CEX, and cationic mixed-mode chromatogra-phy (MMC) at a constant pH.
Figure 5: Mixed-mode chromatography (MMC) elution profile with combined salt and pH gradient.
Figure 6: Elution profile for aggregate separation by size-exclusion chromatography (SEC).
Volume
MMC
Salt co
nc.
CEX, CM-type
CEX, S-type
UV
Ab
sorb
an
ce
Volume
UV
Ab
sorb
an
ceAggregate
pH
Monomer
Salt co
ncentr
ation
Volume
Aggregate
Monomer
UV
Ab
sorb
an
ce
Molecule size should provide a basis to separate out aggregates.
Pharmaceutical Technology Europe March 2015 43
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Product/Service ProfileS
High Potency Solid dosage
capacity and expertise
Alkermes Contract Pharma Services,
has proven expertise in the handling of
highly potent drug substances. We have
over 500M annual solid oral dosage unit
capacity in our high potency suites. We
are capable of handling APIs to OEL 0.1μg/
m3 to commercial high-volume scale. Our
experience and expertise in manufacturing
is committed to providing you with your
exact production needs, delivered to the
highest quality standards and at a fair price.
Key Benefts of working with us
•45+ year history in contract pharma
manufacturing business with a proven
track record
•Experience and expertise handling at
commercial scale high potency
products
•FDA/EMA-licensed sites in both Europe
and U.S. – most recent FDA audits
resulted in no 483s
•Authorized to supply to all other major
territories including supply of product
to Brazil, China and India.
Alkermes contract Pharma Services
www.alkermes.com/contract
complex Sterile contract
Manufacturing
Parenteral manufacturing is a complicated
process. Cytotoxics, antibody-drug
conjugates (ADCs), highly potent
compounds, biologics, and lyophilized
products present many challenges and
require specialized understanding and
expertise. Baxter’s BioPharma Solutions
business brings more than sixty (60)
years of experience in handling complex
sterile manufacturing cytotoxics for global
markets. In 2013, Baxter announced a
third expansion of its fll/fnish cytotoxic
contract manufacturing facility in Halle
(Westfalen), Germany (following previous
expansions in 2007 and 2011) to meet
clients’ growing needs for cytotoxic
manufacturing. The expansion includes
the installation of a new commercial flling
line with two freeze dryers, and a clinical
flling line with an additional freeze dryer.
Both the new commercial and clinical
lines will be equipped with an automated
loading/unloading, capping and inspection
infrastructure. This expansion is expected
to be complete in late 2015, and has
been designed to support international
manufacturing and regulatory requirements
serving the needs of clients globally.
Baxter BioPharma Solutions
www.baxterbiopharmasolutions.com
Pft Powder flow tester
Brookfeld Powder Flow Tester (PFT)
delivers quick and affordable scientifc
testing for powder fow characterization
during gravity discharge in industrial
processing equipment.
The Brookfeld PFT is ideal for
manufacturers who process powders daily
and want to minimize or eliminate the
downtime and expense that occur when
hoppers/silos fail to discharge. With the
PFT customers can perform QC checks on
incoming materials, quickly characterize
new formulations for fowability and
adjust composition to match the fow
behavior of established products.
Powder Flow Pro Software and all
accessories for handling powder samples
are included with the instrument. Test
options including: Flow Function, Time
Consolidation, Wall Friction and Bulk
Density. The operator also has a choice
of graphical or tabular Data Output
Format for each test plus calculations
for arching dimension, rathole
diameter, hopper half-angle, gravity
chute angle and bulk density curve.
Brookfeld engineering laboratories, inc.
www.belusa.com
44 Pharmaceutical Technology Europe March 2015 Pharmtech.com
ES582473_PTE0315_044.pgs 03.10.2015 22:54 ADV blackyellowmagentacyan
The new platform excipient for tablets, sachets and more
• first rate filler-binder properties due to excellent compressibility
• fast and slow disintegrating tablets (chewables, effervescents,
suckables, FDDTs…)
• ideal in sachets for direct oral application
or dry suspensions
• outstanding flow and mixing properties
• high dilution potential and high content uniformity
• very low hygroscopicity and excellent stability
• GMO-free and non-animal origin
BENEO-Palatinit GmbH · Phone: +49 621 421-150 · [email protected] · www.galenIQ.com
The Smart Bulk Excipient
ES582700_PTE0315_045_FP.pgs 03.11.2015 02:37 ADV blackyellowmagentacyan
Product/Service ProfileSProduct/Service ProfileS
catalent Pharma Solutions
Catalent Pharma Solutions, the leading
global provider of advanced delivery
technologies and development solutions
for drugs, biologics and consumer health
products, has invested in its Somerset, NJ
facility to create a Centre of Excellence
for potent handling across the company’s
portfolio of oral solid dose forms.
The investment included an expansion
of facility and engineering controls for
high potency tableting to supplement
existing capabilities, giving additional
capabilities to handle potent compounds
for large scale blending, fuid bed
processing and high shear granulation.
Catalent’s acquisition of Micron
Technologies allows the company to
undertake particle size engineering of potent
compounds, complementing handling and
manufacturing facilities at Somerset.
Investment was announced in 2014
at Catalent’s Kansas City, MO facility
to increase highly potent and cytotoxic
clinical drug packaging capabilities.
Catalent offers end-to-end solutions
for development, analysis and clinical
and commercial manufacturing for oral
solid doses and potent compounds.
catalent Pharma Solutions
www.catalent.com
etQ compliance
Management Software
EtQ is the leading FDA Compliance, Quality,
EHS and Operational Risk Management
software provider for identifying, mitigating
and preventing high-risk events through
integration, automation and collaboration.
Founded in 1992, EtQ has always had a
unique knowledge of FDA Compliance,
Quality, EHS and Operational Risk processes,
and strives to make overall compliance
operations and management systems better
for businesses. EtQ is headquartered in
Farmingdale, NY, with main offces located
in the U.S. and Europe. EtQ has been
providing software solutions to a variety
of markets for more than 20 years. For
more information, please visit http://www.
etq.com or contact us at 800.354.4476.
etQ
www.etq.com
dioSNA ccS 10 in isolator
The advantages of the compact design and
ease of use of Diosna´s pharmaceutical mixer
P1-6 and fuid bed processor Midilab XP are
the main reasons for integrating them in
isolators when granulation equipment for
high potent products at laboratory scale
(approx.. 0.1 kg - 5 kg) is needed. Mixing and
granulating of high potent powders with
an occupational exposure limit (OEL) under
0.1 µg/m³ is then possible. The isolators
are airtight and operate under negative
pressure. The transfer of the high potent
products is performed with rapid transfer
ports or endless liner systems. After
production the decontamination is achieved
by WIP (washing in place) to avoid cross-
contamination and hazards for the operators.
For the integration of granulation equipment
in an isolator the entire process must be
considered for the design of the system.
For this reason a mock-up study in which all
process steps are “played out” is necessary.
dioSNA dierks & Söhne GmbH
www.diosna.com
Product/Service ProfileS
46 Pharmaceutical Technology Europe March 2015 Pharmtech.com
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Product/Service ProfileSProduct/Service ProfileS
flavor Bases for companion
Animal Health Products
Pet Flavors Inc. (PF, Inc.) is the world leading
developer and manufacturer of quality
f avor bases for both pharmaceutical drugs
and nutritional supplements in the animal
health industry. PF Inc. sells several types of
f avor bases for use in formulating palatable
canine, feline, and equine dosage forms
that are sold on a worldwide basis. PF Inc’s
Artif cial Powdered Beef Flavor; PC-0125
is sold to 9 of the top 10 largest animal
health pharmaceutical companies in the
world and has been successfully formulated
in over 20 New Animal Drug Approvals
(NADAs). Our company has over 30 years
of experience with formulation and product
development. With an active ingredient
and our f avor bases we can create
highly palatable chewable tablets, soft
chews or granules. Our services include
improving the palatability of an existing
product, creating product line extensions
or developing entirely new products.
Pet flavors inc.
www.Petflavors.com
oPtiMA pharma for
uncompromising
pharmaceutical applications
Optima Pharma develops and manufactures
f lling, sealing and process technology for
pharmaceuticals. Highly sophisticated,
fully automated systems from Optima
Pharma are used to process blood plasma
products, vaccines, oncology and biotech
products in pref lled syringes, vials, IV
bottles and cartridges. In addition to f lling
and sealing, complementary functions
and process equipment are integrated,
including washing machines, sterilization
tunnels and containment systems.
Pharmaceutical freeze drying and robotic
product handling complete the company’s
extensive portfolio. The division guarantees
quick, professional service with 13
international locations. Optima Pharma is
a member of the OPTIMA packaging group
GmbH (Schwäbisch Hall), which employs
a workforce of 1,900 around the globe.
oPtiMA pharma GmbH
www.optima-pharma.com
Bio/Pharmaceutical GMP
Product testing
Eurof ns BioPharma Product Testing offers
the most complete range of testing
services, harmonized quality systems and
LIMS to more than 800 virtual and large
pharmaceutical, biopharmaceutical and
medical device companies worldwide.
We offer complete CMC Testing Services
for the Bio/Pharmaceutical industry,
including all starting material, process
intermediates, drug substance, drug
product and manufacturing support, as well
as broad technical expertise in
Biochemistry, Molecular & Cell Biology,
Virology, Chemistry and Microbiology.
With a global capacity of more than
50,000 square meters and 14 facilities
located in Belgium, Denmark, France,
Germany, Ireland, Italy, Spain, Sweden and
the U.S., our network of GMP laboratories
and vast experience allow us to support
projects of any size from conception to
market. Further, we have teams of
scientists placed at more than 40 client
facilities throughout Europe and the U.S.
through our award-winning Professional
Scientif c Services (PSS) insourcing program.
eurof ns BioPharma Product testing
www.eurof ns.com/Biopharma
pharma@eurof ns.com
Pharmaceutical Technology Europe March 2015 47
ES582472_PTE0315_047.pgs 03.10.2015 22:53 ADV blackyellowmagentacyan
Product/Service ProfileSProduct/Service ProfileS
i-series - the new driver of
i-volution in HPlc analysis
Shimadzu has introduced the i-series of
integrated HPLC and UHPLC systems. The
analyzers meet the needs of any analytical
environment with high speed, outstanding
performance, maintainability and economic
effciency. The i-series concept combines
innovation, intuition and intelligence for
applications in the food, environmental,
chemical and pharmaceutical industry:
• Innovation, e.g. through higher
efficiency and remote monitoring
• Intuition, e.g. by utilizing a unified
graphical user interface
• Intelligence, e.g. realized in the
automation of routine procedures.
The i-series fts small labs with
limited space, as well as large labs
requiring high-throughput operation. Even
inexperienced operators easily obtain
high quality data and beneft from the
improved and automated workfow.
Shimadzu europa GmbH
www.shimadzu.eu
e-mail: [email protected]
flip-off® Plusru
West’s high-quality, sterile Flip-Off® PlusRU
seals are designed for capping under
Grade A air supply as mentioned in the
European Medicines Agency (EMA) Annex
1 “Manufacture of Sterile Medicinal
Products” guideline. Flip-Off® PlusRU seals are
manufactured using the TrueEdge® technology
production process providing precise and
reproducible seals, and are assembled in a
CNC (Controlled, not Classifed) environment.
A certifed bioburden prior to sterilization
allows cGMP compliant sterilization
validation, enabling clean crimping processes
in accordance with the latest regulations
described in EMA Annex 1. Flip-Off® PlusRU seals
are gamma sterilized and compliant with ISO
11137. They have full validation of sterilization
and packaging, including a comprehensive
certifcation package. When considering clean
crimping and capping process in non-aseptic
environments under Grade A air supply,
West’s vision-controlled Flip-Off® PlusRU
seals are intended to meet operational and
regulatory challenges to achieve consistently
reproducible, safe container integrity for the
drug product and ensure patient safety.
West Pharmaceutical Services, inc.
www.westpharma.com
Sterile Wipes
VAI features a complete range of dry &
saturated, sterile wipers for use in any
cleanroom environment. Our wipers are
knitted with continuous monoflament
polyester and are cut using “FocusEdge”
cutting technology. Every wipe that VAI
produces is available with the same material
for consistency and inexpensive validation.
The wipers are packaged into bags
suitable for use in an ISO Class 4 area and
labeled with lot number and expiration. All
sterile wipers are sterilized via gamma
irradiation at a 10-6 SAL, quality assurance
tested and released to specifcations
defned by IEST and ASTM. All shipments are
delivered with lot specifc documentation.
VAI’s high quality sterile wipers are
available in WipeDown® dry wipes,
Process2Wipe® (USP IPA and WFI Quality
Water), HYPO-CHLOR® WFI Formula in
0.25%, 0.52%, 5.25%, STERI-PEROX® WFI
Formula in 3% and 6%, DECON-CLEAN® RTU
reside remover, individually packaged
ALCOH-WIPES®, ALCOH-GLOVES®, and
STEEL-BRIGHT® Wipes.
veltek Associates, inc.
Sterile.com
48 Pharmaceutical Technology Europe March 2015 Pharmtech.com
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PharmTech.com
NOVEMBER 2014 Volume 26 Number 11
MARKET REPORT
Germany Post AMNOG
TECHNICAL Q&A
Continuous Manufacturing
PEER-REVIEWED
Sublingual Formulations
QbD in
Parenterals
Addressing
Particulate
Contamination
Advancing Development & Manufacturing
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chemicals, water)
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(Fill in ALL that apply)
A ◯ Raw Materials
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ES582699_PTE0315_049_FP.pgs 03.11.2015 02:37 ADV blackyellowmagentacyan
50 Pharmaceutical Technology Europe MARCH 2015 PharmTech.com
ASK THE EXPERT
Siegfried Schmitt, Principal Consultant, PAREXEL
International, discusses good engineering practices.
Q.Our engineering department is managed by a small team of
professionals who supervise and manage a large number of
service suppliers that perform the majority of engineering tasks.
We find that it typically takes more than a month before these
suppliers provide us with necessary documents, such as
calibration reports or updated piping and installation diagrams
(P&IDs). The engineering manager explained that this process
cannot be expedited. We are concerned that this long delay
may lead to a negative observation during our next inspection.
How can we change this pattern?
A.Outsourcing services is a common industry practice in the
pharmaceutical business. The regulatory agencies are well
aware of this fact and have issued rules and regulations governing
outsourced activities (1, 2). These regulations and guidance
documents, however, do not provide information that would define
an acceptable period of time for providing data and records to the
contract giver. In this specific case, the engineering department is
the contract giver, but there are no specific regulations you can cite
to ensure timely documentation. It is important to fix this challenge,
due to the possible impact on operations and quality this
document delay may create.
You mention two examples: calibration and engineering drawings.
There can be major impacts on each of these due to slow response
service suppliers. Let us first look at the calibration data and
records. For both manufacturing operations and process validation,
it is crucial to know the current calibration status of your equipment
and instrumentation. If that information is unavailable, then you
simply cannot proceed, seriously impacting your ability to operate.
Also, in the case of deviations, such missing information can
impede on the root cause investigation. Most companies attempt
to complete this type of investigation within 30 days, which may be
difficult if you must wait even longer for the relevant engineering
information and documents. It is important to note that the
validation in not confirmed until the engineering department verifies
and approves the third party’s report and conclusion.
In the case of the P&IDs, it will be difficult, if not impossible,
to present the as-is build of your facility in case of an inspection.
Without current drawings, making changes to the facility will be
challenging at best. Not having a picture of the as-is situation
may also hinder investigations if and when deviations occur.
In either case, the slow response time of your suppliers can have
critical impact on your engineering department and will need to
be addressed.
The time span from having the activity performed until you
receive the data and reports from your suppliers seems excessively
long, from both a compliance and a business perspective. If
possible, work with your engineering department to review the
quality/technical agreements in place with their suppliers (3). These
should detail defined timeframes and modes of delivery. The
agreement, for example, may specify that sending a scanned copy,
instead of a paper copy, of a report is acceptable. You will find
that a scanned copy may save time. Where suppliers are unable
to deliver within a reasonable amount of time (e.g., days), your
company may need to consider bringing the services back in-house.
Should you find it difficult convincing your engineering
department of the need to improve timelines, you should escalate
this issue to your senior management. After all, senior management
has the ultimate responsibility for quality and compliance. It is in
the best interest off all involved parties to assure your compliance
status reflects current good manufacturing practices.
References1. EC, EudraLex, Vol 4, Chapter 7 “Outsourced Activities,” http://
ec.europa.eu/health/files/eudralex/vol-4/vol4-chap7_2012-06_en.pdf, accessed 19 Jan. 2015.
2. FDA, FDASIA Title VII Drug Supply Chain Provisions, www.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct/SignificantAmendmentstotheFDCAct/FDASIA/ucm365919.htm, accessed 17 Feb. 2015.
3. Quality-Technical Agreements, Pharm. Tech. 38 (5) 70 (2014). PTE
Managing Supplier Data Collection
Alkermes ............................................................................................... 13
Baxter Healthcare Corp ....................................................................... 11
Bend Research ..................................................................................... 25
BENEO GmbH ....................................................................................... 45
Brookfield Engineering ........................................................................43
Butterworth Laboratories ..................................................................... 6
Catalent Pharma Solutions ...........................................................23, 52
DECAGON.............................................................................................. 39
DECHEMA ............................................................................................. 28
Diosna Dierks & Sohne GmbH ............................................................ 19
Dow Europe GmbH .............................................................................. 51
ETQ Inc..................................................................................................... 9
Optima Packaging GmbH ...................................................................... 5
Panreac Quimica SA ............................................................................ 21
Pet Flavors Inc ...................................................................................... 17
Shimadzu Europe ................................................................................... 2
Spectrum Chemical Mfg Corp ............................................................ 35
Starna Scientific .................................................................................... 26
Veltek Associates Inc ............................................................................. 7
West Pharmaceutical Services ........................................................... 15
Ad IndexCOMPANY PAGE
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