solid dosage drug development and manufacturing farmarind wordpress com
eBOOK SERIES
2016
SOLID DOSAGE DRUG DEVELOPMENT
AND MANUFACTURING
SOLID DOSAGE DRUG DEVELOPMENT
AND MANUFACTURING 2016
EXCIPIENTS
EDITORIAL
Editorial Director Rita Peters rpeters@advanstar.com
Senior Editor Agnes Shanley ashanley@advanstar.com
Managing Editor Susan Haigney shaigney@advanstar.com
Science Editor Adeline Siew, PhD asiew@advanstar.com
Manufacturing Editor Jennifer Markarian jmarkarian@advanstar.com
Science Editor Randi Hernandez rhernandez@advanstar.com
Community Manager Caroline Hroncich chroncich@advanstar.com
Art Director Dan Ward
Contributing Editors Jill Wechsler jwechsler@advanstar.com; Jim Miller
info@pharmsource.com; Hallie Forcinio editorhal@cs.com; Susan J. Schniepp
sue.schniepp@mac.com; Eric Langer info@bioplanassociates.com;
and Cynthia A. Challener, PhD challener@vtlink.net
Correspondent Sean Milmo (Europe, smilmo@btconnect.com)
485 Route One South, Building F, Second Floor, Iselin, NJ 08830, USA
Tel. 732.596.0276, Fax 732.647.1235, PharmTech.com
SALES
Publisher Mike Tracey mtracey@advanstar.com
Mid-West Sales Manager Irene Onesto ionesto@advanstar.com
East Coast Sales Manager Joel Kern jkern@advanstar.com
European Sales Manager Linda Hewitt Linda.Hewitt@ubm.com
European Senior Sales Executive Stephen Cleland scleland@advanstar.com
Executive Assistant Barbara Sefchick bsefchick@advanstar.com
4 Excipient Quality and Selection
Irwin B. Silverstein
EXCIPIENT DATABASES
16 Unifying Excipient Databases
Agnes Shanley
NON-GELATIN CAPSULES
20 Establishing a New Performance
Standard for HPMC Capsules
Agnes Shanley
PROCESS SIMULATION
22 Modeling and Simulation
Move Downstream
Agnes Shanley
TABLET COMPRESSION
26 Optimizing Tablet Compression
Frederick J. Murray
CONTINUOUS MANUFACTURING
Address
485 Route One South
Building F, Second Floor
Iselin, NJ 08830, USA
Tel. 732.596.0276, Fax 732.647.1235
PharmTech.com
Sr. Production Manager Karen Lenzen
International Licensing Maureen Cannon mcannon@advanstar.com,
tel. 440.891.2742 or toll-free 800.225.4569 ext 2742, fax. 440.756.5255
Audience Development Manager Rochelle Ballou rballou@advanstar.com
34 Filling the Analysis Gap in
the Move to Continuous Processing
Jamie Clayton
ELEMENTAL IMPURITIES
40 Meeting USP Guidelines for
Elemental Impurity Analysis with
X-ray Fluorescence Spectrometry
Andrew Fussell
GENERIC DRUGS
Pharmaceutical Technology does not verify any claims or other information appearing in any of
the advertisements contained in the publication and cannot take any responsibility for any losses
or other damages incurred by readers in reliance on such content. Pharmaceutical Technology
welcomes unsolicited articles, manuscripts, photographs, illustrations, and other materials but
cannot be held responsible for their safekeeping or return. UBM Life Sciences provides certain
customer contact data (such as customers’ names, addresses, phone numbers and e-mail addresses)
to third parties who wish to promote relevant products, services, and other opportunities which may
be of interest to you. If you do not want UBM Life Sciences to make your contact information available
to third parties for marketing purposes, simply call toll-free 866.529.2922 between the hours of 7:30
am and 5 pm CT and a customer service representative will assist you in removing your name from
UBM Life Sciences’ lists. Outside the United States, please phone 218.740.6477. To subscribe: Call
toll-free 888.527.7008. Outside the US, call 218.740.6477. Single issues, back issues: Call toll-free
800.598.6008. Outside the US call 218.740.6480. Reprints of all articles in this issue and past issues of
this publication are available. Call 877-652-5295 ext. 121 or email bkolb@wrightsmedia.com. Outside
US, UK, direct dial: 281-419-5725. Ext. 121. Direct mail lists: Contact Tamara Phillips, Marketing
Services, tel. 440.891.2773, tphillips@advanstar.com. Display, Web, Classified, and Recruitment
Advertising: Contact Tod McCloskey, tel. 440.891.2739, tmccloskey@advanstar.com. Permissions:
Contact Maureen Cannon, tel. 440.891.2742 or toll-free 800.225.4569 ext 2742, fax. 440.756.5255,
mcannon@advanstar.com.
46 Regulatory Considerations for Controlling
Intermediates in Type-II Drug Master Files for
the Manufacture of Generic Drug Substances
Kandasamy Subburaj, Brian T. Connell, Srinivasa Murthy, Humcha
Hariprakasha, Deborah F. Johnson, Huyi Zhang, and David J. Skanchy
54 Ad Index
Issue Editor: Agnes Shanley.
On the Static Cover: Science Photo Library/Getty Images; Dan Ward.
On the Animated cover: Nanihta photography/DAJ/Tetra Images/Yuri_Arcurs/
Empato/E+/Image Source/Still Factory/Getty Images; Dan Ward.
©2016 UBM. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any
means, electronic or mechanical including by photocopy, recording, or information storage and retrieval without
permission in writing from the publisher. Authorization to photocopy items for internal/educational or personal use, or
the internal/educational or personal use of specific clients is granted by UBM for libraries and other users registered with
the Copyright Clearance Center, 222 Rosewood Dr. Danvers, MA 01923, 978-750-8400 fax 978-646-8700 or visit http://
www.copyright.com online. For uses beyond those listed above, please direct your written request to Permission Dept.
fax 440-756-5255 or email: mcannon@advanstar.com.
P h a r mTe c h . c o m
21ST CENTURY PHARMA
A holistic, systems-based approach to drug
development, manufacture and delivery
FORMULATION
MANUFACTURE
DELIVERY
At PSE we are working with leading pharma
companies to develop a holistic approach to
drug development, manufacture and delivery.
We call it Systems-based Pharmaceutics (SbP).
A systems-based approach considers the entire formulationto-delivery cycle as a single integrated system, relating
formulation and manufacturing decisions directly to drug
delivery KPIs.
SbP is helping pharma companies to accelerate development,
improve manufacturing, enhance drug product performance and
increase R&D efficiency. Contact us to find out more.
More online
«
Download the PSE, Pfizer
and Eli Lilly SbP phase 1
progress report
The Advanced Process
Modelling Company
psenterprise.com
Operations in UK, USA,
Switzerland, Japan, Korea, China,
Taiwan, Malaysia, Thailand and UAE.
UK Head Office
t: +44 20 8563 0888
e: info@psenterprise.com
THE POWER TO BE CERTAIN
Excipients
Excipient Quality
and Selection
Irwin B. Silverstein
Irwin B. Silverstein, PhD, is a
consultant to IPEC-Americas.
4
H
ow does one define quality as applied to excipients? If
we pose the same question for APIs, the response would
be to produce the ingredient under appropriate GMPs,
and to the compendial monograph and the API assay.
Because the monograph provides the minimum requirements, API
quality is improved by reducing the presence of all materials other
than the desired chemical. This is logical because, by definition, the
API is “intended to furnish pharmacological activity or other direct
effect in the diagnosis, cure, mitigation, treatment, or prevention
of disease or to affect the structure and function of the body” (1).
Extraneous substances may be harmful to the patient in that they
may lead to side effects, or they are inert, thus reducing API purity
and thereby compromising efficacy.
Excipient quality is described quite differently. While one would
again refer to compliance with the compendial monograph (if there
is one) or the manufacturer’s specification, a higher assay is not always better. While this may seem counterintuitive, excipients are
often complex mixtures that include constituents arising from raw
materials, catalyst, solvent, initiator residue, or side reactions. The
International Pharmaceutical Excipients Council (IPEC) refers to
these other unavoidable substances in the excipient as concomitant components (2). The performance of many excipients in the
drug formulation may rely on the presence of such substances in
the excipient. Concomitant components in the excipient may aid
in solvating drug components, improving excipient functionality,
etc. Excipient quality, therefore, is characterized as compliance to
the monograph or specification and having a consistent concomitant
composition.
Pharmaceutical Technology SOLID DOSAGE DRUG DEVELOPMENT AND MANUFACTURING 2016 P h a r mTe c h . c o m
IMAGE SOURCE/STILL FACTORY/GETTY IMAGES; DAN WARD
Choosing the right
excipient manufacturer
can help ensure the use
of quality excipients.
Veltek Associates, Inc. offers two garment product lines, which are both pre-folded in
our
system. Comfortably styled and fitted with elastic thumb loops to reduce
shifting, as well as tunnelized elastic wrists and ankles.
1600 Garments
Breathable
Comfortable
High bacterial eiciency
1700 Garments
High iltration eiciency
Low particulate and shedding
performance
Excellent water repelency
Face Masks
Breathable
Reduces goggle fogging due
to absorption eiciency
Soft and comfortable
Excipients
Specified limits for excipients
As required by clause 8.2.4.6 of the ANSI excipient GMP standard, excipient manufacturers are
expected to identify concomitant components
present in the excipient whenever possible and to
specify limits for those components that have been
shown to be either important to excipient performance or known to have an adverse impact to the
patient (3). Impurities known to be present in the
excipient are also required to have specified upper
limits based upon safety considerations, regulatory
requirements, customer requirements, and, if applicable, the compendium.
Povidone and its monograph illustrate these
points. Povidone is the homo-polymerized monomer vinyl pyrrolidone. It is sold in various molecular weights. In the late 1980s, GAF Chemicals,
a manufacturer of Povidone, was made aware of
the presence of hydrazine, a toxic substance, in
Povidone. The company identified the mechanism
of hydrazine formation as a by-product of the polymerization reaction. Through modification of
the process, the level of hydrazine was reduced
to what was deemed acceptable for safe use of Povidone in pharmaceuticals. Because Hydrazine
is not expected to be beneficial in Povidone, it
is thus considered an undesirable component. A
test method was developed, appropriate specified
limits were established, and the compendium was
updated accordingly.
In the early 1990s, vinyl pyrrolidone was identified as a suspect carcinogen. As a consequence,
manufacturing methods were again modified
to reduce the level of residual vinyl pyrrolidone
monomer to a toxicologically safe level. Vinyl pyrrolidone has solvating properties and is a reactive
molecule. Therefore, residual vinyl pyrrolidone in
6
Povidone is more likely than hydrazine to impact
performance of the excipient in some drug formulations. A test method suitable for detecting low levels
of this monomer was developed, and the compendium was updated accordingly.
An additional substance, 2-pyrollidone, was subsequently found in Povidone. This substance is
formed during the polymerization reaction when
some vinyl pyrrolidone decomposes rather than
polymerizes. While it is unlikely that the presence
of hydrazine or vinyl pyrrolidone beneficially impacts the performance of Povidone in the drug formulation, the same conclusion cannot be drawn for
2-pyrrolidone. 2-Pyrrolidone is often used as a solvent, and therefore, its presence in the excipient may
play a beneficial role in certain drug formulations
by helping to solvate the API. While it is possible to
remove this substance through further processing, it
is not feasible for the manufacturer to asses the impact on performance for all drug formulations that
use Povidone. Therefore, it is important to control,
but not limit, the quantity of 2-pyrrolidone so that
the performance of each lot of Povidone is consistent in the various drugs that use this excipient.
Non-homogeneity
These examples with one excipient illustrate how
control of all the components in the material are
needed in order to assure consistent quality. Another aspect that needs equivalent control is the
degree of homogeneity of solid excipients, particularly those supplied in powder form. However,
many excipients are also manufactured in much
larger volumes for other markets where a larger
degree of variation is tolerable.
To illustrate a common cause of non-homogeneity, consider that excipient manufacture often
Pharmaceutical Technology SOLID DOSAGE DRUG DEVELOPMENT AND MANUFACTURING 2016 P h a r mTe c h . c o m
Advancing Drug Delivery
Through Superior Polymer Design
Safe and efective delivery of today’s complex drug molecules is increasingly
a function of collaboration between polymer experts and pharmaceutical
product development teams. Acting on enabling science, producing
superior polymer excipient technology, and creating systems for
optimum bioavailability, Ashland works alongside formulators to
advance drug-speciic delivery platforms.
Explore how you can solve intricate drug formulation
and development challenges with polymer
expertise from Ashland.
Visit us at Ashland.com/pharmaceutical
Ashland
pharmaceutical@ashland.com
www.ashland.com/pharmaceutical
®Registered trademark, Ashland or its subsidiaries, registered in various countries
™Trademark, Ashland or its subsidiaries, registered in various countries
©2016, Ashland
AD-13475
Excipients
involves drying the substance. The ability to
dry material to a consistent residual moisture
throughout the lot is inherently difficult due to
the many operating variables. Spray drying is a
case in point. Operating parameters for the spray
dryer include the temperature and dew point of
inlet air, burner temperature, concentration of
the excipient in the aqueous solution, spray pattern of the excipient solution, rate of drying, and
outlet air temperature. During a 24-hour cycle,
Common impurities in excipients, which are not
needed for excipient performance, may include
residual process aids, additives, by-products, and
material that sheds from filter media. In addition,
contaminants, which are to be avoided, can occur
from environmental factors such as personnel hygiene, equipment failure, contact with packaging,
etc. and include rust, oil, grease, insect fragments,
extractable and leachable materials, etc.
Excipient quality is, therefore, best expressed
as conformance to GMPs
The stability of the excipient can pose a risk as well as to compendia or
a specification and consisif the material is likely to degrade during
tent composition, lot to lot.
storage or shipment when temperature
Consistent composition
and/or humidity are not controlled within
within each lot is also an
acceptable limits.
expression of excipient
quality, but oftentimes
the ambient air temperature and humidity may such consistency is difficult to achieve without
differ considerably from day to night. Also the ex- a blending step.
cipient concentration may vary due to prior manGenerally, it is expected that a more consisufacturing steps. Achieving a consistent moisture tent excipient composition will result in a more
level requires frequent sampling of dried material predictable performance in the final drug forand adjustment of spray-dryer operating param- mulation. In the selection of an excipient for a
eters. As drying conditions become more severe drug formulation, consideration should be to
in order to maintain constant residual moisture, include an excipient whose composition profile
however, it is possible to cause some degradation has known and tolerable variation with minimanifest as charring of the excipient. This is typi- mal number of concomitant components and
cally manifested as burnt particles (4). Consistent impurities.
moisture content in the excipient, therefore, may
be a tradeoff with the quantity of burnt particles Selection of excipient suppliers
in the product.
The European Union Directive Guidelines on the
Formalized Risk Assessment for Ascertaining the
Excipient impurities
Appropriate Good Manufacturing Practice for ExExcipient impurities are specific entities that cipients of Medicinal Products of Human Use (5)
should not be present and/or need to be con- provides the following characteristics for assesstrolled for safety, toxicological, or other reasons. ing the manufacture and supply of excipients:
8
Pharmaceutical Technology SOLID DOSAGE DRUG DEVELOPMENT AND MANUFACTURING 2016 P h a r mTe c h . c o m
Excipients
t Potential presence of transmissible spongiform
encephalopathy (TSE)
t Potential for viral contamination
t Potential for microbiological or endotoxin contamination
t Potential for the presence of impurities
t Supply chain complexity and security
t Excipient stability
t Tamper-evident packaging.
Each of these characteristics can be related to
excipient “quality” and used to assess excipient
suppliers. Note that each of these considerations
is in addition to manufacturing the excipient in
conformance to excipient GMP.
In addition, the ANSI excipient GMP standard (3)
highlights the following criteria to assess for risk to
protect an excipient from contamination:
t Hygienic practices: excipient contamination due
to personnel hygiene, illness, attire, unauthorized access, food, medication, tobacco, etc.
t Infrastructure, building: excipient contamination, cross-contamination, mix-ups
t Infrastructure, equipment: excipient contamination due to material of construction, utilities,
water, process materials, and work environment
(air handling, cleaning/sanitation, pest control
and drainage).
Minimizing contamination risk
Using an excipient manufacturer that produces
the excipient in dedicated equipment is a lower
risk to excipient quality as a result of reduced risk
of cross-contamination. Equipment can be considered dedicated when it is used to manufacture
products utilizing the same chemistry and raw
materials. Equipment used to manufacture an excipient in various particle size, density, viscosity,
10
or molecular weight, therefore, can be considered
dedicated. Also equipment used to produce various grades of an excipient that are then sold in different markets (e.g., food, cosmetic, or industrial
applications), but produced using the same chemistry and raw materials, should also be considered
dedicated.
Using dedicated equipment reduces the risk
that the excipient will be contaminated by the
presence of other substances (e.g., other raw material, intermediate, or finished product residue in
the production equipment). Using multi-purpose
equipment relies heavily on verifying cleaning effectiveness and the ability to detect potential residual contaminants to assure the minimization
of potential cross-contaminants in the excipient.
Where multi-use equipment is used, it is advisable
to review the excipient manufacturer’s cleaning
validation report.
When possible, it is preferable to source the excipient from a supplier that does not use animalderived raw materials at risk for bovine spongiform
encephalopathy (BSE)/TSE in the manufacture of
the excipient. Otherwise, the excipient user will
have to ensure the excipient presents minimal risk
from TSE contaminants. A risk assessment should
include confirmation the animals used in the manufacture of the animal-derived raw material come
from a country designated as negligible TSE risk.
Alternatively, the excipient manufacturer should
demonstrate that the animal-derived raw material
was processed under conditions that have been defined to inactivate the TSE risk materials if present.
TSE risks are also present when the excipient is
manufactured in multi-purpose equipment where
the other products are animal derived. If there is a
risk of TSE material residue on equipment, the ex-
Pharmaceutical Technology SOLID DOSAGE DRUG DEVELOPMENT AND MANUFACTURING 2016 P h a r mTe c h . c o m
Vcaps® Plus Capsules
Not all capsules are
created equal.
Download
Whitepaper
Finally, a superior specialty polymer capsule with proven gelatin-like
performance without cross-linking potential, Vcaps Plus is the new capsule
standard with benefits of narrow weight variability, impressive resistance to
heat and humidity, and validated manufacturing experience. By reducing
variability, Vcaps Plus capsules are quickly becoming a powerful new tool to
reduce timelines in drug product development.
Contact us at 800-845-6973 for our full technical package and
samples for your development review.
8000
Mean Plasma Acetaminophen Concentration (ng/mL)
Vcaps® Plus capsules can optimize capsule disintegration for pharmaceutical
products with the ability to release contents independent of pH and ionic
strength of the test media. And a new in-vivo study demonstrates that
Vcaps Plus capsules are equivalent to gelatin in terms of human
pharmacokinetics profile.
Proven Bioequivalence to Gelatin
Molecule = Acetaminophen Human
cross-over study in 24 subjects
7000
6000
Gelatin
Capsules
5000
Vcaps Plus
Capsules
4000
3000
2000
1000
0
0
2
4
6
8
10
Nominal Hours (hrs) Post Dose
Mean in-vivo acetaminophen plasma
concentration profiles over 12 hours.
True pH and Ionic Media Independence
100
90
80
% Caffeine dissolved
The new standard in HPMC capsules:
Immediate release in-vivo performance
bioequivalent to gelatin and consistent
dissolution across changing pH and
ionic strength.
70
60
pH 1.2 USP
pH 6.8 USP
pH 6.8 JP2
Simulated milk fluid
pH 1.2 – 2 g KCI/L
pH 1.2 – 9 g KCI/L
50
40
30
20
10
0
0
New in-vivo results comparing Vcaps Plus HPMC
Capsules and gelatin capsules demonstrate
bioequivalency of HPMC in multiple dissolution profiles.
Read the full report at VcapsPlus.com.
© 2016 Capsugel Belgium NV All rights reserved.
3
6 9 12 15 18 21 24 27 30 35 40 45 50 55 60 75
Time in minutes
In-vitro dissolution of caffeine in
Vcaps Plus capsules
12
Excipients
cipient manufacturer should demonstrate cleaning
procedures that show residual TSE risk material is
either reduced to an acceptable level on the equipment surface or is inactivated.
The risk of viral, microbiological, or endotoxin
contamination arises from raw materials, water,
and the environment. Where the manufacture of
the excipient uses viral agents or there is a risk of
contamination with viral agents, adequate measures of sanitation or sterilization by the supplier
are expected.
borne particulate to reduce the risk of microbial
contamination only requires use of a HEPA filter
if the excipient is purported to be sterile.
Contamination of the excipient with undersirable components can arise from such sources as
nearby manufacturing operations, processing
equipment (e.g., filters and traps), and utilities.
Filters pose a risk from shedding their material of
construction and from traps that are improperly
maintained, allowing trapped impurities through.
Utilities such as nitrogen, compressed air, and
steam may contaminate the excipient with
The complexity of the supply chain from
i mpu r it ie s such a s
excipient manufacturer to pharmaceutical
compressor oi l a nd
facility is a consideration in selecting a supplier. boiler additives.
It is common for the
Excipient manufacturers should use at least pota- excipient to be produced at a site where many
ble water where water is used in the process after the other products are also manufactured. Some of
starting point for GMP or when water is a potential these other products may be toxic (e.g., herbicides
source of microbial contamination in the finished or pesticides) or they may use toxic ingredients
excipient. Water that is used for temperature control in their manufacture. Where toxic substances are
that does not contact excipient during manufacture volatile enough to become airborne contaminants,
poses minimal risk under normal operating condi- manufacturers should take appropriate measures
tions and therefore need not be potable. For excipi- to minimize the risk of contamination. It is iments that are intended for drug products where the portant for the user to assess the risk of airborne
presence of endotoxin poses a risk to patient safety contamination and the measures taken to protect
and water comes into direct contact with the ex- the excipient during an onsite audit.
cipient during processing, higher purity water such
as United States Pharmacopieal Convention (USP) Supply chain considerations
water for injection may be expected to be used.
The complexity of the supply chain from excipiThere is also the potential for airborne microor- ent manufacturer to pharmaceutical facility is also
ganisms to contaminate the excipient. Generally, a consideration in selecting a supplier. Although
airborne microbes that can contaminate the ex- delivery from an excipient manufacturing site
cipient can be controlled by filtering the air, such directly to the pharmaceutical manufacturing
as when the excipient is exposed to the air during facility provides the least opportunity for the expackaging, to remove particles. Removal of air- cipient to become contaminated or tampered with
12
Pharmaceutical Technology SOLID DOSAGE DRUG DEVELOPMENT AND MANUFACTURING 2016 P h a r mTe c h . c o m
en route; generally direct delivery is uncommon should verify through the paper trail that the shipand only applies to full truckloads of the excipi- ment of an excipient lot has come from the excipient. More often, less-than-truckload quantities are ent manufacturer.
shipped by common carrier. Oftentimes, the shipThe stability of the excipient can pose a risk if
ment goes from the manufacturer to a warehouse the material is likely to degrade during storage or
of the transport carrier. There, the shipment may shipment when temperature and/or humidity are
be cross-docked to a truck heading to the desired not controlled within acceptable limits. Generally,
destination or another intermediate destination. excipients such as inorganic salts, minerals, modiWhile tampering with the excipient at the trans- fied food ingredients, and synthetic substances are
port warehouse is unlikely, there is the possibil- stable materials. Also, many excipients have been
ity for the packaged excipient to be exposed to in commerce for an extended number of years and,
extremes of weather (temperature, humidity, and Where delivery is not direct from the
precipitation), for t he
excipient manufacturer, the pharmaceutical
packaging to be damaged
company should periodically establish the
through mishandling, or
for the tamper-evident seal pedigree of the excipient.
to be accidentally broken.
Excipients are often sold through a distributor. therefore, their stability has been well established
Distributors can sell the excipient in the unopened and characterized. Stability issues occur more
excipient manufacturer’s package or the distributor frequently from exposure to moisture or oxygen
may repackage the excipient into smaller packages. rather than temperature extremes. However, unExcipients may also be shipped in bulk to a manu- less studies have shown the excipient to be affected
facturer’s terminal or a distributor where the excip- by extremes of temperature, humidity, or exposure
ient is either stored in bulk tanks or packaged from to oxygen, there is little cause for concern regardthe tank truck or rail car into discrete containers. ing excipient storage.
Any time the excipient is handled other than in
For moisture- and/or oxygen-sensitive excipients,
the original container is an opportunity for the the excipient packaging should be considered and
excipient to become contaminated, adulterated, or assessed when selecting a supplier. The excipient
otherwise compromised. Therefore, the fewer such supplier should provide evidence for the suitability
activities in the supply chain, the lower the risk.
of the packaging used to protect the excipient from
Where delivery is not direct from the excipi- moisture and oxygen.
ent manufacturer, the pharmaceutical company
Finally, tamper-resistant packaging is an imshould periodically establish the pedigree of the portant consideration in the selection of a supexcipient. As discussed in the IPEC-Americas plier. Though packages can be sealed with tamand IPEC-Europe Excipient Pedigree position per-evident closures, the package materials can be
paper of 2008 (6), the pharmaceutical company susceptible to tampering via a puncture. However,
Pharmaceutical Technology SOLID DOSAGE DRUG DEVELOPMENT AND MANUFACTURING 2016
13
Excipients
impervious packaging such as steel drums may not
be appropriate for some excipients. High-density
polyethylene (HDPE) drums may be compatible
with the excipient and are more resistant to product tampering than fiber drums or bags. Though
bags and supersacks are a challenge to make tamper resistant due to their material of construction,
oftentimes they are the only packaging available.
Package openings should be protected with tamper-evident seals unique to the excipient manufacturer. Such seals are characterized by their having
to be opened to gain access to the excipient, cannot be reapplied if broken or otherwise removed,
and are unique in that they have the manufacturer’s name, logo, or inherent design characteristic. While numbered seals are desirable, they are
impractical for excipients where the number of
containers in a lot often exceeds 100 and can be
in excesses of 1000. Using a tamper-evident seal,
however, provides no benefit if incoming inspection by the pharmaceutical firm fails to match
the appearance of the seal to an authentic seal (or
photo) provided by the excipient manufacturer.
been made and the risk is kept to an acceptable maximum.
t No viral risk material is used in excipient manufacture unless an adequate assessment has
been made and the risk is kept to an acceptable
maximum.
t Adequate measures are taken to control the contamination risk from microbes or endotoxin unless an adequate assessment has been made and
the risk is kept to an acceptable maximum.
t The risk of contamination is mitigated through
the implementation of GMP controls.
t Transport of the excipient from the manufacturer
is directly to the user.
t The excipient is stable under the conditions of
storage and shipment.
t Each excipient package is tamper resistant and, if
feasible, closed with a tamper-evident seal.
These considerations will help to ensure the use
of quality excipients in the manufacture of pharmaceuticals.
Acknowledgement
The author would like to thank those colleagues
Conclusion
at IPEC who took the time to provide comments
Excipient quality is best characterized as confor- to this article.
mance to GMPs and the compendial monograph
or specification with a consistent composition pro- References
1. ICH, Q7, Good Manufacturing Practice Guide for Active Pharfile lot to lot and within lot.
maceutical Ingredient (ICH, November 2000).
In the selection of an excipient supplier, the fol- 2. IPEC, Excipient Composition Guide (IPEC, 2009).
lowing characteristics minimize the risk to excipi- 3. NSF/IPEC/ANSI Standard for Pharmaceutical Excipients, Good
Manufacturing Practices (GMP) for Pharmaceutical Excipients,
ent quality:
363-2014.
t The excipient is manufactured using dedicated 4. IPEC-Americas, Technically Unavoidable Particle Profile Guide
(IPEC, 2013).
equipment or mixed-use equipment with suffi5. EUR-Lex, Official Journal of the European Union, 2015/C95/02,
cient cleaning validation.
21.3.2015, C95/10-C95/13. Website: http://bit.ly/EurLexTC15
t No TSE risk material is used in excipient man- 6. IPEC, IPEC-Europe Excipient Pedigree position paper, www.
ipecamericas.org/ipec-store PT
ufacture unless an adequate assessment has
14
Pharmaceutical Technology SOLID DOSAGE DRUG DEVELOPMENT AND MANUFACTURING 2016 P h a r mTe c h . c o m
An obsession with quality definitely works to your advantage. Thatʼs
why Mikart is the Contract Development and Manufacturing Organization
(CDMO) that delivers the attention to detail you need, plus the speed
and responsiveness you want.
A Textbook Case For
(Quality Control) OCD.
Weʼre quick to respond with personalized
solutions that get your projects completed faster and meet your individual
requirements. All while remaining
fixated on quality.
In addition to Formulation Development, Mikart also provides Clinical
Trial Supplies, Regulatory Filing
Support, plus Manufacturing and
Packaging solutions.
Youʼll find Mikart has everything
youʼre looking for in a pharma
partner: innovative technology and
equipment, highly skilled people and
38 years of solid CDMO experience.
To experience just how responsive
we can be, contact us at
1-888-4MIKART or send us an
email to info@mikart.com
Ready. Responsive.
Mikart, Inc. | 1750 Chattahoochee Avenue | Atlanta GA 30318
www.mikart.com | 1-888-4MIKART
Right for You.
Excipient Databases
Unifying Excipient Databases
Properties data critical, says NIPTE’s Hoag
Agnes Shanley
More databases currently
provide information on
pharmaceutical excipients,
but are they providing
enough information of the
right kind, and can they help
users address variability?
O
nce taken for granted as inactive fillers, excipients play a
vital role in any pharmaceutical formulation. The wrong
excipient can reduce a drug’s efficacy or interact with
APIs or other ingredients, resulting in side effects or worse.
Excipients can also be major sources of variability. Improved analytics have shown significant differences in measured physical properties such as moisture content, particle size, or bulk density, between
the same excipient sourced from different suppliers, and even between different lots sold by the same vendor. Differences that may
seem small can have an impact on final drug product quality.
“We have variability from the excipients, the API, the manufacturing, the processing conditions, and all of these … result in variability of the product,” Stephen Hoag, a professor at the University of
Maryland at Baltimore’s school of pharmacy, commented before an
FDA panel (1). The panel had asked for recommendations for future
generic-drug research funding through the Generic Drug User Fee
Amendments of 2012 (GDUFA). “In terms of risk analysis, that’s
where harm to the patient can come in,” Hoag said.
As recognition increases of the pivotal role that excipients play
in drug safety and quality, and the increasing quality and supplychain risks involved, a growing number of databases are being
developed to provide more information on these materials. One
of the first such projects began in 2009 when FDA funded the
creation of a database by the National Institute for Pharmaceutical
Technology and Education (NIPTE), a consortium of universities
and industry, to catalog physical properties and other information
16
Pharmaceutical Technology SOLID DOSAGE DRUG DEVELOPMENT AND MANUFACTURING 2016 P h a r mTe c h . c o m
EMPATO/E+/GETTY IMAGES
Variability means risk
Excipient Databases
on excipients. Professor Hoag has been leading
these efforts.
The goal of the NIPTE–FDA database, the Excipients Knowledge Base (2), is to offer detailed
information on the physical material properties
of commercial excipients. This is exactly the type
of data that engineers routinely use in other industries, including chemical, automotive, and
aerospace, when developing new products.
“There’s a real lack of knowledge
of how to go from material to
clinical properties.”
—Stephen Hoag,
University of Maryland and NIPTE
The database, which is housed on Pharmahub,
a data sharing community developed at Purdue
University, is designed to be a shared resource for
the global industry with community features that,
for example, allow users to input their experiences.
So far, it has between 500 and 1000 regular users.
FDA’s Inactive Ingredients Database
At around the same time that NIPTE started to
work on their database, FDA began to catalog the
inactive ingredients used in products (in final dosage form) that it had approved. A working group
was established in 2011, involving the International
Pharmaceutical Excipients Council (IPEC), the Generic Pharmaceuticals Association (GPhA), and a
cross-disciplinary team from FDA’s Office of Generic Drugs, to develop FDA’s Inactive Ingredients
Database (IID) (3).
In 2015, the database’s IT underpinnings were
improved, and a more user-friendly interface was
18
introduced. IPEC has continued to provide the
agency with feedback on the effort’s progress (4, 5).
A separate excipient data-gathering effort is the
STEP (Safety and Toxicity of Excipients for Pediatrics) database (6), designed to help pharmaceutical
formulation scientists screen excipients for use in
children’s medications.
Knowledge gaps
Despite the increased focus on gathering information on excipients, significant gaps in knowledge
remain. At the FDA GDUFA hearing, Professor
Hoag said, “There’s a real lack of knowledge of how
to go from material to clinical properties.”
Most of the industry’s knowledge of these relationships, he said, is gained in a hit-or-miss fashion,
based on empirical observation. More fundamental knowledge, and development of models, would
help with change control, he said, and would allow
the industry to deal with unexpected factors.
Hoag has suggested that separate databases be
merged to provide increased functionality and
more information on material properties. He discussed formulation issues and plans for the NIPTE
database with Pharmaceutical Technology.
Future plans for the database
PharmTech: What progress has been made with the
NIPTE database, and what are the plans for its future, both short and long term?
Hoag: FDA funding has come to an end, so we
are looking for funding that would help us to add
more data to improve it. So far, we have had discussions on this topic with both GPhA and IPEC.
We are seeing that more companies are starting to
use the database. Some major upgrades have been
Pharmaceutical Technology SOLID DOSAGE DRUG DEVELOPMENT AND MANUFACTURING 2016 P h a r mTe c h . c o m
made to the underlying Pharma Hub software, including new enhancements to improve security, data
visualization, and calculations based on the data.
IPEC is interested in our work and some member companies have been using it, and adding data,
but in a password-protected way. In March 2016,
NIPTE will be exploring the idea of a new center
for pharmaceutial technology and drug-development research with FDA.
Need for greater depth and functionality
PharmTech: Are companies concerned, as they
were in the early days of the process analytical
technology and quality by design implementations,
that sharing best practices would amount to giving
away competitive advantage?
Hoag: Some suppliers worry about how posting
data will affect their competitive positions. In the
end, some people recognize the need for this database, while others worry about it. We have set it up
as a community tool and a place where people can
share individual experiences and best practices.
There is still a lot of ‘reinventing the wheel,’ and
redundant testing and evaluation going on within
individual pharmaceutical companies. I’ve seen
cases within a company where one lab in the US
does a characterization study, then another of the
company’s labs in Europe runs the same study
without realizing that it had already been done.
The NIPTE database could help prevent wasted
efforts like that.
Our goal is to make people aware of this tool,
and to fund research and work that would improve
it. At this point, the project needs more support.
PharmTech: You’ve noted a ‘proliferation’ of excipient databases today. Do they provide sufficient
information to help industry deal with problems
such as variability and complexity?
Hoag: IPEC is primarily interested in FDA’s IID,
and we’ve talked about how the two databases
might be merged.
PharmTech: How does the philosophy behind
NIPTE’s database differ from that behind the IID?
Hoag: IID is not really a database but more of
a spreadsheet with useful information in it. Our
database is focused on properties and on allowing
users to mine data.
PharmTech: You have repeatedly mentioned the References
1. Transcript, Public Hearing, FDA Generic Drug User Fee
need for better modeling in pharmaceutical deAmendments of 2012 Regulatory Science Initiative, Request for
Public Input for Fiscal Year 2015, Generic Drug Research, Part
velopment and formulation, based on an under15, Public Hearing, Friday, June 5, 2015, www.fda.gov/downstanding of material properties. Is its reliance on
loads/ForIndustry/UserFees/GenericDrugUserFees/
UCM455846.pdf.
batch processes the reason why the pharmaceutical 2. The NIPTE-FDA Excipients Knowledge Base, www.pharmahub.
org/excipientsexplore.
industry has not developed more innovative ap3. The FDA Inactive Ingredients Database, www.accessdata.fda.
proaches to modeling?
gov/scripts/cder/iig/index.cfm.
4. R. Iser, “Inactive Ingredient Database-FDA Update,” GPhA Fall
Hoag: Batch focus is not the main reason, but
Technical Conference, October 30, 2013, www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductgrowing interest in continuous manufacturing
sandTobacco/CDER/UCM375889.pdf.
will drive home the need for some of this work. 5. “IPEC-Americas suggests improvements to FDA’s Inactive Ingredients Database,” Pharmaceutical Technology Sourcing ManCurrently, the biggest holdup appears to be inertia
agement, October 30, 2015, www.pharmtech.com/ipec-americasuggests-improvements-fda-s-inactive-ingredients-database
and investment in the status quo and established
6. S. Salunke et al., International Journal of Pharmaceutics, 457, (1)
ways of doing things.
(November 20, 2013), pp. 310-322. PT
Pharmaceutical Technology SOLID DOSAGE DRUG DEVELOPMENT AND MANUFACTURING 2016
19
Non-Gelatin Capsules
Establishing a New
Performance Standard
for HPMC Capsules
Agnes Shanley
F
or nearly a hundred years, two-piece hard shell capsules
made from gelatin have been the preferred medium for encapsulating solid oral-dosage forms. The market, however,
began to recognize the need for alternatives decades ago.
Gelatin, derived from pork and beef byproducts, posed a concern
for patients with religious or dietary restrictions, but it could also
pose formulation problems when encapsulating hygroscopic and
moisture-sensitive ingredients.
The plant-based material, hydroxypropyl methylcellulose (HPMC),
was developed as an alternative to gelatin for two-piece hard shell
capsules. The first manufacture of the material in capsule form, however, required the use of secondary gelling agents, which resulted
in variability in both disintegration and product dissolution. Approximately eight years ago, a second generation of HPMC-polymer
capsules was introduced. Matt Richardson, PhD, manager, Pharmaceutical Business Development at Capsugel, and Michael Morgen,
PhD, senior principal scientist, Bend Research, a division of Capsugel
Dosage Form Solutions, discussed these next-generation materials
with Pharmaceutical Technology.
HPMC vs. conventional materials
PharmTech: What makes HPMC capsules different, in terms
of performance properties, from conventional gelatin
technology?
Richardson (Capsugel): HPMC capsules, specifically those made by
thermo-gelation, differ from conventional gelatin capsules in several
ways. Gelatin, derived from animal collagen, is composed of amino
acid chains, while HPMC is cellulose-based. The respective poly20
Pharmaceutical Technology SOLID DOSAGE DRUG DEVELOPMENT AND MANUFACTURING 2016 P h a r mTe c h . c o m
IMAGE IS COURTESY OF CAPSUGEL
A new generation of
cellulose-derived materials
addresses the variability in
disintegration and product
dissolution that were seen in
the first generation of
gelatin alternative HPMC
capsules, while offering
in-vitro and in-vivo
performance comparable to
that of gelatin capsules.
mers impart different properties to each capsule.
Compared to gelatin, HPMC has lower moisture
absorption, more flexibility, higher thermal stability, and better resistance to chemical crosslinking.
The manufacture of second-generation HPMC
capsules by thermo-gelation is quite different than
that of first-generation HPMC capsules and gelatin
capsules. Both first-generation HPMC and gelatin
capsules are made by dipping stainless-steel pins into
a hot polymer solution. The polymer is deposited on
the stainless-steel pin and then dried to achieve a targeted water content. In the thermo-gelation process
for second-generation HPMC capsules, heated stainless-steel pins are dipped into a solution of HPMC to
form capsules without use of gelling agents.
PharmTech: What were the specific performance
limitations with first-generation HPMC capsules?
Morgen (Bend Research): First-generation HPMC
capsules avoided gelatin’s potential for crosslinking. They were formulated with gelling systems,
however, and variability in disintegration and
product dissolution rates was often observed, depending on pH and/or ionic strength of the test
media. Second-generation HPMC capsules were
designed to reduce the performance variability of
first-generation HPMC capsules.
PharmTech: What other specific advantages does
the second-generation material offer?
Richardson (Capsugel): HPMC capsules have a lower
average water content (6% compared with roughly
14% for gelatin capsules), making them an excellent
choice for low moisture or hygroscopic formulations. They also demonstrate high levels of thermal
stability and are quite flexible, compared with gelatin capsules, which can occasionally become brittle,
especially with low-moisture APIs and excipients.
Perhaps their most important attribute is that
second-generation HPMC capsules offer disintegration/product dissolution profiles that have been
shown to provide equivalent in-vivo performance
to gelatin capsules for a range of drug molecules.
PharmTech: What are their limitations?
Morgen (Bend Research): HPMC capsules have
higher oxygen permeability than gelatin capsules,
so they may not be ideal for oxidation-sensitive
formulations, or those that have an odor.
Recent in-vivo and dissolution test results
PharmTech: Please discuss the significance of recent
in-vivo and dissolution test results.
Morgen (Bend Research): The most recent study
focused on investigating the clinical performance
of second-generation HPMC capsules relative to
that of gelatin capsules. It aimed to demonstrate
that, in-vivo, the slight disintegration time delay for
second-generation HPMC capsules does not lead
to differences in pharmacokinetics for relatively
soluble, well-absorbed drugs, but that the performance would be equivalent to that of gelatin capsules for these applications. This equivalence was
shown, using three different compounds. Formulation scientists now have more options for optimizing capsule disintegration and product release.
PharmTech: What other innovations are being
investigated for second-generation capsules?
Morgen: For some applications, the capsules
may provide superior bioavailability, particularly
for low solubility drugs, by sustaining supersaturated concentrations of dissolved drug in the gastrointestinal (GI) tract through crystallization inhibition. This is a potential advantage,specifically
for high-energy salt and amorphous drug forms,
as well as for weakly basic drugs that are capable
of supersaturating in the GI tract. PT
Pharmaceutical Technology SOLID DOSAGE DRUG DEVELOPMENT AND MANUFACTURING 2016
21
Process Simulation
Modeling and Simulation
Move Downstream
Agnes Shanley
22
M
any industries use computer-based simulation and
modeling routinely to troubleshoot and improve their
processes. Pharmaceutical manufacturers have not
yet embraced the technology, at least not for downstream applications. Some companies may use non-computer based
simulation to optimize conditions, for example, compaction simulators for tablet compression. Generally, though, the industry’s most
advanced computer-based systems are reserved for pharmacokinetics and early research.
For chemists, engineers, and technicians who work in development and manufacturing, part of the challenge to using models is
that they can be more difficult to develop for batch processes, which
can involve more variability in materials, process conditions, and
other factors. In addition, the physical and material properties data
required for this work, which are freely available to engineers in
petrochemical processing, for instance, via references such as Perry’s
Chemical Engineering Handbook, are not readily available to professionals in pharmaceutical manufacturing and development. Most of
the data on materials depend on the specific run, batch, equipment,
and facility.
Increased interest in continuous processing, however, is convincing more professionals in the industry to study and apply in-silico
technologies and models to gain process knowledge and improve
manufacturing. Modeling could also improve drug development,
enabling development of higher quality, more robust products, and
increasing R&D efficiency.
Indicative of the trend is a new four-year initiative that was
launched in the United Kingdom in January 2016 to help streamline drug development and manufacturing by leveraging better
Pharmaceutical Technology SOLID DOSAGE DRUG DEVELOPMENT AND MANUFACTURING 2016 P h a r mTe c h . c o m
YURI_ARCURS/GETTY IMAGES
Computer-based tools
promise better quality
products, improved process
control, and increased R&D
efficiencies, but will require
different workflows.
Award-Winning
On-Dose
Authentication
& Brand Protection Solutions
• Covert, Inert and Easy to Apply
• Machine-Readable Microtags
• Custom Codes by Product
7UX7DJRHUVDQHɝFLHQWFRVWHHFWLYHVROXWLRQWKDWFRPEDWVFRXQWHUIHLWLQJDQGGLYHUVLRQ
SURWHFWLQJ\RXUSURGXFWIURPSODQWWRSDWLHQW
Contact us now: www.trutags.com/awardwinning
PRODUC
TO
ETY
AF
AWARDS2013
2016
SOLID DOSAGE DRUG DEVELOPMENT
AND MANUFACTURING
SOLID DOSAGE DRUG DEVELOPMENT
AND MANUFACTURING 2016
EXCIPIENTS
EDITORIAL
Editorial Director Rita Peters rpeters@advanstar.com
Senior Editor Agnes Shanley ashanley@advanstar.com
Managing Editor Susan Haigney shaigney@advanstar.com
Science Editor Adeline Siew, PhD asiew@advanstar.com
Manufacturing Editor Jennifer Markarian jmarkarian@advanstar.com
Science Editor Randi Hernandez rhernandez@advanstar.com
Community Manager Caroline Hroncich chroncich@advanstar.com
Art Director Dan Ward
Contributing Editors Jill Wechsler jwechsler@advanstar.com; Jim Miller
info@pharmsource.com; Hallie Forcinio editorhal@cs.com; Susan J. Schniepp
sue.schniepp@mac.com; Eric Langer info@bioplanassociates.com;
and Cynthia A. Challener, PhD challener@vtlink.net
Correspondent Sean Milmo (Europe, smilmo@btconnect.com)
485 Route One South, Building F, Second Floor, Iselin, NJ 08830, USA
Tel. 732.596.0276, Fax 732.647.1235, PharmTech.com
SALES
Publisher Mike Tracey mtracey@advanstar.com
Mid-West Sales Manager Irene Onesto ionesto@advanstar.com
East Coast Sales Manager Joel Kern jkern@advanstar.com
European Sales Manager Linda Hewitt Linda.Hewitt@ubm.com
European Senior Sales Executive Stephen Cleland scleland@advanstar.com
Executive Assistant Barbara Sefchick bsefchick@advanstar.com
4 Excipient Quality and Selection
Irwin B. Silverstein
EXCIPIENT DATABASES
16 Unifying Excipient Databases
Agnes Shanley
NON-GELATIN CAPSULES
20 Establishing a New Performance
Standard for HPMC Capsules
Agnes Shanley
PROCESS SIMULATION
22 Modeling and Simulation
Move Downstream
Agnes Shanley
TABLET COMPRESSION
26 Optimizing Tablet Compression
Frederick J. Murray
CONTINUOUS MANUFACTURING
Address
485 Route One South
Building F, Second Floor
Iselin, NJ 08830, USA
Tel. 732.596.0276, Fax 732.647.1235
PharmTech.com
Sr. Production Manager Karen Lenzen
International Licensing Maureen Cannon mcannon@advanstar.com,
tel. 440.891.2742 or toll-free 800.225.4569 ext 2742, fax. 440.756.5255
Audience Development Manager Rochelle Ballou rballou@advanstar.com
34 Filling the Analysis Gap in
the Move to Continuous Processing
Jamie Clayton
ELEMENTAL IMPURITIES
40 Meeting USP Guidelines for
Elemental Impurity Analysis with
X-ray Fluorescence Spectrometry
Andrew Fussell
GENERIC DRUGS
Pharmaceutical Technology does not verify any claims or other information appearing in any of
the advertisements contained in the publication and cannot take any responsibility for any losses
or other damages incurred by readers in reliance on such content. Pharmaceutical Technology
welcomes unsolicited articles, manuscripts, photographs, illustrations, and other materials but
cannot be held responsible for their safekeeping or return. UBM Life Sciences provides certain
customer contact data (such as customers’ names, addresses, phone numbers and e-mail addresses)
to third parties who wish to promote relevant products, services, and other opportunities which may
be of interest to you. If you do not want UBM Life Sciences to make your contact information available
to third parties for marketing purposes, simply call toll-free 866.529.2922 between the hours of 7:30
am and 5 pm CT and a customer service representative will assist you in removing your name from
UBM Life Sciences’ lists. Outside the United States, please phone 218.740.6477. To subscribe: Call
toll-free 888.527.7008. Outside the US, call 218.740.6477. Single issues, back issues: Call toll-free
800.598.6008. Outside the US call 218.740.6480. Reprints of all articles in this issue and past issues of
this publication are available. Call 877-652-5295 ext. 121 or email bkolb@wrightsmedia.com. Outside
US, UK, direct dial: 281-419-5725. Ext. 121. Direct mail lists: Contact Tamara Phillips, Marketing
Services, tel. 440.891.2773, tphillips@advanstar.com. Display, Web, Classified, and Recruitment
Advertising: Contact Tod McCloskey, tel. 440.891.2739, tmccloskey@advanstar.com. Permissions:
Contact Maureen Cannon, tel. 440.891.2742 or toll-free 800.225.4569 ext 2742, fax. 440.756.5255,
mcannon@advanstar.com.
46 Regulatory Considerations for Controlling
Intermediates in Type-II Drug Master Files for
the Manufacture of Generic Drug Substances
Kandasamy Subburaj, Brian T. Connell, Srinivasa Murthy, Humcha
Hariprakasha, Deborah F. Johnson, Huyi Zhang, and David J. Skanchy
54 Ad Index
Issue Editor: Agnes Shanley.
On the Static Cover: Science Photo Library/Getty Images; Dan Ward.
On the Animated cover: Nanihta photography/DAJ/Tetra Images/Yuri_Arcurs/
Empato/E+/Image Source/Still Factory/Getty Images; Dan Ward.
©2016 UBM. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any
means, electronic or mechanical including by photocopy, recording, or information storage and retrieval without
permission in writing from the publisher. Authorization to photocopy items for internal/educational or personal use, or
the internal/educational or personal use of specific clients is granted by UBM for libraries and other users registered with
the Copyright Clearance Center, 222 Rosewood Dr. Danvers, MA 01923, 978-750-8400 fax 978-646-8700 or visit http://
www.copyright.com online. For uses beyond those listed above, please direct your written request to Permission Dept.
fax 440-756-5255 or email: mcannon@advanstar.com.
P h a r mTe c h . c o m
21ST CENTURY PHARMA
A holistic, systems-based approach to drug
development, manufacture and delivery
FORMULATION
MANUFACTURE
DELIVERY
At PSE we are working with leading pharma
companies to develop a holistic approach to
drug development, manufacture and delivery.
We call it Systems-based Pharmaceutics (SbP).
A systems-based approach considers the entire formulationto-delivery cycle as a single integrated system, relating
formulation and manufacturing decisions directly to drug
delivery KPIs.
SbP is helping pharma companies to accelerate development,
improve manufacturing, enhance drug product performance and
increase R&D efficiency. Contact us to find out more.
More online
«
Download the PSE, Pfizer
and Eli Lilly SbP phase 1
progress report
The Advanced Process
Modelling Company
psenterprise.com
Operations in UK, USA,
Switzerland, Japan, Korea, China,
Taiwan, Malaysia, Thailand and UAE.
UK Head Office
t: +44 20 8563 0888
e: info@psenterprise.com
THE POWER TO BE CERTAIN
Excipients
Excipient Quality
and Selection
Irwin B. Silverstein
Irwin B. Silverstein, PhD, is a
consultant to IPEC-Americas.
4
H
ow does one define quality as applied to excipients? If
we pose the same question for APIs, the response would
be to produce the ingredient under appropriate GMPs,
and to the compendial monograph and the API assay.
Because the monograph provides the minimum requirements, API
quality is improved by reducing the presence of all materials other
than the desired chemical. This is logical because, by definition, the
API is “intended to furnish pharmacological activity or other direct
effect in the diagnosis, cure, mitigation, treatment, or prevention
of disease or to affect the structure and function of the body” (1).
Extraneous substances may be harmful to the patient in that they
may lead to side effects, or they are inert, thus reducing API purity
and thereby compromising efficacy.
Excipient quality is described quite differently. While one would
again refer to compliance with the compendial monograph (if there
is one) or the manufacturer’s specification, a higher assay is not always better. While this may seem counterintuitive, excipients are
often complex mixtures that include constituents arising from raw
materials, catalyst, solvent, initiator residue, or side reactions. The
International Pharmaceutical Excipients Council (IPEC) refers to
these other unavoidable substances in the excipient as concomitant components (2). The performance of many excipients in the
drug formulation may rely on the presence of such substances in
the excipient. Concomitant components in the excipient may aid
in solvating drug components, improving excipient functionality,
etc. Excipient quality, therefore, is characterized as compliance to
the monograph or specification and having a consistent concomitant
composition.
Pharmaceutical Technology SOLID DOSAGE DRUG DEVELOPMENT AND MANUFACTURING 2016 P h a r mTe c h . c o m
IMAGE SOURCE/STILL FACTORY/GETTY IMAGES; DAN WARD
Choosing the right
excipient manufacturer
can help ensure the use
of quality excipients.
Veltek Associates, Inc. offers two garment product lines, which are both pre-folded in
our
system. Comfortably styled and fitted with elastic thumb loops to reduce
shifting, as well as tunnelized elastic wrists and ankles.
1600 Garments
Breathable
Comfortable
High bacterial eiciency
1700 Garments
High iltration eiciency
Low particulate and shedding
performance
Excellent water repelency
Face Masks
Breathable
Reduces goggle fogging due
to absorption eiciency
Soft and comfortable
Excipients
Specified limits for excipients
As required by clause 8.2.4.6 of the ANSI excipient GMP standard, excipient manufacturers are
expected to identify concomitant components
present in the excipient whenever possible and to
specify limits for those components that have been
shown to be either important to excipient performance or known to have an adverse impact to the
patient (3). Impurities known to be present in the
excipient are also required to have specified upper
limits based upon safety considerations, regulatory
requirements, customer requirements, and, if applicable, the compendium.
Povidone and its monograph illustrate these
points. Povidone is the homo-polymerized monomer vinyl pyrrolidone. It is sold in various molecular weights. In the late 1980s, GAF Chemicals,
a manufacturer of Povidone, was made aware of
the presence of hydrazine, a toxic substance, in
Povidone. The company identified the mechanism
of hydrazine formation as a by-product of the polymerization reaction. Through modification of
the process, the level of hydrazine was reduced
to what was deemed acceptable for safe use of Povidone in pharmaceuticals. Because Hydrazine
is not expected to be beneficial in Povidone, it
is thus considered an undesirable component. A
test method was developed, appropriate specified
limits were established, and the compendium was
updated accordingly.
In the early 1990s, vinyl pyrrolidone was identified as a suspect carcinogen. As a consequence,
manufacturing methods were again modified
to reduce the level of residual vinyl pyrrolidone
monomer to a toxicologically safe level. Vinyl pyrrolidone has solvating properties and is a reactive
molecule. Therefore, residual vinyl pyrrolidone in
6
Povidone is more likely than hydrazine to impact
performance of the excipient in some drug formulations. A test method suitable for detecting low levels
of this monomer was developed, and the compendium was updated accordingly.
An additional substance, 2-pyrollidone, was subsequently found in Povidone. This substance is
formed during the polymerization reaction when
some vinyl pyrrolidone decomposes rather than
polymerizes. While it is unlikely that the presence
of hydrazine or vinyl pyrrolidone beneficially impacts the performance of Povidone in the drug formulation, the same conclusion cannot be drawn for
2-pyrrolidone. 2-Pyrrolidone is often used as a solvent, and therefore, its presence in the excipient may
play a beneficial role in certain drug formulations
by helping to solvate the API. While it is possible to
remove this substance through further processing, it
is not feasible for the manufacturer to asses the impact on performance for all drug formulations that
use Povidone. Therefore, it is important to control,
but not limit, the quantity of 2-pyrrolidone so that
the performance of each lot of Povidone is consistent in the various drugs that use this excipient.
Non-homogeneity
These examples with one excipient illustrate how
control of all the components in the material are
needed in order to assure consistent quality. Another aspect that needs equivalent control is the
degree of homogeneity of solid excipients, particularly those supplied in powder form. However,
many excipients are also manufactured in much
larger volumes for other markets where a larger
degree of variation is tolerable.
To illustrate a common cause of non-homogeneity, consider that excipient manufacture often
Pharmaceutical Technology SOLID DOSAGE DRUG DEVELOPMENT AND MANUFACTURING 2016 P h a r mTe c h . c o m
Advancing Drug Delivery
Through Superior Polymer Design
Safe and efective delivery of today’s complex drug molecules is increasingly
a function of collaboration between polymer experts and pharmaceutical
product development teams. Acting on enabling science, producing
superior polymer excipient technology, and creating systems for
optimum bioavailability, Ashland works alongside formulators to
advance drug-speciic delivery platforms.
Explore how you can solve intricate drug formulation
and development challenges with polymer
expertise from Ashland.
Visit us at Ashland.com/pharmaceutical
Ashland
pharmaceutical@ashland.com
www.ashland.com/pharmaceutical
®Registered trademark, Ashland or its subsidiaries, registered in various countries
™Trademark, Ashland or its subsidiaries, registered in various countries
©2016, Ashland
AD-13475
Excipients
involves drying the substance. The ability to
dry material to a consistent residual moisture
throughout the lot is inherently difficult due to
the many operating variables. Spray drying is a
case in point. Operating parameters for the spray
dryer include the temperature and dew point of
inlet air, burner temperature, concentration of
the excipient in the aqueous solution, spray pattern of the excipient solution, rate of drying, and
outlet air temperature. During a 24-hour cycle,
Common impurities in excipients, which are not
needed for excipient performance, may include
residual process aids, additives, by-products, and
material that sheds from filter media. In addition,
contaminants, which are to be avoided, can occur
from environmental factors such as personnel hygiene, equipment failure, contact with packaging,
etc. and include rust, oil, grease, insect fragments,
extractable and leachable materials, etc.
Excipient quality is, therefore, best expressed
as conformance to GMPs
The stability of the excipient can pose a risk as well as to compendia or
a specification and consisif the material is likely to degrade during
tent composition, lot to lot.
storage or shipment when temperature
Consistent composition
and/or humidity are not controlled within
within each lot is also an
acceptable limits.
expression of excipient
quality, but oftentimes
the ambient air temperature and humidity may such consistency is difficult to achieve without
differ considerably from day to night. Also the ex- a blending step.
cipient concentration may vary due to prior manGenerally, it is expected that a more consisufacturing steps. Achieving a consistent moisture tent excipient composition will result in a more
level requires frequent sampling of dried material predictable performance in the final drug forand adjustment of spray-dryer operating param- mulation. In the selection of an excipient for a
eters. As drying conditions become more severe drug formulation, consideration should be to
in order to maintain constant residual moisture, include an excipient whose composition profile
however, it is possible to cause some degradation has known and tolerable variation with minimanifest as charring of the excipient. This is typi- mal number of concomitant components and
cally manifested as burnt particles (4). Consistent impurities.
moisture content in the excipient, therefore, may
be a tradeoff with the quantity of burnt particles Selection of excipient suppliers
in the product.
The European Union Directive Guidelines on the
Formalized Risk Assessment for Ascertaining the
Excipient impurities
Appropriate Good Manufacturing Practice for ExExcipient impurities are specific entities that cipients of Medicinal Products of Human Use (5)
should not be present and/or need to be con- provides the following characteristics for assesstrolled for safety, toxicological, or other reasons. ing the manufacture and supply of excipients:
8
Pharmaceutical Technology SOLID DOSAGE DRUG DEVELOPMENT AND MANUFACTURING 2016 P h a r mTe c h . c o m
Excipients
t Potential presence of transmissible spongiform
encephalopathy (TSE)
t Potential for viral contamination
t Potential for microbiological or endotoxin contamination
t Potential for the presence of impurities
t Supply chain complexity and security
t Excipient stability
t Tamper-evident packaging.
Each of these characteristics can be related to
excipient “quality” and used to assess excipient
suppliers. Note that each of these considerations
is in addition to manufacturing the excipient in
conformance to excipient GMP.
In addition, the ANSI excipient GMP standard (3)
highlights the following criteria to assess for risk to
protect an excipient from contamination:
t Hygienic practices: excipient contamination due
to personnel hygiene, illness, attire, unauthorized access, food, medication, tobacco, etc.
t Infrastructure, building: excipient contamination, cross-contamination, mix-ups
t Infrastructure, equipment: excipient contamination due to material of construction, utilities,
water, process materials, and work environment
(air handling, cleaning/sanitation, pest control
and drainage).
Minimizing contamination risk
Using an excipient manufacturer that produces
the excipient in dedicated equipment is a lower
risk to excipient quality as a result of reduced risk
of cross-contamination. Equipment can be considered dedicated when it is used to manufacture
products utilizing the same chemistry and raw
materials. Equipment used to manufacture an excipient in various particle size, density, viscosity,
10
or molecular weight, therefore, can be considered
dedicated. Also equipment used to produce various grades of an excipient that are then sold in different markets (e.g., food, cosmetic, or industrial
applications), but produced using the same chemistry and raw materials, should also be considered
dedicated.
Using dedicated equipment reduces the risk
that the excipient will be contaminated by the
presence of other substances (e.g., other raw material, intermediate, or finished product residue in
the production equipment). Using multi-purpose
equipment relies heavily on verifying cleaning effectiveness and the ability to detect potential residual contaminants to assure the minimization
of potential cross-contaminants in the excipient.
Where multi-use equipment is used, it is advisable
to review the excipient manufacturer’s cleaning
validation report.
When possible, it is preferable to source the excipient from a supplier that does not use animalderived raw materials at risk for bovine spongiform
encephalopathy (BSE)/TSE in the manufacture of
the excipient. Otherwise, the excipient user will
have to ensure the excipient presents minimal risk
from TSE contaminants. A risk assessment should
include confirmation the animals used in the manufacture of the animal-derived raw material come
from a country designated as negligible TSE risk.
Alternatively, the excipient manufacturer should
demonstrate that the animal-derived raw material
was processed under conditions that have been defined to inactivate the TSE risk materials if present.
TSE risks are also present when the excipient is
manufactured in multi-purpose equipment where
the other products are animal derived. If there is a
risk of TSE material residue on equipment, the ex-
Pharmaceutical Technology SOLID DOSAGE DRUG DEVELOPMENT AND MANUFACTURING 2016 P h a r mTe c h . c o m
Vcaps® Plus Capsules
Not all capsules are
created equal.
Download
Whitepaper
Finally, a superior specialty polymer capsule with proven gelatin-like
performance without cross-linking potential, Vcaps Plus is the new capsule
standard with benefits of narrow weight variability, impressive resistance to
heat and humidity, and validated manufacturing experience. By reducing
variability, Vcaps Plus capsules are quickly becoming a powerful new tool to
reduce timelines in drug product development.
Contact us at 800-845-6973 for our full technical package and
samples for your development review.
8000
Mean Plasma Acetaminophen Concentration (ng/mL)
Vcaps® Plus capsules can optimize capsule disintegration for pharmaceutical
products with the ability to release contents independent of pH and ionic
strength of the test media. And a new in-vivo study demonstrates that
Vcaps Plus capsules are equivalent to gelatin in terms of human
pharmacokinetics profile.
Proven Bioequivalence to Gelatin
Molecule = Acetaminophen Human
cross-over study in 24 subjects
7000
6000
Gelatin
Capsules
5000
Vcaps Plus
Capsules
4000
3000
2000
1000
0
0
2
4
6
8
10
Nominal Hours (hrs) Post Dose
Mean in-vivo acetaminophen plasma
concentration profiles over 12 hours.
True pH and Ionic Media Independence
100
90
80
% Caffeine dissolved
The new standard in HPMC capsules:
Immediate release in-vivo performance
bioequivalent to gelatin and consistent
dissolution across changing pH and
ionic strength.
70
60
pH 1.2 USP
pH 6.8 USP
pH 6.8 JP2
Simulated milk fluid
pH 1.2 – 2 g KCI/L
pH 1.2 – 9 g KCI/L
50
40
30
20
10
0
0
New in-vivo results comparing Vcaps Plus HPMC
Capsules and gelatin capsules demonstrate
bioequivalency of HPMC in multiple dissolution profiles.
Read the full report at VcapsPlus.com.
© 2016 Capsugel Belgium NV All rights reserved.
3
6 9 12 15 18 21 24 27 30 35 40 45 50 55 60 75
Time in minutes
In-vitro dissolution of caffeine in
Vcaps Plus capsules
12
Excipients
cipient manufacturer should demonstrate cleaning
procedures that show residual TSE risk material is
either reduced to an acceptable level on the equipment surface or is inactivated.
The risk of viral, microbiological, or endotoxin
contamination arises from raw materials, water,
and the environment. Where the manufacture of
the excipient uses viral agents or there is a risk of
contamination with viral agents, adequate measures of sanitation or sterilization by the supplier
are expected.
borne particulate to reduce the risk of microbial
contamination only requires use of a HEPA filter
if the excipient is purported to be sterile.
Contamination of the excipient with undersirable components can arise from such sources as
nearby manufacturing operations, processing
equipment (e.g., filters and traps), and utilities.
Filters pose a risk from shedding their material of
construction and from traps that are improperly
maintained, allowing trapped impurities through.
Utilities such as nitrogen, compressed air, and
steam may contaminate the excipient with
The complexity of the supply chain from
i mpu r it ie s such a s
excipient manufacturer to pharmaceutical
compressor oi l a nd
facility is a consideration in selecting a supplier. boiler additives.
It is common for the
Excipient manufacturers should use at least pota- excipient to be produced at a site where many
ble water where water is used in the process after the other products are also manufactured. Some of
starting point for GMP or when water is a potential these other products may be toxic (e.g., herbicides
source of microbial contamination in the finished or pesticides) or they may use toxic ingredients
excipient. Water that is used for temperature control in their manufacture. Where toxic substances are
that does not contact excipient during manufacture volatile enough to become airborne contaminants,
poses minimal risk under normal operating condi- manufacturers should take appropriate measures
tions and therefore need not be potable. For excipi- to minimize the risk of contamination. It is iments that are intended for drug products where the portant for the user to assess the risk of airborne
presence of endotoxin poses a risk to patient safety contamination and the measures taken to protect
and water comes into direct contact with the ex- the excipient during an onsite audit.
cipient during processing, higher purity water such
as United States Pharmacopieal Convention (USP) Supply chain considerations
water for injection may be expected to be used.
The complexity of the supply chain from excipiThere is also the potential for airborne microor- ent manufacturer to pharmaceutical facility is also
ganisms to contaminate the excipient. Generally, a consideration in selecting a supplier. Although
airborne microbes that can contaminate the ex- delivery from an excipient manufacturing site
cipient can be controlled by filtering the air, such directly to the pharmaceutical manufacturing
as when the excipient is exposed to the air during facility provides the least opportunity for the expackaging, to remove particles. Removal of air- cipient to become contaminated or tampered with
12
Pharmaceutical Technology SOLID DOSAGE DRUG DEVELOPMENT AND MANUFACTURING 2016 P h a r mTe c h . c o m
en route; generally direct delivery is uncommon should verify through the paper trail that the shipand only applies to full truckloads of the excipi- ment of an excipient lot has come from the excipient. More often, less-than-truckload quantities are ent manufacturer.
shipped by common carrier. Oftentimes, the shipThe stability of the excipient can pose a risk if
ment goes from the manufacturer to a warehouse the material is likely to degrade during storage or
of the transport carrier. There, the shipment may shipment when temperature and/or humidity are
be cross-docked to a truck heading to the desired not controlled within acceptable limits. Generally,
destination or another intermediate destination. excipients such as inorganic salts, minerals, modiWhile tampering with the excipient at the trans- fied food ingredients, and synthetic substances are
port warehouse is unlikely, there is the possibil- stable materials. Also, many excipients have been
ity for the packaged excipient to be exposed to in commerce for an extended number of years and,
extremes of weather (temperature, humidity, and Where delivery is not direct from the
precipitation), for t he
excipient manufacturer, the pharmaceutical
packaging to be damaged
company should periodically establish the
through mishandling, or
for the tamper-evident seal pedigree of the excipient.
to be accidentally broken.
Excipients are often sold through a distributor. therefore, their stability has been well established
Distributors can sell the excipient in the unopened and characterized. Stability issues occur more
excipient manufacturer’s package or the distributor frequently from exposure to moisture or oxygen
may repackage the excipient into smaller packages. rather than temperature extremes. However, unExcipients may also be shipped in bulk to a manu- less studies have shown the excipient to be affected
facturer’s terminal or a distributor where the excip- by extremes of temperature, humidity, or exposure
ient is either stored in bulk tanks or packaged from to oxygen, there is little cause for concern regardthe tank truck or rail car into discrete containers. ing excipient storage.
Any time the excipient is handled other than in
For moisture- and/or oxygen-sensitive excipients,
the original container is an opportunity for the the excipient packaging should be considered and
excipient to become contaminated, adulterated, or assessed when selecting a supplier. The excipient
otherwise compromised. Therefore, the fewer such supplier should provide evidence for the suitability
activities in the supply chain, the lower the risk.
of the packaging used to protect the excipient from
Where delivery is not direct from the excipi- moisture and oxygen.
ent manufacturer, the pharmaceutical company
Finally, tamper-resistant packaging is an imshould periodically establish the pedigree of the portant consideration in the selection of a supexcipient. As discussed in the IPEC-Americas plier. Though packages can be sealed with tamand IPEC-Europe Excipient Pedigree position per-evident closures, the package materials can be
paper of 2008 (6), the pharmaceutical company susceptible to tampering via a puncture. However,
Pharmaceutical Technology SOLID DOSAGE DRUG DEVELOPMENT AND MANUFACTURING 2016
13
Excipients
impervious packaging such as steel drums may not
be appropriate for some excipients. High-density
polyethylene (HDPE) drums may be compatible
with the excipient and are more resistant to product tampering than fiber drums or bags. Though
bags and supersacks are a challenge to make tamper resistant due to their material of construction,
oftentimes they are the only packaging available.
Package openings should be protected with tamper-evident seals unique to the excipient manufacturer. Such seals are characterized by their having
to be opened to gain access to the excipient, cannot be reapplied if broken or otherwise removed,
and are unique in that they have the manufacturer’s name, logo, or inherent design characteristic. While numbered seals are desirable, they are
impractical for excipients where the number of
containers in a lot often exceeds 100 and can be
in excesses of 1000. Using a tamper-evident seal,
however, provides no benefit if incoming inspection by the pharmaceutical firm fails to match
the appearance of the seal to an authentic seal (or
photo) provided by the excipient manufacturer.
been made and the risk is kept to an acceptable maximum.
t No viral risk material is used in excipient manufacture unless an adequate assessment has
been made and the risk is kept to an acceptable
maximum.
t Adequate measures are taken to control the contamination risk from microbes or endotoxin unless an adequate assessment has been made and
the risk is kept to an acceptable maximum.
t The risk of contamination is mitigated through
the implementation of GMP controls.
t Transport of the excipient from the manufacturer
is directly to the user.
t The excipient is stable under the conditions of
storage and shipment.
t Each excipient package is tamper resistant and, if
feasible, closed with a tamper-evident seal.
These considerations will help to ensure the use
of quality excipients in the manufacture of pharmaceuticals.
Acknowledgement
The author would like to thank those colleagues
Conclusion
at IPEC who took the time to provide comments
Excipient quality is best characterized as confor- to this article.
mance to GMPs and the compendial monograph
or specification with a consistent composition pro- References
1. ICH, Q7, Good Manufacturing Practice Guide for Active Pharfile lot to lot and within lot.
maceutical Ingredient (ICH, November 2000).
In the selection of an excipient supplier, the fol- 2. IPEC, Excipient Composition Guide (IPEC, 2009).
lowing characteristics minimize the risk to excipi- 3. NSF/IPEC/ANSI Standard for Pharmaceutical Excipients, Good
Manufacturing Practices (GMP) for Pharmaceutical Excipients,
ent quality:
363-2014.
t The excipient is manufactured using dedicated 4. IPEC-Americas, Technically Unavoidable Particle Profile Guide
(IPEC, 2013).
equipment or mixed-use equipment with suffi5. EUR-Lex, Official Journal of the European Union, 2015/C95/02,
cient cleaning validation.
21.3.2015, C95/10-C95/13. Website: http://bit.ly/EurLexTC15
t No TSE risk material is used in excipient man- 6. IPEC, IPEC-Europe Excipient Pedigree position paper, www.
ipecamericas.org/ipec-store PT
ufacture unless an adequate assessment has
14
Pharmaceutical Technology SOLID DOSAGE DRUG DEVELOPMENT AND MANUFACTURING 2016 P h a r mTe c h . c o m
An obsession with quality definitely works to your advantage. Thatʼs
why Mikart is the Contract Development and Manufacturing Organization
(CDMO) that delivers the attention to detail you need, plus the speed
and responsiveness you want.
A Textbook Case For
(Quality Control) OCD.
Weʼre quick to respond with personalized
solutions that get your projects completed faster and meet your individual
requirements. All while remaining
fixated on quality.
In addition to Formulation Development, Mikart also provides Clinical
Trial Supplies, Regulatory Filing
Support, plus Manufacturing and
Packaging solutions.
Youʼll find Mikart has everything
youʼre looking for in a pharma
partner: innovative technology and
equipment, highly skilled people and
38 years of solid CDMO experience.
To experience just how responsive
we can be, contact us at
1-888-4MIKART or send us an
email to info@mikart.com
Ready. Responsive.
Mikart, Inc. | 1750 Chattahoochee Avenue | Atlanta GA 30318
www.mikart.com | 1-888-4MIKART
Right for You.
Excipient Databases
Unifying Excipient Databases
Properties data critical, says NIPTE’s Hoag
Agnes Shanley
More databases currently
provide information on
pharmaceutical excipients,
but are they providing
enough information of the
right kind, and can they help
users address variability?
O
nce taken for granted as inactive fillers, excipients play a
vital role in any pharmaceutical formulation. The wrong
excipient can reduce a drug’s efficacy or interact with
APIs or other ingredients, resulting in side effects or worse.
Excipients can also be major sources of variability. Improved analytics have shown significant differences in measured physical properties such as moisture content, particle size, or bulk density, between
the same excipient sourced from different suppliers, and even between different lots sold by the same vendor. Differences that may
seem small can have an impact on final drug product quality.
“We have variability from the excipients, the API, the manufacturing, the processing conditions, and all of these … result in variability of the product,” Stephen Hoag, a professor at the University of
Maryland at Baltimore’s school of pharmacy, commented before an
FDA panel (1). The panel had asked for recommendations for future
generic-drug research funding through the Generic Drug User Fee
Amendments of 2012 (GDUFA). “In terms of risk analysis, that’s
where harm to the patient can come in,” Hoag said.
As recognition increases of the pivotal role that excipients play
in drug safety and quality, and the increasing quality and supplychain risks involved, a growing number of databases are being
developed to provide more information on these materials. One
of the first such projects began in 2009 when FDA funded the
creation of a database by the National Institute for Pharmaceutical
Technology and Education (NIPTE), a consortium of universities
and industry, to catalog physical properties and other information
16
Pharmaceutical Technology SOLID DOSAGE DRUG DEVELOPMENT AND MANUFACTURING 2016 P h a r mTe c h . c o m
EMPATO/E+/GETTY IMAGES
Variability means risk
Excipient Databases
on excipients. Professor Hoag has been leading
these efforts.
The goal of the NIPTE–FDA database, the Excipients Knowledge Base (2), is to offer detailed
information on the physical material properties
of commercial excipients. This is exactly the type
of data that engineers routinely use in other industries, including chemical, automotive, and
aerospace, when developing new products.
“There’s a real lack of knowledge
of how to go from material to
clinical properties.”
—Stephen Hoag,
University of Maryland and NIPTE
The database, which is housed on Pharmahub,
a data sharing community developed at Purdue
University, is designed to be a shared resource for
the global industry with community features that,
for example, allow users to input their experiences.
So far, it has between 500 and 1000 regular users.
FDA’s Inactive Ingredients Database
At around the same time that NIPTE started to
work on their database, FDA began to catalog the
inactive ingredients used in products (in final dosage form) that it had approved. A working group
was established in 2011, involving the International
Pharmaceutical Excipients Council (IPEC), the Generic Pharmaceuticals Association (GPhA), and a
cross-disciplinary team from FDA’s Office of Generic Drugs, to develop FDA’s Inactive Ingredients
Database (IID) (3).
In 2015, the database’s IT underpinnings were
improved, and a more user-friendly interface was
18
introduced. IPEC has continued to provide the
agency with feedback on the effort’s progress (4, 5).
A separate excipient data-gathering effort is the
STEP (Safety and Toxicity of Excipients for Pediatrics) database (6), designed to help pharmaceutical
formulation scientists screen excipients for use in
children’s medications.
Knowledge gaps
Despite the increased focus on gathering information on excipients, significant gaps in knowledge
remain. At the FDA GDUFA hearing, Professor
Hoag said, “There’s a real lack of knowledge of how
to go from material to clinical properties.”
Most of the industry’s knowledge of these relationships, he said, is gained in a hit-or-miss fashion,
based on empirical observation. More fundamental knowledge, and development of models, would
help with change control, he said, and would allow
the industry to deal with unexpected factors.
Hoag has suggested that separate databases be
merged to provide increased functionality and
more information on material properties. He discussed formulation issues and plans for the NIPTE
database with Pharmaceutical Technology.
Future plans for the database
PharmTech: What progress has been made with the
NIPTE database, and what are the plans for its future, both short and long term?
Hoag: FDA funding has come to an end, so we
are looking for funding that would help us to add
more data to improve it. So far, we have had discussions on this topic with both GPhA and IPEC.
We are seeing that more companies are starting to
use the database. Some major upgrades have been
Pharmaceutical Technology SOLID DOSAGE DRUG DEVELOPMENT AND MANUFACTURING 2016 P h a r mTe c h . c o m
made to the underlying Pharma Hub software, including new enhancements to improve security, data
visualization, and calculations based on the data.
IPEC is interested in our work and some member companies have been using it, and adding data,
but in a password-protected way. In March 2016,
NIPTE will be exploring the idea of a new center
for pharmaceutial technology and drug-development research with FDA.
Need for greater depth and functionality
PharmTech: Are companies concerned, as they
were in the early days of the process analytical
technology and quality by design implementations,
that sharing best practices would amount to giving
away competitive advantage?
Hoag: Some suppliers worry about how posting
data will affect their competitive positions. In the
end, some people recognize the need for this database, while others worry about it. We have set it up
as a community tool and a place where people can
share individual experiences and best practices.
There is still a lot of ‘reinventing the wheel,’ and
redundant testing and evaluation going on within
individual pharmaceutical companies. I’ve seen
cases within a company where one lab in the US
does a characterization study, then another of the
company’s labs in Europe runs the same study
without realizing that it had already been done.
The NIPTE database could help prevent wasted
efforts like that.
Our goal is to make people aware of this tool,
and to fund research and work that would improve
it. At this point, the project needs more support.
PharmTech: You’ve noted a ‘proliferation’ of excipient databases today. Do they provide sufficient
information to help industry deal with problems
such as variability and complexity?
Hoag: IPEC is primarily interested in FDA’s IID,
and we’ve talked about how the two databases
might be merged.
PharmTech: How does the philosophy behind
NIPTE’s database differ from that behind the IID?
Hoag: IID is not really a database but more of
a spreadsheet with useful information in it. Our
database is focused on properties and on allowing
users to mine data.
PharmTech: You have repeatedly mentioned the References
1. Transcript, Public Hearing, FDA Generic Drug User Fee
need for better modeling in pharmaceutical deAmendments of 2012 Regulatory Science Initiative, Request for
Public Input for Fiscal Year 2015, Generic Drug Research, Part
velopment and formulation, based on an under15, Public Hearing, Friday, June 5, 2015, www.fda.gov/downstanding of material properties. Is its reliance on
loads/ForIndustry/UserFees/GenericDrugUserFees/
UCM455846.pdf.
batch processes the reason why the pharmaceutical 2. The NIPTE-FDA Excipients Knowledge Base, www.pharmahub.
org/excipientsexplore.
industry has not developed more innovative ap3. The FDA Inactive Ingredients Database, www.accessdata.fda.
proaches to modeling?
gov/scripts/cder/iig/index.cfm.
4. R. Iser, “Inactive Ingredient Database-FDA Update,” GPhA Fall
Hoag: Batch focus is not the main reason, but
Technical Conference, October 30, 2013, www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductgrowing interest in continuous manufacturing
sandTobacco/CDER/UCM375889.pdf.
will drive home the need for some of this work. 5. “IPEC-Americas suggests improvements to FDA’s Inactive Ingredients Database,” Pharmaceutical Technology Sourcing ManCurrently, the biggest holdup appears to be inertia
agement, October 30, 2015, www.pharmtech.com/ipec-americasuggests-improvements-fda-s-inactive-ingredients-database
and investment in the status quo and established
6. S. Salunke et al., International Journal of Pharmaceutics, 457, (1)
ways of doing things.
(November 20, 2013), pp. 310-322. PT
Pharmaceutical Technology SOLID DOSAGE DRUG DEVELOPMENT AND MANUFACTURING 2016
19
Non-Gelatin Capsules
Establishing a New
Performance Standard
for HPMC Capsules
Agnes Shanley
F
or nearly a hundred years, two-piece hard shell capsules
made from gelatin have been the preferred medium for encapsulating solid oral-dosage forms. The market, however,
began to recognize the need for alternatives decades ago.
Gelatin, derived from pork and beef byproducts, posed a concern
for patients with religious or dietary restrictions, but it could also
pose formulation problems when encapsulating hygroscopic and
moisture-sensitive ingredients.
The plant-based material, hydroxypropyl methylcellulose (HPMC),
was developed as an alternative to gelatin for two-piece hard shell
capsules. The first manufacture of the material in capsule form, however, required the use of secondary gelling agents, which resulted
in variability in both disintegration and product dissolution. Approximately eight years ago, a second generation of HPMC-polymer
capsules was introduced. Matt Richardson, PhD, manager, Pharmaceutical Business Development at Capsugel, and Michael Morgen,
PhD, senior principal scientist, Bend Research, a division of Capsugel
Dosage Form Solutions, discussed these next-generation materials
with Pharmaceutical Technology.
HPMC vs. conventional materials
PharmTech: What makes HPMC capsules different, in terms
of performance properties, from conventional gelatin
technology?
Richardson (Capsugel): HPMC capsules, specifically those made by
thermo-gelation, differ from conventional gelatin capsules in several
ways. Gelatin, derived from animal collagen, is composed of amino
acid chains, while HPMC is cellulose-based. The respective poly20
Pharmaceutical Technology SOLID DOSAGE DRUG DEVELOPMENT AND MANUFACTURING 2016 P h a r mTe c h . c o m
IMAGE IS COURTESY OF CAPSUGEL
A new generation of
cellulose-derived materials
addresses the variability in
disintegration and product
dissolution that were seen in
the first generation of
gelatin alternative HPMC
capsules, while offering
in-vitro and in-vivo
performance comparable to
that of gelatin capsules.
mers impart different properties to each capsule.
Compared to gelatin, HPMC has lower moisture
absorption, more flexibility, higher thermal stability, and better resistance to chemical crosslinking.
The manufacture of second-generation HPMC
capsules by thermo-gelation is quite different than
that of first-generation HPMC capsules and gelatin
capsules. Both first-generation HPMC and gelatin
capsules are made by dipping stainless-steel pins into
a hot polymer solution. The polymer is deposited on
the stainless-steel pin and then dried to achieve a targeted water content. In the thermo-gelation process
for second-generation HPMC capsules, heated stainless-steel pins are dipped into a solution of HPMC to
form capsules without use of gelling agents.
PharmTech: What were the specific performance
limitations with first-generation HPMC capsules?
Morgen (Bend Research): First-generation HPMC
capsules avoided gelatin’s potential for crosslinking. They were formulated with gelling systems,
however, and variability in disintegration and
product dissolution rates was often observed, depending on pH and/or ionic strength of the test
media. Second-generation HPMC capsules were
designed to reduce the performance variability of
first-generation HPMC capsules.
PharmTech: What other specific advantages does
the second-generation material offer?
Richardson (Capsugel): HPMC capsules have a lower
average water content (6% compared with roughly
14% for gelatin capsules), making them an excellent
choice for low moisture or hygroscopic formulations. They also demonstrate high levels of thermal
stability and are quite flexible, compared with gelatin capsules, which can occasionally become brittle,
especially with low-moisture APIs and excipients.
Perhaps their most important attribute is that
second-generation HPMC capsules offer disintegration/product dissolution profiles that have been
shown to provide equivalent in-vivo performance
to gelatin capsules for a range of drug molecules.
PharmTech: What are their limitations?
Morgen (Bend Research): HPMC capsules have
higher oxygen permeability than gelatin capsules,
so they may not be ideal for oxidation-sensitive
formulations, or those that have an odor.
Recent in-vivo and dissolution test results
PharmTech: Please discuss the significance of recent
in-vivo and dissolution test results.
Morgen (Bend Research): The most recent study
focused on investigating the clinical performance
of second-generation HPMC capsules relative to
that of gelatin capsules. It aimed to demonstrate
that, in-vivo, the slight disintegration time delay for
second-generation HPMC capsules does not lead
to differences in pharmacokinetics for relatively
soluble, well-absorbed drugs, but that the performance would be equivalent to that of gelatin capsules for these applications. This equivalence was
shown, using three different compounds. Formulation scientists now have more options for optimizing capsule disintegration and product release.
PharmTech: What other innovations are being
investigated for second-generation capsules?
Morgen: For some applications, the capsules
may provide superior bioavailability, particularly
for low solubility drugs, by sustaining supersaturated concentrations of dissolved drug in the gastrointestinal (GI) tract through crystallization inhibition. This is a potential advantage,specifically
for high-energy salt and amorphous drug forms,
as well as for weakly basic drugs that are capable
of supersaturating in the GI tract. PT
Pharmaceutical Technology SOLID DOSAGE DRUG DEVELOPMENT AND MANUFACTURING 2016
21
Process Simulation
Modeling and Simulation
Move Downstream
Agnes Shanley
22
M
any industries use computer-based simulation and
modeling routinely to troubleshoot and improve their
processes. Pharmaceutical manufacturers have not
yet embraced the technology, at least not for downstream applications. Some companies may use non-computer based
simulation to optimize conditions, for example, compaction simulators for tablet compression. Generally, though, the industry’s most
advanced computer-based systems are reserved for pharmacokinetics and early research.
For chemists, engineers, and technicians who work in development and manufacturing, part of the challenge to using models is
that they can be more difficult to develop for batch processes, which
can involve more variability in materials, process conditions, and
other factors. In addition, the physical and material properties data
required for this work, which are freely available to engineers in
petrochemical processing, for instance, via references such as Perry’s
Chemical Engineering Handbook, are not readily available to professionals in pharmaceutical manufacturing and development. Most of
the data on materials depend on the specific run, batch, equipment,
and facility.
Increased interest in continuous processing, however, is convincing more professionals in the industry to study and apply in-silico
technologies and models to gain process knowledge and improve
manufacturing. Modeling could also improve drug development,
enabling development of higher quality, more robust products, and
increasing R&D efficiency.
Indicative of the trend is a new four-year initiative that was
launched in the United Kingdom in January 2016 to help streamline drug development and manufacturing by leveraging better
Pharmaceutical Technology SOLID DOSAGE DRUG DEVELOPMENT AND MANUFACTURING 2016 P h a r mTe c h . c o m
YURI_ARCURS/GETTY IMAGES
Computer-based tools
promise better quality
products, improved process
control, and increased R&D
efficiencies, but will require
different workflows.
Award-Winning
On-Dose
Authentication
& Brand Protection Solutions
• Covert, Inert and Easy to Apply
• Machine-Readable Microtags
• Custom Codes by Product
7UX7DJRHUVDQHɝFLHQWFRVWHHFWLYHVROXWLRQWKDWFRPEDWVFRXQWHUIHLWLQJDQGGLYHUVLRQ
SURWHFWLQJ\RXUSURGXFWIURPSODQWWRSDWLHQW
Contact us now: www.trutags.com/awardwinning
PRODUC
TO
ETY
AF
AWARDS2013