European Journal of Pharmaceutics and Biopharmaceutics 78 (2011) 208–212

Contents lists available at ScienceDirect

European Journal of Pharmaceutics and Biopharmaceutics

journal homepage: www.elsevier.com/locate/ejpb

Commentary

Development of high concentration protein biopharmaceuticals:

The use of platform approaches in formulation development
Nicholas W. Warne ⇑
Pharmaceutics R&D, BioTherapeutics Research and Development, Pfizer Inc., MA, USA

a r t i c l e i n f o a b s t r a c t

Article history: The development of highly concentrated solutions of monoclonal antibodies has become increasingly
Available online 13 March 2011 popular in biotechnology firms as doses increase, and the demand for sub-cutaneous injection formula-
tions rises for reasons of convenience and compliance. Protein concentrations often exceed 100 mg/mL.
Keywords: Unfortunately, the reduced success rate of commercialization of biotechnology products result in a situ-
Monoclonal antibody ation in which the majority of biologics that enter clinical trials have a very low probability of becoming
Platform commercial products. Under these circumstances, the formulation scientist must make judicious use of
Efficiency
his or her available time and resources and must avoid over-investing in early phase 1 compounds. This
Formulation
Dosage form
circumstance has driven many laboratories to develop so-called ‘‘platform formulations’’ in which a suit-
Protein able, high concentration, robust formulation, or dosage form is utilized broadly across a number of early
stage biologics at a savings of time and effort. This highly pragmatic approach increases the efficiency of
developing early clinical candidates with fewer resources, while maintaining clinical flexibility, thus sav-
ing their effort for later stage candidates for which proof of concept has been demonstrated and for which
a more optimized and robust formulation and process, suitable for commercial application, must be
developed.
Ó 2011 Elsevier B.V. All rights reserved.

1. Introduction limited. An FDA report from 2004 indicated that the success rate
from Initial Investigational New Drug (IND) to successful licensure
Monoclonal antibodies are being developed for a variety of is approximately 8% [2–5]. With this poor success rate, one must
indications at increasingly higher doses. They represent the largest ask whether the extensive investment in early stage process and
growing segment of products from the biotechnology industry product development, with the goal of developing commercially
with 26 products currently approved in the United States [1]. The acceptable types of processes and dosage forms, is warranted for
requirement for elevated doses (cetuximab is dosed at 250– an early stage biologic in which so little is known. The develop-
400 mg/m2; efalizumab at approximately 1 mg/kg), as well as a ment of a mature dosage form requires an understanding of dose
strong desire to provide a convenient sub-cutaneous dose, to in- (mg/kg or fixed dose), route of administration (sub-cutaneous,
crease the level of compliance and provide greater flexibility to intra-venous, or intra-muscular), market need (self-administered,
the patient and the health care provider, results in the need for in-home, doctors office, or clinically administered), safety, and effi-
increasingly higher concentration proteins. Recently approved cacy. Often, these parameters are not well defined until late phase
products have pushed the solubility limits for biopharmaceuticals 2 proof-of-concept studies have been completed. Without this
and have yielded very high concentrations (omalizumab is information, the formulation scientist should be less concerned
125 mg/mL post-reconstitution, certolizumab pegol is 200 mg/mL with potential commercializability of the phase 1 product and
post-reconstitution) as well as elevated viscosities. Clearly, there more concerned with providing a flexible and stable dosage form
is an evolving need to routinely generate highly concentrated for phase 1–2 clinical trials. For the clinic, the dosage form must
monoclonal antibody solutions for clinical testing. meet certain quality requirements pertaining to safety, stability,
Despite the need for innovative solutions to unmet medical and purity, but it must also provide the clinician with flexibility
need, the success rate for the development of biotherapeutics is in dosing across a broad range of dose levels (typically 0.1–
20 mg/kg for a monoclonal antibody, depending on target indica-
tion) as well as flexibility across routes of administration (typically
⇑ Pharmaceutics R&D, BioTherapeutics Research and Development, Pfizer Inc.,
sub-cutaneous and intra-venous). As a result, biotechnology firms
One Burtt Road, Andover, MA 01810, USA. Tel.: +1 978 247 4292; fax: +1 978 247
4298. are developing flexible, stable dosage forms that provide monoclo-
E-mail address: Nicholas.warne@pfizer.com nal antibodies at concentrations of approximately 100 mg/mL. This

0939-6411/$ - see front matter Ó 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.ejpb.2011.03.004
 N.W. Warne / European Journal of Pharmaceutics and Biopharmaceutics 78 (2011) 208–212 209

approach has reached patients in the form of commercial products manufacturing process as well as just prior to administration. In
such as efalizumab, palivizumab, and golimumab which are formu- order to assess a suitable pH, however, one does not necessarily
lated at 100 mg/mL. have to perform large numbers of experiments with multiple buf-
fers under a variety of stress conditions. Rather, one may wish to
begin by first learning from the work of others.
2. Rationale for platform approach
Table 1 presents a list of formulations for recently approved
antibodies. The information contained in this table has been taken
Standardized approaches for development and manufacturing
from the publicly available sources provided by the manufacturers,
have been utilized for many centuries. Whether mass production
in particular the appropriate package inserts. Review of Table 1
of automobiles or the efficient utilization of pre-existing technolo-
demonstrates a common theme in terms of pH as well as other
gies for cellular phones, firms and individuals strive to utilize exist-
excipients, often depending on antibody concentration. For exam-
ing, often proprietary approaches and experience and wish to avoid
ple, the average reported pH for all antibodies in Table 1, when re-
having to re-invent already existing technologies. The biotechnol-
ported, is 6.3 ± 0.6 (n = 15). If we focus on the higher concentration
ogy industry is no different. Various laboratories have their pre-
antibodies for which information is available, the range narrows
ferred host cell lines [6], expression media, and purification
slightly to pH 6.0 ± 0.4 (n = 9). Of the 13 antibodies formulated at
processes. Recent publications describe platform purification pro-
P20 mg/mL, 7 utilize L-histidine as the buffer. Further, the six most
cesses for monoclonal antibodies. Tugcu et al. [7] describe the
highly concentrated antibodies, from 90 to 150 mg/mL, utilize
use of a protein A capture step followed by anion and/or cation
L-histidine as the buffer.
exchange chromatography for a three column purification of
Table 1 illustrates that both liquid and lyophilized presenta-
monoclonal antibodies. Kelley et al. [8] describe a two column
tions are utilized for antibody based formulations. As expected,
purification process in which protein A affinity chromatography
the lyophilized powders use a cryo-preservative and/or a bulking
is followed by a weak partitioning anion exchange resin. These
agent to aid in the lyophilization process. Choices of cryo-preserva-
examples illustrate that, at least for monoclonal antibodies, one
tives include sucrose and trehalose while bulking agents include
can utilize routine purification processes which, although they
glycine and mannitol. Of the five most highly concentrated anti-
may need to be slightly modified to accommodate the characteris-
bodies, three (canakinumab, omalizumab, and efalizumab) share
tics of a specific protein or host cell system, should provide an ade-
very similar lyophilized formulations of L-histidine as buffer, su-
quately reproducible and suitably pure drug substance which can
crose as cryo-preservative, and some level of surfactant. Despite
then be utilized in formulation studies. One aspect to consider in
this interest in high concentration lyophilized dosage forms, the
the development of platform approaches, formulation or other-
majority of the antibody formulations in Table 1 are liquid dosage
wise, is that they are not intended to be successful 100% of the
forms (14 of 21). At lower concentrations, sodium phosphate ap-
time. One must be content to cover the majority (e.g. >80%) of
pears to be utilized broadly as a buffer (6 of 8 products at
monoclonal antibodies and benefit from the savings in time and ef-
610 mg/mL) in formulations often similar to phosphate-buffered
fort. Early screening of expression levels, ease of purification and
saline. Sodium chloride is often utilized at lower protein concen-
accelerated stability and solubility studies can help to screen the
trations, but alternate tonicity adding excipients are also utilized
20% of compounds that may not fit into the platform approach.
such as glycine, mannitol, and sorbitol. Finally, 16 of 21 antibody
With regard to formulation design, recent articles have focused
products utilize either polysorbate-20 or polysorbate-80 as a
on the use of broad arrays of formulation approaches to determin-
surfactant.
ing the most suitable formulation for a given product. Specifically,
Review of Table 1 suggests that, for an antibody, the development
high-throughput approaches have been developed for the thor-
of an early clinical dosage form may be based on one’s experience, or
ough screening of conditions for difficult to formulate proteins
the commercial experience of others, rather than exploring a broad
[9,10]. In addition, tremendous experience has been gained in the
formulation space de novo. A typical preformulation screen, for
development of lyophilized powders for proteins. Monoclonal anti-
example, may explore formulation characteristics such as pH (from
bodies, in contrast to cytokines and growth factors, appear to be a
4.0 to 8.0), ionic strength using NaCl, cryo-preservatives such as
more homogenous set of proteins to formulate the majority of the
sucrose and the need for surfactants. Since 16 of the 21 examples
time. One may choose, therefore, to forgo the desire to optimize a
presented in Table 1 contain either polysorbate-20 or polysorbate-
formulation for a monoclonal antibody prior to phase 1 clinical tri-
80, there is value in asking whether it is prudent, when time and
als, especially due to the significant number of unknown elements
materials are limited, to experimentally assess whether one should
associated with a pre-clinical project, and rather adopt the ap-
include polysorbate in the formulation. Based on the commercial
proach of a standardized or platform formulation. What is de-
experience of the formulation scientists who developed the prod-
scribed in the following sections should be considered guidance
ucts described in Table 1, the simple recommendation would be to
pertaining to a platform formulation approach which utilizes a
include some level of polysorbate in the formulation at a concentra-
standardized or platform formulation of defined protein concen-
tion suitable to that required by the protein concentration. Thus, the
tration and excipients.
decision is no longer whether to include a surfactant in the formula-
tion, but rather to ask how much to include based on its intended
3. Platform approaches to dosage form development purpose such as protection from mechanical agitation or possible
assistance during the reconstitution of a lyophilized powder [13].
The first steps to designing a suitable dosage form, and formu- Again, the level of polysorbate may be guided by the experience of
lation, is to gather information on the effect of pH with regard to others.
the protein’s behavior. The pH of the formulation must be selected A similar review of the products described in Table 1 can be ap-
to minimize a wide variety of possible degradation mechanisms plied to pH. Since the majority of the high concentration antibody
including aggregation, poor solubility (partially based on the pI formulations are formulated at pH 6.0 ± 0.4, one must ask whether
of the protein), and chemical degradation by oxidation, deamida- there is value in examining formulations outside this range.
tion, and hydrolysis just to name a few mechanisms [11]. Many Further, given the limited number of choices for a suitable buffer
of these chemical degradation mechanisms can be managed in this range (succinic acid has a pKa of 5.6, L-histidine 6.0 and
effectively by lyophilization [12], however the formulator must sodium phosphate 7.21 all at 20 °C), we must ask why we would
also consider the effect of short-term hold times during the consider a buffer other than L-histidine.
210 N.W. Warne / European Journal of Pharmaceutics and Biopharmaceutics 78 (2011) 208–212

Table 1
Formulations of several commercial antibodies.a

Product name Dosage form Concentration pH Formulation

Ò
ILARIS (canakinumab) Lyophilized 150 mg/mL NA 92.4 mg/mL sucrose, L-histidine and L-histidine HCl, 0.6 mg/mL polysorbate-80
XOLAIRÒ (omalizumab) Lyophilized 125 mg/mL NA 125 mg/mL omalizumab, 90 mg/mL sucrose, 1.7 mg/mL L-histidine hydrochloride
monohydrate, 1.1 mg/mL L-histidine, 0.3 mg/mL polysorbate-20
RAPTIVAÒ (efalizumab) Lyophilized 100 mg/mL 6.2 Approximately 82 mg/mL sucrose, 4.5 mg/mL L-histidine hydrochloride monohydrate,
2.9 mg/mL L-histidine, 2 mg/mL polysorbate-20
SYNAGISÒ (palivizumab) Lyophilized 100 mg/mL NA 47 mM histidine, 3 mM Glycine, 5.6% mannitol
SIMPONIÒ (golimumab) Liquid 100 mg/mL 5.5 0.88 mg/mL histidine and histidine–HCl monohydrate, 41 mg/mL sorbitol,
0.16 mg/mL polysorbate-80
STELARAÒ (ustekinumab) Liquid 90 mg/mL 5.7– 1 mg/mL L-histidine and L-histidine–HCl, 76 mg/mL sucrose, 0.04 mg/mL polysorbate-80
6.3
Ò
HUMIRA (adalimumumab) Liquid 50 mg/mL 5.2 6.2 mg/mL sodium chloride, 0.86 mg/mL sodium citrate, 1.3 mg/mL citric acid monohydrate,
12 mg/mL mannitol, 1 mg/mL polysorbate-80
CAMPATHÒ (alemtuzumab) Liquid 30 mg/mL NA 8 mg/mL sodium chloride, 1.44 mg/mL dibasic sodium phosphate, 0.2 mg potassium chloride,
0.2 mg/mL monobasic potassium phosphate, 0.1 mg/mL polysorbate-80, 0.0187 mg/mL disodium
edentate dihydrate
AVASTINÒ (bevacizumab) Liquid 25 mg/mL 6.2 60 mg/mL trehalose, 5.8 mg/mL sodium phosphate monobasic monohydrate, 1.2 mg/mL sodium
phosphate dibasic anhydrous, 0.4 mg/mL polysorbate-20
Ò
HERCEPTIN (trastuzumab) Lyophilized 21 mg/mL 6 Approximately 20 mg/mL a,a-trehalose dehydrate, 0.5 mg/mL L-histidine HCl, 0.32 mg/mL
L-histidine, 0.09 mg/mL polysorbate-20, 1.1% bacteriostatic water

VECTIBIXÒ (panitumumab) Liquid 20 mg/mL 5.6– 5.8 mg/mL sodium chloride, 6.8 mg/mL sodium acetate
6.0
ROACTEMRAÒ (tocilizumab) Liquid 20 mg/mL 6.5 15 mM phosphate, 50 mg/mL sucrose, 0.5 mg/mL polysorbate-80
ARZERRAÒ (ofatumumab) Liquid 20 mg/mL 6.5 8.55 mg/mL sodium citrate, 0.195 citric acid monohydrate, 5.85 mg/mL sodium chloride
SOLIRISÒ (eculizumab) Liquid 10 mg/mL NA Chloride, phosphate dibasic, phosphate monobasic, polysorbate-80
LUCENTISÒ (ranibizumab) Liquid 10 mg/mL 5.5 10 mM histidine–HCl, 10% trehalose, 0.01% polysorbate-80
REMICADEÒ (infliximab) Lyophilized 10 mg/mL 7.2 50 mg/mL sucrose, 0.05 mg/mL polysorbate-80, 0.22 mg/mL monobasic sodium phosphate
monohydrate, 0.61 mg/mL dibasic sodium phosphate dihydrate
RITUXANÒ (rituximab) Liquid 10 mg/mL 6.5 9 mg/mL sodium chloride, 7.35 mg/mL sodium citrate dihydrate, 0.7 mg/mL polysorbate-80
ZENAPAXÒ (daclizumab) Liquid 5 mg/mL 6.9 3.6 mg/mL sodium phosphate monobasic monohydrate, 11 mg/mL sodium phosphate dibasic
heptahydrate, 4.6 mg/mL sodium chloride, 0.2 mg/mL polysorbate-80
SIMULECTÒ (basiliximab) Lyophilized 4 mg/mL NA 1.4 monobasic potassium phosphate, 0.20 mg/mL disodium hydrogen phosphate (anhydrous),
0.32 mg/mL sodium chloride, 4 mg/mL sucrose, 16 mg/mL mannitol, 8 mg/mL glycine
ERBITUXÒ (cetuximab) Liquid 2 mg/mL 7.0– 8.48 mg/mL sodium chloride, 1.88 mg/mL sodium phosphate dibasic heptahydrate,
7.4 0.42 mg/mL sodium phosphate
Ò
REOPRO (abciximab) Liquid 2 mg/mL pH 7.2 10 mM sodium phosphate, 150 mM sodium chloride, 0.001% polysorbate-80
a
All formulations are expressed as mg/mL after reconstitution. Because of fill volume variability, some concentrations are approximate.

The rationale for the selection of an appropriate pH and the use 80. A simple titration of polysorbate within the formulation, when
of polysorbates in antibody products, demonstrates the concept of suitably stressed, should provide a rationale for selection of an
a ‘‘simple formulation.’’ Protein formulations should be inherently appropriate concentration. Further, this level may be fixed in con-
simple and each excipient should have a clearly defined purpose. junction with a set protein concentration across products.
This purpose, however, may not need to be demonstrated experi- In addition to a buffer, pH range and selection of surfactant, one
mentally for each compound going into phase 1 clinical trials. Re- typically requires a stabilizer to protect the protein from the rigors
cent regulatory guidance [14] suggests that the selected excipients of ultrafiltration, possible lyophilization, and multiple freeze–
and their respective concentrations should be justified on the basis thaws. While the rationale for excipient selection, for lyophilized
of their impact on the product’s stability, bioavailability, and products in particular, has been discussed elsewhere, the princi-
manufacturability. One may wish to consider, for a phase 1 com- ples for stabilizer selection are similar to those of selecting a suit-
pound, whether this needs to be justified for each monoclonal anti- able buffer, pH, and surfactant: learn from experience and do not
body or can it be generalized across a class of proteins. While over-invest your time and effort for a phase 1 product unless the
additional data are collected on these parameters during the late protein shows instability with commonly used excipients. Drug
clinical stage of development, much of this information will not ex- substances are often produced in multiple-liter batches that must
ist during pre-clinical development prior to the preparation of be stored for extended periods ranging from months to years.
early stage clinical supplies. Limited information should encourage While some drug substances, such as antibodies, may be stored un-
the formulation scientist to seek simple solutions to the design of der refrigerated conditions, it is often the case where drug sub-
the formulation space for the protein in question. With this in stances must be frozen to preserve stability and provide
mind, the ‘‘simple formulation’’ approach may be broadly applica- manufacturing flexibility. A cryo-preservative is often utilized to
ble across antibody products. If, for example, 10–20 mM L-histi- protect the protein of interest from the rigors of repeated freeze–
dine, some level of polysorbate, and pH 6.0 works for several thaw as well as freeze-drying. The use of sucrose as a cryoprotec-
antibodies, it is a reasonable starting point to assume that it may tant is well documented as is its use as a stabilizer for lyophilized
apply broadly. Rather than performing a broad pH screen, from dosage forms [15]. Preformulation experiments are critical in
pH 4 to 8, under accelerated storage conditions of 25 °C and determining whether a liquid formulation is feasible based on
40 °C, the formulation scientist may simply wish to verify that the analytical procedures available during the pre-clinical stage
the selection of 10–20 mM L-histidine at pH 6.0 provides adequate of development. The use of sucrose, at neutral pH, provides the
stability for the early clinical dosage form. A similar approach opportunity to either lyophilize the product or develop a liquid for-
could be taken for identification of the level of polysorbate. For mulation that will be stable against freeze–thaw induced damage.
example, the products described in Table 1 encompass a range One aspect to consider, however, is the use of sucrose in liquid dos-
from 0.005% to 0.2% with either polysorbate-20 or polysorbate- age forms where the pH is slightly acidic; in this case, hydrolysis
 N.W. Warne / European Journal of Pharmaceutics and Biopharmaceutics 78 (2011) 208–212 211

may occur even under refrigerated conditions [16]. In these cir- if one were to use the same formulation, protein concentration and
cumstances, one may wish to consider the use of trehalose which container-closure system, then it is reasonable to assume that
has a more stable glycosidic bond. For a lyophilized dosage form, these products could utilize the same lyophilization cycle, mixing
however, the use of sucrose, which is widely accepted, should be process, and sterile filtration process. While these pre-defined pro-
encouraged. For a liquid dosage form, alternate excipients have cesses should be experimentally verified, it is an advantage to have
been utilized, but we must also consider how the drug substance an agreed upon starting point from which to assess the applicabil-
is to be stored and further processed. The use of sodium chloride ity of a defined process.
and mannitol as tonicity agents is well known, however these The platform approach not only applies to formulations and
excipients tend to crystallize on storage at 20 °C which can lead drug product unit operations but also to unit operations within
to loss of protein integrity. As a result, the development of liquid other biotechnology processes (cell line, bioreactor process, purifi-
based formulations must also consider cryo-preservation, when cation process, and analytical development). In addition, there are
frozen storage is required, as well as processes for compounding efficiencies when developing specifications or manufacturing doc-
and storage. uments (batch records) in which having mature, well-accepted
templates further streamline the robustness, repeatability, predict-
ability, and expectations in terms of time and expenses.
4. Broad applicability of a platform approach

5. Phase 3/commercial process and product development

When utilizing a platform approach, or better yet, platform for-
mulations for antibodies at the same concentration (liquid or
Platform approaches can extend beyond phase 1–2 clinical trial
lyophilized), there are several advantages that arise. If one were
materials into phase 3/commercial dosage form development.
to place two or more proteins in the same formulation (as well
While the specific dosage forms may vary depending on the clinical
as the same container-closure system), they could share the same
application (e.g. vialed product for intra-venous injection of an
placebo. This efficiency reduces the need for product-specific pla-
oncology medication; autoinjector presentation for self-adminis-
cebos to be produced for each individual product that enters clin-
tration of a rheumatoid arthritis medication), the general approach
ical trials. Further, the use of platform dosage forms (excipients,
to process and product development should be the same.
container-closure systems) reduces the need to carry released,
Once the dose, route of administration, and presentation (vial,
qualified, expensive cGMP raw materials at a manufacturing site
pre-filled syringe or autoinjector) have been selected, the formula-
for a product that may be unique. Further, if one were to develop
tion and manufacturing process must be developed, optimized,
a standard formulary from which the formulation scientist can
characterized for robustness, and scaled up for commercial produc-
draw, it dramatically simplifies the formulation selection process
tion. Experiments to support the development activities can be
for a phase 1–2 compound which, based on the discussion above,
standardized to ensure an efficient use of time and resources. For
is unlikely to reach phase 3 clinical testing or commercial launch.
example, one can platform a lyophilization robustness approach
The pharmaceutical scientist must consider whether to utilize
to ensure that the majority of potential process deviations are ad-
liquid or lyophilized dosage forms for phase 1 clinical trials. Liquid
dressed. Having a platform approach makes these experiments
dosage forms have several advantages such as ease of manufacture,
more routine and predictable. Similar approaches can be taken to
simplicity in packaging, and ease of use. Further, they may allow
robustness studies pertaining to formulation (defining acceptable
for the generation of a representative stability profile in phase 1
excipient levels or pH range), hold-times, numbers of freeze–thaw
clinical trials materials which enables the establishment of suitable
cycles and filtration steps, compatibility with filling equipment,
release and stability specifications at the latter stage of develop-
mixing, and so on. For phase 3/commercial processes, a platform
ment. An obvious disadvantage is the potential for inadequate sta-
approach is what adds value more than a prescriptive platform
bility which may require an increased number of resupply fills, an
formulation.
unwanted expense. Lyophilized dosage forms have the disadvan-
tage of additional costs associated with development, manufac-
ture, testing, and the need for diluents for reconstitution, but 6. Summary
they are likely to help reduce the number of resupply batches that
may be required because of the superior stability of the lyophilized Platform or standardized approaches have been utilized broadly
dosage form. The level of experience and the sense of risk with the in a variety of industries for hundreds if not thousands of years.
interdisciplinary project team and the formulation scientist should Best practices, once defined and shared, have resulted in tremen-
guide these choices. dous savings of time, effort, and funds. Within biotechnology, re-
In addition to platform formulations or approaches to formula- cent advances in process and formulation development have
tion development, other drug product related processes can be enabled the development of platform approaches for purification,
platformed. For example, it is not unusual for firms to utilize a spe- cell line development and formulation development. These plat-
cific sterile filtration membrane for all of their monoclonal anti- form approaches will become increasingly important as the num-
bodies. Recent work by Ho et al. [17] demonstrated the benefit of ber of molecules (antibodies specifically) entering the clinic
poly-ether sulfone sterile filtration membranes, relative to PVDF increases as well as a mature recognition that the vast majority
for example, for monoclonal antibodies of neutral or basic pI. of these compounds will not enter phase 3 clinical trials. The use
Armed with this type of data, one could select a sterile filtration of platform approaches enables the formulation scientist to effi-
membrane, with a high probability of success, simply on the basis ciently develop suitable, safe, stable, reproducible phase 1–2 dos-
of the pI of the protein. In a similar manner, one could imagine age forms with reduced effort thus creating time and effort to
crafting a platform approach, or standard procedure, for conduct- address additional projects or further the development of novel
ing freeze–thaw studies, shaking studies, and stability studies. technologies.
Having a common manner in which to conduct these studies not
only provides for a streamlined approach that can be utilized
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