Evonik Pharma Polymers News 2 2012
Transcript of Evonik Pharma Polymers News 2 2012
7/16/2019 Evonik Pharma Polymers News 2 2012
http://slidepdf.com/reader/full/evonik-pharma-polymers-news-2-2012 1/8
Pharma Polymers NewsT wslttr Evik’s Prm Plymrs & Srvics rduct li Issu |
Quality by Design(QbD)Pg
New in the teamPg
AAPS poster abstractsPg
Evonik workshops andtrade showsPg
ContentEditrilDr Rdrs,
We’ve changed our name!
Now we are ocially Evonik
Pharma Polymers & Services.The addition o the word “Ser-
vices” reects our strong com-
mitment to empower all aspects
o modern drug delivery through
close partnership with custom-
ers. Our comprehensive services
around our well known unc-
tional polymers EUDRAGIT®,
RESOMER® and LAKESHORE
BIOMATERIALS™ range rom
ormulation and process devel-
opment to commercial manuac-turig d surt wit rgul-tory and toxicological data.
Kig ur clits t t r-rt ivti d c-ig tir mrkt succss: tt is
the goal o Evonik Pharma Poly-
mrs & Srvics.In order to maximize the
reliability and quality o our
rducts d srvics, w vimlmtd Qulity by Dsig
(QbD) stdrds it ur tc-nical services or polymer and
ormulation users. Our cover
story will give you an in-depth
view into a study demonstrating
how the application o QbD
principles resulted in the process
optimization o a sustained re-
ls ctig wit EUDRAGIT®NM 30 D. Additionally, it pro-
vides important acts about QbD
requirements becoming man-
dtry s.
Tis diti Prm Ply-mers News also describes the
scientifc studies we’ll present as
posters at the AAPS Annual
Meeting in Chicago. Appropri-
ately, one o them will introduce
the above-mentioned QbD
study. T vrity d rg poster topics clearly demon-
strates our main principle:
to provide our customers withoptimum support in order to
ensure best success or their
dvlmts.O course, you won’t want to
miss our regular eatures. Get
the latest updates on our new
team members and fnd out
wr t t sws d sm-irs will tk lc.
S rd d jy!
Wrm rgrds,
Dr. thmas RirmirVic PrsidtPrm Plymrs & Srvics
Quality by Design (QbD)– our expertise for your market success
7/16/2019 Evonik Pharma Polymers News 2 2012
http://slidepdf.com/reader/full/evonik-pharma-polymers-news-2-2012 2/8
PAGe 2
Pharma Polymers News 2 | 2012
Qulity by Dsig (QbD) – ur rtis ryur mrkt succssQualiy by Dsig (QbD) is a h pici h wrldwid pharmacuical idus-ry. th U.S. ofc Gric Drugshas mad h “hacd” QbD apprach prduc dvlpm madary rall gric applicais bgiig i Jauary 2013.
The QbD guidelines Q8, Q9 and
Q11, as established by the International
Conerence on Harmonisation o Tech-
nical Requirements or Registration o
Pharmaceuticals or Human Use (ICH),
clearly state the intent o this initiative [1].The key elements named therein are:
• Risk management
• Scientic knowledge
• Process understanding
The FDA advises the use o these
elements to reach the desired condition
o “a maximally ecient, agile, exible
pharmaceutical manuacturing sector thatreliably produces high-quality drug
products without extensive regulatory
oversight.” [2]
At Evonik our major principle is to
support our clients with their development
and production requirements. Hence, theQbD principles have become a crucial
element in that aim, as they help to ensurethe quality o our clients’ products.
In the ollowing case study the
application o QbD principles to processoptimization is presented. As a model,
uid bed coating and subsequent in-
process curing o a sustained release
coating with EUDRAGIT® NM 30 D were
chosen.
eUDRAGIt® nM 30 D i susaidrlas caigs
EUDRAGIT® NM 30 D is one o the
most highly exible EUDRAGIT® poly-
mers, showing an elongation at break o
~ 600 %. Hence, it can be used to applydiusion-controlled coatings or extended
drug release multiparticulates on almost
any substrate, no matter how the pellets,
crystals or granules are shaped. In order
to ensure stable unctionality over the
shel lie o the coated dosage orm, the
coalescence o the polymer latex particlesmust be completed. This can be realized
by an in-process curing step directly aerthe coating.
Quality Target Product Prole
As the frst step o a pharmaceuticaldevelopment, quality, saety and ecacy
o the product have to be defned in a
Quality Target Product Profle (QTPP –
see Table 1). It orms the basis or the de-
velopment o the product, where drug
release and stability are important drug
product quality criteria. For unctional
coatings with EUDRAGIT® NM 30 D thesecriteria are mainly defned by the flm or-mation.
Physics of lm formationThe ormation o a flm rom any
aqueous polymer dispersion can be
described in our steps:
1. Evaporation o water and
densifcation o latex particles
2. Deormation o latex particles
3. Fragmentation and segregation
o hydrophilic shells
4. Interdiusion o latex particles
Tbl : Quality Target Product Prole (QTPP)
Prduct ttribut Trgt ImlictisDsg rm d rut dmistrti Orl mdid rls llts Ctd lltsDs strgt mg rrll Twic dyIdtity
Mtig cmdil r tr licblqulity stdrds Prmcil mtds
AssyCtt uirmityDgrdti rductsDrug rls Sustid rls Dissluti vr (> %)
Srag sabiliy Drug rlas uchagd Disslui sig
Tbl : Risk analysis
Prcssst Filur md
Prtig
Abrsi llts
Abrsi llts
Ctig
Pllts stickig
Pllts stickig
N sryig
Prducti rtsPrtig Filtr clggig
Curig
Icmlt clscc
Icmlt clsccIcmlt clsccDryig N
7/16/2019 Evonik Pharma Polymers News 2 2012
http://slidepdf.com/reader/full/evonik-pharma-polymers-news-2-2012 3/8
PAGe 3
Pharma Polymers News 2 | 2012
Step 2 happens under the condition o
T>MFT, where T is the product tempera-ture and MFT is the minimum flm-
orming temperature.
Step 4 happens under the condition o
T>Tg, where Tg is the glass transition
temperature o the polymer.
In step 4 the appearance o the flm
does not change, but elongation at break,
dielectrical resistance and diusability
properties do. With the application o a
sustained release coating, step 4 obviously
has a major impact on the quality o the
coated drug product, especially since theTg o EUDRAGIT® NM 30 D is only 9 °C.
To control this step, a thermal treatment(curing) is done aer coating, conventio-
nally conducted on trays in a circulating
air cabin at 40 °C over 24 hours. As an
ecient alternative and more adequately
suited or production, the curing can be
perormed in the coating equipment.
Relative humidity, temperature and cu-
ring time have been identifed as actorsinuencing the curing process [3]. Prior
studies on the curing behavior o sus-
tained release ormulations have shown
an operating range o 40–45 °C product
temperature and 45–50 % relative exhaust
air humidity or 30 minutes to be ideal orEUDRAGIT® NE and NM coatings [4, 5].
Risk assessmentA risk assessment begins with a review
o the entire process. For each step the
possible modes o ailure are considered.Thereore, prior knowledge and expertise
are o great importance.
To ensure the best possible outcome,
it is vital that a cross-unctional team
o experts with product knowledge,
ormulation expertise and process know-how perorms the review. This risk
assessment helps in identiying which
material attr ibutes and process parameters
have an impact on Critical QualityAttributes (CQAs) o the product.
Table 2 shows the risk assessment or
the sustained release product using ailure
mode eects analysis as a tool. Curing hasbeen identifed as a signifcant parameter
and was studied through Design o
Experiments (DoE) to achieve a higher
level o process understanding.
Dsig exprims
As part o the control strategy, DoEwas used to gain knowledge on the curingprocess.
Batches o 3 kg pellets were coated in
a uid bed coater (Unilab, Hüttlin GmbH,
A Bosch Packaging Group, Schopheim,
Germany) in bottom spray mode with a
sustained release coating ormulation
based on EUDRAGIT® NM 30 D. Aer-
(S: Svrity, O: Occurc, D: Dtctbility, RPN: Risk Pririty Numbr)
Filur cts Cuss ilur md Ctrls S O D RPN ActisDrug rls ut sc du t icrrti
drug rticls i SR ctig Prtig tim t lg N Prt ctr witut llts
Prtig tim st t miDrug rls ut sc du t icrrti
drug rticls i SR ctig Ilt ir vlum t ig N Ilt ir vlum st t m³/Drug rls ut sc; i llts stick tgtr
surc r will cg d c rls rt Ilt ir tmrtur t igPrduct tmrtur
ssr Prduct tmrtur
st t – °CDrug rls ut sc; i llts stick tgtr
surc r will cg d c rls rt Prcss umidity t ig Humidity ssr Ilt ir vlum st t ust ir
umidity m. % r. .
N ctig Nzzls blckdSryig sussi
wigt ctrl Stirrig ctig sussit vid sdimtti tlc
N ctigSry dryig du t t ig
ilt ir tmrturPrduct tmrtur
ssr Prduct tmrtur
st t – °CItrruti btc Filtr clggig Prssur dirc Cg ltr t rugr ty
Istbl rls rl vr tim Ilt ir tmrtur t lwPrduct tmrtur
ssr Ilt ir / rduct tmrtur
Istbl rls rl vr tim Prcss umidity t lw
Eust ir umidity
ssr Sry rt r wtrIstbl rls rl vr tim Curig tim t srt N TimN/A N/A N/A N
Figur : Cur pl r all rspss a mi curig im
Dissolution 3 hours
T e m p e r a t u r e
Relative humidity [%]
30 35 40 45
35
40
45
5018
2022
24
2628
30
Dissolution 6 hours
Relative humidity [%]
30 35 40 45
35
40
45
5050
5254
5658
6062
64
Dissolution 10 hours
Relative humidity [%]
30 35 40 45
35
40
45
5074
7678
80
82
84 T e m p e r a t u r e
T e m p e r a t u r e
M O D D E 9 . 1
7/16/2019 Evonik Pharma Polymers News 2 2012
http://slidepdf.com/reader/full/evonik-pharma-polymers-news-2-2012 4/8
Pharma Polymers News 2 | 2012
PAGe 4
ReFeRenCeS
. Itrtil Crc Hrmisti Tcicl Rquirmts r Rgistrti Prmcuticls r Hum Us (ICH): QulityGuidli Q Prmcuticl Dvlmt,
g , t: www.ic.rg
. Wdcck:T Dsird Stt: A Mutul Gl Idustry d Rgultrs. ISPE Aul Mtig,Nvmbr 7,
. Amigi t l.:Iuc curig cditis t drug rlsrt rm EUDRAGIT® NE D lm-ctdsustid rls tylli llts,STP Prm Scics, /7
. Dssigr t l.:Scl-u Study Prrll Sustid RlsPllts Ctd wit EUDRAGIT® NE D,APV,
. Albrs t l.:Strg Stbl, I-rcss Curd Sustid R-ls Ctigs Bsd EUDRAGIT® NM D,AAPS,
. Bär, H.:Utrsucug ds Curigs- ud Altrugs-vrlts v EUDRAGIT® NM D Filmübr-züg u Mtrlltrtrt Pllts, Uivrsity Alid Scic. Big,
7. Hsl t l.:Dvlmt Strg Stbl, SustidRls Ctigs Bsd EUDRAGIT® NM D,APV,
wards, the coated pellets were cured at di-
erent conditions in the uid bed coater.
For this in-process curing, product
temperature, exhaust air humidity and
curing time were investigated as actors
in the DoE. Drug releases aer 3, 6 and 10hours were established as responses.
MODDE soware (Modde v. 9.1, MKS
Umetrics AB, Sweden) was used to esti-
mate a design space and thus, a sae region
o operability in which the desired re-
sponse profle could realistically be met.
With this soware it was possible to dis-
play the estimated probability o ailure atthe specifed risk level.
The limits o the DoE design were set
according to prior knowledge [6, 7]. Prod-
uct temperature was set between 32 and
54 °C. Relative exhaust air humidity ran-
ged rom 28 to 54 %. Reecting the hea-
ting capacity o common uid bed coaters,
the design had to be limited to an enthalpyo 140 kJ/kg. The design plan resulted in
11 trials.
As the actual curing process parame-
ters diered slightly rom the designed
actor levels, the experimental process
parameters were used or the interpreta-
tion o the data with MODDE 9.1.
Rsuls ad discussiThe soware predicted a robust model
over the ull area which is visualized or
three time points (Figures 1+2).
The contour plots show the inuence
o temperature and humidity (Figure 1).
Entering the criteria or dissolution
time points into the optimizer unction o MODDE 9.1 allows a risk o ailure estima-tion utilizing a Monte Carlo Simulation.
This results in a Design Space as requiredin an enhanced QbD approach or an
Abbreviated New Drug Application
(ANDA) registration. It also shows how
the working range increases with prolon-ged curing time (Figure 2).
trasr hr quipmThe conditions o in-process curing
mainly depend on the polymer and its or-mulation. However, dierent pieces o
equipment will have dierent heat loss viathe product container, and the sensors orproduct temperature and exhaust air hu-
midity will need to be placed in dierent
locations. By doing this, any curing designspace is dedicated to the equipment. How-ever, previous transers have shown that
ranges overlap almost entirely between
dierent equipment.
CclusiThe principles o QbD paid o, delive-ring a reliable model explaining the cor-
relation o the careully selected parame-ters at a reasonable number o tr ials. Thus,
enhanced knowledge regarding the pro-
cess was obtained and allowed or controlo the parameters during production.
Operating within the Design Space re-sults in higher process saety and a pro-
duct that meets the defned quality. The
size o the Design Space depends on the
risk one is willing to take, while a smaller
risk gives a smaller Design Space. As anelement o the proposed manuacturing
process it can be included in the submis-
sion.
Figur : Dsig Spac pl
T e m p e r a t u r e
[ ° C ]
T e m p e r a t u r e
[ ° C ]
T e m p e r a t u r e
[ ° C ]
Humidity [% r. h.]
CuringTime = 7
Humidity [% r. h.]
CuringTime = 26
Humidity [% r. h.]
CuringTime = 45
Risk of failure [%]
MODDE 9.1
7/16/2019 Evonik Pharma Polymers News 2 2012
http://slidepdf.com/reader/full/evonik-pharma-polymers-news-2-2012 5/8
Pharma Polymers News 2 | 2012
PAGe 5
Dr. Frank Nerenz joined Evonik’s Health Care business line in Ap-ril 2012 as Sales Manager or Southern Germany and Switzerland.
Prior to joining Evonik he worked in custom research at ASM
(Germany) ocusing on business development, R&D projects
and management, as well as supply chain excellence. Beore this,
Frank worked in R&D and technical marketing or Honeywell
Specialty Chemicals Seelze GmbH (Germany) and in technology
transer at an Allied Signal/PFC (Bahamas) cGMP production site.
His academic experience includes a postdoctoral internship at
the School o Pharmacy o the University o Wisconsin-Madison
(USA) and a Ph.D. in Organic Chemistry rom Leibniz University,
Hannover (Germany). Moreover, he authored and co-authored
several research papers, text book chapters and patents.
Dr. Alexandra Steckel joined Evonik’s Health Care business line as
Sales Manager or Northern Germany in February 2012.
Her industrial career started at Losan Pharma GmbH (Germany)
where she worked as Business Development Manager and was
responsible or new projects and customer acquisitions as well as
out-licensing activities.
Alexandra studied Pharmacy at the State University o St. Peters-burg (Russia) and continued her education at the University o Kiel
(Germany) where she received a M.Sc. degree or her scientifc workon nebulizer solutions. For her Ph.D. she worked on topical pharma-ceutical dosage orms and their ormulations and characterization.
Dr. Knut Kreuzer joined Evonik’s product line Pharma Polymers &
Services in June 2011 as Regulatory Aairs Manager or the Asia-
Pacifc region. As a certifed toxicologist, Knut is predestined to
evaluate the saety profles o Evonik’s pharmaceutical polymers
and to prepare drug master fles or non-clinical data.
Prior to joining Evonik he worked or an international
consulting company in regulatory aairs and product saety, therebymainly ocusing on the toxicological and eco-toxicological assessment
o chemicals.
Knut studied Biology and received his Ph.D. in ecology rom
the Technical University in Darmstadt (Germany). While working
or his previous employer, he successully pursued a post-graduate
degree in toxicology at the University o Leipzig (Germany).
Nw i t tm
Dr. Frk NrzSls Mgr Sutr Grmy d Switzrld
Dr. Aldr StcklSls Mgr Nrtr Grmy
Dr. Kut KruzrRgultry Airs Mgr Asi-Pcic
7/16/2019 Evonik Pharma Polymers News 2 2012
http://slidepdf.com/reader/full/evonik-pharma-polymers-news-2-2012 6/8
PAGe 6
Pharma Polymers News 2 | 2012
AAPS Pstr # TTusdy, Octbr , ,: m – : m
Ect dsicct
t stbility lsrzldlyd rls llts
Proton pump inhibitors (PPIs) like lanso-
prazole are susceptible to degradation in
the presence o moisture. For this reason,the impact o a desiccant on the degrada-
tion stability o lansoprozole delayed re-
lease pellets was examined. Dissolution
behavior, impurity profle and appearance
were evaluated over storage.
Results: Lansoprazole delayed releasepellets coated with EUDRAGIT® L 30 D-55were stable with and without desiccants.
This shows that EUDRAGIT® L 30 D-55
can be applied or protecting sensitive
drugs rom acid as well as rom degrada-
tion caused by moisture.
AAPS Pstr # TTusdy, Octbr , ,: m – : m
Frmulti strtgis
r t ctrl druglymr rmti isustid-dlivry micr-rticls
A major challenge in the development o
sustained release microparticles is the
control o drug polymorphs. Several or-
mulation strategies can be used to controltheir ormation. This work demonstrates
how these strategies were applied to a
sustained release microparticle product
containing nimodipine.
Results: Polymorph and amorphous com-ponent ormation in the nimodipine
microparticle ormulations were shown
to impact in-vitro release profles. Addi-
tionally, a conversion o the amorphous
component to Crystalline Form II caused
aggregation o the resultant product, ul-
timately impacting injectability o the
ormulation. In this application, amor-
phous content ormation was minimized
with the control o ormulation parame-ters such as polymer and solvent choice
and drying rate. This resulted in a productwith improved stability and peror-
mance.
AAPS Pstr # TTusdy, Octbr , ,: m – : m
Prrti micr-sizd
slid liid rticls rsustid rls ijctis
Lipid nanoparticles or intravenous
administration have been the subject o
recent research. For subcutaneous and
intramuscular injections, particles in the
micron size range would be advantageousto mitigate opsoniication. In these
experiments, various lipids and lipid-
excipient combinations were used to pre-pare lipospheres between 1–100 µm using
bupivacaine base.
Results: Resultant materials were ree-
owing powders syringeable through ap-propriate needle sizes. Particle size was
easily controlled by suractant selection
and concentration. Controlled release
was more evident when bupivacaine con-centrations were low or an additional ex-
cipient was used to solubilize the drug.
These studies demonstrated solid lipid
particles as a viable sustained release plat-orm.
AAPS scitic str bstrctsW lk rwrd t mtig yu t t str rsttis d tt Evik bt (N. ). All ur scitic strs will b vilblr dwldig by Octbr , t www.vik.cm/-lb
7/16/2019 Evonik Pharma Polymers News 2 2012
http://slidepdf.com/reader/full/evonik-pharma-polymers-news-2-2012 7/8
PAGe 7
Pharma Polymers News 2 | 2012
AAPS Pstr # WWdsdy, Octbr 7, ,: m – : m
Slubility cmt usigmlt trusi: Rl iicitrctis
Polymer selection is a critical step in or-
mulation development using melt extru-
sion. In this study, the role o ionic inter-
actions in the dissolution enhancement o
melt extruded ormulations containingnaproxen was investigated. Melt extru-
sion was perormed at 30 % naproxen
loading with fve commonly used pharma-ceutical polymers with distinct chemis-
tries.
Rsuls: Formulations with EUDRAGIT®
E PO exhibited a solubility enhancement
o 5-old in acidic pH which none o the
other polymers achieved. FTIR scans
showed ionic interactions between the
carboxylic acid group o the naproxenmolecule and the dimethylaminoethyl
group o the EUDRAGIT® E PO, which is
absent in the other ormulations evalu-
ated. Faster onset o action o naproxen
and improved bioavailability are expected,
due to the increased solubility o
EUDRAGIT® E PO extrudates in acidic
pH.
AAPS Pstr # W7Wdsdy, Octbr 7, ,: m – : m
Qulity by Dsig rct timiz i-rcss curig EUDRAGIT® NM D
Storage stability or EUDRAGIT® NM 30 Dcoatings can be achieved via curing in theuid bed at specifc conditions. Aim o this
study was to identiy and investigate the
inuence and correlation o critical proc-ess parameters or in-process curing. To
achieve this objective, a Quality by Design
approach was used.
Rsuls: As critical actors or in-process
curing, product temperature, exhaust
air humidity and curing time were iden-
tifed. Following the QbD approach, the
empirically developed process conditionswere confrmed and even broadened. A
robust and cost ecient process was
achieved.
AAPS Pstr # W7Wdsdy, Octbr 7, ,: m – : m
Imrvd trusi rductusig mlculrly disrsdmcrsrs
Active pharmaceutical ingredients (API)
vary between multiple lots, making or-mulation especially challenging in the
initial development stages o an implant-
able ormulation. A method was examined
here or dispersing the API within the
polymer matrix at a molecular level priorto extrusion processing. The goal o this
work was to compare the proposed
method to traditional blend methods o
API dispersion by evaluating implant
product perormance.
Results: The molecular dispersion
technique showed improved blend and
drug content uniormity compared to
the traditional dry blending technique.
Additionally, a more sustained in-vitro
release profle was obtained or implants
produced using the molecular dispersiontechnique. These advantages can signif-
cantly increase eciency and reprodu-
cibility o the fnal extrusion product.
AAPS Pstr # WWdsdy, Octbr 7, ,: m – : m
Nw EUDRAGIT® E POrmulti r mistur
rtcti d tst mskigr rmcuticl dutrcuticl lictis
EUDRAGIT® E PO (basic methacrylate
copolymer) based coating systems have
largely been used over years or moistureprotection and taste masking o solid
pharmaceutical dosage orms. This study
describes a newly developed EUDRAGIT®E PO ormulation, where the sodium
lauryl sulphate used as suractant in the
standard pharmaceutical ormulation isreplaced by tartaric acid, which is GRAS
listed and has an E-number.
Results:The newly developed EUDRAGIT®
E PO ormulation with tartaric acid
provides excellent moisture protection
which is comparable to the standard
EUDRAGIT® E PO ormulation. It shows
ast disintegration and complies to the
requirement o USP dissolution tests or
dietary supplements, both in HCl and
in water. Similar to the standard
EUDRAGIT® E PO ormulation, it is ad-
vantageous compared to HPMC and PVA
based coatings.
7/16/2019 Evonik Pharma Polymers News 2 2012
http://slidepdf.com/reader/full/evonik-pharma-polymers-news-2-2012 8/8
Pharma Polymers News 2 | 2012
PAGe 8
Wrkss
Trd swsImpri
Tis is ublicti Evik’sPrm Plymrs & Srvics rduct li
Publishd byEvik Idustris AGKirscll64293 DrmstdtGrmy
phone +49 6151 18-4019fax +49 6151 [email protected]/-lbwww.vik.cm/bimtrils
Rspsibl r c Dr. Brigitt Sklsky
LayuMLW KmmuiktisFrmGmbH Wrbgtur, Wrms
® = rgistrd trdmrks
EUDRAGIT® d RESOMER®r rgistrd trdmrks Evik Idustris r its subsidiris.
Lg i t ur li ltrm -Lb t www.vik.cm/-lb t rgistr r ur wrkss i just w sy sts.
Visit us t ts ucmigtrd sws.
AAPSOctbr – , Cicg, IL, USA
Suly Sid WstNvmbr – , Ls Vgs, NV, USA
CPI IdiNvmbr – , Mumbi, Idi
All dts d lctis r subjct t cg
EUDRAGIT® Cmct CursOctbr 7 – , Bus Airs, Argti
EUDRAGIT® Cmct CursNvmbr 7, Pisctwy, NJ, USA
Fcus PLGA applicais:Parral drug dlivry admdical dvicsNvmbr 7, Mil, Itly
EUDRAGIT® Bsic WrksNvmbr – , Drmstdt, Grmy
EUDRAGIT® Bsic WrksNvmbr , Amdbd, Idi
EUDRAGIT® Cmct CursDcmbr , Dubi, Uitd Arb Emirts
MD&M WstFbrury – , Aim, CA, USA
AAOSMrc – , Cicg, IL, USA
SB Aul Mtig & EsitiAril – , Bst, MA, USA