evonik pharma polymers news 2 2012

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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



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



PAGe 3


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


30 35 40 45

35

40

45

5050

5254

5658

6062

64

Dissolution 10 hours


30 35 40 45

35

40

45

5074

7678

80

82

84 T e m p e r a t u r e


M O D D E 9 . 1




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


[ ° C ]


[ ° C ]


[ ° C ]

Humidity [% r. h.]

CuringTime = 7

Humidity [% r. h.]

CuringTime = 26

Humidity [% r. h.]

CuringTime = 45

Risk of failure [%]

MODDE 9.1




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



PAGe 6


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.


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.


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



PAGe 7


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.




PAGe 8

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