Addressing Downstream Challenges with Complex Injectables

The complex injectable market is gaining traction in the injectable therapies, however manufacturing of it is critical. In this webinar, lets brainstorm on the downstream criticalities of these molecules and how to handle the same.

1. The life science business of Merck KGaA,
Darmstadt, Germany operates as
MilliporeSigma in the U.S. and Canada.
Sterile filtration
of complex
injectables
Partha Banerjee
Senior Technology Consultant

2. The life science business
of Merck KGaA, Darmstadt,
Germany operates as
MilliporeSigma in the U.S.
and Canada
2

3. Agenda
1
2
3
Background
Considerations for Sterile
filtration of liposomes
Liposome sterilization
methodology
4
5
Regulatory Guidelines
Essential parameters-
our observations
6
Sterile filtration of viscous
formulations
3
7
Sterile filtration of oils,
emulsions and ointments

4. Background
4

5. •AspertheUSFoodandDrugAdministration(FDA),complexparenteral
productsarethoseformulationswhichcontaineithercomplexingredientsor
API,complex formulation,i.e.,deliverycarrier,complex routeof
administration,complexdosageform,orcomplexdrugdevicecombination
.
•Themanufacturingofthecomplexinjectableproductsisdifferentandagreat
levelofobservationofqualityandcareisrequiredduringtheirmanufacturing,
packaging,distribution,andstorage.
•Complexinjectableshavegainedincreasingattentionduetotheirwidespread
useinlife-threateningandchronicdiseasestreatments.Thecategoryincludes
diabetes,oncology,andhormonaltherapytonamebutafew.
Complex injectables –Background
Sterile Filtration of Complex Injectables5

6. Complex injectables –what are they?
ComplexdrugproductshavebecomesoprevalentthattheFDAhasdefinedthemwiththefollowing
categories:
•Productswithcomplexactiveingredients(e.g.,peptides,polymericcompounds,complexmixturesof
[activepharmaceuticalingredients]);complexformulations(e.g.,liposomes,colloids);complexroutes
ofdelivery(e.g.,locallyactingdrugs,complexophthalmologicalproductsandoticdosageformsthat
areformulatedassuspensions,emulsions,orgels);orcomplexdosageforms(e.g.,implantables,
transdermals,metereddoseinhalers,extended-releaseinjectables
•Complexdrug-devicecombinationproducts(e.g.,auto-injectors)
•Otherproductswherecomplexityoruncertaintyconcerningtheapprovalpathwayorpossible
alternativeapproachwouldbenefitfromearlyscientificengagement.
Complexprocessingchallengesinclude,amongothers,asepticmanufacturing,theinclusionofhighly
potentcompounds,milling/particleengineering,spraydrying,extrusion,andmicrofluidization.
Ref: ANDAs for Certain Highly Purified Synthetic Peptide Drug Products That Refer to Listed Drugs of rDNA Origin, Guidance fo r
Industry, FDA, May 2021.

7. Solubilization &
Bioavailability
Enhancement
Techniques
Drug-Eluting
Systems
The Four Categories of Complex Drug Products
In considering the above, complex drug products encompass a wide range of technologies and dosage
forms. However, we’ve found that these complex products generally revolve around four conversations
or categories:
Sterile complex
injectables
Highly Potent
APIs and/or
Controlled
Substances
Sterile Filtration of Complex Injectables7

8. •TheFDArequirescertaintypesofdrugproductstobe
providedasasteriledosageformstoavoidthepossibilityof
microbialdegradationorinfectionoccurringbecauseoftheir
use.
•Thisincludesseveraltypesofdrug products,
includinginjectables(smallorlargevolumeparenteral
products),ophthalmic drugs,oticdosage forms,
andimplantableproducts.
Sterility of finished dosage forms can be assured via different
processes
Terminal Sterilization
Aseptic Manufacturing
Sterile Filtration
Sterile Complex Injectables
Sterile Filtration of Complex Injectables8

9. •Filtrationisusedforclarificationpurpose
(clarificationfiltration)and/ortosterilizesolution
usingsterilizinggradefiltermembranes(0.2µor
smallerporesizefilters).
•Filtrationofparenteralproductsensuresremoval
ofparticulatematterandcanbeusedeitherfor
clarificationorforsterilizationpurposes.
•Asit’sacriticaloperationweclassifyfiltrationas
per
•Criticalityandpointofuse.
•Usage.
Sterile filtration –Notable points
Sterile Filtration of Complex Injectables9

10. Filter in final fill –top 3 segmentations -
Utility filters
Where process fluids come from
facility-wide systems, are not
tailored to a specific process and
do not have contact with the
drug substance or potential drug
substance.
Part of a No-Impact System -
Where the equipment of system
has no impact, direct or indirect,
on product quality (ISPE
Commissioning & Qualification
Baseline Guide (2001))
Filter does not affect product
quality(e.g. distribution gas
filter, water prefilter)
Critical
•Where process fluids “are in
direct contact with sterile final
product or critical surfaces of
the associated equipment.”
(PDA TR26)
•Part of Direct Impact System -
equipment or system that will
have focused and immediate
impact on product quality
(ISPE Commissioning &
Qualification Baseline Guide
(2001))
•Filter directly affects
product quality(e.g. sterile
hold vessel vent filter, sterile
liquid filter)
Moderately Critical
•Where process fluids “will
not be in direct contact with
exposed sterile product or
surfaces.” (PDA TR40)
•Part of an Indirect Impact
System -equipment or
system expected to have
incidental or secondary
impact on product quality
(ISPE Commissioning &
Qualification Baseline Guide
(2001))
•Filter indirectly affects
product quality(e.g. vent
filter in grade D, bioburden
reduction filter)
Sterile Filtration of Complex Injectables10

11. Filtration Portfolio –classified as per usage
Particulate Control
Sterility Assurance
(LRV: 10
7
CFU/cm
2
)
Bioburden Control
(LRV: 10
6
CFU/cm
2
)
Milligard
®
Polysep
TM
II
Lifegard
TM
Durapore
®
(0.22 um)
Millipore
Express
®
SHR
Millipore
Express
®
SHF
Durapore
®
(0.45 um)
Milligard
®
PES
(0.2 um)
Milligard
®
PES
(0.45)
Milligard
®
PES
(0.8 um)
Millipore
Express
®
PHF
Sterile Filtration of Complex Injectables11

12. Inthispresentationwewillbediscussionthe
sterilefiltrationandfiltervalidationapproachof
Liposomes,nanoemulsionsandviscousfluids.

13. Considerations for
Sterile filtration of
liposomes
13

14. Liposomes Characterization
Size: small, intermediate, or large
Number of lipid bilayers,
composition, and mechanism of
drug delivery
Small unilamellarvesicles (SUV)
−comprise a single lipid bilayer.
Diameter ~25 to 75 nm.
Large unilamellarvesicles (LUV)
−comprise of a single lipid bilayer.
Diameter >75 nm.
Multilamellar vesicles (MLVs)
comprise
−Contain many concentric lipid
bilayers. Diameter ~ 1-5 μm.
14

15. Preparation Methods for Liposomes
Three common approaches
Preparation of globules Size reduction Purification
The liposome preparation method affects purification!
15

16. PDI –Poly dispersity index
PDI is basically a representation of distribution of size populations within a given sample
Degree of non uniformity of size distribution particles
Indicates a monodisperse system.
PDI is a very essential parameter and its analysis helps to understand the size distribution of globule
based formulations.

17. Z Average Value
•Thez-averageis an intensity-based overall average size based on a specific fit to the raw correlation
function data. Basically the particle size.
Zeta Potential
•Thezetapotentialofaparticleistheoverallchargethattheparticleacquiresinaparticularmedium.
Knowledgeofthezetapotentialofaliposomepreparationcanhelptopredictthefateoftheliposomes
invivo.
•MeasurementofthezetapotentialofsamplesisdoneusingthetechniqueoflaserDopplervelocimetry
17

18. Liposome
sterilization
methods
18

19. Liposome Sterilization Methods: Advantages vs disadvantages
Ref: Liposomes as sterile preparations and limitations of sterilisation techniques in liposomal manufacturing ;April 2013;
Asian Journal of Pharmaceutical Sciences8(2):88-95
19

20. Liposome Sterilization
Heat sterilization
•Not generally accepted
oLipid/active not heat stable
oLeakage
oSafety issues
Gamma Irradiation
•Not generally used
•Degradation of lipid and
cholesterol
•Safety issues not assessed
•Cryo-radiation also not
effective
Sterile filtration
20

21. Liposome Sterilization by Filtration –the riddle
Widely used
Limited by vesicle size and size distribution
Very little published information
Challenges:
−allow particles (vesicles) of up to 300 nm to pass through
−retain bacteria that can be as small as 200 nm (width)
Lipid Globule B. Diminuta
21

22. Regulatory
guidelines
22

23. Section3–DiscussiononLiposomedrugproducts–GuidanceforIndustry
DescriptionofManufacturingProcessandProcessControls
Werecommendincludingadetailedprocessflowdiagramandadescriptionofunitoperations
withrangesfortheprocessparametersandprocesscontrols.
Theserangesshouldbesupportedbypharmaceuticaldevelopmentstudies.Theprocessand
mechanismofliposomaldrugloading,aswellastheremovaloffree(un-incorporated)drug
fromtheliposomeformulationviapurificationshouldbedescribedindetail.The
manufacturingprocessshouldbevalidatedtodemonstratemanufacturingprocess
consistencyandreproducibilitybeforecommercialdistribution.
Liposomedrugproductsaresensitivetochangesinthemanufacturingconditions,including
changesinscale(sizeofthebatches).Appropriateprocesscontrolsshouldbeestablished
duringproductdevelopment.
Priorknowledgecanbeleveragedandriskassessmenttechniquescanbeusedtoidentify
manufacturingprocessparametersthatpotentiallyaffectfinishedproductquality.
Someexamplesofmanufacturingprocessparametersthatmayaffectliposomedrug
performanceareshearforce,pressure,pH,temperature,batch-size-relatedholdtimes,
lyophilizationparameters,etc.Youshouldprovideadequatejustificationfortheselectionof
theoperatingrangesfordifferentbatchsizes.
Thephysicalandchemicalcomplexityofliposomedrugproductspresentuniquechallengesto
thesterilizingfiltrationprocess.Forexample,componentsofliposomescouldinteractwiththe
filtermatrixandclogit.Therefore,validatedproduct-specificpurificationandsterilization
methodsshoulddemonstratetheabilityofthemicrobialsterilizingfilterstofunctioncorrectly,
withoutcompromisingtheintegrityandstructureofliposomes.
23
Ref: Liposome Drug Products, Guidance for Industry, FDA, April 2018

24. Regulatory Comments -Sterilizing Filtration of Liposomes
“Bulkholdingtimeshavebeenminimizedoreliminatedtocontrolpotentialmicrobial
contamination.Inresponsetoaconcernraisedwithrespecttomicrobialcontamination,a
pre-sterilizedbioburdenlimitwasadoptedbytheapplicantabovewhichbatcheswillbe
rejected.”
EMEA Scientific Discussion Documents
http://www.emea.eu.int
“The particle size distribution is measured as an important part of the in-process
controls.”
“…..followed by two 0.22 micron sterile filtration steps, aseptic filling, and
lyophilisation.”

25. Or –Can we follow draft guidance?
25
Ref: US Department of Health and Human Services, Food and Drug Administration, CDER: April 2018

26. We accept the potential challenges….Sterile filtration
•Thesterilityofsuchliposomesolutionsistypicallyensuredusing
0.2μmratedsterilizinggrademembranes,butduetothehigh
viscosityandlowsurfacetensionoftheseformulations,theycan
causepre-matureblockingandincreasedriskofbacterial
penetrationthrougha0.2μmsterilizinggrademembrane.
•Thelowsurfacetensionofliposomesolutionsaffectsthecontact
anglewithmembrane andreducesbubblepointleadingto
bacterialpenetrationthroughthemembrane.
•Thisposesagreatchallengetoselectanappropriate
sterilizinggrademembrane foragivenprocessandforfilter
manufacturerstodevelopasterilizinggrademembrane that
specificallyaddressestheseneeds.

27. Can I consider Aseptic Manufacturing?
Raw materials (including
organic and aqueous solvents,
the natural sources of lipid
components as well as other
additives such as buffers) are
sterilised after passing 200
nm filters.
The equipment can
be autoclaved and
sterilised.
Liposomes are
prepared and then
assembled into their
containers via
aseptic filling
Sources of contamination :
environmental air, operating personnel and the water for drainage) should be critically controlled by performing the filling process on work stations
in clean rooms.
Risk of contamination during aseptic processing remains
Especially if the initial raw materials are not sterilised adequately.
Limitations with natural sources of lipid components
Can only be subjected to filtration due to possible physicochemical degradation.
Contaminants
In the raw materials or introduced during manufacturing cannot be removed from the final product during aseptic
manufacturing is performed.
Terminal sterilization -activeprocess of removing
Aseptic filling, and aseptic manufacturing -passiveprocess of avoiding contamination

28. A typical Single use template for fill finish operations -

29. Essential
parameters -
our observations
29

30. 30
The Target
30
Yes No

31. Considering Particle size –Effect of Operating Parameters
31
Increasedstirringrate-
•couldimprovedropletdispersion
•preventdropletcoalescence
•resultsinsmallerapparentparticlesize
Optimum dispersionconditions-
•Thedispersionconditionofthedroplets
changesaccordingtoitsconcentrationin
thepoorsolvent.
•Therefore,theeffectsoffeedrateofgood
solventandpoorsolventratioisimportant
•Itcontrolsthedropletsconcentrationin
poorsolvent,ontheparticlesizeof
nanospheres.
31

32. Considering elevated temperature of feed -
•Atelevatedtemperaturelipidmembrane
passesfromtightlyorderedgelstate(stable)
toaliquidcrystalphase(metastableor
unstable)
•Freedom ofmovement oftheindividual
moleculeishigher.
•Thisisduetothefattyacidchainadoptinga
newconformationotherthanthealltrans
statechainconfiguration,suchasagauche
confirmationstate(chaintiltphenomena)

33. Considering sterile filtration -Case Study 1
Goals:
•Prefilterselection
•Understandtheeffectofhightemp.and
pressureonthefeed.
•Note–Particlesizewasbelow150
micronbutshowedpoorflowinSGF
Observations:
•Depthmediaworkswellcomparedto
membranefilters.
•Highpressuremayfacilitatefiltration,
butequallythereisariskofbleeding
andcoagulationofparticles.
•Ifparticlescoagulate,eventakingthe
feedtemperaturetophasetransition
maynotshowanyadvantageinflowrate
throughsterilizinggradefilters.

34. Considering sterile filtration -Case Study 2
FEED
Goals:
Sterilefiltrationoperation.
•ThePDIwas0.32,particlesizewas84.3
nm,D90was1310nm.
•Pressureappliedwas15PSI,feed
temperatureequivalentto60degreeC.
Observations:
•Itsnotalwaysmeanparticlesize,Inthe
sampleanalysisprovided(Malvernparticle
sizeanalyser)theD90valueis1310(1.3
micron),thisdepictsthat90%ofparticles
arelesserthan1.3micronand10%more
than1.3micron.
•Similarly,theD90valueofthefinished
productis203nm(0.203micron)hence
boththesolutionsaredifficulttofilterby
0.2umfilter
•Itissuggestedthattheparticlesizedistributionshouldbe
controlledintheliposomemanufacturing stage.
•Accordingtoourexperiences150-200nmsamplescanbe
triedandclosertheD90valueisto200nmlesserandlesser
isthethroughput.
34

35. Goal:
sterile filtration.
The PDI was 0.15, particle size
was 90 nm, D90 was 160 nm.
Pressure applied was 15 PSI,
feed temperature RT!!
Observations:
Depth media works well
compared to track itched
membrane.
According to our experiences
150-200 nm samples can be
tried.
The final filtration area was
significantly less and could be
replicated.
Considering sterile filtration -Case Study 3

36. Considerations for
Sterile filtration of
oils, emulsions and
ointments.
36

37. Sterile Filtration of Oils, Emulsions and ointments.
•Mostpharmaceuticalfluidsarewaterbased.ButseveralhydrophobicAPIs(ActivePharmaceutical
Ingredients)areoftendissolvedinanoilybase,suchasvitaminsetc.
•Manyofthesecomponentsareheatsensitiveandthereforesterilefiltrationisthemostpreferredway.
Examplesofoilysubstanceswhicharefilteredaresoybeanoil,castoroil,sesameoil,paraffin(liquid
andsolidatambienttemperature),siliconoilsetc.
•ExamplesforEmulsionsusedinthepharmaceuticalindustryareadjuvantsolutionsforvaccinesor
LiposomeswhicharecapabletosolubilisehydrophobicAPIsinawaterenvironment.Otherexamples
includenarcoticswhichisadministeredinsoybeanoilinwateremulsionwithegglecithin.Many
emulsionsarenon-Newtonianthereforeflowoverpressurecurveisnotlinear.
•Someointmentscanbeheateduptomorethan100°Cbuttherearechancesthatthebacteriaspores
canevensurvive.Forthatreasonthepreparationofoilypharmaceuticalsgotinthefocusofthe
regulatorybodies.Bysterilefiltrationbacteriasporescanbeeliminatedreliably.
37

38. High flow rates
Drying of the
filtration
equipment
Top points to consider while handling these formulation -
Product
specific
integrity
testing
Filter validation
aspects -
Sterile Filtration of Complex Injectables38

39. Optimizing the filtration train –
•Flowrateestimationpriortoafilterabilitytrialroughlycanhelp.ForthisDarcy'sLawutilised.Provided
weareworkingwithanonNewtonianliquid.Veryessentialwhenwedeveloptheformulation.
•Thisequationdescribestheflowofafluidthroughaporousmedium:WhereQisthefluxordischarge
perunitarea,e.g.,m/s.Permeabilityofthemedium,k(Sqm)crosssectionalareaA(Sqm),andthe
pressuredrop(deltaP),alldividedbythedynamicviscosity,μandthelengththepressuredropis
takingplaceover.
•Therearecertainrequirementsforthesterilizinggradefiltrationofoils.Expressrangeoffiltersarethe
mostsuitableforfiltrationofoilcontainingliquids.SoPolyethersulfoneandPolyamidehavegood
chemicalcompatibility.OptimizingrobustprefilterslikeMilligardPES(ofvariedporesizes)canreally
aiduptheoverprocesseconomics.
•Otherimportantconsiderationsincludesingleuseapplicationintheprocess.

40. Filter validation aspects -
•ConsideringValidationaspectsforsterilefiltration
applicationsabacteriachallengetest.(BCT)hasto
beperformed.PriortothistestinaViabilitystudyit
hastobedemonstrated.
•Duetothehighviscosityatambienttemperatureof
differentoilysubstancesthefiltrationisperformedat
60to80°C.Atthistemperaturethereisnoviability
ofthetestbacteriagivenandwemayneedto
performatwostagestudy.
•Unclearcompositionofdifferentoilsavoidsadirect
detectioninthecontactsolutionspecificallyduring
extractionandanalysis.
•Afterfiltrationtheoilyliquidcannotberemovedby
waterflushingfromthemembrane.Forintegrity
testingProductspecificIntegrityTestvaluescanbe
establishedfordirectITmeasurementafterfiltration.

41. Considerations for
Sterile filtration of
viscous
formulations
41

42. Sterile Filtration of Viscous formulations -
•Viscosityenhancersarekeyingredientsinmanylenscaresolutionsandophthalmicprescriptivedrug
products.
•Theseadditivesarecommonlycellulosebasedcompoundsbuthyaluronicacidisbecomingincreasingly
popularinnewformulations.
•Solutionscontainingviscosityenhancerscanpresentdifficultiesduringsterilefiltrationduetobatchto
batchvariability.
•Evenwithcarefuloptimisationofthemixingprocess,prematurefilterblockageisstillcommon
resultinginfrequentfilterchangeoutsmid-batch,productlossandincreasedprocessingtime.
•Andtheyposechallengesforsterilefiltration.

43. •Multiple filter changeouts during batch processing: Premature filter clogging is evident even after
careful optimization of manufacturing process (eg Mixing) and filtration train.
•Product loss –
•The influence of raw materials and process parameters –Which may include granularity of these
cellulose based viscosity enhancers, Mixing techniques.
•Batch to batch variation.
•The temperature of the solution is also a very important factor during the filtration process, increasing
the temperature can promote gelation of the solution that will lead to premature clogging of a filter.
•What about binding of preservatives or essential API of the formulation to filter matrix –when flow rate
is less, contact time is on the higher sides.
•The filterability of solutions can change significantly depending on the time between mixing and
filtration.
•Sterile Filter validation.
Top points to consider while handling these formulation -

44. Optimizing the filtration train -
•Volumemaximizationstudyfollowedbyarecheckduringpilotscaleruns–
•Advantagesofcompositeasymmetricfiltergeometry
•Usageofapropersafetyfactor
Toallowforprocessvariabilityduetofeed,processandmembranedeviceinarobustprocess,asafetyfactoristypicallyincludedtodefinea
requiredfiltrationsurfacearea.Therequiredareaforaprocesswillbetheminimumsurfaceareaforanaverageperformancetimesthe
safetyfactor.Theactualvariabilityofaprocessneedstobedefinedonacase-by-casebasis.Inabsenceofadetailedcharacterizationstudy,
onecouldusethefollowingtypicaleconomicallyrationalizedsafetyfactorsforvariousunitoperationsasdescribedinHerbLutz,Journalof
MembraneScience341(2009)p268–278.Exactsafetyfactorscanbedefinedthroughexperimentation.Incaseofanticipatedlarge
variations(highrelativestandarddeviation.RSD),safetyfactorsmorethanrecommended safetyfactorcanbeincludedindefiningthe
requiredsurfacearea.Incasespecificinformationisavailablearoundlowanticipatedvariability,asmallersafetyfactorcanbeused.
44

45. 45
THINK DIFFERENT

46. Approach 1 –Imitate process -
Complex
Injectables

47. Approach 2 –Pre-screening study (Filter validation)
Conducting the pre-validation screening study is not mandatory. But, if there is passage, it might be
easier to determine the mitigation plan prior to the retention validation instead of a retention test failure
investigation.
Assess –Process
duration, Actual
temperature, Actual
pressure, Actual
scale down volume
Important consideration –
Stable parameters.
Calculate –Scale down
volume, achieved per Square
surface area of the filter
Important consideration –
Process contact time
Pre–screening to be conducted with
one filtration line only.
Important consideration –
Pressure based study and no
recirculation mode.
Inoculation
47

48. Approach 3 –
Considering Standard vs High Area filtration devices.

49. Approach 4 –Selecting a well defined prefilter –
Like Milligard
®
PES
Benefits:
Fast flow and high throughput
Validated bioburden reduction (1.2/0.2 μm nominal and 1.2/0.45 μm pore sizes only)
Predictable scalability from small to production scale devices
High thermal stability: compatible with steam-in place and autoclave sterilization methods
Caustic stable
Gamma stable and available in single use assemblies

50. Points to consider in terms of
Filterability
Filter validation.
Sterile Filtration of Complex Injectables50

51. Filterability
Process considerations:
Keep vesicle size and size distribution small
Incorporate active in bilayer when feasible
Select process temperature in relation to T
cand lipid composition
Pre-wet filters with vehicle/buffer
Increase differential pressure gradually
May need to exceed certain differential pressure to initiate flow
Filter considerations:
Evaluate filterability early in process development
Evaluate different filter media types, hydrophilic PES generally works the best
Use pre-filtration to optimize filterability
51

52. Filter validation -Bacterial Retention study
Evaluate sterilization approach early in process development
Choose synthetic lipids when possible
Keep vesicle size and size distribution small
Evaluate different media pore size ratings and types
Consider “new technology” –Like stacked disc formats (Millipak
®
range of filters
with Durapore
®
membrane, high area device, AMPP (aseptic multi-purpose port)
Hydrophilic PES generally works the best

53. And we stand unique -
M Lab
TM
/
Validation lab.
support
Liquidfilters-
Durapore
®
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Express
®
Gas filtration -
Aervent
®
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Documentation
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autoclaving
•Highthermalandgammastability
•From-buffer/media/protein
intermediatestoviscous/complex
molecules–wideapplication.
•Meantforcriticalapplications
•Sterilityassurance
•Liquidbacterialretention
•Virusaerosolretentiontesting
•Highairorgasflowrate
•Oxidationresistanceforalong
servicelife
•Greaterhydrophobicity
•Stackeddiscmembranes –for
higherflow/lowholdup.
•AMPP–Asepticmultipurposeport–
protects product from
contamination,maintainssterility
•Highareadevice-Uniqueshape,
tallerpleatsandnarrowercore–
doublemembranearea.
•Compositeasymmetricmembranes
–noitsnot2separatelayers.
Facilitating qualification
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54. Product Support Services -Uniqueness continues -
Process Reviews
Filter review
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review
Steam in Place review Training
•Filtration
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& Advanced Troubleshooting.
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Sterile Filtration of Complex Injectables54

55. The vibrant M, Millipore
®
, M Lab™, Aervent
®
, Durapore
®
, Milligard
®
, Millipak
®
, Polysep
®
, Lifegard
®
, and Millipore Express
®
are trademarks of Merck KGaA,
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