Are you choosing the right excipients for your high risk application? Find out how to select the right excipients and enable your process optimization to improve the total cost of ownership. In this webinar, you will learn: • Selection of right excipients for high risk formulation is very critical step • Low Endotoxin and low bioburden limits are important aspect while selecting raw materials • Strong regulatory support is crucial for high risk formulation Excipients selection for high risk formulations like parenteral and ophthalmic applications is very challenging. Excipients should be inert with high purity for such dosage forms because trace amounts of impurities present in excipients can interact with active pharmaceutical ingredient (API) which results in instability of the formulation. This presentation discusses how to select the right excipients for high-risk applications and gives guidance for process optimization by choosing the best combination of filters and excipients to improve the total cost of ownership.

1. The life science business of Merck KGaA,
Darmstadt, Germany operates as
MilliporeSigma in the U.S. and Canada.
Excipients
Selection for
High Risk
Formulations
Dr. Smita Rajput
Field Marketing Manager, Actives & Formulation
India, South East Asia & Oceania

2. 2
Field Marketing Manager, Actives & Formulation, India, S.E.A & Oceania
Dr. Smita Rajput
• 8 years of experience in Pharmaceutical Product
Development
• Expertise in formulation development of
Complex Injectable and Ophthalmic Segment.
With her expertise, she provide consultations for
selection of Excipients in the injectable and
ophthalmic segment
• She has the credit of 5 patents and 7
international publications in different complex
formulation areas
• For working experiences, she was previously
with Dr. Reddy’s, Cadila Healthcare, and Johnson
& Johnson for few years

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

4. Agenda
1
2
3
Introduction
Formulation Challenges
Summary of Formulation
Challenges and Solutions

5. Introduction

6. 488
402
152
72
44
86
572
619
238
96
61
108
0
100
200
300
400
500
600
700
Oral Injectable Topical Ocular Nasal Other
(pulmonarty,
implantable,
etc)
Market Size (in Billion $)
2018 2023
3,2%
Source : Marketsandmarkets
Injectable drug delivery is
the second-fastest-growing
segment in the drug
delivery technology market
and is expected to grow at
a CAGR of 9.0% to reach
USD 619.21 billion by
2023.
Injectable will
dethrone oral
dosage form
within 2023
Injectable drugs market – April 2019
6
9,0%
9,4%
6,0%
6,8%
CAGR
2018/2023

7. Pharmaceutical excipients are any substance other than the active drug
substance which has been appropriately evaluated for safety and is included in
a drug delivery system.
Excipient Basic Understanding
7
 Processing aids in Manufacture Process
 Protect, support or enhance stability, bioavailability
 Modulation of Drug Release
 Enhance effectiveness of the drug product
 Inert and should not have pharmacological action
 Desired functionality/Multifunctionality

8. 8
Pharmaceutical Development : Excipient Role
QTPP CQA
CMA of API
and Excipients
(Quality & Quantity)
Manufacturing
process and
CPP
Control
Strategy
QTPP: Quality target product profile CQA: Critical quality attributes
CMA: Critical material attributes CPP: Critical process parameter
 Excipient selection based on specific/targeted/expected function
 Critical material attributes in excipient should be considered while
developing finished product
 Excipient composition may have direct impact on CQA’s of DP

9. Inert and high purity
Low bioburden and low endotoxin
Unaffected by sterilization or manufacturing process
Salient Features for High Risk Formulation
9

10. Different Types of High Risk Formulations
10
General injectables –
SVP,LVP and
Ophthalmic
Lipid Drug delivery
systems
Injectable formulation of
API, water, organic
cosolvents and surfactants.
High value low volume
products.
A liposome is a spherical
vesicle with lipid bilayer and
is used as a vehicle for
administration of nutrients
and pharmaceutical drugs.
Polymeric microspheres have
advantages as ability to
encapsulate a variety of drugs,
biocompatibility, high
bioavailability and sustained drug
release characteristics.
Polymer based drug
delivery system

11. Excipients Categories for High Risk Formulation
Viscosity
modifier
Buffer
Pre-
servative
Isotonicity
adjuster Anti-
oxidant
Stabilizer Solubilizer
Common requirements for raw materials quality
 Pharma quality
 Low bioburden, Low endotoxins
 IPEC-PQG GMP manufacturing
Specific excipients are applicable to particular dosage forms like
suspensions, emulsions, liposomes, lyophilized or microsphere preparations
11

12. Formulation
Challenges

13. Perspective of the Formulator
Development Challenges for High Risk Formulations
13
Particulate
matter
Microbial
purity
No
interaction
with API
Solubility
enhance-
ment
Trace
amount of
impurities
Stability
Process
optimiza-
tion

14. Perspective of the Formulator
Development Challenges for High Risk Formulations
14
Particulate
matter
Microbial
purity
No
interaction
with API
Solubility
enhance-
ment
Trace
amount of
impurities
Stability
Process
optimiza-
tion

15. FDA Sterile Injectable Drug Recalls 2008-2012
15
Particulate Matter: How does the Reality look like?
22%
22%
9%
47%
Lack of sterility assurance
Visible particles
Impurities/Degradation
Other*
*Includes crystallization, discoloration,
failed pH, impurities/degradation
products and storage temperature
excursions
Steven Lynn, FDA Office of Manufacturing and
Product Quality, March 14, 2013.
 Raw materials
API
Excipients
 WFI
 Filter
 Equipment
 Tubings and gaskets
 Container closure
 Unstable formulation
Root Cause

16. Risk
Mitigation

17. 17
Risk mitigation – Our Holistic Approach
1. Manufacturing of raw materials
 Excipients according to IPEC-PQG GMP
 Manufacturing environment ensuring low
bioburden (housing etc.)
2. Quality Control of raw materials
 Low bioburden
 Emprove® bio/Expert grades
3. Packaging of raw materials
 Paper-free packaging
4. Technically unavoidable Particle Profile
(TUPP) for excipients
5. Filters offering for sterile filtration

18. Poll
Question

19. Perspective of the Formulator
Development Challenges for High Risk Formulations
19
Particulate
matter
Microbial
purity
No
interaction
with API
Solubility
enhance
ment
Trace
amount of
impurities
Stability
Process
optimiza
tion

20. 20
 Low bioburden with controlled limits
on TAMC and TYMC
 Low endotoxin level
Emprove® Expert : Taking care of Microbial Purity

21. Emprove® for Chemicals
21
Addressing High Risk by Emprove® Expert
ESSENTIAL
▪ Designed for
moderate risk levels
▪ Former
EMPROVE® exp
EXPERT
▪ Addresses higher risk
applications
▪ Former EMPROVE® bio
▪ Lowest
microbiological and
endotoxin levels
specified
API
All products produced in Europe according to the ICH Q7 guideline

22. 22
Emprove® Program: Facilitates Risk Assessment
 EMPROVE® Dossier
Library:
 Material Qualification Dossier
 Quality Management Dossier
 Operational Excellence
Dossier
 EMPROVE® Portfolio:
chemicals, filters and single use
components to make, purify and
formulate drugs
EMPROVE®
Raw Materials
Risk-adjusted
Portfolio
EMPROVE®
Suite allows
online Access
to Dossiers
EMPROVE®
Filtration and
Single Use
Program being
rolled out
EMPROVE® dossiers
support Qualification,
Risk Assessment and
Process Optimization
 EMPROVE® Program:
addresses existing and
anticipated regulatory
requirements and expectations
 EMPROVE® Suite:
answers to regulatory questions
for around 400 products
available 24/7
EMPROVE® program supports drug manufacturers’
qualification, risk mitigation and process optimization efforts.
Industry-leading documentation drives confidence
in the transparency and control of our products.

23. Preservatives
23
Preservative selection based on pH of maximum microbial activity
Mixture can be used to target complete microbial population
2
Approximate pH ranges
3 4 5 6 7 8 9
Benzoic Acid
Benzyl Alcohol
Boric Acid
Chlorobutanol
Methyl Paraben & Propyl Paraben
Phenol
Sorbic Acid
Benzyl Benzoate
Thimerosal
Benzalkonium Chloride

24. Pharmacopoeial requirements for individual homologues
 Pharmacopoeia: Ph Eur, NF
 C12 homologue: ≥ 40% w/w
 C14 homologue: ≥ 20% w/w
 C12 + C14 homologues: ≥ 70% w/w
Product differentiation
Benzalkonium Chloride EMPROVE® EXPERT Ph Eur, NF
Higher % of C12 homologue
recommended for higher
microbial efficacy
High batch-
to-batch
consistency
results in
reproducible
efficacy!
C12:C14 always
at 65:35% w/w
24
Product No Description
137123 Benzalkonium Chloride EMPROVE® EXPERT Ph Eur, USP
137124
Benzalkonium Chloride (50% aqueous solution) EMPROVE® EXPERT Ph Eur,
USP
Parameter
s
137123 137124
Batch
number
BCBZ329
0
BCBZ329
1
BCBZ328
9
BCBZ438
5
BCBZ438
7
BCBZ438
6
C12 64.7% 64.7% 64.6% 64.7% 64.8% 64.8%
C14 35.3% 35.3% 35.4% 35.3% 35.2% 35.2%
C12+C14 100% 100% 100% 100% 100% 100%

25. Perspective of the Formulator
Development Challenges for High Risk Formulations
25
Particulate
matter
Microbial
purity
No
interaction
with API
Solubility
enhance-
ment
Trace
amount of
impurities
Stability
Process
optimiza-
tion

26. Functional group Incompatibilities Possible type of reaction
Primary amine Mono and disaccharides Maillard reaction
Ester, cyclic lactose Basic components
Ring opening, ester-base,
hydrolysis
Aldehyde Amine, carbohydrates
Aldehyde-amine, Schiff base or
glycosylamine formation
Carboxyl Bases Salt formation
Alcohol Oxygen
Oxidation to aldehydes and
ketones
Sulfhydryl Oxygen Dimerization
Phenol Metals Complexation
Interaction & Incompatibility of Excipients
26

27. Benzyl Alcohol
27
Photochemical oxidation
products of Benzyl Alcohol
Benzaldehyde impurity present in Benzyl
alcohol interacts with oxidation prone Benzyl
alcohol as well API.
Source: Kishore Hotha et al, (2016) Drug-Excipient Interactions:
Case Studies and Overview of Drug Degradation Pathways,
American Journal of Analytical Chemistry, 7, 107-140

28. We Take Care of Benzyl Alcohol Purity
28
 100981, 100987 and
137043, 137120
 Emprove® Essential &
Expert
 Not for Neonates & with
caution in children
 Applications
 Oral
 Injectable
 Topical
 Nasal
Benzaldehyde :
<0.05%
Emprove® Expert
grade
100987
Benzaldehyde :
<0.01%
Emprove® Expert
grade
137043
Pharmacopeia limits for Benzaldehyde
(USP & Ph.Eur): <0.15%
Lower level of benzaldehyde impurity is important for oxidation prone API.
Benzaldehyde impurity does have negative impact on
drug release of microsphere preparations.

29. Perspective of the Formulator
Development Challenges for High Risk Formulations
29
Particulate
matter
Microbial
purity
No
interaction
with API
Solubility
enhance-
ment
Trace
amount of
impurities
Stability
Process
optimiza-
tion

30. Poll
Question

31. 31
Meglumine: Solubility Enhancement and Stabilizer
 Derivative of sorbitol in which the hydroxyl group in position 1 is replaced by a
methylamino group
 White crystalline powder; melting at 130°C
 pKa value: 9.52
 Solubility in water: 1000 mg/ml
Organic base
used as
pH-adjusting agent,
solubilizing agent,
buffering agent,
stabilizing agent,
counter-ion,
scavenger for formaldehyde impurity

32. 32
Meglumine : Improve the Stability
Source: Fujita, M., Ueda, T., Handa, T., (2009) Generation of Formaldehyde by Pharmaceutical Excipients
and Its Absorption by Meglumine. Chem. Pharm. Bull. 57, 1096-1099.
Many excipients
contain
formaldehyde as
an impurity
Major excipients used in
formulations have been
shown to generate
formaldehyde during storage
(including, Polyols, HPMC,
Polysorbates, Poloxamers,
PEGs)
Formaldehyde can
react with amine
groups and
electron-rich
groups of the API!
Meglumine acts as
a formaldehyde
scavenger

33. 33
HP-β-Cyclodextrin : Solubility Enhancement
 Enhance API solubility
 Enhance API stability
 Enhance corneal penetration
 Reduce local irritation
 Cyclodextrin HPB at concentration of 12.5% well tolerated*
Cyclodextrin HPB EMPROVE® EXPERT Ph.Eur.,NF – item 1.42020.2500
*EMA/CHMP/333892/2013
Marketed Eye drops with
HP-β-Cyclodextrin
 Diclofenac sodium eye drop
 Indomethacin eye drops

34. Why use Cyclodextrin HPB*?
34
*Hydroxypropyl-beta-CD,
official compendial name: Hydroxypropyl-Betadex
SzejtliJ. Past, present and future of cyclodextrinresearch. Pure ApplChem2004;76:1825-45
Davis ME, Brewster ME. Cyclodextrin-based pharmaceutics: past, present and future. Nat Rev Drug Discov2004;3:1023-35.
In comparison to other cyclodextrins:
 Optimal cavity size:
“not too small and not too large”
 Hydrophilic derivative of beta-CD:
Better soluble than the “parent”
beta-CD
 Lower toxicity than the “parent”
beta-CD

35. Protein Formulation with Cyclodextrin HPB
35
Example 1: Ovine growth hormone
 Solubilization with hydroxypropyl-beta-cyclodextrin facilitates physiological pH of 7.4
without cyclodextrin, an extreme pH of 11 is used which results in pain upon i.v. injection
Example 2: Interleukin-2
 Hydroxypropyl-beta-cyclodextrin prevents aggregation after the reconstitution of lyophilized
formulation
Example 3: Bovine insulin
 With hydroxypropyl-beta-cyclodextrin, a parenteral insulin formulation is stable for 1 year at room
temperature
 With the usual pH 7.4 buffer (without cyclodextrin), precipitation occurred after 2 weeks of storage
Source: Brewster, M., M. Hora , et al. (1991). "Use of 2-Hydroxypropyl-β-cyclodextrinas a Solubilizingand Stabilizing Excipient for
Protein Drugs." Pharmaceutical Research 8(6): 792-795.

36. Perspective of the Formulator
Development Challenges for High Risk Formulations
36
Particulate
matter
Microbial
purity
No
interaction
with API
Solubility
enhance-
ment
Trace
amount of
impurities
Stability
Process
optimiza-
tion

37. Tris (hydroxymethyl) aminomethane High Purity
37
Tris: Polyoxymethylene (POM) Impurity
 Highly concentrated Tris solutions (> 20%) Precipitation of POM
Product Product No Description
Tris 108307
Tris(hydroxymethyl)aminomethane high purity
EMPROVE® EXPERT Ph Eur,BP,JPC,USP,ACS
Our Limits Pharmacopiea
Polyoxymethylene (ppm) ≤ 50 ≤ 200
Industry-leading low levels specified!
 Specification:

38. Product Name Parteck® SI 400 LEX (Sorbitol)
Ph Eur,BP,NF,JP
D(-) – Mannitol Emprove® Expert
Product Code 111597 137096
Pharmacopeia Limits ≤ 0.2, 0.3 ≤ 0.2
Our Limits ≤ 0.11 ≤ 0.05
Reducing Sugar Content : an Impurity
38
Maillard Reaction with
amine drugs
Glycation Reaction with
primary protein amine
group
Reduction in
drug potency and
discoloration

39. 39
Formaldehyde : Oxidizing Impurity
Formaldehyde
Amine
Carboxylic
acid
Alcohol
Product Name Polyethylene Glycol 300 Emprove®
Essential Ph Eur
Poloxamer 188 Emprove® Expert
(stabilized with 70ppm BHT) Ph Eur, NF
Product Code 817002 137112
Pharmacopeia
Limits
≤ 30 PPM No Limits
Our Limits ≤ 30 PPM ≤ 15 PPM

40. Formaldehyde
40
API with primary
or secondary
amine
Formaldehyde
impurity in PEG
300 &
Polysorbate 80
Formaldehyde adduct of API
Source: Munir Nassar et al; (2004) Influence of Formaldehyde Impurity in Polysorbate 80 and PEG‐300 on the Stability of a
Parenteral Formulation of BMS‐204352: Identification and Control of the Degradation Product, Pharmaceutical Development
& Technology, 9(2)
 A direct relationship between the levels of formaldehyde in the excipients and the
formation of the formaldehyde adduct as a degradant
 Formaldehydes present in the excipients react with amine containing compounds to form
degradants
 Control Strategy: A limit test on the formaldehyde content in polysorbate 80 and PEG 300
can be set as part of a strategy to limit the formation of the degradation product
 We specifies limit for formaldehyde in polysorbate and PEG 3000

41. Perspective of the Formulator
Development Challenges for High Risk Formulations
41
Particulate
matter
Microbial
purity
No
interaction
with API
Solubility
enhance-
ment
Trace
amount of
impurities
Stability
Process
optimiza-
tion

42. 42
Trehalose in Liposomal Formulation
Source: Bianca Sylvester et al (2018) Formulation Optimization of Freeze-Dried Long-Circulating Liposomes and In-Line Monitoring of the
Freeze-Drying Process Using an NIR Spectroscopy Tool Journal of Pharmaceutical Sciences, 107(1), 139-148
Lyoprotectant:
lipid molar ratio
Control Trehalose Sucrose Sucrose+Mannito
l
Before
freeze
drying
Particle size (nm)
3:1 536.2±42 353.45 ± 18 345.12 ± 25 397.33 ± 23 103 ± 11
5:1 119.55 ± 31 127.93 ± 36 174.0 ± 22
8:1 237.82 ± 24 259.22 ± 12 218.31 ± 16
PDI 0.482± 0.036
3:1 0.323 ± 0.025 0.319 ± 0.033 0.297 ± 0.011 0.104 ± 0.028
5:1 0.123 ± 0.029 0.173 ± 0.053 0.189 ± 0.056
8:1 0.299 ± 0.017 0.243 ± 0.009 0.225 ± 0.013
Encapsulated Drug
(%)
3:1 56.02 ± 0.303 64.07 ± 0.461 62.05 ± 0.319 59.79 ± 0.260 100
5:1 79.23 ± 0.229 73.62 ± 0.189 75.50 ± 0.435
8:1 68.43 ± 0.502 67.61 ± 0.355 65.49 ± 0.192
Residual moisture
(%)
3:1 0.92±0.04 2.86 ± 0.07 3.05 ± 0.09 2.69 ± 0.03 N/A
5:1 0.59±0.05 1.17 ± 0.08 1.89 ± 0.10 1.52 ± 0.06 N/A
8:1 0.67±0.02 1.37 ± 0.05 1.73 ± 0.07 1.71 ± 0.06 N/A
Trehalose is
suitable for
liposomal
formulation
considering
process and
stability of final
formulation
 Nanocort®: Liposomal prednisolone for acute manifestations of inflammatory diseases and Cancer and under
Clinical Phase II

43. 43
Trehalose in Liposomal Formulation
 Nanocort®: Liposomal prednisolone for acute manifestations of inflammatory diseases and Cancer
 Clinical Phase II
No Cryoprotectant With Mannitol With Trehalose
Crystallization
Source: Bianca Sylvester et al (2018) Formulation Optimization of Freeze-Dried Long-Circulating Liposomes and In-Line Monitoring of the
Freeze-Drying Process Using an NIR Spectroscopy Tool Journal of Pharmaceutical Sciences, 107(1), 139-148

44. 44
Trehalose in Ophthalmic Formulations
1. HU00701 Eye Drop (Nanocomposite eye drop): Phase 3
Contains: Cyclosporine and trehalose
Indication: Dry eye syndrome
Company: Huons Global Co. Ltd.
2. Cenegermin Ophthalmic Solution: Marketed in USA
Contains: Cenegermin-bkbj and trehalose
Indication: Eye Diseases, Corneal neurotrophic keratitis
Company: Dompe Farmaceutici S.p.A.
3. Thealoz Duo® Eyedrop: Marketed in France, Canada
Contains: Trehalose
Indication: Dry Eye syndrome
Company: Thea
4. Trehalube® Eye Drops : Marketed in India
Contains : Trehalose and Sodium hyaluaronate
Indication: Dry Eye Syndrome
Company: Micro Labsc
Mechanism of Action of Trehalose
 Rehydrate Tear Film
 Protect Against Future Irritation
 Support Homeostasis of Tear Film
Trehalose Dihydrate

45. Need for RTU
We can be your partner
Lyophilized to Liquid Ready to Use Solutions (RTU)
45
Stability Patient safety LCM
Dispensing Safe alternative
Excipients play vital role
Lactic
Acid
Poloxamer
188
 API is unstable in aqueous media
 API is soluble in acidic media
 API is soluble and stable in
poloxamer 188
 Same surfactant action like
polysorbate
 More stable than polysorbate

46. Perspective of the Formulator
Development Challenges for High Risk Formulations
46
Particulate
matter
Microbial
purity
No
interaction
with API
Solubility
enhance-
ment
Trace
amount of
impurities
Stability
Process
optimiza-
tion

47. Improve Throughput of your Liquid Solutions
47
Sterile filtration with Right Filter
 High flux rates in sterile filtration can
mean substantial cost savings for the
manufacture of ophthalmic solutions.
 Millipore Express® SHF membranes
achieved up to 2 ½ times better
thoughput through filters than
competitive filters.

48. Chose the Right Filter
48
Improve Benzalkonium Chloride Filtration
 Many preservatives do usually bind or are
adsorbed by membrane filters which
cause a loss of the appropriate amount of
preservatives in the final product.
 The test results with a 0,01 %
Benzalkonium Chloride (BAK) solution
showed the lowest BAK binding = lowest
BAK loss in final product
 Test membranes have been been all 0.2
mm sterilizing-grade and composed of
either PES or polyvinylidendiflupride
(PVDF)
®

49. Viscosity Profile of Different Grades of PVA
Ophthalmic Drug Delivery System
49
PVA polymer:
According to US FDA
llD database
- 1.4 % (w/v)

50. 50
Aseptic Sterile Filtration of PVA solution
Ophthalmic Drug Delivery System
0
5000
10000
15000
20000
25000
30000
35000
PVA 4-88 PVA 5-88 PVA 8-88 PVA 18-88PVA 26-88PVA 28-99PVA 40-88
Vmax
(L/m
2
)
Vmax
PVDF
PES
PVA polymer solution can be sterile filtered using 0.2 µm both PVDF and PES
membranes. However, PES filters are showing better results regrading Vmax and
mean flux.
0
1000
2000
3000
4000
5000
6000
7000
8000
9000
10000
PVA 4-88 PVA 5-88 PVA 8-88 PVA 18-88 PVA 26-88 PVA 28-99 PVA 40-88
Mean
Flux
(L/m
2
/h)
Mean Flux
PVDF
PES
Polyvinyl Alcohol - Role in Ophthalmics

51. Summary of
Formulation
Challenges and
Solutions

52. Perspective of the Formulator
Development Challenges for High Risk Formulations
52
Particulate
matter
Microbial
purity
No
interaction
with API
Solubility
enhance-
ment
Trace
amount of
impurities
Stability
Process
optimiza-
tion
TUPP and GMP
manufacturing
Paper free packaging
Emprove® Expert
Benzyl Alcohol
Meglumine
HP-β-Cyclodextrin
Control on
Reducing sugar
Formaldehyde
Trehalose
Low binding of
preservative with high
throughput: PES filter
Preservatives

53. Q&A

54. Field Marketing Manager, A&F,
India, S.E.A & Oceania
smita.rajput@emdgroup.com
Dr. Smita Rajput
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respective owners. Detailed information on trademarks is available via publicly accessible resources.
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