View the recording: https://bit.ly/31jxI7p Keeping the cost low is one of the key challenges in formulation development and manufacture and depends on multiple variables. This webinar will point out the benefit to focus on total cost of ownership and shows possible solutions on how to optimize your TCO. In pharmaceutical formulation and manufacture cost is a major point of concern. Regardless whether you are looking at alternative processes or excipients when developing a formulation, scaling it up for production, a way to optimize a running production or if you are considering a new investment – everyday decisions are made which have consequences on the economics. Total cost of ownership (TCO) is a concept well known in many industries. The basic idea we realize also in private life: the cheap choice is not always the most economical one. Since TCO takes into account many different cost factors, it is important to see the “big picture” and how each variable might influence your TCO. But how does this concept apply to pharmaceutical manufacture? Especially, the choices you have as a formulator are key to future economics of the drug life cycle. There are decisions to be taken about formulation composition and process design which are cost relevant in many aspects. Most of these decisions are related to the choice of excipients. Key is: cost of the formulation is not equal to the sum of all material cost. There are many more cost contributors related to the choice of excipients. Consider the cost created by a batch failure and product recall for the whole batch from the market in case of impurities resulting from “cheap” excipients. In this webinar you will: - Gain insights into critical aspects in formulation development and manufacture - Learn how choosing suitable excipients will help you to reduce the total cost of ownership of your final drug product

1. The life science business of Merck KGaA,
Darmstadt, Germany operates as
MilliporeSigma in the U.S. and Canada.
Total cost of ownership
– how the choice of excipients
makes your economics
Dr. Leo Ohrem
15 October, 2019

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

3. Agenda
1
2
3
Choice of manufacturing
process
Faster throughput by
higher tableting speed
API stability
4
5
Risk mitigation &
Registration effort
Development time

4. This is called Total Cost of Ownership!
Cost efficient formulation = lowest material cost?
Total cost of ownership - how the choice of excipients makes your economics | 15.10.20194
Introduction
Economics = material cost + ….
 labor cost
 equipment cost
 development cost
 registration cost
 cost for recalls and quality issues
 logistic handling cost
 cost for low stability

5. Choice of
manufacturing
process

6. Cost comparison of different tableting processes
Total cost of ownership - how the choice of excipients makes your economics | 15.10.20196
Choice of manufacturing process
By avoiding the granulation process, cost savings can be achieved in spite of using more
expensive DC Excipients.

7. Limitations in direct compression
Choice of manufacturing process
Total cost of ownership - how the choice of excipients makes your economics | 15.10.20197
1.
Content
uniformity
2.
Compressibility
3.
Flow

8. Limitations in direct compression
Total cost of ownership - how the choice of excipients makes your economics | 15.10.20198
Choice of manufacturing process
Content Uniformity
 according to regulations (Ph.Eur. /ICH) the content of API in each tablet has to be
in a defined range
 ± 15% of target dosage
 producer has to prove!
Problem for low dose (< 1% API) and micronized API

9. Improving content uniformity
Choice of manufacturing process
Total cost of ownership - how the choice of excipients makes your economics | 15.10.20199
Spray dried DC Mannitol
+ 1% Asco
Parteck® M 200
+ 1% Asco
Reason: ordered mixtures by adsorption of API

10. A low dose water-sensitive active should be directly compressed.
Direct compression with low dose actives (I)
Choice of manufacturing process
Total cost of ownership - how the choice of excipients makes your economics | 15.10.201910
Avicel is a registered trademark of FMC Corporation, Delaware, USA.
Compritol is a registered trademark of Gattefossé SAS, Saint-Priest, France.
 Low dose water-sensitive active
(0.5 mg/120 mg)
 API premixed with 15% Parteck® M 200
 Direct compression on Korsch PH230
(7mm, 9.1 kN)
 Speed: 40,000/80,000 tablets/h
Parteck® M 200
74%
Avicel® PH-101
19%
Crospovidone
2%
Compritol® 888
4%
API
0.4

11. Parteck® M: DC with low dose actives
Total cost of ownership - how the choice of excipients makes your economics | 15.10.201911
Faster throughput by higher tableting speed
 No significant deviations in tablet weight or hardness were observed
 The good flow and compressibility of Parteck® M is optimal for high throughput production on fast
rotary presses
 Content uniformity was in defined range (± 1.8%)
40,000 Tab/h 80,000 Tab/h
Tablet weight 120.1 mg (rel.sd.: 0.6%) 118.8 mg (rel.sd.: 0.9%)
Hardness 178 N (rel.sd. 4.1%) 173 N (rel.sd: 4.1%)
Disintegration 3'25'' 3'22''
Structured surface enables perfect content uniformity

12. Limitations in direct compression
Choice of manufacturing process
Total cost of ownership - how the choice of excipients makes your economics | 15.10.201912
1.
Content
uniformity
2.
Compressibility
3.
Flow

13. Limitations in direct compression
Total cost of ownership - how the choice of excipients makes your economics | 15.10.201913
Choice of manufacturing process
Compressibility
 Problematic for high dose API ≥ 40% of formulation
 API dilutes binding of excipient
 reduces tablet strength
 increases friability
Functional excipients enable high dose (≤ 70%) in DC

14. Excellent compressibility
Total cost of ownership - how the choice of excipients makes your economics | 15.10.201914
Choice of manufacturing process
0
100
200
300
400
500
600
0 5 10 15 20 25 30 35
Tablethardness[N]
Compression force [kN]
Calcium diphosphate anhydrate
Calcium diphosphate dihydrate
Lactose monohydrate
Mannitol, granulated
Mannitol, spray-dried A
Microcrystalline cellulose
Sorbitol
Sorbitol, spray-dried
Sorbitol and spray-dried mannitol deliver superior compressibility

15. Compressibility of different mannitols
Choice of manufacturing process
Total cost of ownership - how the choice of excipients makes your economics | 15.10.201915
Tablethardness[N]
0
100
200
300
400
0 5 10 15 20 25 30 35
Compression force [kN]
Parteck® M 200
Mannitol SD
Gran. Mannitol
Method
Formulation:
99% test material + 1% magnesium stearate;
5 min mixing
Compression:
single punch press (Korsch EK0 DMS, rpm:
54, punch: 11 mm, flat, facetted)
Tablet weight:
500 mg (rel. SD: 0.5)
All 3 applied mannitols are commercially
available mannitols for direct compression.

16. Excellent binding vs fast disintegration
Total cost of ownership - how the choice of excipients makes your economics | 15.10.201916
Choice of manufacturing process
Textbook knowledge:
stronger tablets
Slower disintegration

17. Parteck® M: high compressibility
Total cost of ownership - how the choice of excipients makes your economics | 15.10.201917
Choice of manufacturing process
Formulation:
98.5% mannitol; 1.5% Mg-
stearate
Compr. force 15 kN
99% lactose, 1% Mg-
stearate
Compr. force 15 kN
0
20
40
60
80
Parteck® M DC-Mannitol Lactose/starch-
granules
Tablettose
Tablethardness[N]

18. Parteck® M: fast disintegration
Choice of manufacturing process
Total cost of ownership - how the choice of excipients makes your economics | 15.10.201918
0
10
20
30
Parteck® M DC-Mannitol Lactose/starch-
granules
Tablettose
Disintegrationtime[min]
Formulation:
98.5% mannitol; 1.5% Mg-
stearate
Compr. force 15 kN
99% lactose, 1% Mg-
stearate
Compr. force 15 kN

19. Parteck® M performance: How can we explain that?
Total cost of ownership - how the choice of excipients makes your economics | 15.10.201919
Choice of manufacturing process
SEM of DC- mannitol SEM of Parteck® M

20. Polymorph and BET-surface
Total cost of ownership - how the choice of excipients makes your economics | 15.10.201920
Choice of manufacturing process
Product Polyform Appr. BET [m²/g]
Parteck® M 100 beta 3
Parteck® M 200 beta 3
Mannitol A (SD) alpha 0.6
Mannitol B (SD) alpha 0.5
Mannitol C beta 0.5
Mannitol D beta 0.4
Mannitol E beta 0.3
Mannitol F (SD) alpha 0.5
Mannitol DC Granul. A beta 0.3
Mannitol DC Granul. B beta 0.5
Mannitol DC Granul. C beta 0.4

21. Limitations in direct compression
Choice of manufacturing process
Total cost of ownership - how the choice of excipients makes your economics | 15.10.201921
1.
Content
uniformity
2.
Compressibility
3.
Flow

22. Parteck® M: Excellent flowability
Choice of manufacturing process
Total cost of ownership - how the choice of excipients makes your economics | 15.10.201922
Material Angle of repose
Parteck® M 200 25.3

23. Faster throughput by
higher tableting speed

24. Parteck® M: DC with low dose actives
Total cost of ownership - how the choice of excipients makes your economics | 15.10.201924
Faster throughput by higher tableting speed
 No significant deviations in tablet weight or hardness were observed
 The good flow and compressibility of Parteck® M is optimal for high throughput production on fast
rotary presses
 Content uniformity was in defined range (± 1.8%)
40,000 Tab/h 80,000 Tab/h
Tablet weight 120.1 mg (rel.sd.: 0.6%) 118.8 mg (rel.sd.: 0.9%)
Hardness 178 N (rel.sd. 4.1%) 173 N (rel.sd: 4.1%)
Disintegration 3'25'' 3'22''
good flow leads to constant performance

25. Experience of customers show
Total cost of ownership - how the choice of excipients makes your economics | 15.10.201925
Faster throughput by higher tableting speed
Increase of throughput by optimizing the excipient
choice
 Switch from 90,000 tablets/h to 180,000 tablets/h
 More reliable operations over years
Old formulation New formulation
Product Name
DC Mannitol Parteck® M 200
Compression force 18 kN 2 kN
Hardness 40 N 55 N

26. Production with Parteck® M in a DC-Process
Total cost of ownership - how the choice of excipients makes your economics | 15.10.201926
Faster throughput by higher tableting speed
 Switch from
90,000 tablets/h
to 180,000 tablets/h
 Lower compression force
 Higher hardness
 More reliable operations
over years

27. API Stability

28. Factors affecting API stability
API stability
Total cost of ownership - how the choice of excipients makes your economics | 15.10.201928
2.
Impurities
3.
Compression
force
2.
Granulation
process
1.
Moisture
Content &
hygroscopicity

29. Substance Water content
Starch ≤ 15 %
MCC ≤ 7 %
Isomalt ≤ 7 %
Excipient System A ≤ 5.75 %
Excipient System B ≤ 3.5 %
Excipient System C ≤ 3 %
Lactose monohydrate ≤ 1 %
DC-Sucrose ≤ 1 %
DC-Mannitol ≤ 0.3 %
Excipients systems A-C are ready-to-use
systems of the following composition:
 A: lactose monohydrate, povidone,
crospovidone
 B: lactose monohydrate, cellulose
 C: lactose monohydrate, maize starch
Moisture content of excipients
Total cost of ownership - how the choice of excipients makes your economics | 15.10.201929
API stability
Sources: Rowe, R. C., P. J. Sheskey, et al., Eds. (2009). Handbook of
Pharmaceutical Excipients. 6th Edition. London, Washington, DC,
Pharmaceutical Press and American Pharmacists Association or
manufacturer’s information.
Mannitol is the best choice to use with moisture sensitive APIs

30. Hygroscopicity: Comparison of filler excipients
Total cost of ownership - how the choice of excipients makes your economics | 15.10.201930
API stability
Sorbitol works well, if humidity can be controlled in
manufacturing and final packaging

31. Total cost of ownership - how the choice of excipients makes your economics | 15.10.201931
2.
Impurities
3.
Compression
force
2.
Granulation
process
1.
Moisture
Content &
hygroscopicity
Factors affecting API stability
API stability

32. Excipients and their impurities (I)
Total cost of ownership - how the choice of excipients makes your economics | 15.10.201932
API stability
Drug Impurity Excipient Drug loading (w/w)
BMS-203452 Formaldehyde PEG 300 or Tween
®
80 1%
Fluoxetine HCl Reducing sugars Lactose 10%
Org-30659 Lactose phosphate Lactose 0.10%
Compound A Peroxides Povidone/Copovidone 2–3%
Compound B Peroxides Povidone/Copovidone 2–3%
Raloxifene Peroxides Povidone/Copovidone 12.50%
CP448187 Free radicals/peroxides Microcrystalline Cellulose 0.50%
BMS-A Free radicals/peroxide/red. sugars Microcrystalline Cellulose 0.83%
Vigabatrin Reducing sugars, aldehydes Microcrystalline cellulose –
Irbesartan Formaldehyde PEG in film coating Low strength
Haloperidol Furfuraldehyde Lactose 0.575%
Varenicline Formic acid/formaldehyde PEG 0.68%
Hydralizine Aldose Starch 10%
Wu Y, Levons J, Narang AS, Raghavan K, Rao VM. Reactive Impurities in Excipients: Profiling, Identification and Mitigation
of Drug–Excipient Incompatibility. AAPS PharmSciTech. 2011;12(4):1248-1263. doi:10.1208/s12249-011-9677-z.

33. Excipients and their impurities (II)
Total cost of ownership - how the choice of excipients makes your economics | 15.10.201933
API stability
Excipient Impurity
MCC Water, glucose (reducing sugar), hydrogen bonding (-> retardation),
aldehydes, free radicals/peroxides
Lactose Water, aldehydes, formic acid, reducing sugar
HPMC Water, reducing sugar, aldehydes
PEG, Tween® Water, reducing sugar, retardation, aldehydes
Povidone Peroxides, aldehydes, retardation
Crospovidone Peroxides, aldehydes
Keep it simple!
What you leave out, you do not need to worry about
Wu Y, Levons J, Narang AS, Raghavan K, Rao VM. Reactive Impurities in Excipients: Profiling, Identification and Mitigation
of Drug–Excipient Incompatibility. AAPS PharmSciTech. 2011;12(4):1248-1263. doi:10.1208/s12249-011-9677-z.

34. Total cost of ownership - how the choice of excipients makes your economics | 15.10.201934
API stability
With a reducing sugar level below pharmacopoeial requirements and
specifications, Parteck® M supports the stability of your formulation.
Reducing sugars in Parteck® M

35. Risk mitigation and
registration effort

36. Total Cost of Ownership
Total cost of ownership - how the choice of excipients makes your economics | 15.10.201936

37. Emprove® Program: Supporting EU Risk Assessment Guidelines
Risk mitigation and registration effort
Emprove® Operational
Excellence Dossier
 Product quality report [4.1]
 Elemental impurity information
[2.3, ICH Q3D]
 Analytical procedure [2.6]
 TUPP [2.3]
Emprove® Material
Qualification Dossier
In line with CTD chapter 3 quality
(adapted for excipients) [2.3]
 General information
 Manufacture
 Characterization
 Reference standard
 Certificates
Emprove® Quality
Management Dossier
Product Quality Self Assessment
[2.6, 2.3]
 Audit report summary [2.6]
 Supply chain Information [2.3]
 Stability data [2.3, ICH Q8]
[*] No. of supported chapter of Guideline on formalized risk assessment for excipients EU/C 95/210
[3.3]
Total cost of ownership - how the choice of excipients makes your economics | 15.10.201937
Chapter 2: Determination of appropriate GMP based on type and use of excipient
 2.3. For each excipient identify risk throughout the entire process until final dose form
 2.6. Consider high level GMP elements
Chapter 3: Determination of the excipient manufacturer’s risk profile
 3.3. Certification of quality systems and/or GMP held by the excipient manufacturer
Chapter 4: Confirmation of application of appropriate GMP
 4.1. Performance of ongoing risk reviews
*

38. EXCiPACT™ certificate
Risk mitigation and registration effort
Total cost of ownership - how the choice of excipients makes your economics | 15.10.201938
Challenge:
Drug manufacturer needs to
verify excipient
manufacturer’s risk profile
High burden of audits
Solution:
 No on-site audit need
 EXCiPACT™ audit report is
available free of charge on
request (after signing a
CDA)
 Available for 450 products

39. Total cost of ownership - how the choice of excipients makes your economics | 15.10.201939
Largest
portfolio
in the
Industry
ConvenienceThird
Party
Audit
Reports
Cross-
validated
compendial
methods
Elemental Impurity
+ Product quality
report
CTD
Format
Access to
Emprove® Suite
Supply
chain & mfg
process
information
Supplier
audit
report
eOMT
Access to all
dossiers in one
place
Online information
of original
manufacturers
Chain of custody
and manufacturing
flow chart
Ensuring
appropriate GMP
at our suppliers
ICH Q3D + product
consistency
Multi-compendial
specs and method
validation
Excipact
reports
Internationally
recognized
structured format
Emprove® – Benefits & Value
Risk mitigation and registration effort

40. Shorten
development
time

41. How?
Total cost of ownership - how the choice of excipients makes your economics | 15.10.201941
Shorten development time
Proven excipients performance → Lower failure rates
Formulation support → Rapid formulation development
Broad portfolio for all applications → Reduction of qualification time and efforts
Regulatory support → Reduced documentation effort
Simplified manufacturing process → Greater process efficiency
… by implementing the right solutions

42.  Enhancement of drug bioavailability
 Improved stability of drug
 Ease of low- and high-dose formulation
 Facilitated work with micronized APIs
Total cost of ownership - how the choice of excipients makes your economics | 15.10.201942
Formulation support for rapid formulation development
Shorten development time
R&D Center for Formulation,
Darmstadt, Germany

43. Email:
hans-leonhard.ohrem@emdgroup.com
Dr. Leo Ohrem