As single-use technologies continue to expand in pharmaceutical manufacturing processes, the risk assessment for extractables and leachables becomes increasingly complex. Join this webinar to obtain guidance on how to perform risk evaluation on a process with multiple single-use components. A Single-Use System (SUS) is typically designed for a specific process step. In many cases, single-use components are chosen based on their functionality. The challenge arises when there are multiple processing steps-- as the different applications and product matrices are evaluated, the complexity of the risk assessment increases. Complexity includes component evaluation, process conditions, and model solvents streams which ultimately relates to the patient safety risk. This webinar will evaluate the different single-use components with respect to compatibility and extractables and leachables. A case study will be used to demonstrate the complexity and potential concerns when performing a risk evaluation on the manufacturing process. In this webinar, you will learn: - Risk assessment of extractables - Single-use component evaluation - Complexity when evaluating multiple assemblies

1. The life science business of Merck KGaA, Darmstadt, Germany
operates as MilliporeSigma in the U.S. and Canada.
Challenges using
Multiple Single-use
Systems:
Functionality versus
Extractables and
Leachables
Jessica Shea
April 18, 2019

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

3. Agenda
Regulatory Environment
Complexity and Risk with
SUS
Risk Evaluation: TFF Risk
Mitigation
1
2
3
4
5
Risk Evaluation: Application
of USP <665> and <1665>
draft
Conclusion

4. Regulatory
Environment

5. Extractables and Leachables
Regulatory Requirements
FDA EU
European Commission, EUDRALEX Volume 4,
“Good Manufacturing Practices, Medicinal Products for
Human and Veterinary Use”, Chapter 3, “Premise and
Equipment”, 2003 “
Production equipment shall not present any hazard
to the product. The parts of the production
equipment that come into contact with the product
must not be reactive, additive or absorptive to
such an extent that it will affect the quality of the
product and thus present any hazard.”
FDA, Code of Federal Regulations,
Part 211, “Current Good Manufacturing
Practice for Finished Pharmaceuticals”,
Part 211.65, “Equipment Construction”, 2005
“Equipment shall be constructed so that surfaces
that contact components, in-process materials, or
drug products shall not be reactive, additive, or
absorptive so as to alter the safety, identity,
strength, quality, or purity of the drug
product beyond the official or other
established requirements.”
Challenges Using Multiple Single-Use Systems5

6. Regulatory expectation
Risk-based approach is recommended by
regulators
• CBER recommends a risk-based approach to evaluate extractables and leachables. Where you take
multiple aspects into account (e.g., indication, safety issues, product characteristics, dosage,
formulation, and stability profile).
• If there’s no relevant risk associated with the (materials in question), vendor data can be cross
referenced and a detailed justification for the application of these data and a justification for no
additional testing should be submitted.
• Where there is relevant risk, the drug sponsor may have to determine toxicity based on
maximum dosage of potential leachables based on extractables data.
• If the maximum dosage of potential leachables presents a safety risk, leachable evaluation and
testing may be necessary.
• Additionally, if product quality could be affected by potential leachable, studies may need to be
performed to assess the effect on product quality, including efficacy.
Destry M. Sillivan – Senior Regulatory Review Officer, CBER, FDA. IBC’s 7th International Single Use Application for Biopharmaceutical
Manufacturing Conference, la Jolla, CA, June 14, 2010
Challenges Using Multiple Single-Use Systems6

7. Why Worry?: FDA Warning Letters
“Please provide data from an extractables/leachables study conducted
on the vessel, tubing and filters used for drug product
manufacturing. Please ensure that the studies are conducted taking
into account the nature of the non-aqueous vehicle used in your
proposed drug product.”
“We recommend you to conduct a leachable study for the filtration
system with the drug solution to ensure the absence of leachable in
the drug product after filtration.”
Challenges Using Multiple Single-Use Systems7

8. Industrial References: PDA Technical Report 66
Application of Single-Use Systems in Pharmaceutical Manufacturing
2014: Implementation of SUS
1
2
Regulatory Environment For Filters And
Single Use Equipment
Compendial Standard: USP <665> Draft
Plastic Components and Systems Used in Pharmaceutical Manufacturing:
Focus on defining extractables standards
3 Regulations: EMA/CHMP/BWP/187338/2014
Guideline on process validation for the manufacture of biotechnology-derived
active substances and data to be provided in the regulatory submission
Defining requirements for single use equipment
Challenges Using Multiple Single-Use Systems8

9. Evolving Industry Guidance Expectations
PDA Technical Report 66, 20141
•“Supplier documentation may be sufficient for certain applications
where risk is low (such as, short term exposure, no contact with drug
product, or position in the process stream); but more detailed
studies may be required where significant risk (such as longer
term contact and extreme conditions) exists.”
•Extractables is essential step in the accurate prediction of leachables
•To check the impact of E&L by risk assessment on process, patient
safety and product quality
•If high, leachables data may be need
How to use
supplier’s data
Step wise
approach
Challenges Using Multiple Single-Use Systems9
Source: Parenteral Drug Association

10. 2 USP <665> Draft March 2019: Plastic Components and Systems Used in Pharmaceutical
Manufacturing
Emprove® Program For Filters and Single Use
Evolving Industry Guidance Expectations
• Addresses the qualification of plastic components used in the manufacture of both pharmaceutical and
biopharmaceutical active pharmaceutical ingredients (APIs) and drug products (DPs)
• Risk assessment based on dosage form (i.e., oral solid/liquid is low risk) and application
• Extraction requirements:
Solution Composition Tests Performed
Acid/salt buffer, pH 3 Organic extractables
Phosphate buffer, pH 10 Organic extractables
Ethanol and water (50:50) Organic extractables. Low risk tests
Challenges Using Multiple Single-Use Systems10

11. EMA/CHMP/BWP/187338/2014 (28 April 2016)
Guideline on process validation for the manufacture of biotechnology-derived
active substances and data to be provided in the regulatory submission
Chapter 6.1.3.: General issues related to single use equipment
▪ “…consideration should be given to leachables* and extractables.”
▪ “Information should be provided on the nature and amount of potential leachables*,…”
▪ “Besides data, this normally includes a risk assessment.”
▪ “Data do not necessarily need to be generated under actual process conditions, for example
supplier data or data generated under representative model conditions may be suitable.”
▪ “For verification studies, commercial scale equipment should be used.”
▪ “Various batches of disposable components should be used, as appropriate,…”
*leachables can be done only under process conditions, here we offer the Bioreliance services.
Emprove® Dossiers: Support Fulfilling Regulatory
Requirements
3
Challenges Using Multiple Single-Use Systems11

12. Complexity and
Risk with SUS

13. Biopharma Market
Trends
Market: $200 B, CAGR 15%
1. Greater focus on
manufacturing efficiency and
productivity improvements
2. Survey responses stated
the use of single-use and
disposable devices improved
the biomanufacturing
performance
Top Reasons for
Implementing
Single-Use
1. Reduce capital investment
with facility and equipment
2. Eliminate cleaning
requirements with associated
validation
3. Reduced time in getting
facility up and running
4. Decrease risk of product
cross contamination
Top Single-Use Product
Attributes
1. Reliable lead-time & faster
delivery
2. Extractables & leachables
data is the top reason for
restricting use.
3. Quality of product
4. Cost of product
Single-use Adoption Enables Desired Process Efficiency
Improvements in Biomanufacturing
Source: Bioplan 2016, 13th Annual report of Biopharmaceutical manufacturing capacity and production
Challenges Using Multiple Single-Use Systems13

14. Product & Process
Single-Use Assembly DrawingsTesting for E&L
Assembly Train Sequence
Flow Path on Drawing
Challenges Using Multiple Single-Use Systems
Evaluation Process
1
2
5
4
3
14

15. Introduction to Single-Use Systems
Challenges Using Multiple Single-Use Systems15

16. 16
Compatibility: Choosing the right material for the application
Compatibility
• Understand the materials of construction
and its compatibility with the process
stream
• Minimize temperature and duration with
more difficult process streams.
• Minimize the risk for patient safety and
potential leachables
USP <665> draft
• Components are characterized depending
on the level of risk associated with their
application in a particular manufacturing
operation
Quantity
and
Type
Material of Construction
Process
Stream
Process
Conditions
Temp and duration
Challenges Using Multiple Single-Use Systems16

17. Grouping SU
components
for
Extractables
Studies.
Components Extractables Test Strategy
Can we group components?
What
type of
MOC?
Which
Resin is
used?
Any
process-
ing
aids?
How are
they
manufac
-tured?
Who are
the
vendors?
Resin
Group
2
Resin
Group
n
Resin
Group
1
Challenges Using Multiple Single-Use Systems
17

18. ConnectorsBags
Challenges Using Multiple Single-Use Systems
 Pureflex® Film
 Pureflex Plus® Film
 Pharma® 50, 60, 80
Tubing
 APT® Tubing
 Braided Tubing
 C-Flex® Tubing
 All other tubing
 Lynx S2S® Connectors
 Lynx ST® Connectors
 Kleenpak® Connectors
 Readymate®
Connectors
 Aseptiquik®
Connectors
 Steam Connectors
 Needles with
Polycarbonate Over-
Mold
Tubing Needle
Components to Validate
18

19. Challenges Using Multiple Single-Use Systems
Examples:
Flow Path & Components to Validate
19

20. Classes of E&L from Single-Use Systems
Stabilizer Irgafos® 168
Slip agents
Erucamide
Lubricants
Plasticizer
DEHP
Pigment
Degradation Products
BHT
OH
O
O
OH
O O
OH
O
O
OH
O
O
Irganox® 1010
Antioxidants
Monomers
Styrene
Extractables and Leachables
Challenges Using Multiple Single-Use Systems20

21. Risk Evaluation:
TFF Risk
Mitigation

22. Most Unit Operations Consist of Polymeric Components
Monoclonal
Antibody
Typical monoclonal
antibody processes
can be multi-use or
single-use.
High Risk
ClearanceChallenges Using Multiple Single-Use Systems22

23. Cleaning Validation of the UF/DF Device
First Use and Re-use Qualification
 Prior to implementation of a UF/DF step, the
process must be validated, including
validation of two cleaning procedures.
 The first cleaning procedure is to remove
the preservative solution from the device.
 The Re-use cleaning process between runs
to restore the membrane that was stored in
sanitizing solution
Removal during TFF Processing Step
Diafiltration is a conventional method used to
achieve high purification of macrosolutes
 In the diafiltration mode the permeate is
sent to waste and a makeup buffer is
added to the reservoir to maintain the
volume.
 This process also reduced leachables that
are present from previous processing steps
Challenges Using Multiple Single-Use Systems
Risk Reduction – 2 Ways
Tangential Flow Filtration
23

24. Challenges Using Multiple Single-Use Systems
Removal during TFF Processing Step
Tangential Flow Filtration
Ultrafiltration/ Diafiltration: Testing was performed in the diafiltration modes and recycle mode.
The study demonstrate a >3x log reduction of Bisphenol-A (BPA)
Removal of Leachables by Ultrafiltration and Diafiltration (2018). MilliporeSigma Technical Brief TB4663EN00
24

25. Conclusion
 Studies demonstrated the ability of an TFF
membrane to remove leachables generated
upstream of the product stream.
 The risk is reduced for steps prior to the UF/DF
step.
 Basic information of the materials are sufficient
for steps prior to the UF/DF step due to the low
risk level.
Challenges Using Multiple Single-Use Systems
Removal during TFF Processing Step
Tangential Flow Filtration
Diafiltration Mode
An example of typical clearance for the seven potential E/L from single-use
technologies in Protein 4 and its associated buffer control run.
Magarian, N., Lee, K., Nagpal, K., Skidmore, K., & Mahajan, E. (2016). Clearance of Extractables and Leachables from Single-Use
Technologies via Ultrafiltration/Diafiltration Operations. Biotechnol. Prog., 32:718–724
25

26. Validation of the cleaning procedure includes:
 Determine the flush volume necessary to remove the preserving
solution. The flush volume is typically determined using a Total
Organic Carbon (TOC) endpoint.
 Fill the device with a sanitizer (e.g. alkali solution) and determine
how much contact time is needed to reduce the bioburden.
(Typically, companies have established minimal hold times)
 Determine the volume required to remove the sanitizer. Sanitize
the TFF device with an alkaline solution. This second flush volume
is usually determined using conductivity.
Result
 TFF unit operation is low risk and need not be subjected to
extractables studies when it can be restored to water for
injection (WFI) like conditions with specifications of < 500
ppb TOC.
Challenges Using Multiple Single-Use Systems
Cleaning Validation of the UF/DF Device
Tangential Flow Filtration
26
Agalloco,James, (1992). Points to Consider in the Validation of Equipment Cleaning Procedures. J. Parent. Sci. and
Technol., 46(5), 163-168
Bader, FG, A Bum, BD Garfinkle, D MacFarland, T Massa, and TL Copmann, (1992). Multiuse Manufacturing
Facilities for Biologicals. Biopharmaceuticals, 5(7), 34-42
FDA, Guide to Inspection of Validation of Cleaning Processes, US GPO, Wash. DC, July 1993

27. Challenges Using Multiple Single-Use Systems
Mitigating Factors - USP <1665> Draft
 Post-contact processing step that clears extracted substances
 Reduce the concentration of extractables by diluting them via
the process stream
mitigating factor = 1
 Tangential Flow Filtration
27
Understood by Regulations
Risk Assessment

28. Risk Evaluation:
Application of
USP <665> and
<1665> draft

29. Risk Dimensions for Consideration
USP <1665> Draft
Plastic
component
Chemical nature of
process stream
Duration of contact
Temperature of
contact
Material of
construction
The risk evaluation matrix considers four dimensions that address the risk that a polymeric
component will be leached to such an extent that its extractables may be impactful. These
dimensions include:
29 Challenges Using Multiple Single-Use Systems

30. Challenges Using Multiple Single-Use Systems
Clinical Use Mitigating Factors - USP <1665> Draft
1 The dosage form is a solid or liquid oral
2 The duration of clinical use is <7 days
3 The daily dose volume is <10 mL
Lowering the Risk Level
30

31. Challenges Using Multiple Single-Use Systems
Other Mitigating factors
Clearance
(TFF)
Significant
Dilution
(pH adjustment)
Material
Consideration:
Flushing
31

32. Challenges Using Multiple Single-Use Systems
USP <665> Draft
Risk
Level
Biological Reactivity Chemical Assessment Extraction Solution Component Testing
Low None Partial 50% Ethanol
NVR, pH Differential, UV
absorbance
Medium
USP <87>,
Biological reactivity
in vitro
Limited
50% Ethanol
1. Low-risk tests
2. Organic extractables
profiling
High
1. USP <87>
Cytotoxicity tests
2.USP <88>
Systemic Injection
Test, Intracutaneous
Test
Full
1. 0.2M KCl, pH 3
2. 0.1M Phosphate
buffer, pH 10
3. 50% EtOH
1. Low risk tests
2. Standard
extractables protocol
3. Extractable elements
(as necessary and
appropriate)
32

33. Case Study

34. Challenges Using Multiple Single-Use Systems
Final Filling – Single-use
Risk Assessment – Example
5’’ Express
PES Filter
10L Pureflex
plus Bag
34

35. • Water, 2% API, 0.02% PS80, 2% dextrose, pH 5
Drug Product
• 8 hours
Filter Contact Time
• 25 °C
Filtration Temperature
Typical Injectable Application
Challenges Using Multiple Single-Use Systems35

36. Challenges Using Multiple Single-Use Systems
Risk Matrix - USP <1665> Draft
If the process streams contain multiple solubilizers, e.g. protein and
surfactant, the risk is compounded.
organic
solvents (by
volume)
surfactants
(by weight)
blood/blood-derived
substances (by
weight)
lipids and
proteins
(by weight)
pH
Aqueous
Level 1
<5% <0.1% blood-derived <1% <1% ≥ 3 and ≤ 9
Somewhat
organic
Level 2
5-40% 0.1-0.5% blood-derived 1-25% 1-5%
Highly
organic
Level 3
>40% >0.5%
blood or blood-
derived >25%
>5% <3 or >9
Process
stream
36

37. Challenges Using Multiple Single-Use Systems
Risk Matrix - USP <1665> Draft
Additives (by weight)
Treatment for
sterilization
Processing
Inert
Level 1
<0.1%
Intermediate
Level 2
0.1-1%
chemical
adhesives/bonding of
component's
materials
Reactive
Level 3
>1%
irradiation/chemi
cal treatment
chemical
adhesives/bonding of
component's
materials
Material
Flushing/rinsing can be
used to reduce the
material reactivity
terms by one level,
37

38. Challenges Using Multiple Single-Use Systems
Risk Matrix - USP <1665> Draft
Temperature (°C) Duration
Level 1 Frozen (<-10) < 24 hrs
Level 2
refrigerated (2-8)
Ambient (15-25) 1-7 days
Level 3 Elevated (>30) > 7 days
Temperature duration
38

39. Challenges Using Multiple Single-Use Systems
Table A-2. Linking the Numerical Risk Sequence with a Level of Characterization
Risk Matrix - USP <1665> Draft
If... And... Then the Characterization Level is...
Four dimension scores are Level 3 There is no additional qualifier (3333) Level C (High Risk)
Three dimension scores are Level 3
The other dimension score is Level 2 (3332) Level C
The other dimension score is Level 1 (3331) Level C
Two dimension scores are Level 3
The other two dimension scores are both Level 2
(3322) Level C
One dimension score of Level 2 (3321)
Level B (Moderate Risk) or C (High
Risk)a,b
The other two dimension scores are Level 1 (3311) Level A or Bb,c
One dimension score is Level 3
All of the other dimension scores are Level 2
(3222) Level B
One of the other dimension scores is Level 1 (3221)Level B
Two of the other dimension scores are Level 1
(3211) Level A or Bb,c
All of the other dimension scores are Level 1
(3111) Level A
No dimension score is Level 3
All of the dimension scores are Level 2 (2222) Level B
Not all of the dimension scores are Level 2 Level A
a If the Level 2 score is in temperature, solvent, or duration dimensions, then Level C; otherwise, Level B.
b In these cases the temperature, solvent, or duration dimensions have a greater influence on risk than do material
considerations.
c If one of the Level 1 scores is in the material considerations dimension, then Level A; otherwise, Level B.
Flushing
39

40. Case Study

41. Increased Contact Time and Formulation Change
Challenges Using Multiple Single-Use Systems41
• Water, 2% API, 0.1% PS80, 2% dextrose, pH 5
Drug Product
• 30 Days
Filter Contact Time
• 25 °C
Filtration Temperature

42. Challenges Using Multiple Single-Use Systems
Risk Matrix - USP <1665> Draft
If the process streams contain multiple solubilizers, e.g. protein and
surfactant, the risk is compounded.
organic
solvents (by
volume)
surfactants
(by weight)
blood/blood-derived
substances (by
weight)
lipids and
proteins
(by weight)
pH
Aqueous
Level 1
<5% <0.1% blood-derived <1% <1% ≥ 3 and ≤ 9
Somewhat
organic
Level 2
5-40% 0.1-0.5% blood-derived 1-25% 1-5%
Highly
organic
Level 3
>40% >0.5%
blood or blood-
derived >25%
>5% <3 or >9
Process
stream
42

43. Challenges Using Multiple Single-Use Systems
Risk Matrix - USP <1665> Draft
Additives (by weight)
Treatment for
sterilization
Processing
Inert
Level 1
<0.1%
Intermediate
Level 2
0.1-1%
chemical
adhesives/bonding of
component's
materials
Reactive
Level 3
>1%
irradiation/chemi
cal treatment
chemical
adhesives/bonding of
component's
materials
Material
Flushing/rinsing can be
used to reduce the
material reactivity
terms by one level,
43

44. Challenges Using Multiple Single-Use Systems
Risk Matrix - USP <1665> Draft
Temperature (°C) Duration
Level 1 Frozen (<-10) < 24 hrs
Level 2
refrigerated (2-8)
Ambient (15-25) 1-7 days
Level 3 Elevated (>30) > 7 days
Temperature duration
44

45. Challenges Using Multiple Single-Use Systems
Table A-2. Linking the Numerical Risk Sequence with a Level of Characterization
Risk Matrix - USP <1665> Draft
If... And... Then the Characterization Level is...
Four dimension scores are Level 3 There is no additional qualifier (3333) Level C (High Risk)
Three dimension scores are Level 3
The other dimension score is Level 2 (3332) Level C
The other dimension score is Level 1 (3331) Level C
Two dimension scores are Level 3
The other two dimension scores are both Level 2
(3322) Level C
One dimension score of Level 2 (3321)
Level B (Moderate Risk) or C (High
Risk)a,b
The other two dimension scores are Level 1 (3311) Level A or Bb,c
One dimension score is Level 3
All of the other dimension scores are Level 2
(3222) Level B
One of the other dimension scores is Level 1 (3221)Level B
Two of the other dimension scores are Level 1
(3211) Level A or Bb,c
All of the other dimension scores are Level 1
(3111) Level A
No dimension score is Level 3
All of the dimension scores are Level 2 (2222) Level B
Not all of the dimension scores are Level 2 Level A
a If the Level 2 score is in temperature, solvent, or duration dimensions, then Level C; otherwise, Level B.
b In these cases the temperature, solvent, or duration dimensions have a greater influence on risk than do material
considerations.
c If one of the Level 1 scores is in the material considerations dimension, then Level A; otherwise, Level B.
45

46. • Total quantity below the AET (Analytical Evaluation Threshold)
• Individual quantitation
• Scale data to surface area
• Sum the quantitation if present in more than one component
Extractables Identification
• Manufacturing process
• Posology
Exposure Assessment
• Evaluate based on the TTC (Threshold of toxicological concern)?
• Establish a PDE (Permitted daily exposure)?
Safety Evaluation
Single-Use Component Evaluation
Assessing the Risk
46 Challenges Using Multiple Single-Use Systems

47. Patient Safety
Evaluation of Organic Extractables
No
Yes
Quantity
above the
TTC/PDE?
Risk Mitigation
Leachables?
Dilution?
Material/ Process
Change?
Risk is acceptableQuantity of Each
Extractable
Challenges Using Multiple Single-Use Systems47

48. Conclusion

49. More than Extractables Data
Emprove® Program and BioReliance® Validation Services
49
Emprove® program offers…
• Support on material qualification, risk assessment
& process optimization efforts through three well-
organized Emprove® Dossiers:
− Material Qualification Dossier
− Quality Management Dossier
− Operational Excellence Dossier
• The Operational Excellence dossier aligns with
the BPOG standardized extractables testing
protocol & the USP 665 (draft chapter)
• Complete profile of extractables over a wide
scope of the filtration, chromatography and single
use portfolio
• Provides seamless access to most updated
documents anytime anywhere saving valuable
customer resources
Online 24/7 access through
Emprove® suite
Certificates & custom extractables
reports
Customer extractables and
leachables studies
Patient safety evaluation (risk
assessment)
Consultancy and risk mitigation
1
3
4
5
6
2
Operational Excellence dossier
(standard extractables report aligned
with BPOG & USP 665)
Challenges Using Multiple Single-Use Systems49

50. More than Extractables Data
Emprove® Program and BioReliance® Validation Services
50
BioReliance® Validation Services
offers…
Assistance in:
 Analyzing data of the Operational Excellence
dossier and conducting risk assessment
 Preparing product- and process-specific
extractables reports
 Designing and executing custom extractables and
leachables studies
 Determining if the resulting drug product presents
any toxicological risks
 Recommending mitigation steps if necessary
 Other services: complete Validation of sterilizing
filters & Mobius® Single use technology used in
critical process steps
Online 24/7 access through
Emprove® suite
Certificates & custom extractables
reports
Customer extractables and
leachables studies
Patient safety evaluation (risk
assessment)
Consultancy and risk mitigation
1
3
4
5
6
2
Operational Excellence dossier
(standard extractables report aligned
with BPOG & USP 665)
Challenges Using Multiple Single-Use Systems50

51. Challenges Using Multiple Single-Use Systems
Component Selection
 Choose the appropriate materials for
the process
 Ensure functionality and compatibility.
TFF processing Step
 UF/DF provides clearance of
extractables and leachables from the
previous step
 Reduces risk to the patient
51

52. Clinical Use
 Short term use and low volume dosages
lower the risk.
Downstream Processing
 Highest risk to the patient
 No dilution of potential leachables
 Consider flushing to reduce risk
Leachables and Patient Safety
 Ensuring the quantity of leachables is below
the concern levels
Challenges Using Multiple Single-Use Systems
Risk Assessment
52

53. jessica.shea@milliporesigma.com
https://www.linkedin.com/feed/upd
ate/urn:li:activity:65170940416943
26785
Jessica Shea
Thank You
© 2019 Merck KGaA, Darmstadt, Germany and/or its affiliates. All Rights Reserved. Merck, the vibrant M, and BioReliance
are trademarks of Merck KGaA, Darmstadt, Germany or its affiliates. All other trademarks are the property of their
respective owners.
Detailed information on trademarks is available via publicly accessible resources.