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1. Extractables and
Leachables for Medical
Devices
Tim Hulme and Keith Scott

2. Chemical Analysis: Where we work
Support for Pharmaceutical, Biopharmaceutical and Medical Devices
Supporting clients across
the globe from
laboratories in
Shropshire, UK and
Akron, OH
Chemical analysis
projects in over 40
countries since 2015
60% of the top 20
pharmaceutical
companies globally
supported in past
2-3 years
Chemical analysis capabilities complemented by expertise in:
Materials, Drug Delivery Device Function, Packaging and Distribution
Page 2 | © Smithers, 2021

3. Extractables and Leachables for
Medical Devices
Course Outline
• Introduction to Extractables and Leachables
• Regulatory
• Chemical characterisation
• Experimental

4. Your Instructors
Page 4 | © Smithers, 2021

5. Tim Hulme
Principal Project Manager
Tim is part of Smithers’ Extractables and Leachables (E&L) team at Shawbury in the
UK. He has been working at Smithers for 12 years and with E&L for about 10 years.
Tim has over 35 years’ experience in chemical analysis, both with classical
techniques and a wide variety of instrumental techniques. Before working at
Smithers, Tim worked for ConvaTec (wound care/medical devices company) as an
analytical scientist and before that at Glaxo Group Research (pharmaceutical
company), also as an analytical scientist
Qualifications
Tim has an MSc in Pharmaceutical Analysis. Tim is a Chartered Chemist (CChem),
Chartered Scientist (CSci), a Member of the Royal Society of Chemistry and a
Fellow of the Royal Microscopical Society.
Page 5 | © Smithers, 2021

6. Keith Scott
Senior Project Manager
Keith is part of Smithers’ Extractables and Leachables (E&L) and Chemical Analysis
consultancy team in the UK. He has been working at Smithers for 37 years and with
E&L for over 15 years.
Keith began being involved in managing E&L studies in 2003. In 2007 he became a
commercial manager responsible for the Medical and Pharmaceutical sector,
developing profitable relationships with new and existing clients to retain business
and expand sales.
In January 2018 he took up a Senior Project Manager role in the Extractables and
Leachables (E&L) and Chemical Analysis consultancy team providing technical
leadership for analytical testing services to external and internal clients and acting
as subject matter expert on the design and delivery of technical packages of work.
Qualifications
Keith has a BSc in Chemistry, and an MPhil (Lancaster).
Page 6 | © Smithers, 2021

7. Questions and Discussion
• Please send through any questions you have on the Q&A tab.
• After each section we will review the questions.
• We can open up your microphone if you have any comments
or queries at the end of each section. “Raise your hand” if you
want to contribute.

8. Introduction to
Extractables and Leachables

9. 1862
President Lincoln appoints a chemist, Charles M. Wetherill, to serve in the new Department of Agriculture. This was the
beginning of the Bureau of Chemistry, the predecessor of the Food and Drug Administration.
1906
The original Food and Drugs Act is passed by Congress on June 30 and signed by President Theodore Roosevelt. It prohibits interstate
commerce in misbranded and adulterated foods, drinks and drugs.
The Meat Inspection Act is passed the same day.
Shocking disclosures of insanitary conditions in meat-packing plants, the use of poisonous preservatives and dyes in foods, and cure-all
claims for worthless and dangerous patent medicines were the major problems leading to the enactment of these laws.
1927
The Bureau of Chemistry is reorganized into two separate entities. Regulatory functions are located in the Food, Drug, and Insecticide
Administration.
9
Some History

10. 1937
Elixir of Sulfanilamide, containing the poisonous solvent diethylene glycol, kills 107 persons, many of whom are children,
dramatizing the need to establish drug safety before marketing and to enact the pending food and drug law.
1938
The Federal Food, Drug, and Cosmetic (FDC) Act of 1938 is passed by Congress.
1962
Thalidomide, a new sleeping pill, is found to have caused birth defects in thousands of babies born in western Europe. News reports on the
role of Dr. Frances Kelsey, FDA medical officer, in keeping the drug off the U.S. market, arouse public support for stronger drug regulation.
1979
GLP was instituted in US following cases of fraud generated by toxicology labs in data submitted to the FDA by pharmaceutical
companies. FDA published Proposed Regulations on GLP in 1976, with the establishment of the Final Rule in June 1979 (21
CFR 58).
10
More History

11. EPREX – Anemia Treatment
• EPREX prefilled used to treat anemia
• Increased incidence of “Pure Red Cell Aplasia”
11

12. Red Cell Aplasia
12

13. Medical Devices?
Spinal fusion stimulators
13
• In April 2017 33 implantable spinal fusion stimulators were recalled— a device inserted into a
patient’s back during spinal fusion surgery to increase the possibility of permanently connecting two
or more bones.
• During its “routine monitoring procedure”, the US company found that two different spinal fusion
products contained high levels of potentially harmful chemicals that may be toxic to surrounding
tissues and organs in a patient’s body.
• The FDA said using these products may lead to several serious adverse health consequences —
including chronic infections, long-term hospitalisation caused by additional surgical procedures,
paralysis, and death.
• An urgent medical device removal notification was sent to all affected customers, advising them to
quarantine the products in question until the company could send a sales representative to remove
them from the hospital.

14. What are Medical Devices?
14
Center for Devices and Radiological Health (CDRH) – part of FDA
An instrument, apparatus, implement, machine, contrivance, implant or in vitro reagent, or other
similar or related article, including any component, part, or accessory, which is:
• Recognized in the official National Formulary, or the United States Pharmacopoeia, or any
supplement to them,
• Intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment,
or prevention of disease, in man or other animals, or
• Intended to affect the structure or any function of the body of man or other animals, and which does
not achieve its primary intended purposes through chemical action within or on the body of man or
other animals and which is not dependent upon being metabolized for the achievement of its primary
intended purposes.

15. What are Medical Devices?
15
EU Directive
Any instrument, apparatus, appliance, software, material or other article, whether used alone or in
combination, intended by the manufacturer to be used for human beings for the purpose of:
• Diagnosis, prevention, monitoring, treatment or alleviation of disease,
• Diagnosis, monitoring, treatment, alleviation of or compensation for an injury or handicap,
• Investigation, replacement or modification of the anatomy or of a physiological process,
• Control of conception,
and which does not achieve its principal intended action in or on the human body by pharmacological,
immunological or metabolic means, but which may be assisted in its function by such means.

16. Combination Devices?
16
• A combination product is defined as two or more regulated products such as drug-
medical device, biologic-medical device, drug-biologic, vaccine-medical device, or
drug-medical- device-biologic.
• Therefore, due to the multiple modalities involved, more than one regulatory agency
office often reviews the sponsor’s submission.
• Center for Drug Evaluation and Research (CDER)
• Center for Biologics Evaluation (CBER)
• Center for Devices and Radiological Health (CDRH)
• A DPI (Inbrija) was assessed as a combination device – collaboration between CDER
and CDHR

17. Why extractables testing?
2016 CDRH Biocompatibility Guidance - Section VII Chemical
Assessment
• “Inherent in the review of medical devices is an understanding of the body’s entire exposure to the
medical device, including all chemical entities contained within the device.”
• “chemical analyses can be used to assess the toxicological risk of the chemicals that elute from
devices . For example, chemical analysis using exhaustive extraction techniques (per ISO 10993 12)
can also be helpful to evaluate long term toxicity endpoints such as potential carcinogens…In
addition, the outcomes of chemical analyses are often sensitive to the parameters of the test.
Extraction solvents should be selected to optimize compatibility with the device materials”
17

18. Medical Device Materials
•Synthetic polymers (plastics)
•Metals and Alloys
•Ceramics
18

19. Why are plastics used in medical devices?
•Modern healthcare would not be possible without the
use of plastic materials.
•Applications include: MRI machines, tubing, disposable
syringes, intravenous blood bags and heart valves
•Compared to glass, metals and ceramics, plastics offer:
•lighter weight, better biocompatibility and lower cost
19

20. What plastics are used in medical devices?
• Polycarbonates (PC)
• Polypropylene (PP)
• Polyethylene (PE)
• Polyvinyl chloride (PVC)
• Polystyrene (PS)
• Nylon (PA)
20
• Polyethylene terephthalate (PET)
• Polyimide (PI)
• Acrylonitrile butadiene (ABS)
• Polyetheretherketone (PEEK)
• Polyurethane (PU)

21. Public Perception
21

22. Introduction to Extractables and Leachables
22
Extractables – definition
Substances that are released from a medical device or material of
construction when it is extracted using laboratory extraction conditions
and solvents.
(May be assessed using exaggerated, exhaustive or simulation conditions.)
Leachables - definition
Substances that are released from a medical device or materials during its
clinical use.

23. The component supply-chain
Material Manufacturer
N-3
Device
Component
Fabricator
N-2
Device
Manufacturer
N-1
23

24. Polymer supply-chain
24

25. Component fabrication – injection molding
Injection Molding machines
Images provided by Bespak Europe
25

26. Tertiary/ancillary packaging systems
Environmental
leachables/migrants?
26

27. What are some potential sources for leachables?
Extractables/leachables are derived from a variety of sources and exhibit extensive chemical diversity.
Primary sources of include:
• Chemical additives in individual elastomeric/polymeric device components and raw materials,
including contaminants in these additives
• Monomers and higher molecular weight oligomers derived from incomplete polymerization
• Secondary and tertiary packaging component migrants, such as inks, label adhesives and volatiles
from cardboard shipping containers, plastic storage bags, and wooden pallets
• Surface residues, such as heavy oils and degreasing agents on metal canisters and containers
• Chemical substances on the surfaces of component fabrication machinery or other drug product
manufacturing systems, such as mold release agents, antistatic and antislip agents
• Chemical additives, monomers/oligomers, contaminants, etc. in various parts of component
fabrication machinery or other drug product manufacturing systems
27

28. Examples of chemical additives
CH
H
H
CH3
CH3
HOOC
CH3
CH3
O P
O
O
28

29. Mechanical additives
• Nucleating agents
• processing properties, lower temperatures, etc.
• Cross-linkers
• mechanical strength
• 3-dimensional structure
• Fillers
• typically inorganics such as clay, heavy metal oxides or carbon black
• Plasticizers
• impart flexibility and resistance to cracking
• natural and synthetic oils, phthalates
29

30. Structures of mechanical additives
O
O O
O
O
O
O
O
S
S
S
S
S
S S
S
30

31. Chemical additives
• Antioxidants
• polymers have high oxidation potential (lots of hydrogen)
• hindered phenols, sacrificial hindered phosphines
• flame retardants
• Clarifiers
• UV stabilizers/photoinitiators
• prevent color changes
• inhibit oxidation
• label ink fixation
31

32. Structures of chemical additives
OH
O
H
O
O
P
O
O
O
32

33. Electrical additives
• Anti-static surface modifiers
• To dissipate surface charges, aliphatic amines, amides, quaternary amines, polyols
• Antislip agents
33

34. Structures of electrical additives
N
OH
OH
ONa
S
O
O
O
NH2
O
O N
HO
OH
34

35. Additive chemistry
O P
O
O O P
O
O
O
Hydroperoxide
(ROOH)
Irgafos 168
35

36. Reaction of hindered phenols with singlet oxygen
OH
CH3
OH
CH3
C(CH3)3
(CH3)3C
(CH3)3C
OH
CH3
C(CH3)3
O
C
H3 OOH
(CH3)3C
O
C
H3 OOH
C(CH3)3
O
OOH
C
H3
(CH3)3C C(CH3)3
OH OH
CH2OCH3
CH3
(CH3)3C C(CH3)3
OH
O
C
H3 OOH CH2OCH3
(CH3)3C C(CH3)3
OH
CH2OCH3
OH
CH2OCH3
(CH3)3C C(CH3)3
OH
O
C
H3 OH CH3
(CH3)3C
O
C
H3 OH
C(CH3)3
O
C
H3 OH
1O2
36

37. What’s in a name?
5 . 0 0 1 0 . 0 0 1 5 . 0 0 2 0 . 0 0 2 5 . 0 0 3 0 . 0 0
0
2 0 0 0 0 0
4 0 0 0 0 0
6 0 0 0 0 0
8 0 0 0 0 0
1 0 0 0 0 0 0
1 2 0 0 0 0 0
1 4 0 0 0 0 0
1 6 0 0 0 0 0
1 8 0 0 0 0 0
2 0 0 0 0 0 0
2 2 0 0 0 0 0
2 4 0 0 0 0 0
2 6 0 0 0 0 0
2 8 0 0 0 0 0
3 0 0 0 0 0 0
3 2 0 0 0 0 0
T i m e - - >
A b u n d a n c e
T I C : 0 8 1 9 0 3 0 5 . D
Abietic acid
37

38. Don’t forget elementals
5 . 0 0 1 0 . 0 0 1 5 . 0 0 2 0 . 0 0 2 5 . 0 0 3 0 . 0 0
0
2 0 0 0 0 0
4 0 0 0 0 0
6 0 0 0 0 0
8 0 0 0 0 0
1 0 0 0 0 0 0
1 2 0 0 0 0 0
1 4 0 0 0 0 0
1 6 0 0 0 0 0
1 8 0 0 0 0 0
2 0 0 0 0 0 0
2 2 0 0 0 0 0
2 4 0 0 0 0 0
2 6 0 0 0 0 0
2 8 0 0 0 0 0
3 0 0 0 0 0 0
3 2 0 0 0 0 0
T i m e - - >
A b u n d a n c e
T I C : 0 8 1 9 0 3 0 5 . D
38

39. Medical Device Extractables and Leachables
• Information about the potential for harmful substances to be
present in medical devices and so present a possible risk to
patient health needs to be assessed.
• Regulatory requirement.
• Plastics used in medical devices contain many substances with
widely differing chemical properties which may give a risk to
patient health.
• Testing may be required to assesses these substances.
39

40. Questions and discussion
40