Rubber Components Selection for Optimal Drug Packaging Simon

Rubber components selection for optimal drug packaging

Simon Kervyn Manager Material Development March 11th, 2019 Agenda

1. Composition of pharmaceutical rubber

2. Extractables and leachables from rubber

3. Expectations of extractables information sharing

4. Different rubber compositions to steer properties

5. Compound for gamma sterilisation

2 Rubber components selection for optimal drug packaging, March 11th, 2019 / © Datwyler, www.datwyler.com Stability and strength of a large industrial group

Swiss origin, established in 1915

Revenues of approx. CHF 1,200 million

Focused industrial player with two divisions: Sealing Solutions & Technical Components

Listed on the SIX Swiss Exchange

3 Rubber components selection for optimal drug packaging, March 11th, 2019 / © Datwyler, www.datwyler.com Multi-industry knowhow

4 Rubber components selection for optimal drug packaging, March 11th, 2019 / © Datwyler, www.datwyler.com Datwyler Sealing Solutions – Health Care offer overview

High quality components and closures for injectable drugs

Rubber components selection for optimal drug packaging, March 11th, 2019 / © Datwyler, www.datwyler.com Datwyler Sealing Solutions – Health Care offer overview

High quality components and closures for injectable drugs Vials

Rubber components selection for optimal drug packaging, March 11th, 2019 / © Datwyler, www.datwyler.com Datwyler Sealing Solutions – Health Care offer overview

High quality components and closures for injectable drugs Vials Syringes and cartridges

Rubber components selection for optimal drug packaging, March 11th, 2019 / © Datwyler, www.datwyler.com 1. Composition of Pharmaceutical Rubber

8 Rubber components selection for optimal drug packaging, March 11th, 2019 / © Datwyler, www.datwyler.com Types of elastomeric closures

– Compounded material of: 1. Elastomer

2. Filler

3. Cure system 4. Pigment 5. Other ingredients

Rubber components selection for optimal drug packaging, March 11th, 2019 / © Datwyler, www.datwyler.com Composition – 1. Elastomers

– Halobutyl (BromoButyl, ChloroButyl) – Natural rubber / Polyisoprene – Cleanest curing system – Natural rubber : latex allergy discussions – Lowest permeability – Historically the oldest elastomer type – High resistance to ageing – Need complex curing systems – Good elastic properties – Regular butyl still on the market, and also – Polyisoprene (synthetic) replaces Natural newer types like BIMS (Brominated rubber isobutylene para-methylstyrene)

– Nitrile rubber – Typically used for mineral oil based drugs

– Silicone rubber – High permeability – Typically not used for parenteral applications – SBR (styrene-butadiene rubber) – Intermediate permeability – EPDM rubber – Typically used for pre-assembled EtO – For niche applications sterilized components (e.g. Needle Shields)

Rubber components selection for optimal drug packaging, March 11th, 2019 / © Datwyler, www.datwyler.com Composition – 2. Fillers

• Fillers give mechanical strength (stiffness) to a rubber • Attributes physical properties to a rubber compound • More filler = Harder compound Better for gliding profile plungers Better against stickiness in bulk Worse for stopper piercing (coring!)

• Inorganic fillers (‘white compounds’) – Aluminum silicate (clay) – Magnesium silicate (talc) – [Calcium carbonate] (calc)

• Carbon black (‘black compounds’) – Undesired for cleanliness reasons – May be associated with PNA’s

Rubber components selection for optimal drug packaging, March 11th, 2019 / © Datwyler, www.datwyler.com Composition – 3. Curing agents

• Cure system: – Crosslinking agent – Activator : gives the onset of vulcanization – Accelerator : speeds up the vulcanization • Easily extractable organic molecules such as thiurams, sulfonamides, thiazoles, ...

• Modern cure systems – Aim at giving little extractables Sx

• Historic cure systems – Use easily extractable organic accelerators

Rubber components selection for optimal drug packaging, March 11th, 2019 / © Datwyler, www.datwyler.com Composition – 4. Color pigments

• Inorganic pigments – Grey colors: – Titanium dioxide  White – Traces of carbon black  Black – Red colors: – Oxides of iron  Red

• Organic pigments – Avoided in modern compounds

Rubber components selection for optimal drug packaging, March 11th, 2019 / © Datwyler, www.datwyler.com Composition – 5. Other ingredients

• Halobutyl polymer stabilizers – Calcium stearate – Epoxydized soybean oil (ESBO) • Anti-oxidants – Already present in halobutyl elastomer – Hindered phenol type anti-oxydants – Additionally added to improve environmental stability (ageing) • Plasticizer, Waxes, Oils – High polymeric weight plasticizers, Paraffinic oil – To tune a formulation (e.g. reduce coring) • Processing aids

Rubber components selection for optimal drug packaging, March 11th, 2019 / © Datwyler, www.datwyler.com 2. Extractables and leachables from rubber

15 Rubber components selection for optimal drug packaging, March 11th, 2019 / © Datwyler, www.datwyler.com E&L of elastomeric closures – Extractables profiles

– Too many ingredients should Monomer (Isobutylene) be avoided : negative impact Rubber Oligomers (C13, C14) on E-profile Calcium Stearate Fatty acids (Stearic, Palmitic)  “what you don’t put in, Elastomer can’t come out” Anti-Oxidant (BHT, Irganox 1010) Br-/Cl- ions Residual solvent Filler Metallic ions (Mg, Al, Si, Ca) Sulphur, Sulphur derivates Phenol formaldehyde resin Cure System Rubber Metallic ions (Zn, Mg) Peroxyde Pigment Metallic ions (Ti, Fe) Low molecular fragments (Plasticizers) Additives Paraffinic oil, Waxes Anti-oxidants Impurities (Phenol derivates,Alkanes) Unknowns Unknown additives (AO, inhibitors) And many more… 

Rubber components selection for optimal drug packaging, March 11th, 2019 / © Datwyler, www.datwyler.com Significant improvements in recipes and raw material selection

Curing Color Fillers Additives systems Pigments

Sterically High Inorganic Silicates hindered molecular (TiO2, C, (Talc, Clay) curing weight, Fe3O4) agents purified

No Carbon No doubtful No organic No simple Black, accelerators colorants waxes, oils No Calc

17 Rubber components selection for optimal drug packaging, March 11th, 2019 / © Datwyler, www.datwyler.com E profile : OLD vs MODERN

Difference in Extractable Results for an OLD vs MODERN rubber (IPA Extract; GC/MS analysis)

Internal Standard “OLD” RUBBER

“MODERN” RUBBER

Rubber components selection for optimal drug packaging, March 11th, 2019 / © Datwyler, www.datwyler.com E profile : MODERN vs MODERN COATED

Difference in Extractable Results for a Coated vs Uncoated rubber, for the same rubber grade (IPA Extract; GC/MS analysis)

Internal Standard

COATED “MODERN” RUBBER

UNCOATED “MODERN” RUBBER

Rubber components selection for optimal drug packaging, March 11th, 2019 / © Datwyler, www.datwyler.com Extractable profile over time

– Extractables study is performed on the same batch at manufacturing date (0 year), after 1 year, 2 years and [ongoing:7 years]

• Negative trend in volatiles (Anti-Oxidant, Oligomers)

• No trend in non-volatiles (Fatty acid)

20 Rubber components selection for optimal drug packaging, March 11th, 2019 / © Datwyler, www.datwyler.com 3. Expectations of Extractables information sharing

21 Rubber components selection for optimal drug packaging, March 11th, 2019 / © Datwyler, www.datwyler.com Information transfer

Sharing Pharmacopeial data

E-documentation from supplier

NDA

L-study set up : Drug details drug company & E-doc. from supplier NDA

– Note : Rubber compositions are extremely sensitive information to closure manufacturers – Rubber compound recipes are in general not patented – ‘Trust <-> control’

22 Rubber components selection for optimal drug packaging, March 11th, 2019 / © Datwyler, www.datwyler.com Extractables documentation throughout the years

Pharmacopeial Potential Potential Controlled testing Extractables list Extractables study Extractables study

Theoretical list

+ actual study + semi-quantitative

+ screening + extra extract. media + gamma (if applicable)

23 Rubber components selection for optimal drug packaging, March 11th, 2019 / © Datwyler, www.datwyler.com Nelson Labs – Datwyler Partnership … more than a decade

bringing analytical and rubber compounding experts together enabling the best services

• A premium service to the pharmaceutical packaging industry enabling a fast and safe regulatory approval. • Common R&D programs show the ambition to continue offering the best-in-class knowledge and expertise in pharmaceutical elastomer formulations. • Enjoy a discount for all your analytical study work.

24 Rubber components selection for optimal drug packaging, March 11th, 2019 / © Datwyler, www.datwyler.com 4. Different rubber formulations to steer properties

25 Rubber components selection for optimal drug packaging, March 11th, 2019 / © Datwyler, www.datwyler.com Smart selection of ingredients can tune a rubber compound

E.g. recipe based on E.g. blend of hydrophobic E.g. MgO replaces halobutyl and SBR ingredients will show ZnO to avoid Zn-ion can tune the better E-profile with extraction permeability aqueous drugs.

E.g. low water E.g. Omniflex coated E.g. soft compound absorption rubber for for multi piercings compounds for lyo sensitive/large with needle applications molecule drugs

26 Rubber components selection for optimal drug packaging, March 11th, 2019 / © Datwyler, www.datwyler.com Smart selection of ingredients can tune a rubber compound

E.g. recipe based on E.g. blend of hydrophobic E.g. MgO replaces halobutyl and SBR ingredients will show ZnO to avoid Zn-ion can tune the better E-profile with extraction permeability aqueous drugs.

E.g. low water E.g. Omniflex coated E.g. soft compound absorption rubber for for multi piercings compounds for lyo sensitive/large with needle applications molecule drugs

27 Rubber components selection for optimal drug packaging, March 11th, 2019 / © Datwyler, www.datwyler.com blend of halobutyl and SBR can tune the permeability

Ethylene oxide or steam sterilization :

NS or TC material must be permeable to gas (EtO or steam) !!

28 Rubber components selection for optimal drug packaging, March 11th, 2019 / © Datwyler, www.datwyler.com Smart selection of ingredients can tune a rubber compound

E.g. recipe based on E.g. blend of hydrophobic E.g. MgO replaces halobutyl and SBR ingredients will show ZnO to avoid Zn-ion can tune the better E-profile with extraction permeability aqueous drugs.

E.g. low water E.g. Omniflex coated E.g. soft compound absorption rubber for for multi piercings compounds for lyo sensitive/large with needle applications molecule drugs

29 Rubber components selection for optimal drug packaging, March 11th, 2019 / © Datwyler, www.datwyler.com Omniflex coated rubber for sensitive/large molecule drugs

– Key attribute : barrier effect ! – Simplified extractables profile – Improved compatibility with drugs/excipients

30 Rubber components selection for optimal drug packaging, March 11th, 2019 / © Datwyler, www.datwyler.com Smart selection of ingredients can tune a rubber compound

E.g. recipe based on E.g. blend of hydrophobic E.g. MgO replaces halobutyl and SBR ingredients will show ZnO to avoid Zn-ion can tune the better E-profile with extraction permeability aqueous drugs.

E.g. low water E.g. Omniflex coated E.g. soft compound absorption rubber for for multi piercings compounds for lyo sensitive/large with needle applications molecule drugs

31 Rubber components selection for optimal drug packaging, March 11th, 2019 / © Datwyler, www.datwyler.com Low water absorption compounds for lyo applications

Figure4: Weight decrease in mg/gram stopper material by drying at 110°C after a steam sterilisation process (starting from delivery state condition)

8,00 FM460/0Low moisture 7,00 FM140/1Std Chloro 6,00 FM457/0Std Bromo FM259/0Coated Bromo OF+ 5,00 4,00

3,00

material 2,00 1,00

0,00 -1,00

-2,00 t = 0 Steam + 1 hr +2 hrs +5 hrs +7 hours +12 hrs +24 hrs mg weight increase / decrease in mg/gram stopper stopper mg/gram decrease / in weightincrease mg sterilised 110°C 110°C 110°C 110°C 110°C 110°C

32 Rubber components selection for optimal drug packaging, March 11th, 2019 / © Datwyler, www.datwyler.com 5. Compound for gamma sterilization: FM457

33 Rubber components selection for optimal drug packaging, March 11th, 2019 / © Datwyler, www.datwyler.com Elastomers throughout the years

Exxpro Coated

FM457 OMNIFLEX3G

Natural Butyl Halobutyl New halobutyl FM460 FM257 FM140 Coated

OCP

FM480 FM703

1950’s 1970’s 1990’s 2008 2018

Gamma sterilized Ready to Use (RTU) components

34 Rubber components selection for optimal drug packaging, March 11th, 2019 / © Datwyler, www.datwyler.com Significant improvements in recipes and raw material selection

– Regular halobutyl still on the market, and also newer types like BIMS (Brominated isobutylene Elastomers para-methylstyrene)

HALOBUTYL STAYS THE KEY ELASTOMER

Cleanest curing system Lowest permeability High resistance to ageing No double bonds along the polymer chain.

35 Rubber components selection for optimal drug packaging, March 11th, 2019 / © Datwyler, www.datwyler.com Physical properties

The physical properties are similar before and after irradiation.

36 Rubber components selection for optimal drug packaging, March 11th, 2019 / © Datwyler, www.datwyler.com Physical properties

± 5 ± 5 ± 5

Measure of the elasticity of the rubber Measure of the capability to reshape after deformation The physical properties are similar before and after irradiation.

37 Rubber components selection for optimal drug packaging, March 11th, 2019 / © Datwyler, www.datwyler.com Functional properties

Penetrability Self-sealing

Fragmentation Limit: 10 N Limit: no leak

The functional properties are similar before and after irradiation.

Limit: 5 fragments

38 Rubber components selection for optimal drug packaging, March 11th, 2019 / © Datwyler, www.datwyler.com Chemical properties

Gamma sterilized compounds are compatible for contact with WFI after irradiation.

39 Rubber components selection for optimal drug packaging, March 11th, 2019 / © Datwyler, www.datwyler.com E profile : OLD vs MODERN

Difference in Extractable Results for an OLD vs MODERN rubber (IPA Extract; GC/MS analysis)

Internal Standard “OLD” RUBBER

“MODERN” RUBBER

Rubber components selection for optimal drug packaging, March 11th, 2019 / © Datwyler, www.datwyler.com E profile : MODERN vs MODERN COATED

Difference in Extractable Results for a Coated vs Uncoated rubber, for the same rubber grade (IPA Extract; GC/MS analysis)

Internal Standard

COATED “MODERN” RUBBER

UNCOATED “MODERN” RUBBER

1. Extractables can be complex and depends on the compound.

“What we don’t put in cannot come out”

2. The composition of the rubber is never shared but detailed extractables reports are available.

3. Rubber properties can be steered to suit for a specific application.

4. Compounds specifically adapted for gamma sterilization are available.