Best Practices for OINDP Pharmaceutical Development Programs Leachables and Extractables

1
Best Practices for OINDP Pharmaceutical
Development Programs Leachables and
Extractables II. OINDP Container Closure
Systems PQRI Leachables Extractables Working
Group PQRI Training Course September 20-21,
2006 Washington, DC
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Container Closure System Components

• Primary Packaging Components, which are or may be
  in direct contact with the dosage form. These
  include containers (e.g., ampules, vials,
  bottles), container liners, closures (e.g., screw
  caps, stoppers, metering valves), closure liners,
  stopper overseals, container inner seals,
  administration ports, overwraps, etc.
• Secondary Packaging Components, which are not or
  will not be in direct contact with the dosage
  form. These include container labels,
  administration accessories, shipping containers,
  etc. Note that even though secondary packaging
  components are not in direct contact with the
  drug product, they may still contribute
  leachables under certain conditions.

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Critical Components

• Critical components of an OINDP container
  closure system are defined as those that contact
  either the patient or the formulation, components
  that affect the mechanics of the overall
  performance of the device, or any necessary
  secondary protective packaging.

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MDI Critical Components

• Dose metering valve
• Metering chamber
• Stem(s)
• Seals/gaskets
• Sealing rings
• Canister
• Coated?
• Mouthpiece/actuator

MDI Schematic Provided by Bespak Europe
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OINDP Container Closure System Components
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DPI
Images provided by Bespak Europe
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DPI Critical Components ARCHaler
Drug reservoir
Air in
Dose metering arc
Note that the ARCHaler is a complete
fabrication. Any resemblance to any existing
drug product or container closure system is
purely coincidental.
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What are some potential sources for leachables
and extractables?

• Chemical additives present in individual
  elastomeric/polymeric container closure system
  components, including contaminants in such
  additives (e.g. PAHs and N-nitrosamines).
• Monomers and higher molecular weight oligomers
  derived from incomplete polymerization reactions.
• Migrants from secondary packaging components,
  such as inks and label adhesives.
• Surface residues, such as heavy oils and
  degreasing agents on the surfaces of metal
  canisters and containers.
• Chemical additives on the surfaces of container
  closure system component fabrication machinery,
  such as mould release agents, antistatic and
  antislip agents, etc.
• Chemical entities from the storage environment
  (i.e., very secondary packaging components),
  such as volatiles from cardboard shipping
  containers or plastic storage bags.

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Examples of Chemical Additives
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Whats in a name?
Abietic acid
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Additive Chemistry
Hydroperoxide (ROOH)
Irgafos 168
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Reaction of Hindered Phenol with Singlet Oxygen
1O2
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Information Required

• The elastomeric/polymeric or other material
  constituting the principal structure of the
  component (e.g., High Density Polyethylene,
  Ethylene-Propylene-Diene rubber, stainless steel,
  etc.)
• The polymerization/cross-linking/curing process,
  or processes, for the component base polymer,
  including any chemical additives employed.
• The compounding/fabrication process, or
  processes, including any additives designed to
  assist in compounding/fabrication.
• All individual chemical additives/ingredients in
  the component, including the composition and
  chemistry of each individual additive.
• Any cleaning/washing processes for finished
  components, including knowledge of cleaning,
  washing, or other agents.
• The storage/shipping environment for both
  components and drug product, if the potential for
  environmental leaching exists.

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Raw Materials Supply Chain
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Raw Materials - Supply Chain
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Component Fabrication
Images provided by Bespak Europe
Moulding machines
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Deep Drawing Process
deep-drawing tool
metal rolls
Images provided by Presspart
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Deep Drawing Process
finished canisters
Images provided by Presspart
degreasing process
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Rubber Formulation A (Sulfur Cured)

• Ingredient
• CALCINED CLAY 8.96
• BLANC FIXE (barium sulfate) 25.80
• CREPE 38.22
• BROWN SUB MB 16.84
• 1722 MB 2.11
• ZINC OXIDE 4.04
• 2, 2 METHYLENE-BIS (6-TERTIARY BUTYL-4-ETHYL
  PHENOL) 0.56
• COUMARONE-INDENE RESIN 1.12
• PARAFFIN 1.12
• TETRAMETHYLTHIURAM MONOSULFIDE 0.11
• ZINC 2-MERCAPTOBENZOTHIAZOLE 0.29
• SULFUR 0.84

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What do we know?

• Carbon black is a known source of PAHs and has
  also been shown to be involved in N-nitrosamine
  formation in rubber (special cases).
• Thiurams are known precursors of N-nitrosamines.
• 2-Mercaptobenzothiazole is a known special
  case.
• Paraffin and Coumarone-indene resin are natural
  product materials and are likely complex mixtures
  of related structures.
• Individual additives are likely GC-able.

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Sulfur Cured Rubber Extractables Profile by
GC/MS
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Polypropylene Formulation

• Ingredient wt
• Primary Stabilizers
• Tetrakis (methylene(3,5-di-t-butyl-
• 4-hydroxyhydrocinnamate)) methane
• Irganox 1010 (Ciba) 0.08 wt
• Anox 20 (Great Lakes)
• Secondary Stabilizers
• Bis(2,4-di-t-butylphenyl)pentaerythritol
  diphosphite
• Ultranox 626 (GE) 0.05 wt

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Polypropylene Formulation

• Ingredient
• Corrosion Inhibitors
• Calcium Stearate 114-50 (Ferro) 0.03 - 0.4 wt
• Antistatic
• Vegetable oil derived
• 90 alpha monoglycerides (soybean)
• Pationic 901 (Patco) 0.3 wt
• Dimodan HS-KA (Danisco)
• Nucleating Agents
• 3,4 -dimethyl dibenzylidene sorbitol
• Millad 3988 (Milliken) 0.2 wt

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What do we know?

• Polypropylene is known to contain many soluble
  oligomers.
• Individual additives will likely require analysis
  by HPLC based methods.
• Individual additives could be both chemically
  complex and have complex degradation chemistries.
• No reason to suspect the presence of special
  cases

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Polypropylene Extractables Profile by LC/UV/MS
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Polypropylene Extractables Profile by GC/MS
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Rubber Formulation B (Peroxide Cured)

• Ingredient
• IMSIL A25 (silicone dioxide) 24.01
• MISTRON CYPRUBOND (magnesium silicate) 19.21
• BROMOBUTYL 2030 38.42
• VISTALON 404 (ethylene propylene copolymer) 9.61
• WHITE OIL 2 1.44
• 420 BLUE MB 0.12
• TITANIUM DIOXIDE 1.68
• PARAFFIN 0.96
• MAGNESIUM OXIDE 0.60
• STEARIC ACID 0.48
• POLYETHYLENE WAX 1.44
• P-800 2.03

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Rubber Formulation B (Peroxide Cured)

• Ingredient
• CONTENTS OF 420 BLUE MB
• SBR-3
• PIGMENT BLUE 15
• ANOX 9
• CONTENTS OF P-800
• 2,5 DI METHYL-2, 5-DI (T-BUTYL PEROXIDE)
  HEXANE 68.00
• PRECIPITATED SILICA 32.00

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What do we know?

• Registry Number 78-63-7
• Formula C16 H34 O4
• CA Index Name Peroxide, (1,1,4,4-tetramethyl-1,
  4-butanediyl)bis(1,1-dimethylethyl) (9CI)
• Other Names Peroxide, (1,1,4,4-tetramethyltetra
  methylene)bistert-butyl (6CI,8CI)
  (1,1,4,4-Tetramethyltetramethylene)bis(tert-butyl
  peroxide) 101XL 2,5-Bis(tert-butyldioxy)-2,5-dim
  ethylhexane 2,5-Bis(tert-butylperoxy)-2,5-dimethy
  lhexane 2,5-Di(t-butylperoxy)-2,5-dimethylhexane
  2,5-Di(tert-butylperoxy)-2,5-dimethylhexane
  2,5-Di-tert-butyl-2,5-dimethylhexyl peroxide
  2,5-Dimethyl-2,5-bis(tert-butyldioxy)hexane
  2,5-Dimethyl-2,5-bis(tert-butylperoxy)hexane
  2,5-Dimethyl-2,5-di(t-butylperoxy)hexane
  2,5-Dimethyl-2,5-di(tert-butylperoxy)hexane
  2,5-Dimethyl-di(tert-butyl)peroxyhexane
  2,5-Dimethylhexane-2,5-di-tert-butylperoxide
  2,5-Methyl-2,5-di(tert-butylperoxy)hexane 25B40
  AD AD 40C APO APO 40S C 15 C 15 (peroxide)
  C 8 C 8 (vulcanizer) C 8A CR 05 CT 8 CT 8
  (crosslinking agent) HC 4 HC 4 (peroxide)
  Interox DHBP Interox DHBP 45IC/G Kayahexa AD
  Kayahexa AD 40 Kayahexa AD 40C L 101 LX 101
  Link-Cup DBPH Luperco 101X45 Luperco 101XL
  Luperox 101 Luperox 101XL Luperox 101XL45
  Lupersol 101 Lupersol 101XL Lupersol L 101 NSC
  38203 Perhexa 2.5B Perhexa 2.5B40 Perhexa 25B
  Perhexa 25B40 RC 4 RC 4 (peroxide) RC 450P RC
  8 RPZ 101 Sanperox APO TC 8 TC 8 (catalyst)
  Trigonox 101 Trigonox 101-40D Trigonox
  101-40MD-GR Trigonox 101-50 Trigonox 101E10
  Trigonox 101E5 Trigonox XQ 8 Varox Varox 50
  Varox DBPH Varox DBPH 50 Varox Liquid Yinox
  101
• 2261 references in chemistry database (7 related
  to analytical studies)

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Peroxide Cured Rubber Extractables Profile by
GC/MS
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Summary of PQRI Recommendations

• The pharmaceutical development team should obtain
  all available information on the composition and
  manufacturing/fabrication processes for each
  component type to the extent possible, and
  determine which components are critical,
  before beginning extractables and leachables
  studies on a given OINDP and its associated
  container/closure system components.
• Component formulation should inform component
  selection.
• Risk Assessment should be performed during the
  selection of components and materials.
• Extractables testing, including Controlled
  Extraction Studies and the development and
  validation of Routine extractables testing
  methods, should be accomplished for all critical
  OINDP components.

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Best Practices for OINDP Pharmaceutical
Development Programs Leachables and
Extractables Early Safety Assessment of Potential
Leachables PQRI Leachables Extractables
Working Group Douglas J. Ball, MS, DABT PQRI
Training Course September 20-21, 2006 Washington,
DC
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Early Evaluation Process

• Form a team
• Pharmaceutical Sciences
• Analytical Chemistry
• Toxicology
• Regulatory
• Review Drug Product Specifications
• Determine and agree what are the Critical
  Components of the DP
• Is the actuator trigger a Critical Component?

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Supplier Evaluation

• Is the Supplier willing to share information?
• What type of data will be shared
• Controlled extraction data
• ISO 10993/USP lt87gt, lt88gt reports
• MSDS
• Other toxicology data
• May require confidentiality agreements
• Allow time to get agreements in place
• Can the Supplier provide medical grade materials
• Has the Supplier filed DMFs for the materials?
• Is Supplier willing to provide DMF
• Can non-medical grade material be used
• Can the Supplier provide information on prior use
  of material for approved DP?

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ExampleDrug Product with Delivery System

• An already approved DP is being revamped
• New/Improved delivery system
• Global Registration anticipated
• DP evaluation team formed
• Based on DP configuration, 5 Critical Components
  have been Identified

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Critical Components
Critical Component Contact Supplier Identified Confidentiality Agreement
Ring Seal Patient/Product Yes No
Plunger Insert Product Yes Yes
Plunger Seal Product Yes Yes
Chamber Product Yes Yes
Valve Seal Product Yes In Process
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Ring Seal

• Supplier has limited experience with
  pharmaceutical applications
• Is hesitant to provide detailed information on
  material
• Trade secret may compromise exclusivity of
  material if data shared with DP manufacturer
• Will not disclose
• Chemical/Physical composition
• Safety/Risk information

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Ring Seal - Options

• Pharmaceutical Sciences
• Material is optimal and compatible with the
  delivery system
• Pharm Sci prefers to stay with this material
• Alternatives that were evaluated were not
  considered optimal
• Analytical Sciences
• Will need to conduct a preliminary extraction
  study
• Will have no data from supplier to compare with
• Toxicology
• Evaluate extractable profile for potential red
  flags
• PNAs, nitrosamines, MBT, etc.
• Potential for extensive in silico risk assessment
  of extractable profile

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Ring Seal Issues/Risks

• FTE burn by Analytical Chemistry and Toxicology
• Potential exists that an unacceptable extractable
  is identified
• May need to identify alternative material
• Potential delay in development/registration of DP

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Plunger Insert

• Material is HDPE
• Chemical information supplied
• Physical Properties - Yes
• Composition - Yes
• Toxicology information supplied
• Indirect Food Additive cross reference

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Plunger Insert - Composition
Chemical Component Range (weight )
Ethylene-Octene-1 copolymer CAS 26221-73-8 (Sanctioned under 21 CFR 177.1520) 99.92 99.97
Octadecyl 3,5-di-tert-butyl 4 hydroxyhydrocinnamate CAS 2082-79-3 (Sanctioned under 21 CFR 178.2010) 0.025 0.065
Calcium Stearate CAS 1592-23-0 (Sanctioned under 21 CFR 178.2010) 0.005 0.015
Safe use of polyolefin articles intended for
direct food contact Safe use of
antioxidants/stabilizers in polymers for indirect
food contact
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Plunger Seal

• Material is PP
• Chemical information supplied
• Physical Properties - No
• Composition - Yes
• Toxicology information supplied
• None

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Plunger Seal - Compositon
Chemical Component Content (Weight )
1-propene, polymer with ethene CAS 9010-79-1 94.48
Dimethyl succinate polymer with 4-hydroxy-2,2,6,6-tetramethyl-1-piperidineethanol CAS 65447-77-0 0.2
2,2-oxamido bis-ethyl 3-(3,5-di-tert-butyl-4-hydroxyphenol)propionate CAS 70331-94-1 0.07
di(stearyl) penta-erythritol diphosphite CAS 3806-34-6 0.1
synthetic hydrotalcite CAS 11097-59-9 0.05
calcium stearate CAS 1592-23-0 0.1
LLDPE CAS 25087-34-7 5
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Issues

• No Toxicology data supplied
• Inquire on availability of toxicology data
• ISO/USP test results
• MSDS
• Other
• Limited Chemical Profile
• Additional data requested
• e.g., antioxidants

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Resolution

• Analytical Chemistry
• In-house controlled extraction studies will be
  conducted to obtain comprehensive profile
• Toxicology
• Can perform initial assessment on information
  supplied
• May determine bad actors when additional
  information from controlled extraction studies
  are evaluated

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Initial Risk Assessment (1)

• Obtain chemical structures of each extractant
• Conduct SAR Analysis
• DEREK - Deductive Estimation of Risk from
  Existing Knowledge
• MultiCase
• SAR will typically report genotoxicity,
  mutagenicity, carcinogenicity
• Limited value for reprotoxicology, irritation,
  sensitization

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Risk Assessment (2)

• Perform Literature Search
• Agency for Toxic Substances and Disease Registry
• Chemical Hazards Response Information System
• Material Safety Datasheet Database
• New Jersey Hazardous Substance Fact Sheet
• Micromedex
• National Toxicology Program Testing Information
• National Institute of Occupational Safety and
  Health Registry of Toxic effects of Chemical
  Substances
• Occupational Safety and Health Technical Links to
  Safety and Health Topics
• Toxnet (National Library of Medicine Specialized
  Information Services)
• Registry of Toxic Effects of Chemical Substances
• Center for Drug Evaluation and Research and the
  Integrated Risk Information System
• National Institute of Environmental Health
  Sciences
• Environmental Protection Agency Integrated Risk
  Information System
• Technical Information Exchange Syste

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Risk Assessment (3)

• Evaluate available inforamation
• Assume worst case scenario all extract leaches
  into DP
• Provide initial risk assessment to team
• Identify any/all potential issues
• Make recommendations on further use of material
  based on risk assessment profile

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Conclusions

• Data from suppliers may be limited in scope
• May not provide a total extract profile
• May not provide significant toxicity information
• May require a preliminary extraction study
• Obtain more comprehensive profile of the material
• Risk Assessment is only as good as the data that
  is available