Transcript Slide 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
Container Closure System Components
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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.
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.”
MDI “Critical
Components”
•Dose metering valve
•Metering chamber
•Stem(s)
•Seals/gaskets
•Sealing rings
•Canister
•Coated?
•Mouthpiece/actuator
MDI Schematic Provided by Bespak Europe
OINDP Container Closure System Components
DPI
Images provided by Bespak Europe
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.
What are some potential sources for
leachables and extractables?
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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.
Examples of Chemical Additives
What’s in a name?
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Additive Chemistry
Hydroperoxide
(ROOH)
Irgafos 168
Reaction of Hindered Phenol with Singlet
Oxygen
1O
2
Information Required
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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.
Raw Materials – Supply Chain
Raw Materials - Supply Chain
Component Fabrication
Images provided by Bespak Europe
Moulding machines
Deep Drawing Process
deepdrawing tool
metal rolls
Images provided by Presspart
Deep Drawing Process
finished canisters
Images provided by Presspart
degreasing process
Rubber Formulation A (Sulfur Cured)
Ingredient
%
CALCINED CLAY
BLANC FIXE (barium sulfate)
CREPE
BROWN SUB MB
1722 MB
8.96
25.80
38.22
16.84
2.11
ZINC OXIDE
2, 2’ METHYLENE-BIS (6-TERTIARY BUTYL-4-ETHYL PHENOL)
COUMARONE-INDENE RESIN
PARAFFIN
TETRAMETHYLTHIURAM MONOSULFIDE
ZINC 2-MERCAPTOBENZOTHIAZOLE
SULFUR
4.04
0.56
1.12
1.12
0.11
0.29
0.84
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.
Sulfur Cured Rubber – Extractables Profile by
GC/MS
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Polypropylene Formulation
Ingredient
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wt %
Primary Stabilizers
Tetrakis (methylene(3,5-di-t-butyl4-hydroxyhydrocinnamate)) methane
Irganox 1010 (Ciba)
Anox 20 (Great Lakes)
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0.08 wt%
Secondary Stabilizers
Bis(2,4-di-t-butylphenyl)pentaerythritol diphosphite
Ultranox 626 (GE)
0.05 wt%
Polypropylene Formulation
Ingredient
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Corrosion Inhibitors
Calcium Stearate 114-50 (Ferro)
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0.03 - 0.4 wt%
Antistatic
Vegetable oil derived
90% alpha monoglycerides (soybean)
Pationic 901 (Patco)
Dimodan HS-KA (Danisco)
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%
0.3 wt%
Nucleating Agents
3,4 -dimethyl dibenzylidene sorbitol
Millad 3988 (Milliken)
0.2 wt%
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”
Polypropylene – Extractables Profile by
LC/UV/MS
Reflux PP Disc/CH2Cl2
4
10.55
03270311
100
280 nm
ANALOG
5.22e5
12
20.92
%
2
5.34
9
18.90
3
8.44
33.92
0
03270311
8
18.36
100
Scan APTIC
1.27e7
11
20.25
12
4
10.64
%
3.17 5.02
3
8.55
7
16.02
5
13.50
34.01
9
10
25.63
31.38
37.86 40.31
6
0
44.91
Time
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15.00
20.00
25.00
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35.00
40.00
Polypropylene – Extractables Profile by GC/MS
A b u n d a n c e
T IC : J A N 3 1 1 0 8 .D
1 1 0 0 0 0
2 - p r o p a n o l R e f lu x
1 0 0 0 0 0
9 0 0 0 0
3
2
1
8 0 0 0 0
7 0 0 0 0
6 0 0 0 0
5 0 0 0 0
4 0 0 0 0
3 0 0 0 0
2 0 0 0 0
1 0 0 0 0
0
5 .0 0
T im e - - >
1 0 .0 0
1 5 .0 0
2 0 .0 0
2 5 .0 0
3 0 .0 0
3 5 .0 0
Rubber Formulation B (Peroxide Cured)
Ingredient
%
IMSIL A25 (silicone dioxide)
MISTRON CYPRUBOND (magnesium silicate)
BROMOBUTYL 2030
VISTALON 404 (ethylene propylene copolymer)
WHITE OIL 2
420 BLUE MB
TITANIUM DIOXIDE
PARAFFIN
MAGNESIUM OXIDE
STEARIC ACID
POLYETHYLENE WAX
P-800
24.01
19.21
38.42
9.61
1.44
0.12
1.68
0.96
0.60
0.48
1.44
2.03
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
PRECIPITATED SILICA
68.00
32.00
What do we know?
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Registry Number: 78-63-7
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Formula:
C16 H34 O4
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CA Index Name:
Peroxide, (1,1,4,4-tetramethyl-1,4-butanediyl)bis[(1,1-dimethylethyl) (9CI)
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Other Names:
Peroxide, (1,1,4,4-tetramethyltetramethylene)bis[tert-butyl (6CI,8CI); (1,1,4,4Tetramethyltetramethylene)bis(tert-butyl peroxide); 101XL; 2,5-Bis(tert-butyldioxy)-2,5-dimethylhexane; 2,5-Bis(tertbutylperoxy)-2,5-dimethylhexane; 2,5-Di(t-butylperoxy)-2,5-dimethylhexane; 2,5-Di(tert-butylperoxy)-2,5dimethylhexane; 2,5-Di-tert-butyl-2,5-dimethylhexyl peroxide; 2,5-Dimethyl-2,5-bis(tert-butyldioxy)hexane; 2,5Dimethyl-2,5-bis(tert-butylperoxy)hexane; 2,5-Dimethyl-2,5-di(t-butylperoxy)hexane; 2,5-Dimethyl-2,5-di(tertbutylperoxy)hexane; 2,5-Dimethyl-di(tert-butyl)peroxyhexane; 2,5-Dimethylhexane-2,5-di-tert-butylperoxide; 2,5Methyl-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
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2261 references in chemistry database (7 related to analytical studies)
Peroxide Cured Rubber – Extractables Profile
by GC/MS
Abundance
TIC: 02280324.D
4000000
3500000
3000000
2500000
2000000
1500000
1000000
500000
0
Time-->
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Summary of PQRI Recommendations
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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.
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
Early Evaluation Process
•
Form a team
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•
•
•
•
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?
Supplier Evaluation
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Is the Supplier willing to share information?
 What type of data will be shared
► Controlled extraction data
► ISO 10993/USP <87>, <88>
► MSDS
► Other toxicology
reports
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
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Can the Supplier provide information on prior use of
material for approved DP?
Example
Drug Product with Delivery System
► An
already approved DP is being revamped
 New/Improved delivery system
 Global Registration anticipated
► DP
evaluation team formed
on DP configuration, 5 Critical
Components have been Identified
► Based
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
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
Ring Seal - Options
►
Pharmaceutical Sciences
►
Analytical 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”
 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
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
of DP
delay in development/registration
Plunger Insert
►
Material is HDPE
► Chemical
information supplied
 Physical Properties - Yes
 Composition - Yes
► Toxicology
information supplied
 Indirect Food Additive cross reference
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
Plunger Seal
► Material
is PP
► Chemical
information supplied
 Physical Properties - No
 Composition - Yes
► Toxicology
 None
information supplied
Plunger Seal - Compositon
Chemical Component
1-propene, polymer with ethene
CAS 9010-79-1
Content
(Weight %)
94.48
Dimethyl succinate polymer with 4-hydroxy-2,2,6,6-tetramethyl-1piperidineethanol
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
Issues
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No Toxicology data supplied
 Inquire on availability of toxicology data
►
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ISO/USP test results
MSDS
Other
Limited Chemical Profile
 Additional data requested
►
e.g., antioxidants
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
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
Risk Assessment (2)
Perform Literature Search
►
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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
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
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