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Baseline Requirements for Materials used in Orally
Inhaled and Nasal Drug Products (OINDP):
An Update to the 2011 Document
Authored by the IPAC-RS OINDP Materials
Working Group
Thomas N. Feinberg, Ph.D.
14 May 2015
Who We Are: The IPAC-RS Consortium
1989: International Pharmaceutical Aerosol
Consortium (IPAC) formed to address regulatory
consequences for MDIs of Montreal and Kyoto
Protocols
1999: IPAC formed a Working Group to prepare
comments on the FDA draft CMC Guidances for
MDIs, DPIs, Nasal Sprays, and Inhalation
Solutions/Suspensions
2001: International Pharmaceutical Aerosol
Consortium for Regulation and Science (IPACRS) formed as a separate Consortium
Mission: To advance consensus-based, scientifically driven standards
and regulations that facilitate availability of high-quality, safe and
efficacious orally inhaled and nasal drug products to patients.
2
IPAC-RS Members
3M
Actavis
AstraZeneca
Boehringer Ingelheim
Catalent
Chiesi
GlaxoSmithKline
Hovione
Lupin Pharmaceuticals
MannKind Corporation
Merck & Co
Mylan
Novartis
Sunovion
Teva
Vectura Ltd.
Supplier Members:
Aptar
Medspray
West
3
IPAC-RS Workstreams
CMC and Product Development Tests
•Cascade impaction
•DDU/PTIT
•GRRO
•Communic.
Techn.
Delivery
Systems
•Devices
•OINDP Materials
•Patient Concordance
•Population
Bioequivalence
Clinical and
IVIVC
4
Materials Working Group
Mission:
To improve packaging and device materials
quality and integrity, reduce supply chain
problems and promote rational testing
approaches.
Impact:
The Patient is best served when we provide
quality packaging and device components
that are both safe and effective through the
shelf life of the drug product.
5
Materials Working Group Initiatives
2004
Formation
of Group
2005
2006
2008
2010
2012
2014
2016
Publications & Presentations to Suppliers, Pharma & Regulators
(e.g., Webinar Series; Presentations to CFDA regulators)
Workshops for Pharma, Suppliers & Regulators
Development of Testing Paradigm
for Supply Chain
Baseline Requirements
Discussed, Proposed and Revised
Risk Management
of OINDP Materials
Slide 6
CS9
the alignment has been adjusted to be consistent with timings and symmetry of objects
Cheryl Stults, 5/12/2015
Material Quality Affects Product Quality
Drug
Formulation
Packaging
System
Delivery
Device
“Quality refers to the physical, chemical, microbiological, biological,
bioavailability, and stability attributes that a drug product should maintain
if it is to be deemed suitable for therapeutic or diagnostic use.” FDA 1999
(Packaging Guidance)
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Risk Management (FDA)
Examples of Packaging Concerns for Common Classes of Drug Products
Risk Associated with OINDP (US Perspective)
Risk category
Degree of Concern
Associated with the
Likelihood of Packaging Component-Dosage Form
Interaction
Extracted from USP <1664> “Assessment of Drug Product Leachables
Associated with Pharmaceutical Packaging Delivery Systems
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Material Quality Attributes
Suitable for intended use:
Performance
Functionality
Compatibility
Loss of Potency
Degradation
Precipitation
Discoloration
pH change
Brittleness of Package
Safety
Chemical composition
(Extractables)
Chemical migration
(Leachables)
Protection
Temperature
Light
Solvent/gases/moisture
Microbes
9
Risk Associated with OINDP (EMA Perspective)
Plastic packaging material for drug products
for oral and topical, non-ophthalmic
Solid dosage form
inhalation, parenteral and ophthalmic administration
Non-solid dosage
forms
Solid dosage form
Non-solid dosage
forms
Compliance to appropriate monographs of the European Pharmacopoeia or
the monograph of the pharmacopoeia of a Member State should be demonstrated.
if not
if not
Compliance with foodstuff legislation
yes
•description
•identification
•mechanical,
physical or other
characteristic
properties
•description
•identification
•mechanical,
physical or other
characteristic
properties
Source: EMEA Guideline on plastic immediate packaging materials,
19 May 2005 (CPMP/QWP/4359/03)
if not
if not
no
•description
•identification
•characteristic
properties
•identification of
main additives and
colorants
•nature and
amount of
extractables
•description
•identification
•mechanical,
physical or other
characteristic
properties
•description
•identification
•characteristic
properties
•identification of
main additives and
colorants
•nature and
amount of
extractables
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Pharma Supply Chain Links
SUPPLY CHAIN
N-3
N-2
N-1
N
INGREDIENT
SUPPLIER
MATERIAL
SUPPLIER
CONVERTER/
ASSEMBLER
PHARMA
MONOMERS,
ANTI–STATICS,
ADDITIVES
POLYMER,
METAL,
ELASTOMER
MOULDER,
DEVICE MFR,
VALVE MFR,
PKG MFR
11
Supply Chain Risk
N-3
N-2
N-1
Control
Ingredient
Material
Converter/
Pharm
Quality
Throughout
the
Supply Chain
Supplier
Supplier
Assembler
Mfr
Patient
Foil
Extractables
Ingredients
Leachable
Sources of L/E: Additives, Ambient Contaminants, Processing Aids
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Key Documents (circa 2005)
1993 CDRH - Reviewer Guidance for Nebulizers, Metered Dose
Inhalers, Spacers and Actuators
1998 FDA - MDI/DPI Draft Guidance
1999 FDA - Guidance for Industry: Container Closure Systems for
Packaging Human Drugs and Biologics
2002 FDA – Guidance on Inhalation solution, suspension, spray and
nasal spray products
2002 EU Directive 72, Food Contact
2005 CHMP, CVMP - Guideline for Plastic Immediate Packaging
Materials
21CFR 170-189
EP 3, USP <381>, <660>, <661> (Physicochemical)
ISO10993, USP<87>, USP<88> (Biocompatibility)
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Testing Paradigm (circa 2005)
Material
Supplier
Converter/
Assembler
Pharmaceutical
Manufacturer
No Extractables Testing
Performed
No Sharing of Information
with Converter/Assembler
Routine Extractables Testing
•No sharing of results with
Material Supplier
•No sharing of composition
information with Pharma
•Controlled Extraction Studies
•Leachables Studies
•Routine Extractables Testing
Difficult to Achieve
Correlation between
Extractables and Leachables
Profiles
Inadequate Understanding of Material
Testing Redundancy
Production Delays
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Key Documents (2006 - 2011)
2006 PQRI – Safety Thresholds & Best Practices For
Extractables & Leachables in OINDP
2006 Health Canada/EMA Guidance – Pharmaceutical
Quality of Inhalation and Nasal Products
2007 European Parliament/Council –Medical Device
Directive 93/42/EEC as amended
21CFR 170-189; COMMISSION REGULATION (EU) No
10/2011 (Food contact)
15
2009 EU & US Forum Discussion Topics
All parties within the supply chain discussed the following issues with
great enthusiasm:
Communication - breaking the barriers
Confidential information/data – can it be shared?
Extraction/Biocompatibility studies – who conducts the testing?
Material variability – what’s acceptable?
Lifecycle management – managing post approval changes
Regulatory expectations – what Pharma requires to file a drug
product?
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2009 Discussion Forum Proposals
Rationale as to why extraction studies should be conducted
by suppliers – inclusion of extraction studies expectation in
baseline requirements
Use of analytical thresholds in extraction studies
Establishing a reasonable threshold/limit
36 month availability of material
Adequate notice period (minimum 12 months)
Last-call option to allow bulk purchase before production
discontinuation
Notification of changes
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Improved Testing Paradigm (circa 2010)
Limited Extractables Testing
Performed
Sharing of Information
with Converter/Assembler
Converter/
Assembler
Routine Extractables Testing
Controlled Extraction Studies
•Dialogue on results with
Material Supplier
•Sharing of composition
information with Pharma
Pharmaceutical
Manufacturer
•Controlled Extraction Studies
•Leachables Studies
•Routine Extractables Testing
Improvement in
Correlation between
Extractables and Leachables
Profiles
Material Supplier
Improved (limited) Understanding of Materials
Testing Redundancy
Production Delays
18
2010 – Drafted Baseline Requirements
Provide guidance to suppliers
Provide information that pharmaceutical
manufacturers can adopt for OINDP high risk
material
Address all levels of supply chain
Address all types of materials
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Baseline Requirements (2011 Version)
Table demonstrating kinds of testing/evaluation should be
performed by suppliers in the supply chain
Flowcharts
Describing the main supply and processing steps in development of
plastic, metal, foils, and elastomeric components
Assigning the testing/evaluation to specific types of suppliers in the
supply chain
Appendices describing:
Rationale for security of supply
Rationale for “one-time” testing
Rationale for Controlled Extraction Studies
Rationale for Routine Extractables Testing
Key references
20
“Baseline Requirements” (2011)
http://ipacrs.org/assets/uploads/outputs/Baseline_Requirements_for_OINDP_M
aterials.doc
21
Proposed Information Flow (2011)
Knowledge Sharing; Material,
Processing, Stability &
Extraction Study Design
Molder/Converter
Masterbatch Producer
Controlled Extraction Studies
Routine Extractables Testing
on each batch
Share results and methods with
Masterbatch Producers;
Share results with
Pharmaceutical Manufacturers
Share Results
with Molder/Converter
Regulations/Compliance
Data Generation
Specification Setting
Pharmaceutical Manufacturer
Leachables Studies
Identify critical components
Correlate extractables profiles
with leachables profiles
CES Study Design
Data Interpretation
Process Understanding
Efficient Testing Processes
Potential Elimination of Routine Extractables End Testing
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OINDP Supplier & MFR Communication
Business
Communication
Early and Often
Technical
Communication
Early and Often
OINDP
SUPPLIERS
Design Quality
Into the Product
OINDP
MANUFACTURERS
Requirements
Discussed Early And
Often
GMP Guideline for Suppliers Of OINDP
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Relevancy: “New” and Emerging Documents
2011 IPAC-RS, PQG, CQI PS 9000:2011 “Pharmaceutical packaging materials for
medicinal products, with reference to Good Manufacturing Practice (GMP)”
2012 IPAC-RS (Wiley) Leachables and Extractables Handbook
2012 EU cGMPs Chapter 7, “Outsourced Activities”
2013 Draft, FDA Guidance “Contract Manufacturing Arrangements for Drugs: Quality
Agreements”
2013 Draft USP <232> “Elemental Impurities-Limits”
2014 ICH Q3D “Guideline for Elemental Impurities” (Step 4)
2014 Draft USP <661> “Plastic Packaging Systems and Their Materials of Construction”
2014 Draft USP <661.1> “Plastic Materials of Construction”
2014 Draft USP <661.2> “Plastic Packaging Systems for Pharmaceutical Use”
2014 Draft USP <1661> “Evaluation of Plastic Packaging Systems and Their Materials of
Construction with Respect to Their User Safety Impact”
2015 August USP <1663> “Assessment of Extractables Associated with Pharmaceutical
Packaging/Delivery Systems”
2015 August USP <1664> “Assessment of Drug Product Leachables Associated with
Pharmaceutical Packaging/Delivery Systems”
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Continuous Improvement (initiated 2015)
• How can the “Baseline Requirements” be kept relevant to
current scientific, manufacturing, and regulatory context?
- Development and manufacturing processes are changing
- Risk management, control, and testing paradigms are changing
• Who is using them?
• How are they being used?
• What are “critical components”?
• Can these requirements be expanded to other “high-risk”
dosage forms?
25
Revision Planning
• Materials WG create draft
• Set-up meetings with stakeholder to receive feedback
- IPAC-RS Members
- Material Suppliers
- Contract Manufacturers
- Contract Analytical Testing Laboratories
- Regulators
• Final Draft Circulated
• Plan workshop
26
Requirement I: Material Availability
• Minimum 36 months rolling availability of unchanged material* including:
- Shelf-life of material
- Adequate notice period (minimum 12 m) to qualify new material according to
regulatory requirements
- Last-call option to allow bulk purchase before production discontinuation
Examples
Material #1
Material #2
Material #3
*subject
Notice Period
with Last Call
Option
12 months
12 months
18 months
Raw Material
Shelf Life
--12 months
12 months
Finished
Resulting Material
Component Shelf
Availability
Life
24 months
36 months
12 months
36 months
6 months
36 months
to contractual agreements for specific materials between individual suppliers and their customers
27
Requirement II: Compliance/Conformance
• Food Additive Compliance
- US: 21 CFR Parts 172-189
Requirements
for Materials used in Orally
- EU: Commission Regulation (EU) No 10/2011
Inhaled
and Nasal
Drug
Products
(OINDP)
IIpaper boards,
- Other materials
and food additive
requirements,
e.g. printing
inks, adhesives,
silicone, rubber
• TSE (BSE, “mad cow disease”)
- ISO 22442 Medical devices utilizing animal tissues and their derivatives
- Compliance with 2003/32/EC, EN ISO 22442 (see above bullet), EP 5.2.8 ; guidances:
CPMP/EMEA 410/01, MEDDEV 2.11/1.
• REACH
• RoHS
• Directive 94/62/EC
- Pb, Cd, Cr-VI, Hg (<0.01%)
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Expectation I: Additional Information
• Pigments
- BfR Requirements, 21 CFR 178
Requirements
for Materials used in Orally
• Phthalates Content
Inhaled
and
Nasalas amended
Drugby 2007/47/E
Products (OINDP) II
- Compliance
with 93/42/EEC
- Canadian Requirement: Notice to Manufacturers of Licensed Class II, III, and IV Medical Devices
• BPA Content (Canadian)
• Aromatic Amines Content
• Epoxy derivatives
- EC 1895/2005
• MBT
• Nanomaterials
• Nitrosamines: EC Directive 93/11/EEC
• Polycyclic Aromatic Hydrocarbons (PAH) content
• Latex
• Electronics
29
Requirement III: Quality Information
• Confidentiality and Quality Agreement
• Change Control
• Composition, Process & Quality Control
• DMF Access, if available
30
Assign Quality Responsibilities
Example responsibility matrix from PS 9000:2011
Item
Component Specifications
Customer
Specifications against which material is
tested by the organization
X
Supply/procurement projections
X
Testing in-process/release
Testing on receipt
Supplier
X
X
X
Certification Certificate of Analysis(CoA),
Certificate of Compliance (CoC) or CoT
X
Retained samples
X
X
Supply agreement
X
X
Quality agreement
X
X
Design file
X
X
31
Expectation II: Material Testing for Critical Components
• Performance Criteria
• Pharmacopeial Compliance
- Physicochemical & Biocompatibility
• Foreign Particulates
• CES using PQRI recommendations at a minimum including:
- Three solvents of varying polarity
- One or more extraction techniques
- At least two analytical methods
- Quantification and identification to 10 ppm
- Detailed protocol for Controlled Extraction Studies
• L&E Handbook, ELSIE, BPSA, ISO 10993
• Routine Extractable Testing, if needed based on risk evaluation
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Expanded and Generalized Material Categories
Elastomer
Plastics
Metal/Glass
Foil
Production of Raw
Materials/Ingredients,
Masterbatch
(Category 1)
Production of
Ingredients
(Category 1)
Raw material
(Category 1)
Production of Ingredients
(Category 1)
Mixing/compounding
(Category 1)
Production of
Base polymer (with additives)
(Category 2)
Production of cured
rubber materials
(Category 3)
Production of
compounded pellets,
Masterbatch
(Category 3)
Fabrication
(Category 3)
Production of plastic films,
aluminum foil, etc
(Category 3)
Component production
(Category 4)
Component
production
(Category 4)
Component production
(including cleaning or
passivation)
(Category 4)
Foil laminate
Production
(Category 4)
Finishing treatment
(washing or surface
treatments)
(Category 4)
Finishing treatments
(de-flashing,
annealing, etc)
(Category 4)
Finishing treatment
(application of coating,
chemical rxn, etc)
(Category 4)
Finishing treatments
(cutting/sizing,
printing, etc)
(Category 4)
Delivery system
assembler
Delivery system
assembler
Delivery system
assembler
Delivery system
assembler
Production of
Base polymer (with additives)
(Category 2)
33
Category Simplification (2015)
Test
Biocompatibility—based on
compliance with ISO 10993 or
USP <87> and <88>.
Category 1
Category 2
One-time test
for plastics only
Deliverable:
Certificate of Compliance
(required) and report with test
results (upon request)
One-time test*
One-time test*
Deliverable:
Compliance
with EP3.1
Certificate of Compliance
(required); Certificate of Analysis
(upon request)
No test
Controlled Extraction Studies
Deliverable:
Report with results (complete
data package)
Should
provide
composition
information.
One-time test*
Or, at the least,
provide
composition
and processing
aids or
additives
i
Deliverable:
Certificate of Analysis
i
Category 4
One-time test*
Physicochemical Testing
Routine Extractables Testing
Periodic, (e.g., per batch),
Quantitative / Qualitative
Validated method
Category 3
Compliance with
EP Chapter 3,
USP <661>,
<381>, (optional
JP XV)
One-time test*
Or, at the least,
provide
composition
and processing
aids or
additives
One-time test*
Routine Test.
Can be done at
the request of
customer, in
connection with
Category 4
routine
extractables
testing
Routine Test.
Commercial
requirement may
be adjusted
based on
development
testing results
(e.g., no
leachables of
concern)
Routine Extractables Testing to be performed depending upon outcome of formal risk analysis
34
Effective Risk-Based Testing Strategy
• Testing point - where the relevant knowledge exists
• Risk evaluation of safety or performance – Mitigate by testing
vs. process controls
• Critical quality attributes - properly determined
• Testing methodology- appropriate to the proposed failure mode
35
Proposed Testing Paradigm (2015)
Knowledge Sharing; Material,
Processing, Stability &
Extraction Study Design
Molder/Converter
Material Characterization Studies
Masterbatch Producer
Material Characterization Studies
CofA Testing (Release)
Share Results
with Molder/Converter
Data Generation
Specification Setting
Regulations
Quality Agreements
Change Control Procedures
Share results and methods with
Masterbatch Producers;
Share results with
Pharmaceutical Manufacturers
Pharmaceutical Manufacturer
Controlled Extraction Studies
Leachables Studies
CES Study Design
Identify critical materials
Correlate extractables profiles
with leachables profiles
Process Understanding &
Risk Assessment
Data Interpretation
Efficient Testing Processes
Potential Elimination of Routine Extractables End Testing
36
Future Activities
• Stay tuned for IPAC-RS WG updates
• Join Forums
• Pull down current document and provide feedback
- If you were to apply for your dosage form, what changes?
www.ipacrs.org
37
Acknowledgments
Arthur Bailey, Mannkind
James Conners, Sunovion
Andrew Feilden
Sara Miller, 3M
Lee Nagao, IPAC-RS
Jonathan Petersen, Merck & Co
Gaby Reckzuegel, Boehringer Ingelheim
Cheryl Stults
www.ipacrs.org
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