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Baseline Requirements for Materials used in Orally
Inhaled and Nasal Drug Products (OINDP):
An Update to the 2011 Document
Thomas N. Feinberg, Ph.D.
14 May 2015
Authored by the IPAC-RS OINDP Materials
Working Group
� 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 (IPAC-RS) 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.
Who We Are: The IPAC-RS Consortium
2
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
IPAC-RS Members
3
•Cascade impaction
•DDU/PTIT
CMC and Product Development Tests
•Devices
•OINDP Materials
•Patient ConcordanceDelivery
SystemsClinical and
IVIVC
•Population
Bioequivalence
•GRRO
•Communic.
Techn.
IPAC-RS Workstreams
4
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.
Materials Working Group
5
Materials Working Group Initiatives
2004 2006 2008 20102005 2012
Publications & Presentations to Suppliers, Pharma & Regulators
(e.g., Webinar Series; Presentations to CFDA regulators)
Workshops for Pharma, Suppliers & Regulators
Formation
of Group
Development of Testing Paradigm
for Supply Chain
Baseline Requirements
Discussed, Proposed and Revised
2014 2016
Risk Management
of OINDP Materials
Slide 6
CS9 the alignment has been adjusted to be consistent with timings and symmetry of objectsCheryl Stults, 5/12/2015
Material Quality Affects Product Quality
“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)
Drug
Formulation
Delivery Device
Packaging System
7
Risk Associated with OINDP (US Perspective)
Extracted from USP <1664> “Assessment of Drug Product Leachables
Associated with Pharmaceutical Packaging Delivery Systems
8
Examples of Packaging Concerns for Common Classes of Drug Products
Degree of Concern Associated with the
Likelihood of Packaging Component-Dosage Form Interaction
Risk category
Risk Management (FDA)
Material Quality Attributes
� 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
Suitable for intended use:
9
Risk Associated with OINDP (EMA Perspective)
Plastic packaging material for drug products
•description
•identification
•mechanical,
physical or other
characteristic
properties
•description
•identification
•mechanical,
physical or other
characteristic
properties
•description
•identification
•characteristic
properties
•identification of
main additives and
colorants
•nature and
amount of
extractables
if not
Compliance to appropriate monographs of the European Pharmacopoeia or
the monograph of the pharmacopoeia of a Member State should be demonstrated.
Non-solid dosage
forms
Solid dosage form
for oral and topical, non-ophthalmic
Source: EMEA Guideline on plastic immediate packaging materials,
19 May 2005 (CPMP/QWP/4359/03)
•description
•identification
•mechanical,
physical or other
characteristic
properties
•description
•identification
•characteristic
properties
•identification of
main additives and
colorants
•nature and
amount of
extractables
Non-solid dosage
forms
inhalation, parenteral and ophthalmic administration
Solid dosage form
Compliance with foodstuff legislationif not
if not
yes no
if not
10
SUPPLY CHAIN
N - 3 N - 2 N - 1 N
INGREDIENT
SUPPLIER
MONOMERS,
ANTI–STATICS,
ADDITIVES
MATERIAL
SUPPLIER
POLYMER,
METAL,
ELASTOMER
CONVERTER/
ASSEMBLER
MOULDER,
DEVICE MFR,
VALVE MFR,
PKG MFR
PHARMA
11
Pharma Supply Chain Links
Quality Throughout the Supply ChainIngredient Supplier
Material Supplier
Converter/ Assembler
Pharm Mfr
Sources of L/E: Additives, Ambient Contaminants, Processing Aids
Patient
N-1N-2N-3 Control
12
Supply Chain Risk
Foil
Extractables
Leachable
Ingredients
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)
13
Material Supplier
Converter/Assembler
Pharmaceutical Manufacturer
No Extractables TestingPerformed
Routine Extractables Testing
•Controlled Extraction Studies•Leachables Studies
•Routine Extractables Testing
No Sharing of Informationwith Converter/Assembler
•No sharing of results with Material Supplier
•No sharing of composition information with Pharma
Difficult to Achieve Correlation between
Extractables and LeachablesProfiles
Inadequate Understanding of Material
Testing Redundancy
Production Delays
14
Testing Paradigm (circa 2005)
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?
16
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
17
Improved Testing Paradigm (circa 2010)
Material Supplier
Converter/Assembler
Pharmaceutical Manufacturer
Limited Extractables TestingPerformed
Routine Extractables TestingControlled Extraction Studies
•Controlled Extraction Studies•Leachables Studies
•Routine Extractables Testing
Sharing of Informationwith Converter/Assembler
•Dialogue on results with Material Supplier
•Sharing of composition information with Pharma
Improvement inCorrelation between
Extractables and LeachablesProfiles
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
19
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
21
http://ipacrs.org/assets/uploads/outputs/Baseline_Requirements_for_OINDP_M
aterials.doc
“Baseline Requirements” (2011)
Proposed Information Flow (2011)
Masterbatch Producer
Routine Extractables Testing
on each batch
Share Results
with Molder/Converter
Molder/Converter
Controlled Extraction Studies
Share results and methods with
Masterbatch Producers;
Share results with
Pharmaceutical Manufacturers
Pharmaceutical Manufacturer
Leachables Studies
Identify critical components
Correlate extractables profiles
with leachables profiles
Efficient Testing Processes
Potential Elimination of Routine Extractables End Testing
Regulations/Compliance
Data Generation
Specification Setting
CES Study Design
Data Interpretation
Process Understanding
Knowledge Sharing; Material, Processing, Stability & Extraction Study Design
22
OINDP Supplier & MFR Communication
Requirements
Discussed Early And
Often
Business
Communication
Early and Often
GMP Guideline for Suppliers Of OINDP
Technical
Communication
Early and Often
Design Quality
Into the Product
OINDP
MANUFACTURERS
OINDP
SUPPLIERS
23
24
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”
25
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?
26
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
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
Notice Period
with Last Call
Option
Raw Material
Shelf Life
Finished
Component Shelf
Life
Resulting Material
Availability
Material #1 12 months --- 24 months 36 months
Material #2 12 months 12 months 12 months 36 months
Material #3 18 months 12 months 6 months 36 months*subject to contractual agreements for specific materials between individual suppliers and their customers
27
Requirements for Materials used in Orally
Inhaled and Nasal Drug Products (OINDP) II
• Food Additive Compliance
- US: 21 CFR Parts 172-189
- EU: Commission Regulation (EU) No 10/2011
- Other materials and food additive requirements, e.g. printing inks, adhesives, paper boards,
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%)
28
Requirement II: Compliance/Conformance
Requirements for Materials used in Orally
Inhaled and Nasal Drug Products (OINDP) II
• Pigments
- BfR Requirements, 21 CFR 178
• Phthalates Content
- Compliance with 93/42/EEC as amended by 2007/47/E
- 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
Expectation I: Additional Information
Requirement III: Quality Information
• Confidentiality and Quality Agreement
• Change Control
• Composition, Process & Quality Control
• DMF Access, if available
30
Assign Quality Responsibilities
31
Example responsibility matrix from PS 9000:2011Item Customer Supplier
Component Specifications X
Specifications against which material is
tested by the organization
X
Supply/procurement projections X
Testing in-process/release X
Testing on receipt 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
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
32
33
Expanded and Generalized Material Categories
Production of
Base polymer (with additives)
(Category 2)
Production of
Ingredients
(Category 1)
Production of
compounded pellets,
Masterbatch
(Category 3)
Raw material
(Category 1)
Fabrication
(Category 3)
Production of
Base polymer (with additives)
(Category 2)
Production of Ingredients
(Category 1)
Production of plastic films,
aluminum foil, etc
(Category 3)
Production of Raw
Materials/Ingredients,
Masterbatch
(Category 1)
Mixing/compounding
(Category 1)
Production of cured
rubber materials
(Category 3)
Elastomer Plastics Metal/Glass Foil
Component
production
(Category 4)
Component production
(including cleaning or
passivation)
(Category 4)
Foil laminate
Production
(Category 4)
Component production
(Category 4)
Finishing treatments
(de-flashing,
annealing, etc)
(Category 4)
Delivery system
assembler
Finishing treatment
(application of coating,
chemical rxn, etc)
(Category 4)
Delivery system
assembler
Finishing treatments
(cutting/sizing,
printing, etc)
(Category 4)
Delivery system
assembler
Delivery system
assembler
Finishing treatment
(washing or surface
treatments)
(Category 4)
34
Category Simplification (2015)
Test Category 1 Category 2 Category 3 Category 4
Biocompatibility—based on compliance with ISO 10993 or USP <87> and <88>.
Deliverable:
Certificate of Compliance (required) and report with test
results (upon request)
One-time test
for plastics only One-time test*
Physicochemical Testing
Deliverable:
Certificate of Compliance (required); Certificate of Analysis (upon request)
One-time test*
Compliance with EP3.1
One-time test*
Compliance with EP Chapter 3, USP <661>,
<381>, (optional JP XV)
Controlled Extraction Studies
Deliverable:
Report with results (complete
data package)
No test
Should
provide composition information.
One-time test*
Or, at the least, provide
composition
and processing aids or
additives
One-time test*
Or, at the least, provide
composition
and processing aids or
additives
One-time test*
Routine Extractables Testingi
Periodic, (e.g., per batch), Quantitative / Qualitative
Validated method
Deliverable:
Certificate of Analysis
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)
i Routine Extractables Testing to be performed depending upon outcome of formal risk analysis
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)
Masterbatch Producer
Material Characterization Studies
CofA Testing (Release)
Share Results
with Molder/Converter
Molder/Converter
Material Characterization Studies
Share results and methods with
Masterbatch Producers;
Share results with
Pharmaceutical Manufacturers
Pharmaceutical Manufacturer
Controlled Extraction Studies
Leachables Studies
Identify critical materials
Correlate extractables profiles
with leachables profiles
Efficient Testing Processes
Potential Elimination of Routine Extractables End Testing
Data Generation
Specification Setting
CES Study Design
Data Interpretation
Process Understanding & Risk Assessment
36
Regulations
Quality Agreements
Change Control Procedures
Knowledge Sharing; Material, Processing, Stability & Extraction Study Design
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
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
38
Acknowledgments
