Development of Baseline Requirements for Materials and · PDF fileDevelopment of Baseline Requirements for Materials and a Rationalized Testing Paradigm ... CQI PS 9000:2016 “Pharmaceutical

Development of Baseline Requirements for Materials and a Rationalized Testing Paradigm

Cheryl LM Stults, PhD09 Sep 2016

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: IPAC-RS seeks to advance the science of orally inhaled and nasal drug products (OINDP) by collecting and analyzing data, and

conducting joint research and development projects.

Who We Are: The IPAC-RS Consortium

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IPAC-RS Members

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3MActavisAstraZenecaBoehringer IngelheimCatalentChiesiGlaxoSmithKlineHovioneLupin PharmaceuticalsMundiPharma

Merck & Co (MSD)MylanNovartisSunovionTevaVectura

Supplier Members:AmcorAptarMedsprayWest

•Cascade impaction•DDU

•APSD

CMC and Product Development Tests

•Devices •Instructions for Use

•Human Factors•Change Mgmt

•OINDP MaterialsDeliverySystems

BA/BE andIVIVC

•PopulationBioequivalence•Modified chi-

square ratio test

•Emerging mkts•Outreach

•Collaboration

IPAC-RS Workstreams

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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 throughout the shelf life of the drug product.

Materials Working Group

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Materials Working Group Initiatives2004 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 RequirementsDiscussed, Proposed and Revised

2014 2016

Risk Management of OINDP Materials

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)

DrugFormulation

Delivery Device

Packaging System

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Risk Associated with OINDP (US Perspective)

Taken from USP <1664> “Assessment of Drug Product Leachables Associated with Pharmaceutical Packaging/Delivery Systems”

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Risk category

Risk Associated with OINDP (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:

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Risk Associated with OINDP (EMA Perspective)

Plastic packaging material for drug products

•description• identification•mechanical,

physical or other characteristic properties

•description•identification•mechanical,


•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,


•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

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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

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Pharma Supply Chain is Complex

Quality Throughout the Supply Chain

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Controls Needed Throughout Supply Chain

Material Supplier

Extractables

Component Mfr

Filler/ Assembler

Pharm Mfr

Sources: Additives, Ambient Contaminants, Processing Aids

Patient

Leachable

N-1N-2N-3 Control

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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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 MaterialTesting Redundancy

Production Delays

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Testing Paradigm (circa 2005)

Key Documents (2006 - 2011)

2006 PQRI – Safety Thresholds & Best Practices For Extractables & Leachables in OINDP

2006 Health Canada/EMA – Guideline on the 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)

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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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2009-2010 Follow-up Discussion with Suppliers

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)

Material Supplier

Converter/Assembler


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 MaterialsTesting RedundancyProduction Delays

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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

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http://ipacrs.org/assets/uploads/outputs/Baseline_Requirements_for_OINDP_Materials.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


Leachables StudiesIdentify critical componentsCorrelate extractables profileswith leachables profiles

Efficient Testing ProcessesPotential 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

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OINDP Supplier & MFR Communication

Requirements Discussed Early And Often

Business CommunicationEarly and Often

GMP Guideline for Suppliers Of OINDP

Technical Communication Early and Often

Design QualityInto the Product

OINDP MANUFACTURERS

OINDP SUPPLIERS

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2011-2016: “New” and Emerging Documents 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” 2014 ICH Q3D “Guideline for Elemental Impurities” (Step 4) 2015 USP <1663> “Assessment of Extractables Associated with Pharmaceutical

Packaging/Delivery Systems” 2015 USP <1664> “Assessment of Drug Product Leachables Associated with

Pharmaceutical Packaging/Delivery Systems” 2016 USP <232> “Elemental Impurities-Limits” 2016 USP <661> “Plastic Packaging Systems and Their Materials of Construction” 2016 USP <661.1> “Plastic Materials of Construction” 2016 USP <661.2> “Plastic Packaging Systems for Pharmaceutical Use” 2016 USP <1661> “Evaluation of Plastic Packaging Systems and Their Materials of

Construction with Respect to Their User Safety Impact” 2016 IPAC-RS, PQG, CQI PS 9000:2016 “Pharmaceutical packaging materials for

medicinal products, with reference to Good Manufacturing Practice (GMP)”

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Update of Baseline Requirements (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?

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Revision Plan

• Materials WG create draft

• Set-up meetings with stakeholder to receive feedback- IPAC-RS Members

- Material Suppliers

- Contract Manufacturers

- Contract Analytical Testing Laboratories

- Regulators

• Circulate Final Draft

• 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

ExamplesNotice Period with Last Call

Option

Raw Material Shelf Life

Finished Component Shelf

Life

Resulting Material Availability

Material #1 12 months --- 24 months 36 monthsMaterial #2 12 months 12 months 12 months 36 monthsMaterial #3 18 months 12 months 6 months 36 months*subject to contractual agreements for specific materials between individual suppliers and their customers

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Requirement II: Quality Information

• Quality Agreement that addresses:- Customer and supplier responsibility

- Compliance requirements - e.g., ISO 9001, GMPs, ISO 13485

- Change control and notification

- Cleanliness and environment

- Raw material supplier requirements

- Controlled documents – specifications, batch records, test methods, etc.

- Processes related to product – equipment qualification, process validation, sampling, testing, release, storage, deviations, resolution of quality issues, complaints, recalls, etc.

- Audit standards – e.g., PS 9000

• Supplier Audits

• Change Control

• Material Composition, Process & Quality Control per agreement

• DMF Access, if available

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Requirement II: Quality Information Example

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Example responsibility matrix from PS 9000:2016Item Customer OrganizationComponent 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 CoA, CoC or CoT X

Retained samples X X

Supply agreement X X

Quality agreement X XDesign file X X

Requirements for Materials used in Orally Inhaled and Nasal Drug Products (OINDP) II

• Food Additive Compliance

- US: 21CFR Parts 172-189

- EU: COMMISSION REGULATION (EU) 2015/174 amending and correcting Regulation (EU) No 10/2011on plastic materials and articles intended to come into contact with food

- WHO: Codex Alimentarius

- EU: Other materials (ceramics, gaskets, etc)

- Other food additive requirements, e.g. printing inks, adhesives, paper boards, silicone, rubber

• TSE (BSE, “mad cow disease”) Compliance

- ISO 22442 Medical devices utilizing animal tissues and their derivatives

- Compliance with 2003/32/EC, EP 5.2.8 ; guidances: CPMP/EMEA 410/01, MEDDEV 2.11/1.

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Requirement III: Compliance/Conformance


• Elemental Impurities

- ICH Q3D

- Directive 94/62/EC; Pb, Cd, Cr-VI, Hg (<0.01%)

• REACh, if applicable

- Regulation (EC) No 1907/2006

• WEEE, if applicable

- Directive 2012/19/EU

• RoHS, if applicable

- Directive 2011/65/EU

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Requirement III: Compliance/Conformance (cont’d)


• Chemicals of concern:

- Phthalates: 93/42/EEC as amended by 2007/47/E

- BPA:Health Canada, Notice to Manufacturers of Licensed Class II, III, and IV Medical Devices

- Nitrosamines: EC Directive 93/11/EEC

- Mercaptobenzothiazole21CFR: 175.105, 176.300, 177.2600

- Polycyclic Aromatic Hydrocarbons (PAH) Agency for Toxic Substances and Disease Registry(ATSDR): Toxicity of Polycyclic Aromatic Hydrocarbons (PAHs) 2009

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Expectation I: Additional Information


• Other material concerns:

- Aromatic Amines Content: Regulation 10/2011

- Epoxy derivatives: EC 1895/2005

- Nanomaterials: Regulation 10/2011

- Genotoxic impurities: ICH M7

- Latex:Recommendations for Labeling Medical Products to Inform Users that the Product or Product Container is not Made with Natural Rubber Latex -Guidance for Industry and Food and Drug Administration Staff. US FDA 2014

- Electronics – conflict minerals, batteries (UL 1642, US 2054, EN 60086-1), medical electrical equipment (EN 60601)

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Expectation I: Additional Information (cont’d)

Expectation II: Material Testing for Critical Components

• Performance Criteria• Pharmacopeial/Standards Compliance

- Physicochemical & Biocompatibility

• Foreign Particulates• Controlled Extraction Studies at a minimum including:

- Solvents of varying polarity

- One or more extraction techniques

- At least two analytical methods

- Quantification and identification to 10 ppm

- Example protocols for Controlled Extraction Studies

• See L&E Handbook, PQRI, ELSIE, BPSA, BPOG, ISO 10993

• Routine Extractable Testing, if needed based on risk evaluation

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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

Componentproduction

(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)


Finishing treatments(cutting/sizing,

printing, etc)(Category 4)



Finishing treatment(washing or surface

treatments)(Category 4)

Effective Risk-Based Testing Strategy

• Testing point - where the relevant knowledge exists

• Risk evaluation of safety or performance – Mitigate by testing to gain additional information and/or implement process controls

• Critical quality attributes - properly determined

• Testing methodology- appropriate to the proposed failure mode

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Category Simplification (2015)

Test Category 1 Category 2 Category 3 Category 4 Biocompatibility—based on compliance with ISO 10993 or USP <87> and <88>. De liverab le: Certificate of Compliance (required) and report with test results (upon request)

One-time test for plastics only

One-time test for plastics only One-time test*

Physicochemical Testing De liverab le: Certificate of Compliance (required); Certificate of Analysis (upon request)

One-time test*

One-time test*

Controlled Extraction Studies De liverab le: Report with results (complete data package)

No test

Should provide

composition information.

One-time test* Or, at least, provide

composition and processing aids or

additives

One-time test* Or, at least, provide

composition and processing aids or

additives

One-time test*

Routine Extractables Testingi Periodic, (e.g., per batch), Quantitative / Qualitative Validated method De liverab le: 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)

* Test once at the beginning of materials selection, or if significant change has occurred. ▲ Test each batch/lot for OINDP, periodically for PDP

Proposed Testing Paradigm (2016)

Masterbatch Producer

Material Characterization StudiesCofA 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 ManufacturerControlled Extraction StudiesLeachables Studies

Identify critical materialsCorrelate extractables profileswith leachables profiles

Efficient Testing ProcessesPotential Elimination of Routine Extractables End Testing

Data Generation

Specification SettingCES Study Design

Data Interpretation

Process Understanding & Risk Assessment

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RegulationsQuality Agreements

Change Control Procedures

Knowledge Sharing; Material, Processing, Stability & Extraction Study Design

Summary

• Combination products that include infusion products, injectables and OINDP are generally categorized as having a high level of concern for patient safety and require high quality materials and controlled processes throughout the supply chain

• Development of appropriate control and testing strategies begins with an emphasis on selection and qualification of materials followed by adequate process controls and testing at appropriate points in the supply chain

• Use of the baseline requirements enables appropriate material selection and qualification

• Quality agreements are an essential tool for communication between pharma and suppliers to ensure product quality and patient safety

• To effectively manage product or material changes regular communication of information and notification of change is essential throughout a complex supply chain.

www.ipacrs.org 39

http://www.ipacrs.org/



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Acknowledgements

James Conners, SunovionJason Creasey, GSKAndrew FeildenJames McLean, CatalentSara Miller, 3MLee Nagao, IPAC-RSJonathan Petersen, MSDGaby Reckzuegel, Boehringer IngelheimIan Vaughan, Mylan

www.ipacrs.org
