5/11/2015
Product Suitability for
Intended End Use
Excipientfest 2015
Dora Meissner
Director of Regulatory Affairs
Presentation Goals
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Define the suitability of an ingredient
Discuss the importance of an excipient and its
role in a drug product
Determine how to ensure you are using an
ingredient suitable for use as an excipient
Our Mutual Goal:
Ensure the safety of the Consumer
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5/11/2015
Introduction
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Dora Meissner
Education
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BS, Chemistry/Biology
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MS in Quality Assurance and Regulatory Affairs
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Experience
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University of Pittsburgh
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Temple University - 2015
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11+ years experience in Quality-based management of the
manufacturing and supply of ingredients to drug product
manufacturers
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Quality Control
Quality Assurance
Quality Compliance
Supply Chain Management
Current Role:
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Director of Regulatory Affairs at BioSpectra
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Overseeing Quality, EHS and Technology
Supply Chain Management- Domestic and Global
BioSpectra
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Manufacturer of Active Pharmaceutical
Ingredients and Excipients
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Biological Buffers
Carbohydrates
Amino Acids
Process Intermediates
Custom/Contract Manufacturer for
Pharmaceutical Ingredients
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Importance of an Ingredient’s
Suitability
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Multi-Use Chemical Ingredients will
vary by:
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Usage: in multiple industry applications
Specifications: may change based on the
end use
Manufacturing guidelines, controls or
expectations: may differ based on its end
use
Example of a Multi-Use Ingredient
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Common Sodium Chloride applications
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Industrial - Road Salt
Food - Table Salt
Technical - Lab Reagent
Pharmaceutical - Excipient
Drug Product - API
Sterile - Injectable
Criteria to determine approval for each end use
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Specifications
Manufacturing Controls
Documentation and Traceability
Packaging
Handling and storage conditions
Product suitability is determined by
intended end use
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5/11/2015
Product Suitability
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Product ~ an Ingredient used in the formulation
of a drug product
Suitability ~ Appropriateness, proper fit,
suitable for its use
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Miriam- Webster
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“the quality or state of being especially suitable or
fitting”
Why is an ingredient’s suitability
important?
Are these suitable for their intended end uses?
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Suitability of An Ingredient
Building the criteria and defining the
characteristics of the ingredient
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What is its intended end use?
• What are the quality characteristics needed for
the ingredient for the intended end use?
• What compliance characteristics are needed for
the ingredient for the intended end use?
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When the ingredient is an excipient,
what standards need to be followed?
Food, Drug and Cosmetic Act
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As Per FD&C Act --- A drug is considered to be:
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Articles recognized in the official United States
Pharmacopoeia
Articles intended for use in the diagnosis, cure,
mitigation, treatment, or prevention of disease in man or
other animals; and
Articles (other than food) intended to affect the structure
or any function of the body of man or other animals;
Articles intended for use as a component of any article
specified in clause
Excipients are used as a component of a
drug product.
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Components of a Drug Product
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Drug Products contain:
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Active Pharmaceutical Ingredients
Excipients
Why are Excipients in a drug product?
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Route of Administration
Bioavailability
Stability
How do you know if your ingredient is
suitable for use as an Excipient?
Industry Guidance for Excipients
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Guidance for Excipients
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IPEC-PQG
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GMPs
Distribution Practices
Qualification of Excipients for use in
Pharmaceuticals
Excipient Information Packet
WHO
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Good Trade and Distribution Practices for
Pharmaceutical Starting Materials
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5/11/2015
Excipient Quality And Compliance
Quality and Compliance Characteristics
Supply Chain
Management
Regulatory
and Quality
Support
Excipient
Manufacturing
Controls
Release
Testing
Supply Chain
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Raw Material Synthesis
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Compliance and controls of Chemical Synthesis
Management of Supply Chain
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Responsibility of Raw Material Manufacturer
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Quality Inspection and Verification
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Capacity and Capabilities
Audits
Questionnaires
• Continuous Communication
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Testing of Material - Receiving Criteria
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Inspection of Material and Packaging
Each lot tested before use to confirm predetermined
specifications are met
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5/11/2015
Manufacturing Controls
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Process Development
Product Characteristics
Equipment for Manufacturing
• Consistent manufacturing meeting predetermined
specifications
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Equipment Qualification
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Verify that equipment
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Has been installed as per specifications
Operates as necessary for the developed process
Performs as intended for consistent product manufacturing
Process Validation
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Prove process works as intended
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Proven acceptable ranges
In-process controls are tested and accepted
Product meets predetermined specifications
Release for Approval
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Product Meets Specifications
In-Process controls are achieved
• Testing the product to ensure conformance to
specifications
• Certificate of Analysis issued to represent the
quality of a product
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Product Manufacturing conforms to process
controls and limits
Manufacturing records are in compliance
• Full traceability is evident
• All steps of manufacturing are completed,
reviewed and approved
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5/11/2015
Regulatory / Quality Support
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Impurity and Degradation Profile
Stability
Regulatory Information
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Documentation to support Regulatory Fillings
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Traceability
Transparency
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DMF Type IV
Customer Audits
Management of Change
Life Cycle of the Excipient
Raw Materials
Excipient
Manufactured
Excipient
Approved for
Use
Use of the
Excipient
How is the excipient used in the drug product?
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Functionalities of Excipients
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Excipients in Solid
Dosage
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Diluents
Disintegrants
Binders
Lubricants
Glidants
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Excipients in Liquid
Dosage
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Solvent/Co-Solvent
Buffering Agent
Anti-Microbial
Anti-Foaming
Agents
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Thickening
Sweetening
Flavoring
Considerations for Suitability of Excipients
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Not always inert substances
Some shown to be toxic
• FDA – Guidance for safety evaluation of new
excipients for use in human consumption
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Factors to consider
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Perform risk based assessment
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Establish permissible and safe limits
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What ingredient is necessary and why?
How much of the ingredient is necessary?
Provide supporting documentation for use
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What is the function in the drug formulation?
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Impacts and Risks
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Address Impact and Risk from synthesis to end use
application
Ingredient – Synthesis
• Raw materials used in synthesis
• Multi-Use Equipment
• Potential Byproducts
• Critical Parameter Controls
• Handling
• Additional Manufacturing
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How does the additional manufacturing impact the
characteristics of the excipient?
What level of purity is the final released material?
Are processes controlled to produce a product suitable for
its intended end use?
Supply Chain Distribution
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What are the impacts to storage and distribution of the
material?
Excipient Interactions
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Drug - Excipient Interactions
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Undesirable Interactions - Incompatibilities
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Changes that may occur:
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Physical
Chemical
Therapeutic properties of the dosage form
Color and appearance
Potency
Stability / Degradation products
Product characteristics
Predict incompatibilities and interactions and
provide justification for selection of excipient
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5/11/2015
What Factors Need to Be Addressed
Impacts
Communication
Excipient
Drug
Product
Excipient
Manufacturer
Patient
Drug Product
Manufacturer
Communication
• Honest
• Transparent
• Continuous
• Drug Product Manufacturer must communicate specific needs to
Excipient Manufacturer.
• Excipient Manufacturer must provide traceability and
transparency to Drug Product Manufacturer.
Product Suitability
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Goal is to provide a product suitable for its
end use application
Conformance to Product Characteristics
• Excipient manufacturer must provide an
excipient suitable for its specific use in a drug
product
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Communication: intended use, quality, compliance,
specifications, changes and concerns
Drug Product Manufacturer needs to provide a
product suitable for end patient consumption
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Communication: intended use, dosage,
contraindications, concerns with end product use, etc.
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Suitability Declaration
Considerations For Excipients
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Meets requirements for use in drug product
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Safety, quality, identity and purity
Manufactured in a controlled manner, designed
for use as an excipient, exhibiting consistent purity
and absence of contamination
• Compliance Characteristics of Product and Supply
Chain
• Supporting Documentations for Drug Application
and drug product manufacturing
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Considerations listed are presented in a
convenient and simplified version
“Key Compliance Attributes”
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Product Grade Selection Guide
Key Compliance Attributes
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Supply chain traceability
Validated and qualified processes
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Using qualified and consistent raw materials
Validated test methods
Supplier audits
Regulatory packets
Process and product documentation
Origin statements
• Process flow diagram
• Release testing criteria
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5/11/2015
Key Compliance Attributes
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Grade of Product Specific to intended end use
needs
Increase grade based on necessary
compliance attributes
Reagent
• Excipient
• Active Pharmaceutical Ingredients
• Sterile
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Each grade intended to support the
development of a drug product
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From development through commercial
manufacturing for human consumption
Tools for Compliance Attributes
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Continuous Communication
Supply Agreements
Quality Agreements
Verification and certification of attributes
Intended end use statements
Certificates of Analysis
Scheduled Questionnaires
Recurring Inspections
Attributes considered in the selection of a grade
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5/11/2015
Attribute Examples
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Suitable for Research and
Diagnostic
Each Batch 100% Analyzed
Validated Analytical Methods
Compendial Testing
Trace Metals Analyzed
Two Year Stability
Validated Manufacturing Process
Supply Chain Audit Trail
US Manufactured
Manufactured in FDA Registered
Facility
IPEC GMP Compliant
Manufactured
Product Origin Statement
Suitable for use as Excipient
Multi-Compendial Testing
Enzyme Tested
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Microbial / Endotoxin Tested
Management of Change
Customer Quality Audits
Customized Additional
Specifications
Customized Manufacturing
Schedule
Custom Regulatory Packet
Accelerated Stability
Type IV Drug Master File
Video Conference access to Sites
Complete access to Product
Traceability
Access to Supply Chain Information
ICH Q7 Qualified Utilities
ICH Q7 Compliant Manufactured
Suitable for use as Active Ingredient
Type II Drug Master File
Excipient Needs
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Important Aspects of an Excipient
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Safety
Suitability
Compatibility
Does your supplier meet these needs?
Does the actual manufacturer know and
understand these needs?
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End user requirements
Communication of needs
Distribution channel impacts
Manufacturer knowledge and understanding
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5/11/2015
Distribution Channel
Base
Chemical
Manufacturer
Base
Chemical
Distributor
Excipient
Manufacturer
Excipient
Distributor
Drug Product
Manufacturer
With Cooperative Interaction
Base
Chemical
Manufacturer
Excipient
Distributor
Excipient
Manufacturer
Base
Chemical
Distributor
Drug Product
Manufacturer
Partnership – Manufacturer/Customer
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Partnership- Defined as “the state or condition
of being a partner; participation; association;
joint interest.”
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Joint Interest •
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Safety of the consumer
Consistent Supply
Sales
Eliminate areas of non-compliance
Assuring the Partnership •
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Supply Agreements
Quality Agreements
Inspection
Approval
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Benefits of Appropriate Suitability
for Intended End Use
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Consumer safety
Correct value point at each stage of
development
Consistent supply of product for consistent
and suitable end use
Shared responsibility for
the intended end use
Appropriate supply chain
transparency
Thank You
Questions
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