International Pharmaceutical Excipients Council Collaborative solutions for excipient industry stakeholders
Multiplestakeholders;one objective.
First Annual PDA-IPEC Excipient
Workshop
March 4, 2020
International Pharmaceutical Excipients Council Collaborative solutions for excipient industry stakeholders
Multiplestakeholders;one objective.
The Impact of Composition and
Excipient Variability on QbD and Drug
PerformanceMarch 4, 2020
David R. Schoneker, IPEC Americas
Vice Chair for Science and Regulatory [email protected]
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The views, thoughts, and opinions expressed in the presentation
belong solely to the author, and not necessarily to the author’s
employer, organization, committee or other group or individual.
Disclaimer
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Who We Are
IPEC is the industry association that develops, implements, and promotes global use of appropriate quality, safety, and functionality standards for pharmaceutical excipients and excipient delivery systems.
IPEC Federation and its members serves as the primary international resource on excipients for its members, governments and public audiences.
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IPEC Offers Excipient Stakeholders a Regional Voice with Global Reach
The IPEC Federation, established in 2009 and based in Belgium, is composed of regional IPEC organizations
IPEC-Americas Representing North, South and Central America
IPEC Europe Representing Europe, North Africa, Middle East
IPEC Japan IPEC China IPEC India
IPEC Federation seeks to harmonize guidelines across regional organizations
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IPEC Guides….. Significant Change Risk Assessment Certificates of Analysis (CoA) Excipient Qualification (EQ) Excipient Stability Program Excipient Information Package (EIP) Excipient Composition Technically Unavoidable Particle Profile Quality Agreement (QA) IPEC-PQG Good Manufacturing Practices (GMP) Good Distribution Practices (GDP) U.S. Drug Master File Guide QbD Sampling Guide
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Copyright 2019, All Rights Reserved, IPEC-Americas
IPEC Guides….. Significant Change Risk Assessment Certificates of Analysis (CoA) Excipient Qualification (EQ) Excipient Stability Program Excipient Information Package (EIP) Excipient Composition Technically Unavoidable Particle Profile Quality Agreement (QA) IPEC-PQG Good Manufacturing Practices (GMP) Good Distribution Practices (GDP) U.S. Drug Master File Guide QbD Sampling Guide
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Excipient Composition
2009 2019
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Excipients are very different than APIs and CANNOT be treated in the same manner as APIs
Excipients typically are mixtures made up of a number of components – they are usually NOT PURE!! – composition profile is important!
Depending on the excipient, there will always be a certain amount of variability that will exist – this MUST be accepted! Robust formulations must be developed which are not
impacted by this inherent variability
Excipient Realities
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Excipient Composition
What comprises excipients? The nominal excipient What else?
It depends! On the source of the raw materials (feedstock) How the excipient is manufactured How the excipient is processed Are there any additives?
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Excipients are Diverse Materials Chemical synthesis (polymer mixtures, cellulose
derivatives) substances often less defined than APIs
Mining of minerals Harvesting of vegetation Formulated products Biotechnology & fermentation Animal by-products
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The scale of manufacture is usually much larger than for standard APIs and normally only a small portion of the stream is
used as an “excipient”
Manufacturing of Excipients
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Often small scale batch processes
Typical API Manufacture
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Often manufactured by continuous production in an industrial chemical facility and packaged in bulk
Manufacturing of Excipients
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Excipient Composition
Most Excipients are not pure substances and probably wouldn’t perform the same if they were. Many excipients are multi-component materials.
Residual and trace materials present in excipients are important inherent components which can impact the key functionality of the excipient when used in a drug product formulation.
Other components in an excipient are not considered impurities – purer is not necessarily better with excipients
Other components in an excipient may vary from supplier to supplier due to different raw materials, mfg. processes, additives and processing aids used.
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Finishing
Final isolation
Sources of Excipient Components
1. Concomitant components2. Residual solvents3. Residual catalysts4. By-products
Processing steps
PackagedExcipient
Processing aid
Additives
Starting material(s)
(Feedstock)
Co-processing component
1. Residual solvents
Bulk finished excipient
Excipient composition1. ‘Nominal’ component(s)2. Additive(s)3. Processing aid(s)4. Concomitant components5. Residual processing aids6. Residual solvents7. Residual catalysts8. By products9. Unreacted starting materials10. Starting material components
Co-processing component
1. Concomitant components2. Unreacted starting material3. Other components from starting
materials4. Starting material impurities
IPEC Excipient Composition Guide, 2009
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Excipient Components
Nominal chemical Polymer molecular weight distribution
Concomitant components Reaction by-products Residual starting materials and reagents Processing aids
Undesirable components Potentially toxic components, e.g. monomer residues in
some polymers
Residual solvents Elemental residues Water Additives
May not be known by the User!!
Typically present! No problem if Non-Toxic
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Additives and Processing Aids in Excipients
There is a lot of misunderstanding in this area: There are additives (and residual processing aids)
that have been present for many years, but have not been declared: Many excipient manufacturers have been unaware of the
specific labeling requirements of USP-NF (and other compendia) General Notices concerning additives
Intellectual property issues surrounding additives and processing aids.
Some so-called ‘additives’ are actually ‘residual processing aids’ carried over from earlier stages in the processing or extraction of the excipient.
Additives and residual processing aids should not be regarded as ‘bad’!
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Example: BHT in some PEGs
IPEC-Americas has submitted a request to the US FDA to discuss this issue and determine a way forward which will allow for disclosure that additives or residual processing aids may be present to the customer but allow for methods (such as a DMF) to be used for sharing the specific confidential details on what exactly is present and how much with the FDA – stay tuned!!
Additives and Processing Aids in Excipients
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Excipient Performance
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Excipient Performance
It is not always known what correlates with the performance of an excipient in a particular application (formulation). Unknown Unknowns
It can be said that performance must arise from a combination of: The chemical composition of the excipient The chemical nature of the nominal excipient The composition profile of the excipient■ Including concomitant components!
Molecular weight distribution for polymers The physical properties of the excipient The physical form of the excipient
Excipient performance will change with the application (formulation). KEY POINT!!
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How can we assess excipient performance?
Excipient performance is application (formulation) specific. How an excipient functions in one formulation may have
no bearing on how it performs in another formulation.
Assess each delivery of excipient by manufacturing a preliminary small-scale batch? Inefficient in terms of time and materials.
Surrogate tests? To mimic the intended application. But, which tests? USP-NF <1059> Excipient Performance - preferred Ph.Eur. – Functionality-Related Characteristics (FRCs) –
not preferred due to FRCs in monographs
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Challenges in understanding the link between Excipient Composition and Excipient Performance
We can see the effects of poor understanding in failed product batches: But is it the API, the excipient, the process or a combination
of them?
We can sometimes link poor performance to a particular material attribute, but only for a specific application: We do not have a universal understanding of the link
between excipient composition, physical properties and performance. Is there one?
We frequently do not properly understand what we need to measure, and we very often do not have adequate methods with which to measure the parameter.
We know what we know……BUT we do not know how much we don’t know!
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Excipient Variability
This Photo by Unknown Author is licensed under CC BY-NC-ND
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Excipient Variability
There is variability in everything, and excipients are no exception. We must accept that there will be variability and come to
terms with it.
Excipient variability may contribute to product variability; but it is not the only potential source of product variability. Variability in API and process parameters can also impact
product variability.
We can sometimes see the effects of excipient variability in ‘failed’ product batches. Can we adequately control excipient variability? Do we know what to test, and how to test?
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What is a Robust Formulation? A formulation that is able to accommodate the
typical variability seen in: API
Excipients
Processes
Without compromising the manufacture, stability, performance or any other attribute of the product critical to the patient’s care or well being. (Moreton)
“Ability of a process to tolerate variability of materials and changes of the process and equipment without negative impact on quality.”
Process robustness, in ICH Q8(R2) August 2009)
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IPEC QbD Sampling Guide
IPEC-Americas recentlypublished a new QbD SamplingGuide to provide assistance when assessing what samples may be useful to evaluate therobustness of a drug product formulation
The Guide is available on the IPEC-Americas website for free
Very helpful when doing DOE studies
Recognizes the limitations of what suppliers can and cannot provide
Information exchange is critical to all QbD Projects
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Improved Communication is Critical
Two-way communication between the excipient user and manufacturer is key!
Excipient suppliers will typically have a much better understanding of an excipient’s compositional profile than excipient users
Excipient users should consider their suppliers as partners as well as suppliers and be prepared to exchange information (under CDAs) on how they are using the excipient to allow their suppliers to better help them.
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New QbD Guide Under Development
DRAFT
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Introduce Quality-by-Design (QbD) and pharmaceutical formulation development concepts to excipient manufacturers and suppliers.
Provide an explanation of how the changes in pharmaceutical formulation practices, due to the introduction of QbD, impact excipients, manufacturers, and suppliers.
Provide understanding for excipient manufacturers and suppliers as to what their customers will likely require for QbD formulation projects.
Provide understanding to excipient users and regulatory authorities regarding what may or may not be possible when incorporating excipient variability into QbD formulation projects.
This Guide is intended to:
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This Guide includes recommendations regarding the impact of excipient variability on finished drug product quality during development and to justify management of excipient variability in the control strategy.
It contains useful explanations and suggestions for both makers and users of pharmaceutical excipients.
Overall Purpose of the QbD Guide
Coming Soon!!!
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Questions