First Annual Multiple PDA-IPEC stakeholders; Excipient one objective. Workshop · 2020-03-09 · Workshop March 4, 2020 International Pharmaceutical Excipients Council ... IPEC-PQG

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]

Copyright 2019, All Rights Reserved, IPEC-Americas

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


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


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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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


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



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?


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


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


Often small scale batch processes

Typical API Manufacture


Often manufactured by continuous production in an industrial chemical facility and packaged in bulk

Manufacturing of Excipients



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.


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


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


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’!


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


Excipient Performance


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!!


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


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!


Excipient Variability

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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?


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)


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


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.


New QbD Guide Under Development

DRAFT


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:


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!!!


Questions

Documents

First Annual Multiple PDA-IPEC stakeholders; Excipient one objective. Workshop · 2020-03-09 · Workshop March 4, 2020 International Pharmaceutical Excipients Council ... IPEC-PQG