What is it? ICH Q3D and USP & Current ... - Elemental...Finished Product Analysis ICH Option 3....

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The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.

®

Current Implementation Status of ICH Q3D in the U.S

and Europe - Industry Perspectives

David R. Schoneker

Director of Global Regulatory Affairs

Vice Chair of Science & Regulatory

Policy – IPEC-Americas

Email: [email protected]

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What is it? – ICH Q3D and USP <232> & <233>

■ICH Q3D

A Requirement for Drug Manufacturers: − Requires an risk assessment of the potential elemental impurities present in drug

products.

− PDE compliance required for drug products.

■ USP <232> & <233>

<232> Specifies limits for the amounts of elemental impurities in drug products.

<233> describes two analytical procedures for the evaluation of the levels of the elemental impurities.

− The chapter also describes criteria for acceptable alternative procedure.

Potential sources of elemental Impurities :

Drug substance, Excipients, Manufacturing equipment & Packaging.



■ Applies to:

ICH Q3D: All human drug products.

USP : All Drug products.

■ Does not specifically apply to:

ICH Q3D – Components, i.e. Drug Substance/ Excipients

USP – Excipients and Drug Substance (except where specified

in the monographs)

Emphasizes the use

of Risk Assessment as opposed to testing

wherever possible


Recent ICH Activities





•The ICH Q3D EWG is currently working on

developing an appropriate approach for topical

drug formulations since the definition of a dose

is not defined clearly at this time for these

drugs.

•A draft guideline is expected in late 2018

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■ Key point – the PDE requirements apply ONLY to the drug product itself! Responsibility for compliance is placed completely with the drug manufacturer.

■ There is NO compliance requirement for excipient suppliers other than to share what they may know and what they do not know about EI in their excipients – may be very little!

■ This is appropriate since many of these materials are primarily produced for other markets and the risk to the patient is from the drug product, not the ingredient!


Pharmaceutical Excipient Industry –

Different than Drugs!

Majority of Pharmaceutical Excipient Suppliers are Chemical Industry

subsidiaries

Products targeted at Food, Beverage, Industrial and Cosmetic.

Small fraction of Main Production Volumes for excipient –

sometimes less than 0.1% of business

Varying degrees of dedicated R&D related to excipient uses

Specifications-driven by main market (usually not Pharma)

Global Market and Manufacturing Base


What is the Excipient Industry?

Diverse Materials Base

Chemical synthesis (Polymer mixtures, Cellulose derivatives –

substances often less defined than low

mol wt entities)

Mining of minerals

Harvesting of vegetation

Formulated Products

Biotechnology &

Fermentation

Genetic Modification

Animal by-products

Excipients may come from the farm or natural

environment and are processed and packaged

into excipients.


Excipient Realities

Typical Mining Pit Operation

Talc extraction in TrimounsTalc Mine,

Midi-Pyrenees, France Kaolin mine near Kaznejov, Czech Republic


Excipient Realities

Iron Oxides

–from scrap

metal to

oxidation

tanks

Raw Material

for Iron Oxide

Manufacturing


Excipient Realities

Cellulose

Sources –for

MCC, Cellulose

derivatives, etc.

Brown Seaweed –used to

manufacture Sodium Alginate

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Risk Assessment – Scope of ICH Q3D

■ ICH Q3D Approach to Risk Assessment

• ICH Q3D defines a science and risk based assessment process to identify,

evaluate, and define controls to limit elemental impurities in drug products.

• Identify known and potential sources of elemental impurities that may find

their way into the drug product.

• Evaluate the presence of a particular elemental impurity in the drug product

by determining the observed or predicted level of the impurity and comparing

with the established PDE.

• Summarize and document the risk assessment. Identify if controls built into

the process are sufficient or identify additional controls to be considered to

limit elemental impurities in the drug product.


Risk Assessment

■ Risk Process – General Principles

ICH Q3D advocates a 3 step process:

• Identify

• Evaluate

• Summarize Control

■ Component Approach

Different approaches to each stage are examined

through a series of actual risk assessments.

− ICH Q3D option 1, 2A or 2B.

− Assess potential elemental impurities from

each component of the drug product (API,

excipients, container closure system).

− Assess each component for potential

sources of elemental impurities.

− Identify known or likely elemental

impurities.

− Determine the contribution of each

component or source of elemental impurity

to the levels in the final drug product.


Risk Assessment -

■ Finished Product Analysis

ICH Option 3.

Assessment of potential elemental impurities in the

drug product

− Identify potential elemental impurities and their source(s).

(API, excipients, container closure system).

− Initially analyze for elemental impurities in finished drug

product.

− Decide whether to routinely test for elemental impurities in

finished product.


LIFE CYCLE MANAGEMENT

Initial

Elemental

Impurities

Risk

Assessment

completed

An understanding of how changes in the product/process and/or

components may impact the Elemental Impurity risk assessment and the need for a control strategy on the drug product.


Risk Potential for Elemental Impurities in Excipients

Elemental Impurities

in Excipients

Mined (e.g. Talc)

Synthesized with Metal Catalyst (e.g. mannitol)

Plant Origin (e.g. cellulose derivatives)

Animal Origin (e.g. lactose & gelatin)

Synthesised without Metal Catalyst (e.g. colloidal SiO2)

Increasing

Potential Risk of

Contributing

Elemental

Impurities

What data exists today?


Unknowns - Analysis by FDA lab

Q1 2012

Law office for IPEC

–Americas collected,

blinded and

submitted excipient

samples to FDA lab

for analysis

Q2-Q4 2012

FDA

analyzed

samples using

ICP-MS

Q1 2013

Law office un-

blinded and

sent results to

original

submitters.

Q1 2013

Additional

samples

sent to FDA

2014

Study

completed -

Industry

assessed FDA

results vs

industry results

FDA & IPEC

published data

in journal

- Fall 2015

IPEC Americas

request for “blinded samples” to be tested by FDA lab

http://www.google.co.uk/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRw&url=http://www.toxikon.be/services/EandL_Parenteral_injectables.cfm&ei=CKD9VJ-FNMuBPabSgLAE&bvm=bv.87611401,d.d2s&psig=AFQjCNGQvyFG1USDfp7zu6cgy28dg5B1_A&ust=1425994112173701

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LHASA Database

■Database Development:

• Database created by EI Pharma Consortium to gather a critical mass of data for excipients.

• Aid in risk assessment and overall understanding of excipient risks.

• Intent to publish key findings to de-risk common excipients.

• Current membership mainly from big pharma in partnership with Lhasa.

• Contact: Crina Heghes ([email protected])

■Appropriate Use of Published Data – Data is blinded so it will be important to establish a scientifically sound bridge from this data to the grades and suppliers actually used in the drug product – cannot simply use the data in your risk assessment!


The Problem with Available Data

■Data in the literature (such as the FDA study) or that may exist from shared study information (such as Lhasa) is general and not specific to the actual grade and supplier of an excipient used in your particular drug product!

■This information may be useful to give you an idea of what elemental impurities “might” exist in the excipients you use in your drugs, however, without knowing that the data applies specifically to the grades you use, this data is fairly irrelevant for use in a risk assessment of the components in YOUR drug product!

■Users must still do appropriate testing of their grades or get supplier specific information to properly do their risk assessments

■The suppliers of the excipients which were included in the FDA study were provided with the results for their specific samples through the blinding exercise. Therefore, they have some good information about what might be present in the grades they supply.


Supplier Information (API and Excipient)

■ Some excipient suppliers are fully engaged with this initiative, while others will not

engage at all.

■ This will depend on whether the pharmaceutical uses of the excipient make up a

significant share of their business or not – business potential will drive decisions,

not regulatory requirements

■ Most suppliers will only have EI information for elements which may have previously

been listed in a compendial monograph or is of interest to their other markets which

usually will drive their testing (ie; food, electronics, industrial)

■ Most suppliers do not plan to do any additional routine testing for elemental impurities

due to ICH Q3D/ USP <232> <233> and have no intention of agreeing to any new

specifications – there may be some exceptions

■ Some suppliers have done some designed studies on a limited number of batches to

improve their knowledge of potential EI in their products so they can provide some risk

assessment assistance to their customers

The level of information provided will typically vary quite a bit from supplier to supplier.


®

Can we Really Predict EI Levels in

Various Types of Excipients?

Sometimes……..but not Always!


EI Content from Excipient Sources

Plant-derived Excipients

− Grown in soil (e.g. cellulose derivatives)

− Harvested from the ocean (e.g. alginates,

carageenan)

Synthetic Excipients

− Derived from oil through synthetic processes –

may use metal catalysts (e.g. povidone, PEG,

silicones)

Mineral-based Excipients

− Conversion of ores from mines (e.g. TiO2)

Metal content is often inherent (due to sourcing) and cannot

be “easily” reduced or removed

Excursion Potential


Excursions - Potential Normal Variation

■Many metal impurities are naturally present (e.g. lead) in mined excipients and cannot be further processed out; therefore, it is important to understand the actual levels present

Normal

variation can

be expected

from

excursions

that occur in

the raw

material

source –

CANNOT be

predicted!

Ongoing trend analysis will need to

be done by excipient manufacturers

and users for materials with a

potential for excursions for certain

elements. Various methods can be

used.

Excursions

can occur in

any excipient

derived from

nature

depending

on process

capability

mailto:[email protected]

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Potential for Predictability of EI Content

■Plant-derived Excipients

− Depending on the understanding of source

variability and level of processing, worst case

predictions may be able to be made

− Probably need a significant test result history for

accurate predictions – MORE THAN 3-6

batches!

■Synthetic Excipients

− Dependent on process capability – highest

likelihood of predictability

■Mineral-based Excipients

− CANNOT be accurately predicted unless

significant processing is done

− Years of data needed for a semi-accurate idea

of worst case! – MORE THAN 3-6 batches!


Compendial Requirements – USP and PhEur

■ The EI requirements are now official in the USP and PhEur since January 1, 2018

■ This applies to both new drugs and existing drugs in the U.S. and Europe

■ All drug products in the U.S and Europe now need to comply with the PDE requirements

■ Routine testing is NOT required if a scientifically justified risk assessment has been performed.

■ However, some testing may need to be done by users to do an adequate risk assessment depending on how much information they may have on their raw materials and the level of the raw materials in their formulation – typically supplier information alone may not be enough if the API or excipient make up a fairly large portion of the final drug formulation and there may be a significant risk involved depending on the type of excipient used


Specific Metal tests in Monographs USP

NOTE: Limit tests and references to element specific chapters are

included in about 1000 monographs

■ USP published a Stimuli Article: Future of Element –

Specific Chapters in the USP–NF

What will be the future of USP chapters that provide specific

information regarding the analysis of individual elements (Arsenic

⟨211⟩, Lead ⟨251⟩, Selenium ⟨291⟩, Mercury ⟨261⟩, and others?

What about USP monographs that may have limit tests for specific

elements and refer to their respective element-specific chapters for

methodology?

What about USP monographs that include limits for specific elements

that differ from the limits established in ⟨232⟩?


Specific Metals Tests in Monographs Industry Assistance

■ IPEC-Americas assisted USP in developing a priority list of monographs containing specific metals.

■ IPEC-Americas has requested Industry to supply historical data/information to USP directly on specific metals in the monographs.

■ USP will evaluate the historical and literature data/information and determine if any changes are needed in the monographs or if certain elements can be removed – monograph modernization

■ If changes are needed they will proceed through the normal USP Pharmacopeial Forum (PF) process.

■ The European Phamacopeia is also working on specific elements

in monographs but in a different way! They intend to remove all requirements for elements that are covered in the drug product by ICH Q3D except for certain mined excipients

Could lead to harmonization issues with USP and JP


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The Need for Improved Communication

between Users and Makers is Significant to

Improve Understanding of the Realities!


Sharing Information between Makers & Users

IPEC Template Information Exchange Request

IDEAL WORLD….

Pro-actively completed

by suppliers and sent

to users

download THE

TEMPLATE

URGENT industry need for BASE-LINE DATA!

REAL WORLD…

A limited number of

suppliers have data or

will complete and

return the form to

users

download THE

LETTER

PDE Calculator

also available on

IPEC-Americas

website to assist

in Risk

Assessment

http://ipecamericas.org/system/files/IPEC_Elemental_Impurities_template_ICH_Step_2b_FiNAL.docx

http://ipecamericas.org/system/files/IPEC_Elemental_Impurities_template_ICH_Step_2b_FiNAL.docx

http://ipecamericas.org/system/files/Cover_letter_elemental_impurities_template_FINAL.doc

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What is it? ICH Q3D and USP & Current ... - Elemental...Finished Product Analysis ICH Option 3....

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