ICH Q3D Elemental Impurities - Multiple Implementation ... · products should control elemental...

International Pharmaceutical Excipients Council

Collaborative solutions for excipient industry stakeholders

Multiple

stakeholders;

one objective.

ICH Q3D Elemental

Impurities -

Implementation

Considerations

ExcipientFest 2017

Phyllis Walsh: Vice Chair for

Harmonization and Compendial

Monographs

Dave Schoneker: Vice Chair for

Science & Regulatory Policy

Copyright 2017, All Rights Reserved, IPEC-Americas 2

Elemental Impurities Workshop Agenda

Back Ground Information on Elemental

Impurities

Scope of ICH Q3D Guideline

Compendial Requirements

Specific Metals Tests in Monograph

EMA Guideline

Draft FDA Guideline

ICH Q3D Developments for Topicals

Pb As Hg

Cd Co V

Ni ???



Implementation by Region

Implementation Timelines & ICH regions - Regulatory Filings

Developments in other countries

Life Cycle Management



Analytical and Risk Assessment Challenges

Methodologies concerns

Collaborative study performed

PQRI Phase 2 testing initiated

Lhasa database

Supplier information (API and Excipient)

Risk Assessment Approaches

Q&A



Case studies – ICH Modules

Solid Oral Dosage

Working Example

Copyright 2017, All Rights Reserved, IPEC-Americas

Back Ground Information on Elemental Impurities

6



Specific Metals Tests in Monograph

EMA Guideline

Draft FDA Guideline



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 Process – General Principles

ICH Q3D advocates a 3 step process:

Identify

Evaluate

Summarize Control

Different approaches to each stage are examined through a series of actual risk assessments.


Risk Assessments

ICH allows you to use the Component Approach or Finish Product Analysis.

The Component Approach is ICH Q3D option 1,

2A or 2B.

The Finish Product Analysis is option 3.


Risk Assessments

Finish Product Analysis

The Finish Product Analysis is option 3.

Assessment of potential elemental impurities from

each component of the drug product (API,

excipients, container closure system).

Need to know what potential elemental impurities

are present.

May need to test finished product.


Risk Assessments

Component Approach

The component approach is ICH Q3D option 1, 2A or 2B.

Assessment of 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.


Potential Sources of Elemental Impurities

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



USP

General Chapters <232> & <233> are

official but not yet implemented.

<232> revisions proposed in PF to align with ICH Q3D

General Notices 5.60.30 Elemental Impurities official

01-Jan-2018.

General Notices 5.60.30 Elemental Impurities official on

January 1, 2018 is the date on which General Chapter

<232> will become broadly applicable to drug products.

Heavy Metals General Chapter <231>

Chapter will be deleted from USP-NF on 01-Jan-2018.



European Pharmacopoeia (Ph. Eur.)

Prior to 2008 No guideline for safety limits

only Heavy Metals General Chapter.

2008 EMA guideline on specification limits for

residues of metal catalysts or metal reagents

(known metals).

General Chapter 5.20

2014 ICH Q3D development and implementation

(Official 01-Jan-2018 Ph. Eur. 9.3)

Replace General Chapter 5.20 - Only parts of the

introduction and the scope of ICH Q3D together with

information specific to Q3D in the Ph. Eur.

Will not republish entire ICH Q3D into Ph. Eur.



European Pharmacopoeia (Ph. Eur.) (cont.)

General method 2.4.20 Determination of elemental

impurities.

Editorial revision to align the wording with the ICH Q3D

guideline will be published in Ph. Eur. 9.3.

“metal catalyst and metal reagent residues” to “elemental

impurities.

General Method 2.4.8 Heavy Metals

Will not be deleted since needed for Veterinary use.

All references in monographs for Human products is

deleted.



European Pharmacopoeia (Ph. Eur.)

(cont.)

General monograph on Substances for

Pharmaceutical use (2034):

Introduce requirements for the control of elemental

impurities intentionally added during production and

explains the absence of a test for elemental impurities from

individual monographs except for special cases.

The identity of the elemental impurities derived from

intentionally added catalysts and reagents is known and

strategies for controlling them should be established by

using the principles of risk management.



European Pharmacopoeia (Ph. Eur.) (cont.)

General monograph on Pharmaceutical Preparations (2619)

Refers to chapter 5.20, rendering it and by extension the ICH Q3D guideline legally binding.

Clarification for medicinal products outside of the scope of ICH Q3D guideline manufacturers of these products remain responsible for controlling the levels of elemental impurities using the principles of risk management.

■ If appropriate, testing is performed using suitable analytical procedures according to general chapter 2.4.20 Determination of elemental impurities.

■ Elemental Impurities should at least be considered in risk management strategy


Specific Metals Tests in Monographs - USP

USP published a Stimuli Article Future of

Element - Specific Chapters in the USP–NF

with questions on specific metal tests in monographs.

What will be the future of USP chapters that provide specific

information regarding the analysis of individual elements, such as arsenic (As) Arsenic ⟨211⟩, lead (Pb) Lead ⟨251⟩, selenium

(Se) Selenium ⟨291⟩, mercury (Hg) 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⟩?

Limit tests and references to element specific chapters are

included in about 1000 monographs


Specific Metals Tests in Monographs Industry Concerns

Industry response to USP Pharmacopeias should not change an existing monograph

specific element requirement (methods/limits) unless evaluated as part of an individual monograph modernization activity designed to include specific metal requirement.

Existing element limit requirements and test methods should stay in the monographs and not be removed – to allow for comparisons with historical methods/data.

History supports limits/test methods which can be used in risk assessments as worst case examples AND provide useful information to users since actual detailed information is limited.

No changes should be made to the limits and no new elements should be added based on a limited amount of batch testing, since excursions won’t show up except over long-term history.


Specific Metals Tests in Monographs Industry Concerns

Industry response to USP (cont.) Current monograph limits and test methods are linked,

USP should not change the monographs to use the approaches for methodology and analysis in <233> or the existing limits unless validation work conducted demonstrates that the current methods in the monograph and any alternative methods give equivalent results

API suppliers: Elemental Impurities is for the finished drug product not the Drug Substances.

Removing specific metal tests from USP would impact API supplier, FDA would not allow deletion without justification.


Specific Metals Tests in Monographs Industry Assistance

IPEC-Americas is assisting USP in developing a priority list of monographs containing specific metals.

IPEC-Americas is requesting Industry to supply historical data to USP directly on specific metals in the monographs.

USP will evaluate the historical data and determine if any changes are needed in the monographs.

If changes are needed they will proceed through the normal PF process.


Specific Metals Tests in Monographs Ph. Eur.

In Ph. Eur. approx. 300 monographs describe more than 450 specific metal tests

Concerns - Specific Elemental Impurities in

individual monographs

Historical reason for the presence of the test in the

monograph

No change control for updating production pathways

(intentionally added metals)

Substances of natural origin (e.g. mined excipients) =>

Elemental Impurities potentially present but not intentionally

added



EDQM announced actions:

Test for heavy metals (method 2.4.8) will be deleted from all individual monographs except from monographs of substances for veterinary use only (9th edition).

Other tests for specific Elemental Impurities in individual monographs will be reviewed by groups of experts on a case by case basis. Secretariat provided lists of monographs concerned to the groups.

Specific tests in individual monographs for elements not covered by ICH Q3D will remain untouched but may be considered upon discussion of a monograph in the group.



EDQM decided to keep the published specific

elemental impurities tests in monographs on

substances of Natural Origin only.

Given the intrinsic nature of elemental impurities in Natural Origin

substances, they are amongst the major potential sources of elemental

contamination in medicinal products.

Recommended keeping the different tests for elements for which no

Permitted Daily Exposure limits have been established, i.e. those

identified as “other elements” in the ICH Q3D guideline (such as

aluminum and iron), in individual monographs.

Specific elemental impurities tests will be deleted from monographs on

other substances (i.e. not from natural origin), unless otherwise justified.

Specific tests for elemental contaminants originating from the

production process will be deleted.



EDQM Focus: Substances of Natural

Origin (mainly mined excipients)

Obtain batch data and revise tests / or add new

ones, if necessary based on batch data

Need for more expertise and support (especially

from manufacturers) to revise / maintain the tests


EMA - Implementation Strategy of ICH Q3D Guideline

EMA Implementation strategy of ICH Q3D guideline published as final on 08-Mar-2017

Same Risk Assessment Approaches as ICH Q3D for Drug Product or Component

Particulars for Intentionally Added Element(s) Any element intentionally added during manufacturing

must be included in the description of the drug substance manufacturing process in the marketing authorization dossier, an ASMF or a CEP application, as well as its fate and the need for any controls (for instance the use of a metal catalyst in the last step of the synthesis).


FDA Draft Guidance FDA draft Guidance for Industry published June 2016

Scope

How applicants submitting new drug applications (NDAs) or abbreviated new drug applications (ANDAs) for non-compendial drug products should control elemental impurities as described in ICH Q3D. ICH Q3D contains recommendations on applying a risk-based approach to control elemental impurities and permitted daily exposure (PDE).

How manufacturers of compendial drug products that are not marketed under an approved NDA or ANDA can comply with USP General Chapters Elemental Impurities—Limits and Elemental Impurities—Procedures and the Federal Food, Drug, and Cosmetic (FD&C) Act.

How holders of NDAs or ANDAs for compendial drug products should report changes in chemistry, manufacturing, and controls specifications to FDA to comply with General Chapters and 21 CFR 314.70.

How manufacturers of non-compendial drug products that are marketed without an approved NDA or ANDA should control elemental impurities.


FDA Draft Guidance

FDA Final Guidance is expected soon

Expected clarity on Biologics.

Expected clarity on OTC products documentation.

Expected filings by Annual Reports.


FDA Advice to Industry

Risk Assessment: Potential considerations during review

Intentionally added elements.

Contributions from raw materials derived from plant or marine origins.

Contributions from raw materials that are mined, e.g., Inorganic drug substances and excipients.

Contributions from manufacturing, e.g., high shear micronization using metal discs.

Leachable elemental impurities from container/closure.

Extractables information from container/closure components typically included in a supplier Type III DMF.



Currently topicals fall under ICH

“Other Routes of Administration”.

ICH Q3D announced the start of Q3D(R1) - Revised PDEs for the cutaneous and transdermal Route of Administration on September 15, 2016.

Develop PDEs for EIs for products administered on skin and its appendages (e.g., hair, nails); these products remain the largest area where PDEs for EIs have not been established.

Cutaneous and transdermal PDEs were not developed at that time due to the late request for inclusion (post Step 2). These products include both prescription and over-the-counter products.

Since the intact skin serves as a barrier to absorption, it is possible that not all EIs in Q3D will require cutaneous and transdermal PDEs, streamlining the risk assessment process for these products.


Implementation by Region

31

Implementation Timelines & ICH regions -

Regulatory Filings.

Developments in other Countries.

Life cycle management.


Implementation Timelines for US

FDA Draft Guidance Recommendations and Timelines for risk assessment and documentation of risk assessment:

New NDA and ANDA applications submitted after June 1, 2016 should follow the recommendations of Q3D.

Consistent with the EMA implementation timeline

For existing marketed products, manufactures should follow the recommendations of Q3D and/or comply with USP <232> by January 1, 2018. Consistent with USP implementation timeline for <232>

and <233>.


ICH Regions - Regulatory Filings - FDA

Anticipates most approved drug products marketed in the United States do not contain any elemental impurities that exceed the Q3D/ <232>PDEs.

Products that meet PDE recommendations of Q3D or comply with <232>PDEs.

Perform risk assessment to determine if additional controls (e.g. upstream controls, specifications) are needed by 1 January 2018.

Document changes in the next Annual Report.


ICH Regions - Regulatory Filings - FDA

New NDAs or ANDAs. Include a summary of the risk assessment application. Cite

supporting material (e.g., controls) as warranted.

The P.2 section (Pharmaceutical Development) is an appropriate location for the risk assessment summary.

Approved NDAs or ANDAs. Include a summary in the next Annual Report following the

completion of the risk assessment. Document changes to controls.

See FDA Draft Guidance for details if drug products exceed PDEs and changes are implemented to reduce EI levels

For drug products not approved under an NDA or ANDA. Include risk assessment in the documentation maintained at

the manufacturing site for Agency review during an inspection.


Implementation Timelines for EU

CHMP recommendations and timelines:

New MA for new product (new active substance).

Implementation date June 2016

New MA for product with existing active substance.

Implementation date June 2016

Marketed products including new MR applications of already approved products.

Implementation date December 2017


ICH Regions - Regulatory Filings - EU

New Marketing Authorizations:

Compliance with the Q3D PDEs.

Should document the risk assessment and the

control approaches.

The documentation of the risk assessment should be

kept available for inspection on site.

A summary of the Risk Assessment and any

measures taken to ascertain compliance is needed

in the regulatory filing.

The overall Control Strategy for elemental impurities

including any specifications included in the

regulatory filing.



Existing Marketed Products

Risk Assessment should be performed, documented

and be kept available.

No variation is necessary if the Risk Assessment shows

compliance: No further controls on elemental impurities to materials such as

the designated active substance starting material, synthesis

intermediates, active substance, excipients or the finished

product are needed.

No replacement or change of quality of materials such as the

designated active substance starting material, synthesis

intermediates, active substance, excipients or of the

manufacturing equipment is needed.

No change of the manufacturing process is needed.



Existing marketed products

In other cases a variation is needed:

Categorized according the Variation Guidelines

(Official Journal 2013/C 223/01)

Accompanied with the documentation required in

the Variation Guideline.

In addition contain a summary of the Risk

Assessment and the conclusions drawn.



Submission expectation

A Summary of the Risk Assessment to be submitted.

Full documentation of Risk Assessment available at site.

What should the Summary look like?

Should follow the principles lined out in ICH Q3D

Contain what is needed to evaluate the appropriateness and

completeness of the elemental impurities Risk Assessment.

Tell a story to the assessor on what has been considered,

done and concluded.

Raw data not expected, but summary of findings may be

necessary.

The justification for the Control Strategy (what to control and

not to control).



Where to be put in the dossier?

It is suggested: Summary of the Risk Assessment

3.2.P.5.5 Characterization of impurities (DP) (rather

than 3.2.P.2 Pharmaceutical development)

Depending on the outcome, data may also go into e.g.:

3.2.S.3.2 Impurities (DS)

3.2.S.4.5 Justification of specification (DS)

3.2.P.4 Control of Excipients

3.2.P.5.6 Justification of specification


Implementation Timelines for Japan

Japan MHLW recommendations and timelines:

For New Drugs – Implementation date: April 1, 2017.

For Marketed Products – Application of Q3D to

existing products approved before April 1, 2017 will

not be expected to 36 months (January 1, 2018) after

publication of the ICH guideline.

Official date on application to existing Marketed

products have not been announced.

The sponsor should study the feasibility of Q3D.

MHLW will evaluate applicability of Q3D to existing

products.


Developments in other Countries Australia TGA Q3D applies to registration

applications for prescription medicines.

The date for coming into effect aligns with implementation in the EU. New products containing new drug substance/s:

from June 2016.

New products containing existing drug substance/s: from December 2017.

No official statement for current marketed product.


Developments in other Countries Health Canada

Document for new

application/supplement Implementation date

Submission of a new abbreviated new

drug submission (ANDS) or drug

identification number (DIN) application

for a drug product should include the

content requirements as per Q3D.

Submissions received after

December 31, 2016.

Submission of a new Supplemental

(A)NDS or Post-DIN Change for a major

change to an existing Drug Product as a

result of the risk assessment per Q3D.

Submissions received after

December 31, 2016.



Document for marketed drugs Implementation date

Completion of the risk assessment for

elemental impurities. January 1, 2018.

Implementation of any manufacturing

changes to control the levels of elemental

impurities.

January 1, 2018.

Updated drug product specifications with a

statement confirming compliance with ICH

Q3D.

January 1, 2018.



OTC should comply with Q3D; natural health products

excluded

The risk assessment should be documented and

available for inspection

The locations where the elemental impurities-related

information can be placed for new submissions

Summarized in Module 2.3.P.5: Control of Drug Product of the

Quality Overall Summary, QOS.

Module 3.2.P.5.6 Justification of Specifications.

Risk assessment for the container closure system may be cross-

referenced to a master file.



The locations where the elemental impurities-related information can be placed for currently marketed products.

Quality Overall Summary Module 2.3.P.5: Control of Drug Product: a summary of the Module 3 locations where the elemental impurities-related information can be found.

Module 3.2.P.5.6 Justification of Specifications includes the overall risk assessment summary for elemental impurities.

Appropriate data to support any changes made to comply with Q3D or Canadian changes guidance.


Developments in other Countries Swissmedic

For New Drugs or Existing drugs.

Both new drug substances and existing drug

substances apply Implementation date: July 1, 2016.

For Marketed products

Implementation date: January 1, 2018.

Complied with Ph. Eur. Supplement 9.3.

During the transition period companies should

perform a risk assessment covering all potential

sources of elemental impurities.


Developments in other Countries Taiwan FDA

For New Drugs

Both new drug substances and existing drug

substances apply.

Implementation date: July 1, 2016.

For Marketed Products

Implementation date is not published.

Guiding principle would be:

Perform risk-based assessment according to Q3D Guideline.

Reduce regulatory reviewing burden without oversight.


Developments in other Countries

China, India, or South American Countries have not indicated the implementation of

ICH Q3D or any timelines for implementation at this time.

China may start discussions on ICH Q3D in 2020.


Summary on Implementation of ICH Q3D

New drugs (new drug substances and existing

drug substances).

The Health Authorities in US, EU, Japan, Canada,

Switzerland, Australia and Taiwan announced the

Q3D implementation schedule.

Currently marketed products.

The Health Authorities in US, EU, Canada and

Switzerland announced the Q3D implementation

schedule.

Risk assessment is a must

Australia, Japan and Taiwan are still in the planning

stage.


Lifecycle Management

The Lifecycle approach is to ensure ongoing compliance to Elemental Impurity requirements.

It is defined as an understanding of the product and/or process changes which have the potential to change the Elemental Impurity content of the final product and therefore may require a re-evaluation of the overall risk assessment and control strategy to ensure ongoing compliance to Elemental Impurity requirements.


Lifecycle Management Essential to Lifecycle management is 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.

Changes Potentially Impacting Elemental Impurities:

Risk Assessment Fishbone Diagram

Elemental

Impurities in

Drug Product

Drug

Substance Excipients

Manufacturing

Equipment

Utilities (e.g.,

Water)

Container

Closure

System



Lifecycle Approach



Possible Changes to a Drug Product

Examples of changes which may lead to reviews of

the original risk assessment and control strategy are:

Synthetic routes

Excipient suppliers / changes to the source or

manufacturing process of the excipient

API suppliers

Materials

Processing equipment

Container closure

Water supply



55

Initial

Elemental

Impurities

Risk

Assessment

completed


Lifecycle Management Summary

Elemental Impurity Lifecycle Management ensures that a change to the product and/or process have been properly evaluated for the potential to change the elemental impurity content of the final product.

Changes made to any of the 5 components of the Drug Product (Manufacturing Equipment, Water Systems, Container closure, API and Excipient) require review and potentially revision of the risk assessment and control strategy.

Risk Management principles and Global Change Management processes are key to ensuring ongoing compliance to Elemental Impurities.


Analytical and Risk Assessment Challenges

57

Methodology Concerns

Collaborative study performed

PQRI Phase 2 testing initiated

Lhasa database

Supplier information (API and Excipient)

Risk assessment approaches



Analytical Testing Considerations:

Difficult sample matrices— implications for sample preparation and subsequent analysis.

Fundamentals of ICP-MS with respect to solving problems for pharmaceutical samples.

Contract lab perspective on common misconceptions and practical aspects of sample analysis and validation.

API and excipient supplier perspectives demonstrating risk assessment principles.

Alternative methods—WD-XRF as a complimentary technique to ICP-MS.



Risk assessment requires some basis in data.

Key question for industry and the regulatory community. How reliably can we measure elemental impurities in drug

products, APIs and excipients at the levels outlined in ICH Q3D and USP <232>/<233>?

Variety and complexity of pharmaceutical samples.

Many labs expanding capabilities. Pharmaceutical labs adapting to ICP-MS analysis

Existing spectroscopy labs adapting to the requirements of <233>

Technical/Analytical Challenges Project Team formed in 2013 as a sub-team of the Coalition for Rational Implementation – now working with PQRI.

TECHNICAL/ANALYTICAL CHALLENGES PROJECT TEAM

Team Chartered June 2013

Membership (42+ colleagues)

• Comprised of scientists from – Coalition companies

• 5 pharmaceutical companies

• 7 raw material suppliers (API/excipient)

– 8 Contract laboratories

– 1 Government laboratory

– 1 University laboratory

Examples of Key Challenges

• Sample Preparation

– Ensure appropriate and effective solution preparation

– Total metal extraction implies clear solutions

• Instrumental Analysis

– System suitability/data integrity

– Options for sample introduction and interference reduction

• Sample introduction accessories, reaction gasses & collision cells, correction equations, etc.

– Calibration & LOQs

• LOQ can be a concern for large dose products and for raw material analysis

• Data review & interpretation

– Recognition of issues

• Drift, carryover/memory, interferences or element-specific pitfalls, non-ideal recoveries

– Reportable data

• Multiple modes of analysis possible

• No pharmaceutically relevant reference materials available

61

Inter-laboratory Study Objectives

• Address some of the key technical challenges faced by industry in preparation for compliance to ICH Q3D and USP <232>/<233>

• Provide a data-driven way to discuss technical aspects and expected variation of ICP-MS analysis of elemental impurities

• More specific objectives:

– Inter-laboratory data comparison for standardized samples

– Inter-laboratory evaluation of effectiveness of microwave digestion

– Comparison of acid leach/extraction techniques to total metal extraction

– Examination of the correlation (good or bad) between the analysis of individual components (summation) vs. the formulated tablet analysis

– Comparison of ICP-MS and alternative techniques (ICP-OES and XRF)

• First round study reported preliminary results at PQRI 2015, final results at AAPS 2015, and XRF arm at PQRI 2016

• Second round benefits from PQRI Sponsorship—allows wider participation

& Study Administrator—RTI International

62

Second Round Design Improvements & Best Practices

General

• Consistency among alternative techniques and digestion methods to ensure adequate data for comparison

• ICP-OES (14) and XRF (6) analysis considered proactively

• Raw materials distributed widely for summation approach comparison

Uniform Sample Preparation

• Specify parameters such as sample size, sampling technique, acid mixtures, and digestion temperature/pressure

• Document type of digestion vessels and microwave model used

Uniform Analysis

• Define procedures around LOQs, calibration, and data reporting

• Document interference management (reaction/collision gases, correction equations, etc.) and internal standards

63

Evaluation Samples and Analysis

64

Second Round Improvements— Evaluation

Samples

• Liquid sample to assess instrumental variation

• Evaluation samples with higher EI levels overall

• Multiple powdered or tableted evaluation samples targeting different levels

• EI source from pharma materials wherever possible

Powdered or tableted material at three concentrations and liquid

sample are aliquoted and shipped to each participating laboratory.

Samples extracted in triplicate using the

uniform method. Alternate extraction

methods may be used if available in

addition to the uniform method.

Uniform method

sample extracts/liquid

sample must be

analyzed by ICP-MS.

Optional alternate

method sample

extracts are analyzed

by ICP-MS.

Replicate results and average/SD reported by extraction method and

analysis method. Total samples for ICP-MS analysis are 12, alternative

digestion and analysis techniques will be in addition to basic results.

Minimum samples: 12, maximum: 36.

Uniform method

sample extracts, liquid

may be analyzed by

ICP-OES or other

instrument.

Samples extracted in

triplicate using the uniform

acid leaching method.

Samples extracted by

acid leaching method

must be analyzed by

ICP-MS.

Results for replicates and

average/SD are reported. Total

samples for acid leach analysis

are 12.

Recruiting

• Distributed participant questionnaire for analytical laboratories in early August 2016.

• 29 laboratories enrolled

• Pharma manufacturers: 16 laboratories

• Contract/CRO: 9 laboratories

• Instrument manufacturers: 2 laboratories

• Government: 2 laboratories

65

1 lab

11 labs

17

labs

Next Steps

• Tablet and liquid sample production – Partnering with Liverpool John Moore’s University

• Uniform method and acid leach method development—critical step – To be developed with finalized tablets prior to distribution

• Package assembly & shipment

• Sample analysis during summer months

• Results readout at PQRI in November

66


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 will be 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!


Supplier Information (API and Excipient)

There is NO regulatory requirement for API or Excipient suppliers to perform or supply elemental impurity information to pharmaceutical users.

Some suppliers will want to provide some useful information to support their customers but this will depend on the amount of business done in the pharmaceutical market.

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

Users should not try to pressure suppliers for EI data that may not exist, otherwise supplier may leave the market and availability will then be a problem.

Requests should be for whatever information the supplier is willing to share about their products and processes but not focus on the development of specifications since many suppliers will not agree to specifications on EI.

IPEC-Americas developed an information sharing mechanism which is well used throughout the industry.

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…

Few 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



ICH Q3D is a global policy for limiting elemental impurities in drug products.

Harmonised, safety-based limits for elemental impurities, especially those of highest toxicological concern.

Selection of elements to control.

Methodology for establishing safety-based limits.

Permitted daily exposure for specific elements.

Appropriate risk-based approach to ensure control for elements likely to be present in drug products and ingredients.

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



ICH Q3D guideline has different options (1, 2 and 3).

Option 1, & 2 are Component Approach

Option 3 Finished Product Approach

Regulatory authorities accept any of these options.

It may be easier for Industry to use Component

option to set control strategies per component.



Potential considerations during review of Risk

Assessments:

Intentionally added elements

Contributions from raw materials derived from plant or marine origins.

Contributions from raw materials that are mined, e.g.,

Inorganic drug substances and excipients.

Contributions from manufacturing, e.g., high shear micronization using metal discs.

Leachable elemental impurities from container/closure.

Extractables information from container/closure components typically included in a supplier Type III DMF.


Risk Assessment Reports

The Risk Assessment Reports tell the story of the risk assessment thinking / process.

Risk Assessment Reports are kept at the company manufacturing sites.

Risk Assessment Reports may be requested by regulatory agency inspectors.

Complete Risk assessment reports are not sent to

the FDA or EMA.

FDA updated through Annual Reports process

containing a summary of the risk assessment.



Title page

Generic Name

Introduction

State purpose of report - ICH Q3D risk assessment.

Formulation

The manufacturing formulation for the finished product.

If report will cover different strengths of the same product then each formulation should be included.

Dosing information from label

List the range of doses. Identify the maximum possible dosing per day (This is needed to determine the PDEs).



Risk Assessment section (Major portion of the report is based on the fish bone diagram in the ICH guidance).

Include the fish bone diagram with the elements

/sections.

Manufacturing Equipment Brief Summary of the

manufacturing steps

Process flow diagram

Overview of summary of worksheets

Conclusion

If necessary, what testing or other control measures will be

put in place

Elemental

Impurities in

Drug Product

Drug


Manufacturing

Equipment

Utilities (e.g.,

Water)

Container

Closure

System



Water system Statement of grade(s) of water used.

Source of water


Conclusion


put in place

Container closure Summary description of the

container closure system including

materials of construction


Conclusion


put in place

Elemental

Impurities in

Drug Product

Drug


Manufacturing

Equipment

Utilities

(e.g., Water)

Container

Closure

System

Elemental

Impurities in

Drug Product

Drug


Manufacturing

Equipment

Utilities

(e.g., Water)

Container

Closure

System


Risk Assessment Reports API

Brief Summary of the manufacturing

steps


Conclusion


put in place

Excipient

Summary of the excipients used in

the formulation including suppliers


Conclusion


put in place.

Elemental

Impurities in

Drug Product

Drug


Manufacturing

Equipment

Utilities

(e.g., Water)

Container

Closure

System

Elemental

Impurities in

Drug Product

Drug


Manufacturing

Equipment

Utilities

(e.g., Water)

Container

Closure

System



Excipient and API - ICP/MS Procedure –

include only if data generated Method (Sample preparation and analysis)

Statement on validation including description of the

validation.

Summary of Patient exposure risk compared to PDEs.

Identify any areas of risk and the sources.

Summary/ Conclusion.

Discussion if additional controls are needed.


QUESTIONS

79


CASE STUDIES

80


Case Studies – ICH Modules

Solid Oral Dosage – Initial Information

Greatstuff Tablets is a new drug product for the treatment of hypertension.

It is film coated and available in 2 strengths 50 & 100 mg.

Intended to be dosed once per day with a maximum daily dose of 100 mg.

The drug product is packaged in individual blister packages (PVC-91 Aclar) and HDPE bottles.

Samples tested were from Manufacturing and Development sites:

Drug substance development: Anywhere, Kansas

Drug product development: Anywhere, Kansas

Drug substance and drug product manufacturing: Humacao, Puerto Rico


Case Studies – ICH Modules

See ICH Q3D Case Study 1A for discussion

Handout of Module ICH Q3D Case Study 1A


ICH Q3D Elemental Impurities

Thank You

Pb As Hg

Cd Co V

Ni ???

ICH Q3D Elemental Impurities - Multiple Implementation ... · products should control elemental...

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