elemental impurities – excipient realities and challenges · − ich is developing q3d metal...

Elemental Impurities –Excipient Realities and

ChallengesDave Schoneker*

IPEC-Americas Vice Chair – Maker & Distributor Relations

Director of Global Regulatory Affairs – [email protected]

May 1, 2013

* Presentation co-developed with Pricilla Zawislak and Kathy Ulman

Agenda

Metal Impurity Background & Realities Industry Response

Elemental impurities Workshop Industry Coalition Meetings/Activities

ConcernsActions Tools

Current Industry Needs

KNOWN

4

What do we know today about the levels of metal impurities in excipients?

Kaolin & Talc mines

www.ipecamericas.org

Known – at least12 to 55 ppm Leadfrom periodic testing

Kaolin mine near Kaznejov, Czech Republic

Talc extraction in Trimouns Talc Mine, Midi-Pyrenees, France

Known – Current USPSpec <10 ppm Lead – onlytested once per year

• Semi quantitative, non-specific for individual metals (use Pb limit test)

• Compendial methods & metals not harmonized

Current Compendia Methodologies


USP <231> EP 2.4.8 JP 1.07• 3 methods described• Uses Pb ref. std + CH3C(S)NH2-glycerine-base TS

• Permissible limit expressed in ppm for Pb

• 8 methods described.• Use of Pb ref. std + CH3C(S)NH2 or Na2S Reagent


• 4 methods described. • Use of Pb ref. std. + Na2S Reagent


Trends and Implementation plans

Global desire to control metals with known toxicological concerns in finished drug products Today, there are no known metal impurity issues impacting patient safety HOWEVER, to enhance future monitoring,

− ICH is developing Q3D Metal Impurity Guideline, − USP proposed General Chapters <232> Elemental Impurities - Procedures and

<233> Elemental Impurities – Methods − PhEur is implementing 2.4.20 Determination of Metal Catalyst or Metal Reagent

Residue and 5.20 Metal Catalyst or Metal Reagent Residues Regulators and industry need to establish a consistent/reliable set of

expectations to ensure a “right first time” approach to implementation Regulators and industry need to carefully plan and phase-in

implementation timelines and approaches for these new requirements in order to allow adequate preparation by suppliers and drug manufacturers and prevent disruption of the drug supply.


ICH Q3D EWG

Scope criteria and limits− Applies to new drug products

Excipients outside the scope of the guideline Does not include metals intentionally part of the drug product

Approach similar to EU Metal Catalysts & Reagents; however, EU focuses on metals utilized in the manufacturing process (catalyst) whereas USP and ICH have extended well beyond metals utilized in the manufacturing process.

Limits based on published safety & toxicology data Compendia responsible for methodology, as appropriate Scheduled to advance the proposed guideline to Step 2 in June

2013 Public comment period will occur before the guideline goes to

Step 4.


ICH Q3D Pre-Step 2 Draft Guideline

Incorporates Risk Assessment, Risk Management and Risk Mitigation concepts

Testing is not the default; however, where necessary− Methods are outside the scope of ICH Q3D− Appropriate, validated analytical methods should be used− Tests should be specific for each metal (e.g. ICP-AES/ICP-MS)

Assessments for each metal of interest based on− Permitted daily exposure (PDE) for each metal of

toxicological concern− Permitted use of defined metal impurities concentrations

when daily “drug product” dose is NMT (not more than) 10 g/day


USP currently unilaterally implementing two elemental impurity general chapters which became official on 1 Feb 2013 − Elemental Impurities - Limits <232> 15 elements defined, some with different limits than ICH Q3D

− Elemental Impurities - Procedures <233> Inductively Coupled Plasma-Atomic Emission Spectroscopy (ICP-AES)

Inductively Coupled Plasma-Mass Spectroscopy (ICP-MS)

Other methods shown to be “equivalent”

Conformance with <232> and <233> in applicable monographs proposed for May 1, 2014 implementation

Proposed removal of all references to USP General Chapter <231> Heavy Metals will also occur on May 1, 2014.

Other metal references /limits within monographs and chapters??

USP <232> and <233>


The European Pharmacopoeia Commission adopted general chapter

− Metal catalysts or metal reagents residues (5.20) method

− Determination of metal catalysts or metal reagent residues (2.4.20).General approach for determination of metal catalysts or metal reagent residues in substances for pharmaceutical use, to be applied wherever possible. Method and measurement techniques noted include:

Atomic Emission Spectroscopy (AES)

Atomic Absorption Spectroscopy (AAS)

X-ray Fluorescence spectroscopy (XRFS)

Inductively Coupled Plasma-Atomic Emission Spectroscopy (ICP-AES)

Inductively Coupled Plasma-Mass Spectroscopy (ICP-MS)

PhEur 2.4.20 & 5.20

11

Official for pharmaceutical ingredients in September 2013

User Realities

What does this all mean to Pharma Companies?

USP <232> & <233>?

ExcipientRealities?

ICH Q3D ?

Confusion ?


PhEur2.4.20 &

5.20?

Realities for Implementation

Requirements will be on the dosage form, NOT the excipients. Excipients do not have to “comply” to Q3D!

ICH Q3D metals and limits have not yet been finalized.

Many excipients contain metal impurities at the 1 to 10 ppm level.

Many users may try to set specifications on excipients; HOWEVER, many suppliers may NOT be willing or able to agree to excipient specifications below those currently required to comply with monographs or other regulatory requirements.

Pharmaceutical companies may find it necessary to perform significant elemental testing of excipients and/or drug products in order to determine actual drug product impurity levels and whether they comply with final PDE limits


Realities for Implementation

For many excipient companies their pharmaceutical business is a minor part of their sales. Pressures for these companies to perform routine testing or reduce specification limits could lead to:

− Cease supporting product sales to pharmaceutical industry

− Increase pricing to cover additional costs needed to address new requirements.

Some drug products may require changes in excipient sourcing, and perhaps even reformulation in order to meet PDE requirements.

Collective implementation efforts will require time to do properly.


15

• Purpose – Raise industry awareness, gather industry feedback and share

feedback with ICH EWG– Introductory session included:

• Review expected impact of Q3D from excipient maker and user perspectives

• Review “blinded” data on metal impurities from industry• Review ICH Q3D EWG history and strategy

• Targeted audience– Excipient and API manufacturers,– Innovators and generic pharmaceutical companies – OTC manufacturers

• Workshop discussion topics– Risk-based assessment and control strategy development– Methodology & bioavailability issues– Excipient realities & communication tools

IPEC-Americas, CHPA and SOCMA BPTF ICH Q3D Elemental impurities Workshop

16

April 4th & 5th, 2012

Validated Metal Impurity Realities

Today little data exists to perform a scientific risk assessment of metal content Unknown Unknowns

− Most excipients have not been routinely tested; therefore, current metal concentrations and variability is often UNKNOWN!

− Communication between pharma industry and suppliers is critical to best understand what is known and NOT known about metal impurity levels in excipients and APIs

Lack of industry data required to confirm actual vs theoretical metal impurity levels

− It will take a long time to develop enough data to understand normal variation needed for a science-based risk assessment


Validated 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 often inherent (due to sourcing) and cannot be “easily” reduced or removed

Validated 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 excursionsthat occur in the raw material source

Knowns – Limited Industry data

Item Description Supplier/Manufacturer

Asppm

Cappm

TotalPb

ppm

Inorganic Hgppm

Crppm

Cuppm

Nilppm

TITANIUM DIOXIDE, USP/FCC/EP/JP Supplier A 1.0 max 0.2 max 10.0 max 1.0 max 1.9 max 0.5 max N/A

TITANIUM DIOXIDE USP/EP/JP Supplier B 3.0 max 1.0 max 10.0 max 1.0 max N/A N/A N/A

CALCIUM CARBONATE EP Supplier C 3 max 1 max 10 max N/A N/A N/A N/A

CALCIUM CARBONATE USP - PRECIPITATED Supplier D N/A N/A 3 max 0.5 max N/A N/A N/A

TALC USP/FCC/EP/JP - Supplier E 3 max N/A 10 max N/A N/A N/A N/A

TALC MICRONIZED USP/EP Supplier F 4 max N/A 10 max N/A N/A N/A N/A

TALC USP/EP Supplier G 3 max N/A 5 max N/A N/A N/A N/A

Unknowns: The following additional metal impurities were not specifications or reported on the Suppliers COAs: Mn, Mo, Pd, Pt, V, Os, Rh, Ru, Ir

Metal impurity examples for mineral based excipients - Supplier COAs

Unknowns - Analysis by FDA lab

21

Q1 2012Law office for IPEC –Americas collected,

blinded and submitted excipient samples to FDA

lab for analysis

Q2-Q4 2012FDA analyzed samples using

ICP-MS

Q1 2013Law office un-blinded

and sent results to original submitters.

Q1 2013Additional

samples sent to FDA

CurrentIndustry

waiting for additional FDA

results

FDA to publish data in journal

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

Industry Coalition Meetings & Activities

Other trade associations and many IPEC‐Americas member companies in the United States and Europe

Coalition for the Rational Implementation of the USP Elemental Impurities Requirements

Coalition Goals

Ensure harmonization and alignment of USP <232> and <233> implementation timelines with ICH Q3D Guideline

Develop risk assessment concepts for evaluating the potential for metal impurities in excipients, APIs and drug products

Evaluate a realistic timeframe for implementation based on limits in pre-Step 2 document

Meet with high-level FDA officials to share coalition activities, findings and tools to help facilitate implementation and propose more realistic timeframe for implementation of USP chapters.

− Work with FDA to establish a flexible process for use when some PDEs are exceeded (e.g. short dosing regime, life-saving drugs)

Ask FDA to ensure implementation of a harmonized standard approach of USP & ICH Q3D requirements throughout FDA CDER for NDA, ANDA, OTC and possibly CVM

− Avoid a repeat of the residual solvents problems!


Coalition 2012 Activities

Called for Data for submission to ICH Q3D EWG

Designed “Information Exchange Request” (to gather data)

Published Pharmaceutical Technology article on Elemental/Metal Impurities

Filed Formal Appeal with USP Requesting Withdrawal of Elemental Impurities General Chapters and General Notices

Established initial FDA meeting (Nov. 20, 2012) to present concerns with USP non-harmonized approach and timeline

Developed Tools to help support elemental impurity assessment


NOTE: Many Coalition members participated in a blinded study involving submission of samples to the FDA labs (J. Kauffman) for metal impurity analysis.

The Coalition’s – Call for Data

Coalition compiled and submitted “data” to the ICH Q3D EWG to help provide them with

Extractable metal test methodologies and data comparing total metal concentrations vs extractable metal concentrations.

Actual data for excipient and API metal content/levels, where known and available

Actual data for finished drug product metal content/levels, where known and available.

* Provided to ICH Q3D EWG for translation /review during ICH Q3D EWG November, 2012 meetings


NOTE: both API and excipient manufacturers are encouraged to utilize the Information Exchange request template form to proactively develop their own product documentation/information.

Developed standardized request letter and form templates to help facilitate industry communication between users and makers of APIs and excipients. Template created and designed to help pharmaceutical companies:

gather information from suppliers pertaining to potential metals/concentrations in both APIs and excipients used in the production of drug products.

use information from suppliers to determine potential presence / concentration of each metal in the assessment of a finished drug product Permitted Daily Exposure (PDE) level.

Information Exchange Request



USP <232> Elemental Impurities and ICH Q3D Metal Impurities Information ExchangeRequest

This document and the attached Information Exchange Request Form have been designed and developed by IPEC Americas to initiate

a “high level” exchange of information between manufacturers and users ofingredients used in the formulation of drug products. It is hoped that through completion of the request form and consolidation of theresponses, both parties can begin to gain a better understanding of the potential elemental impurity levels for excipients used in drugproducts in preparation for the new compendia requirements in USP General Chapter <232> Elemental Impurities Limits.

The purpose of this request is to solicit information from suppliers of ingredients used in drug products to try to develop anunderstanding of metals and metal contributions that may be present in these materials. Thisinformation will be helpful to users in their assessment of potential metals and their contribution in drug product formulations for

compliance to USP <232> compendia requirements. Suppliers are encouraged to provideinformation that may be available to assist their customers in meeting these requirements which are mandatory forfinished drug products. However, users need to recognize that suppliers may nothave all of this information readily available.

The attached format has been developed by IPEC-Americas to facilitate the exchange of information between users andmanufacturers. We encourage using this form to ensure consistency in the information received. However, if your company has alreadydeveloped information related to this topic and you have an information sheet or other document which can answer these questionsadequately, please forward that document instead of filling out this form.


IDEAL WORLD….Pro-actively

completed by suppliers and sent to

users

Templates and request letter: http://ipecamericas.org/content/i

ch-q3d-information-exchange-request

URGENT industry need for BASE-LINE DATA!

REAL WORLD…Few suppliers have

data or will complete and return the form to

users

IPEC-America posted initial version Q3 2012• One member company mailed out ~300

requests for information / data to their raw material suppliers.

• Of their top 100 raw material suppliers:(after 2-3 months)

– 12 returned forms with some questions completed; however, ~ 2-3 provided usable information, others responded with NA or left most questions blank.

– 24 did not respond at all, even upon follow-up

– 64 sent historical, outdated heavy metal statements or EU Catalyst statement


29

EU Catalyst Statement

HISTORICAL Heavy metal statement

Pharmaceutical Technology Article

Article entitled “Elemental Impurities – An Industry Perspective on Harmonization and Implementation of ICH and USP” published in November 2012 issue of Pharmaceutical Technology and included:− Background: Compendial and regulatory changes affecting

EI limits in pharmaceuticals− History of elemental impurities− Review of Implementation Plans and Timelines− Outline and Concerns over Implementation Realities− The role of GMPs, QbD, and risk analysis in metals testing− Coalition activities and the path forward

http://www.pharmtech.com/pharmtech/Feature+Articles/An-Industry-Perspective-on-Harmonization-and-Imple/ArticleStandard/Article/detail/795602


Formal Appeal/Comments to USP

Oct 19, 2012

Submitted formal appeal to USP

requesting withdrawal of April 2012 draft Chapter

<232> & <233>

Nov 15, 2012

USP postponed publication of <232> and <233> pending review of

industry appeals

http://www.usp.org/usp-nf/official-text/revision-bulletins/elemental-impurities-limits-and-elemental-impurities-methods


Feb 1, 2013

USP published <232> and <233> and

retained May 1, 2014 implementation date

March 27, 2013

Comments sent to USP concerning the May 2014 planned implementation

timeline

AppealDenied

1/25/2013

FDA Meeting – Nov 20, 2012

Coalition representatives met with FDA to share and make a presentation to them concerning: Need for alignment and harmonization of USP and ICH Q3D Contrast between Residual Solvents and Elemental Impurities Significant differences between ICH Q3D and USP

approaches Examples of various technical issues & challenges (e.g. new

tools) Need for ongoing dialog concerning implementation Implementation concerns, including potential Impact of

non-alignment


– November 20, 2012

Industry concerns include


Current USP <232> limits not completely aligned with the pre-Step 2 ICH Q3D limits (several metals have different limits)

Currently USP <232> only includes a subset of metals covered by the ICH Q3D guideline

Currently USP <232> intended for all delivery forms (including mucosal, topical / transdermal)

Currently USP <232> “risk assessment” options vague, at best.

Once implemented (May 1, 2014), if not aligned with ICH Q3D could result in extra, unnecessary efforts by the industry.

Many organizations involved with the pharmaceutical industry are worried that USP is not currently fully aligned with ICH Q3D scope and time-lines and there is significant industry concern that the approach of USP is unrealistic!

FDA Meeting – Nov 20, 2012

Goals and Desired Outcomes Coalition promoting FDA and USP alignment with ICH Q3D

initiatives from both a content and timing perspective

Coalition’s request included:

− Alignment of enforcement compliance between USP’s Elemental Impurity and ICH Q3D Metal Impurity requirements.

− Harmonize technical requirements, operational approaches and implementation timeline in order to allow for a successful global implementation of these requirements by industry.

− Documented Guidance(s) and Q&A from FDA well in-advance of mandatory implementation date for elemental/metal impurities.


Elemental Impurity Assessment Tools

Implementation Timeline Model

PDE calculator for component metal information

− Sample formulations for dosage forms

Examples of industry data comparing total metals vs extractable metals.


Elemental Impurity Timeline Model

36

Industry Components

Description

Adjusted

Duration*

Impact Assessment

Establish Risk Based Assessment 4.0

ID mtls, compile ingredients, def. max PDE 3.0

Educate suppliers on EI needs/gather EI info 8.2

Answer supplier questions 2.0Total 17.2

Establish Equipment

Identify, purchase & receive equipment 25.0

Install, validate and document Equipment 10.0

Train chemists in use of equipment 3.0Total 38.0

Establish Methods

Define EI(s) to evaluate 1.0Method Development 13.8Method Transfer 4.0

Total 18.8

Establish DataTest/Confirm Compliance 3.1Investigate Outliers/ Resolve Data 1.0

Total 4.1

Document, File & Resolve

Conflicts

Document assessment/test needs 1.0Document alternate limits needed 1.0

File 2.0

Remediate Issues 6.0

Total 10.0

NOTE: adjusted duration is a variable dependent on the applicable events and number of occurrences

Time-line components• Impact assessment• Equipment • Methodologies• Data• Documentation• Filings/Conflict

resolutions10 – 85 weeks

PDE Calculator

PDE Calculator


Designed by Andrew Teasdale, Astra Zeneca - UK

tablet effervescent oral solution

oral suspension

cough syrup

gel caps

solution for single IV

large volpareneral lyophile

PDE Calculator – model dosage forms

38

Variable field for doses/day

mg/day x g/g /1000 = ppm

Sum of metal “ppm” for all components dosage forms

Total Metal vs Acid Leached Metal

As, ppm Pb, ppm Cd, ppm

HCl Leach* <233> Digestion** HCl Leach <233> Digestion HCl Leach <233> Digestion

Purified Bentonite NF 0.4 0.7 6.9 12.9 0.03 0.08

MAS NF Type 1A 0.3 1.5 5.5 10.8 0.02 0.09

MAS NF Type 1B <0.1 1.4 3.8 9.2 0.01 0.08

MAS NF Type 1C 0.3 2.1 4.4 10.9 0.02 0.08

MAS NF Type 2A 1.0 1.6 8.6 15.3 0.02 0.08

* Dilute HCl extraction based on the Pb test in the MAS NF monograph; ICP‐MS

** Closed vessel microwave digestion with HNO3; ICP‐MS

Pb analyses using Acid leach tests vs direct biorelevant simulated gastric fluid extraction

Magnesium Aluminum Silicate NF Type 2A (Smectite Clay) Pb, ppm

Simulated Gastric Fluid Extraction, 2hr (SGF extraction + ICP‐MS) 5.9

Monograph specification test (dilute HCl extraction + AA) 9.5

HCl Leach (dilute HCl extraction + ICP‐MS) 8.6

“Total” Pb content (closed vessel microwave digestion with HNO3 + ICP‐MS) 15.3

As, Pb and Cd in Smectite Clay Excipients

ACTIONS

• Complete Information exchange requests/provide available information– Suppliers complete initial assessment for each excipient

– Users compile information from forms to determine next steps… to be used, as available for PDE calculator and Risk Assessment

• Establish / validate equipment (ICP-AES/ICP-MS) or identify external test facility

• Develop “sample preparation” and “analysis” methodologies

• Train personnel

• Develop base-line elemental impurity levels for each ingredient used in a drug product – where necessary, monitor for excursions

• Collaboratively work together (drug manufacturers / ingredient suppliers) to develop (via risk assessment) future testing / reporting strategy for each ingredient used in a drug product.

• Drug manufacturers use PDE calculator and risk assessments to assure compliance of elemental impurity levels in finished drug product formulations

Current Industry Needs

41

Acknowledgements

Priscilla Zawislak– Ashland

Kathy Ulman – Dow Corning


elemental impurities – excipient realities and challenges · − ich is developing q3d metal...

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