PDF%5CExtractableLeachableFleitman[1]

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EXTRACTABLE/LEACHABLE TESTING ANDEXTRACTABLE/LEACHABLE TESTING ANDEXTRACTABLE/LEACHABLE TESTING ANDEXTRACTABLE/LEACHABLE TESTING AND

REGULATORY REQUIREMENTS FORREGULATORY REQUIREMENTS FORREGULATORY REQUIREMENTS FORREGULATORY REQUIREMENTS FOR

OPHTHALMIC DOSAGE FORMSOPHTHALMIC DOSAGE FORMSOPHTHALMIC DOSAGE FORMSOPHTHALMIC DOSAGE FORMS

Jeffrey Fleitman, Ph.D.

Senior Director

Pharmaceutical Analysis & Microbiology

AOAC-SCS/WCDG

Nov. 5, 2009

Allergan Fleitman 11/5/2009


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EXTRACTABLE/LEACHABLEEXTRACTABLE/LEACHABLEEXTRACTABLE/LEACHABLEEXTRACTABLE/LEACHABLE

IDENTIFICATION AND ANALYSIS HAVEIDENTIFICATION AND ANALYSIS HAVEIDENTIFICATION AND ANALYSIS HAVEIDENTIFICATION AND ANALYSIS HAVE

BECOME A MASSIVE COMPONENT OFBECOME A MASSIVE COMPONENT OFBECOME A MASSIVE COMPONENT OFBECOME A MASSIVE COMPONENT OFSOMESOMESOMESOMEREGISTRATION STABILITYREGISTRATION STABILITYREGISTRATION STABILITYREGISTRATION STABILITY

STUDIESSTUDIESSTUDIESSTUDIES

AllerganFleitman 11/5/2009


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Industry Scientist Responsibilities


Develop test methods

Qualify packaging components

Plastics

Inks

Adhesives

Elastiomers Cartons

Shrink wrap

Qualify manufacturing components

Tubing Filters


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Industry Scientist Responsibilities


Perform stability studies

Identify E and L Support toxicology assessment of E and L

Set product specifications

Author CTD regulatory submission sections (methods, stability,

etc.)

Negotiate specifications with regulatory agencies

Support post-approval issues with unknown impurities

from E and L


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DOES UNIFORM REGULATORYDOES UNIFORM REGULATORYDOES UNIFORM REGULATORYDOES UNIFORM REGULATORY

GUIDANCE EXIST FOR TESTING,GUIDANCE EXIST FOR TESTING,GUIDANCE EXIST FOR TESTING,GUIDANCE EXIST FOR TESTING,

IDENTIFICATION AND REPORTING OFIDENTIFICATION AND REPORTING OFIDENTIFICATION AND REPORTING OFIDENTIFICATION AND REPORTING OF

EXTRACTABLES/LEACHABLES?EXTRACTABLES/LEACHABLES?EXTRACTABLES/LEACHABLES?EXTRACTABLES/LEACHABLES?



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EarlyEarlyEarlyEarly Extractable Guidance/ConcernsExtractable Guidance/ConcernsExtractable Guidance/ConcernsExtractable Guidance/Concerns


Glass leachables into parenterals (particulate emphasis)

Elastomeric stoppers

Filters/filling lines

Latex and IV components Compatibility studies (1987 Stability Guidance?)

Non CFC propellants and component qualification


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USP GUIDANCEUSP GUIDANCEUSP GUIDANCEUSP GUIDANCE


USP BIOLOGICAL REACTIVITY

USPCONTAINERS-PLASTICS

USPBIOCOMPATIBILITY OF MATERIALS


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ISO Guidance


ISO-10993-Biological Evaluation of Medical Devices

Toxicokinetic guidance


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USP GUIDANCEUSP GUIDANCEUSP GUIDANCEUSP GUIDANCE


USP BIOLOGICAL REACTIVITY

USPCONTAINERS

CONTAINERS FOR OPHTHALMICS -- PLASTICS

Plastics for ophthalmics are composed of a mixture of homologous

compounds, having a range of molecular weights. Such plastics frequently

contain other substances such as residues from the polymerization

process, plasticizers, stabilizers, antioxidants, pigments, and

lubricants. Factors such as plastic composition, processing and cleaning

procedures, contacting media, inks, adhesives, absorption, adsorption

and permeability of preservatives, and conditions of storage may also

affect the suitability of a plastic for a specific use.


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Ph. Eur. GuidancePh. Eur. GuidancePh. Eur. GuidancePh. Eur. Guidance


3.1 raw material extractions

3.2 general sections on finished containers the plastic container chosen for any particular preparation should be such

that

The ingredients of the preparation in contact with the plastic material are

not significantly adsorbed onto its surface and do not significantly migrate

into or through the plastic

The plastic material does not release substances in quantities sufficient to

affect the stability of the preparation or to present a risk of toxicity


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FDA GUIDANCE ON CONTAINER CLOSURE SYSTEMSFDA GUIDANCE ON CONTAINER CLOSURE SYSTEMSFDA GUIDANCE ON CONTAINER CLOSURE SYSTEMSFDA GUIDANCE ON CONTAINER CLOSURE SYSTEMSMAY 1999MAY 1999MAY 1999MAY 1999


USP TESTING

EXTRACTABLE LIMITS

BATCH-TO-BATCH MONITORING OF

EXTRACTABLES

ADDITIONAL GUIDANCE ON EXTRACTION MEDIA


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ICH Q6A May 2000ICH Q6A May 2000ICH Q6A May 2000ICH Q6A May 2000


Extractables: Generally, where development and stabilitydata show evidence that extractables from thecontainer/closure systems are consistently below levelsthat are demonstrated to be acceptable and safe,elimination of this test can normally be accepted. This

should be reinvestigated if the container/closure system orformulation changes.


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ICH Q6A May 2000(cont.)ICH Q6A May 2000(cont.)ICH Q6A May 2000(cont.)ICH Q6A May 2000(cont.)


Where data demonstrate the need, tests and acceptancecriteria for extractables from the container/closure systemcomponents (e.g., rubber stopper, cap liner, plastic bottle,

etc.) are considered appropriate for oral solutionspackaged in non-glass systems, or in glass containers withnon-glass closures. The container/closure componentsshould be listed, and data collected for these componentsas early in the development process as possible.


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Q6AQ6AQ6AQ6A----SpecificationsSpecificationsSpecificationsSpecifications


The experience and data accumulated during the development of anew drug substance or product should form the basis for the

setting of specifications.

It may be possible to propose excluding or replacing certain tests

on this basis. Some examples are:

extractables from product containers where it has been reproducibly shown

that either no extractables are found in the drug product or the levels meet

accepted standards for safety


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ICH Q3BICH Q3BICH Q3BICH Q3B


Impurities in New Drug Products

Oct 1999

Rev 2003


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Q3B(R)-IMPURITIES IN NEW DRUG

PRODUCTS


IMPURITY SPECIFICATIONS ESTABLISHED AS A FUNCTION OFMAXIMUM DAILY DOSE ADMINISTERED

IDENTIFICATION AND QUALIFICATION LIMITS ARE A FUNCTION OFDRUG PRODUCT CONCENTRATION AND MAXIMUM DAILY DOSE

E & L specifically excluded

TDI approach for reporting, ID and qualification

In reality specs are based on stability data quality not safety issue


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ICH Q3CICH Q3CICH Q3CICH Q3C


Impurities Guidelines for Residual Solvents

1997


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Q3CQ3CQ3CQ3C----RESIDUAL SOLVENTSRESIDUAL SOLVENTSRESIDUAL SOLVENTSRESIDUAL SOLVENTS


If theoretical calculations result in levels below guideline, noproduct testing needed

Higher levels of residual solvents may be acceptable in short

term (


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USP guidance ICH guidance

Food/beverage/water standards

Compatibility studies

EP guidance case-by-case with regulatory agency

GUIDANCE AS OF 2001


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PQRI LEACHABLES AND EXTRACTABLESPQRI LEACHABLES AND EXTRACTABLESPQRI LEACHABLES AND EXTRACTABLESPQRI LEACHABLES AND EXTRACTABLES

WORKING GROUPWORKING GROUPWORKING GROUPWORKING GROUP

FEB. 2002FEB. 2002FEB. 2002FEB. 2002


INHALATION AND NASAL PRODUCTS

COMPONENT QUALIFICATION TO REDUCE OR

ELIMINATE ROUTINE FINISHED PRODUCT TESTING threshold concept


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FDA GUIDANCE FOR NASAL ANDFDA GUIDANCE FOR NASAL ANDFDA GUIDANCE FOR NASAL ANDFDA GUIDANCE FOR NASAL AND

INHALATION PRODUCTSINHALATION PRODUCTSINHALATION PRODUCTSINHALATION PRODUCTSJULY 2002JULY 2002JULY 2002JULY 2002


SIMILAR RECOMMENDATION TO PQRI

conceptual agreement with PQRI recommendation


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CHMP GUIDELINE ON THE PHARMACEUTICALCHMP GUIDELINE ON THE PHARMACEUTICALCHMP GUIDELINE ON THE PHARMACEUTICALCHMP GUIDELINE ON THE PHARMACEUTICAL

QUALITY OF INHALATION AND NASAL PRODUCTSQUALITY OF INHALATION AND NASAL PRODUCTSQUALITY OF INHALATION AND NASAL PRODUCTSQUALITY OF INHALATION AND NASAL PRODUCTS

Feb. 2005Feb. 2005Feb. 2005Feb. 2005



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2005 EMEA/CHMP Guidance on

Plastic Immediate PackagingMaterials


Active substance

Drug product Links to CTD and EP

Provides extractable guidance


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Safety Thresholds and Best Practices for

Extractables and Leachables in Orally Inhaledand Nasal Drug Products


PQRI Sept. 2006


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PQRI Sept. 2006


Establishing safety concern and qualification thresholds forleachables

Incorporate TDI approach

Risk assessment

Component selection Share info with suppliers

Safety evaluation during development

Controlled extraction studies

Leachable studies during stability testing


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PQRI Sept. 2006(cont.)


E & L correlation may obviate future testing/specs

Toxicology assessment process defined

Safety assessment process defined


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Why Not Expand PQRI ApproachWhy Not Expand PQRI ApproachWhy Not Expand PQRI ApproachWhy Not Expand PQRI Approach

to Other Dosage Forms?to Other Dosage Forms?to Other Dosage Forms?to Other Dosage Forms?



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Pharma knows how to test for extractables and leachables!

Pharma knows how to report E & L results!

Filings are consistent along dosage forms and across regulatory

agencies!

USP, EP, ICH, EMEA,CHMP

GUIDANCE AVAILABLE!!


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REALITY...REALITY...REALITY...REALITY...



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DILEMNADILEMNADILEMNADILEMNA


One time approach (is there such a thing?) vs ongoing

stability program


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Should Trace Level Leachables beShould Trace Level Leachables beShould Trace Level Leachables beShould Trace Level Leachables be

Monitored?Monitored?Monitored?Monitored?


Leachable peak in Drug Product Formulation: 3.3ppm

Daily dose-dependent intake: O.2ppm/day

Benzene in API per ICH Q3C: 2ppm

Daily dose-dependent intake: 20ppm/day

Benzene in Drinking Water: 2ppm/day


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How Low to Go??How Low to Go??How Low to Go??How Low to Go??



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Analytical Methodologies forAnalytical Methodologies forAnalytical Methodologies forAnalytical Methodologies for

Profiling/Identifying LeachablesProfiling/Identifying LeachablesProfiling/Identifying LeachablesProfiling/Identifying Leachables


General Screening Methods

-Temperature programmed GC/FID and GC/MS foridentification

-RP-gradient HPLC with UV detection (210 nm) for

general profiling and LC/MS for structural identification

Product HPLC methods


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Identification of LeachablesIdentification of LeachablesIdentification of LeachablesIdentification of Leachables


LC/MS

GC/MS

Authentic standards unavailable

Proprietary info


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REPORTING LEACHABLE RESULTSREPORTING LEACHABLE RESULTSREPORTING LEACHABLE RESULTSREPORTING LEACHABLE RESULTS


% OF LABEL STRENGTH REPORTING BIASES

FORMULATIONS WITH LOW ACTIVE DRUG CONC.


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Toxicology Assessment


How to correlate trace amount found with route of

administration and perform toxicology study for a compound

found at trace levels below PDE for most toxic compounds?


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Specification Setting and RegulatorySpecification Setting and RegulatorySpecification Setting and RegulatorySpecification Setting and Regulatory

Approval StrategiesApproval StrategiesApproval StrategiesApproval Strategies


Leachable stability data is utilized to determine maximum level

expected in product Maximum levels determined for product are toxicologically assessed

based on total daily intake defined by product dosing regimen

Proposed leachable specifications determined collaboratively withregulatory agency


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For EU Regulatory submissions, leachables below levels demonstrated

to be toxicologically safe can be eliminated from product

specifications per ICH Q6A.

For U.S. regulatory submissions, ICH guidelines on leachables

specifications and controls may not be sufficient for FDA. Product

quality may be cited to justify specifications and controls.


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Identified leachables with toxicological profile-May not require specifications/controls if observed levelsare sufficiently below toxicological thresholds

Unidentified leachables

0.1% of active have requiredreporting specifications based on stability data

Contrast to TDI/SCT threshold driven PQRI recommendations


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Regulatory Strategy: Experiences inRegulatory Strategy: Experiences inRegulatory Strategy: Experiences inRegulatory Strategy: Experiences in

Setting Leachable Limit SpecificationSetting Leachable Limit SpecificationSetting Leachable Limit SpecificationSetting Leachable Limit Specification


Acceptable total daily intake (TDI) and specification setting should be thekey safety parameter for determining allowed exposure level as described inICH Q6A

EU leachable requirements for submissions follow ICH Q6A whereas U.S.(FDA) requirements in many cases are more stringent

In practice, for U.S. submissions, the limit specification is often data drivenbased on stability trend data as a quality parameter for the product

For U.S. submissions, the observed leachable concentration is often verymuch less than allowed TDI from toxicological data


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ConclusionsConclusionsConclusionsConclusions


Experiences in leachable specification setting for U.S.submissions indicates specification is driven by actual trend

data although toxicological assessment may justify asignificantly higher specification

For EU submissions, toxicological considerations have

dictated whether leachable specifications and controls arerequired per ICH Q6A


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New ICH Guidelines:New ICH Guidelines:New ICH Guidelines:New ICH Guidelines:Impact on E and L Guidance, TestingImpact on E and L Guidance, TestingImpact on E and L Guidance, TestingImpact on E and L Guidance, Testing

Approaches and SpecificationsApproaches and SpecificationsApproaches and SpecificationsApproaches and SpecificationsTBDTBDTBDTBD


ICH Q7

ICH Q8

ICH Q9


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E & L REGULATORY PERSPECTIVESE & L REGULATORY PERSPECTIVESE & L REGULATORY PERSPECTIVESE & L REGULATORY PERSPECTIVES FDA EUROPE

ORALLY INHALEDOPHTHALMICTOPICAL,etc


Extractables and Leachables in


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Extractables and Leachables in

Pharmaceutical Dosage Forms


QUALITYQUALITYQUALITYQUALITYSAFETYSAFETYSAFETYSAFETY

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PDF%5CExtractableLeachableFleitman[1]