EXTRACTABLE/LEACHABLE TESTING AND REGULATORY REQUIREMENTS FOR OPHTHALMIC DOSAGE FORMS

Jeffrey Fleitman, Ph.D. Senior Director Pharmaceutical Analysis & Microbiology

AOAC-SCS/WCDG Nov. 5, 2009

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EXTRACTABLE/LEACHABLE IDENTIFICATION AND ANALYSIS HAVE BECOME A MASSIVE COMPONENT OF SOME REGISTRATION STABILITY STUDIES

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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 REGULATORY GUIDANCE EXIST FOR TESTING, IDENTIFICATION AND REPORTING OF EXTRACTABLES/LEACHABLES?

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Early Extractable Guidance/Concerns Early

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 GUIDANCE
USP<87> BIOLOGICAL REACTIVITY USP<661>CONTAINERS-PLASTICS USP<1031>BIOCOMPATIBILITY OF MATERIALS

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ISO Guidance
ISO-10993-Biological Evaluation of Medical Devices
Toxicokinetic guidance

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USP GUIDANCE
USP<87> BIOLOGICAL REACTIVITY USP<661>CONTAINERS
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. 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 SYSTEMS MAY 1999

USP TESTING EXTRACTABLE LIMITS BATCH-TO-BATCH MONITORING OF EXTRACTABLES ADDITIONAL GUIDANCE ON EXTRACTION MEDIA

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ICH Q6A May 2000

Extractables: Generally, where development and stability data show evidence that extractables from the container/closure systems are consistently below levels that are demonstrated to be acceptable and safe, elimination of this test can normally be accepted. This should be reinvestigated if the container/closure system or formulation changes.

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ICH Q6A May 2000(cont.)

Where data demonstrate the need, tests and acceptance criteria for extractables from the container/closure system components (e.g., rubber stopper, cap liner, plastic bottle, etc.) are considered appropriate for oral solutions packaged in non-glass systems, or in glass containers with non-glass closures. The container/closure components should be listed, and data collected for these components as early in the development process as possible.

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Q6AQ6A-Specifications
The experience and data accumulated during the development of a new 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 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 OF MAXIMUM DAILY DOSE ADMINISTERED
IDENTIFICATION AND QUALIFICATION LIMITS ARE A FUNCTION OF DRUG 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 Q3C
Impurities Guidelines for Residual Solvents
1997

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Q3CQ3C-RESIDUAL SOLVENTS
If theoretical calculations result in levels below guideline, no product testing needed Higher levels of residual solvents may be acceptable in short term (<30 days) or topical application

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GUIDANCE AS OF 2001
USP guidance ICH guidance Food/beverage/water standards Compatibility studies EP guidance case-by-case with regulatory agency

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PQRI LEACHABLES AND EXTRACTABLES WORKING GROUP FEB. 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 AND INHALATION PRODUCTS JULY 2002

SIMILAR RECOMMENDATION TO PQRI
conceptual agreement with PQRI recommendation

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CHMP GUIDELINE ON THE PHARMACEUTICAL QUALITY OF INHALATION AND NASAL PRODUCTS Feb. 2005

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2005 EMEA/CHMP Guidance on Plastic Immediate Packaging Materials

Active substance Drug product Links to CTD and EP Provides extractable guidance

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PQRI Sept. 2006

Safety Thresholds and Best Practices for Extractables and Leachables in Orally Inhaled and Nasal Drug Products

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PQRI Sept. 2006

Establishing safety concern and qualification thresholds for leachables
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 Approach to Other Dosage Forms?

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USP, EP, ICH, EMEA,CHMP GUIDANCE AVAILABLE!!

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!

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REALITY...

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

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Should Trace Level Leachables be 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??

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Analytical Methodologies for Profiling/Identifying Leachables

General Screening Methods -Temperature programmed GC/FID and GC/MS for identification -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 Leachables
LC/MS GC/MS Authentic standards unavailable Proprietary info

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REPORTING 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 Regulatory Approval 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 with regulatory agency

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Specification Setting and Regulatory Approval Strategies

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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Specification Setting and Regulatory Approval Strategies

Identified leachables with toxicological profile -May not require specifications/controls if observed levels are sufficiently below toxicological thresholds Unidentified leachables 0.1% of active have required reporting specifications based on stability data
Contrast to TDI/SCT threshold driven PQRI recommendations

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Regulatory Strategy: Experiences in Setting Leachable Limit Specification

Acceptable total daily intake (TDI) and specification setting should be the key safety parameter for determining allowed exposure level as described in ICH 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 driven based on stability trend data as a quality parameter for the product For U.S. submissions, the observed leachable concentration is often very much less than allowed TDI from toxicological data
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Conclusions
Experiences in leachable specification setting for U.S. submissions indicates specification is driven by actual trend data although toxicological assessment may justify a significantly higher specification For EU submissions, toxicological considerations have dictated whether leachable specifications and controls are required per ICH Q6A

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New ICH Guidelines: Impact on E and L Guidance, Testing Approaches and Specifications TBD
ICH Q7 ICH Q8 ICH Q9

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E & L REGULATORY PERSPECTIVES

FDA EUROPE ORALLY INHALEDOPHTHALMICTOPICAL,etc

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Extractables and Leachables in Pharmaceutical Dosage Forms

QUALITY

SAFETY

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