case study – topical dosage form elemental...

Case Study – Topical Dosage Form Elemental Impurities

David J. Fillar

PQRI Workshop November 2016

Case Study – Topical Dosage Form

Key Points to be considered • Q3D Training Module 1, page 7. “Oral bioavailability over estimates dermal bioavailability” • Q3D Training Module 6, page 9 & 12. “If the risk assessment fails to demonstrate that an EI level is consistently below the control threshold, then controls need to be established to ensure the EI level does not exceed the PDE” “The control threshold is defined as 30% of the PDE.”

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1.0 Introduction

This document is used to identify and evaluate elemental impurity risks that may be present in the drug product. Elemental impurity risks will be identified from assessment of the raw materials and the finished drug product. This specific assessment has been prepared for PQRI Lotion, 1%. Details below:

• Product Code: Q3D • Product Name: PQRI Lotion, 1% • Packaging: 2 oz HDPE Bottle • Route of administration: Topical • Max Daily Dose1: 56.7 g/day • Manufacturing Location: Bronx, New York • Packaging Location: Bronx, New York

1 The product labeling gives an indefinite dosage: “a sufficient amount.” Therefore, the weight of the contents of the 2 oz bottle will be listed as the daily maximum dose (56.7 grams).


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2.0 Formulation

A summary of the drug product composition is provided in Table I. The calculated grams per day and % formula for each component are included to facilitate risk assessment.

Component Max Daily Intake (g/day) based upon a 56.7 grams/day maximum dosing

Table I: Product Composition

Component g/day % FormulaPQRI Active 0.565 1.00%Glyceryl Monostearate 2.5 4.41%Formaldehyde Solution USP 0.25 0.44%Polyoxyethylene 2 Cetyl Ether 2.25 3.97%Polyoxyethylene 20 Cetyl Ether 2 3.53%Glycerin USP 1.5 2.65%Methyl Paraben 0.05 0.09%Propyl Paraben 0.01 0.02%Purified Water 47.575 83.91%

Sum 56.7 100%


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Note Purified Water:

In an effort to insure that the purified water system does not pose a risk as a raw material ingredient, As, Cd, Pb, Hg, Cr, Mo, Ni, & V will be listed as elements with potential. There is no data to indicate that these elements pose a risk in product PQRI Lotion, 1% however they will be added into the risk assessment to drive the evaluation of these elements across multiple years of manufacturing. This approach will be taken to confirm that the current controls associated with the purified water system are sufficient.

3.0 Raw Material Evaluation – Identification of Potential Elemental Impurities

An evaluation of the elemental impurity risk associated with each raw material is summarized in Table II. The raw material evaluations used to compile Table II have been confirmed to consider all elements that apply to an oral dosage form per ICH Q3B. Elements listed in Table II are based upon Supplier information, inclusion of the Class 1 Elements in the absence of a significant body of data, and elements defined as potential from water systems.


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Note API PQRI:

Based upon information received from the supplier of PQRI API, Platinum (Pt) is utilized as a catalyst in production process. The process of manufacturing the PQRI API has demonstrated that Pt conforms to a control limit of < 1 ug/g. No other sources of Pt have been identified. The maximum potential contribution of Pt in the finished product is as follows:

Max Pt concentration (ug/g) x Max PQRI API (g/day) = Max Pt Daily Exposure (ug/day)

(1 ug/g) x (0.565 g/day) = 0.565 ug/day

Max Pt Daily Exposure (ug/day) x (100%) / Pt PDE (ug/day) = % PDE for Pt

(0.565 ug/day) x (100%) / (100 ug/day) = 0.6% PDE for Pt


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Table II: Identification of Potential Elemental Impurities

Material Intentionally

added (Catalyst)

Potential elemental impurities with a relatively high abundance and/or are

impurities in raw materials

Potential elemental impurities from manufacturing

equipment

Potential elemental impurities from

container closure systems

PQRI Active Pt As, Cd, Pb, Hg, None None

Glyceryl Monostearate None As, Cd, Pb, Hg None None

Formaldehyde Solution USP None As, Cd, Pb, Hg None None

Polyoxyethylene 2 Cetyl Ether None As, Cd, Pb, Hg None None

Polyoxyethylene 20 Cetyl Ether None As, Cd, Pb, Hg None None

Glycerin USP None As, Cd, Pb, Hg None None

Methyl Paraben None As, Cd, Pb, Hg None None

Propyl Paraben None As, Cd, Pb, Hg None None

Purified Water None As, Cd, Pb, Hg, Cr, Mo, Ni, V None None


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Supplier Survey – Example #1


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Supplier Survey – Example #2


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4.0 Manufacturing and Utilities

This product is a topical dosage form and the drug product manufacturing equipment train is composed of stainless steel components. Water is part of the product composition with no harsh solvents being utilized in the manufacturing process. The product is not likely to corrode or degrade contact surfaces within the manufacturing train, however the product will be evaluated for Ni, Co, and V as confirmation (potential impurities from stainless steel). No other risks are identified from manufacturing and utilities.

5.0 Packaging Evaluation This product is a topical dosage form. Interaction of the drug product with packaging materials resulting in the migration of elemental impurities into the drug product is a low risk. Finished Product testing in the final container will be performed to confirm this assessment. Testing will include samples beyond the product expiration period.


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6.0 Finished Drug Product Testing Evaluation

This product is a topical dosage form. In an effort to evaluate the risk associated with PQRI Lotion, 1% samples from current production, product samples that are approximately one year old, and samples greater than 2 years of age (post expiry) were tested for their elemental impurity content. Table III is a summary of Drug Product testing from finished packaging containers.


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Table III – Testing Results for PQRI Lotion, 1% Finished Product

Batch A current Batch B 1 year Batch C expired

PDE

ug/day

Test Result (ug/g) ug/Day % PDE



As 15 < 0.02 < 1.134 < 7.6% < 0.02 < 1.134 < 7.6% < 0.02 < 1.134 < 7.6% Cd 5 < 0.006 <0.3402 <6.8% < 0.006 <0.3402 <6.8% < 0.006 <0.3402 <6.8% Pb 5 < 0.006 <0.3402 <6.8% < 0.006 <0.3402 <6.8% < 0.006 <0.3402 <6.8% Hg 30 < 0.03 < 1.701 < 5.7% < 0.03 < 1.701 < 5.7% < 0.03 < 1.701 < 5.7% Co 50 < 0.06 < 3.402 < 6.8% < 0.06 < 3.402 < 6.8% < 0.06 < 3.402 < 6.8% Cr 11000 < 12.5 < 708.8 < 6.4% < 12.5 < 708.8 < 6.4% < 12.5 < 708.8 < 6.4% Mo 3000 < 4 < 226.8 < 7.6% < 4 < 226.8 < 7.6% < 4 < 226.8 < 7.6% Ni 200 < 0.22 < 12.47 < 6.2% < 0.22 < 12.47 < 6.2% < 0.22 < 12.47 < 6.2% Pt 100 < 0.11 < 6.237 < 6.2% < 0.11 < 6.237 < 6.2% < 0.11 < 6.237 < 6.2% V 100 < 0.11 < 6.237 < 6.2% < 0.11 < 6.237 < 6.2% < 0.11 < 6.237 < 6.2%


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All results were below the limit of quantitation (LOQ) for the method of analysis. The finished product testing data demonstrate that none of elements have potential to be present at levels above 10% of the daily PDE for elemental impurities identified in the risk assessment. This analysis also indicates that no additional testing controls are required based upon the ICH Q3D 30% Control Threshold


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7.0 Conclusion

Based upon ICH Q3D, a risk assessment was performed to determine the probability of inclusion of elemental impurities in PQRI Lotion, 1% and to establish the appropriate controls to insure the quality of the drug product. This assessment examined the risk associated with the ingredients, the drug product manufacturing process, and packaging components.

All elements identified in the risk assessment from Table II as having potential were confirmed to be at levels less than 10% of the PDE for each element as defined by ICH Q3D Table A.2.1 Additionally, the API supplier has provided information that demonstrates that Platinum (Pt) levels within PQRI API conforms to a material control limit of <1 ug/g. This corresponds to a maximum potential Pt contribution of <1% of the PDE for the finished product.

The Risk Assessment confirms that PQRI Lotion, 1% complies with ICH Q3D and USP <232>. Details associated with each elemental impurity identified as having potential are included in Table IV: Product Element Assessment. This product does not require any additional controls for elemental impurities at this time. The product release specification will reflect compliance with ICH Q3D and USP <232>. If the manufacturing process is modified or if suppliers of the ingredients and/or components are changed, the impact of the changes will be evaluated and this risk assessment will be updated as necessary.


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Table IV: Product Element Assessment

Element Expected % PDE

Risk Determination Justification Action

As <10%

Impurity levels assessed through finished product testing:

• Product testing is below the LOQ. The total potential As exposure from this drug product is below the 30% control threshold.

No further controls required

Cd <10%


• Product testing is below the LOQ. The total potential Cd exposure from this drug product is below the 30% control threshold.


Pb <10%


• Product testing is below the LOQ. The total potential Pb exposure from this drug product is below the 30% control threshold.

No further controls required at this time

Hg <10%


• Product testing is below the LOQ. The total potential Hg exposure from this drug product is below the 30% control threshold.


Co <10%


• Product testing is below the LOQ. The total potential Co exposure from this drug product is below the 30% control threshold.


Cr <10%


• Product testing is below the LOQ. The total potential Cr exposure from this drug product is below the 30% control threshold.


Mo <10%


• Product testing is below the LOQ. The total potential Mo exposure from this drug product is below the 30% control threshold.


Ni <10%


• Product testing is below the LOQ. The total potential Ni exposure from this drug product is below the 30% control threshold.


Pt <10%


• Product Testing below the LOQ The total potential Pt exposure from this drug product is below the 30% control threshold.

• Data from Supplier support a <1% PDE of Pt.


V <10%


• Product testing is below the LOQ. The total potential V exposure from this drug product is below the 30% control threshold.



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Revision History

Revision Author Date Change

01

Prepared By: Date:

Preparer’s Name: Title:

Reviewed By: Date:

Reviewer’s name: Title:

Approved: Date:

Approver’s name: Title:

Case Study – Topical Dosage Form Some Key Notes: • “consistently below the control threshold”. No definition. • No Labeled Max Daily Dose. Use of Full Container. The exception

might be single dose containers. • In the absence of a significant body of data and/or data over multiple

years, design a testing protocol to cover these risks.

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