PQRI PODP Extractables & Leachables Workshop · 4/9/2018 · DP 12 50 50 mg/mL drug, Iso-omotic saline, acetate buffer 4.0 – 5.5 Notes: (1) DP = drug product with unnamed API

PQRI PODP Extractables & LeachablesWorkshop

Presented by: Dennis Jenke,Chair, PQRI PODP Chemistry Working Team

The Simulation Study in Action –

Establishing a Design Space for Terminally Sterilized Aqueous Drug Products in a Plastic Packaging System

April 2018

PQRI PODP E&L WorkshopApril 18-19, 2018

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Problem Statement

OBJECTIVE: The most definitive way to establish the patient safety risk associated with leachables present in a pharmaceutical drug product is to measure and assess all leachables present in the drug product at levels above an generally accepted acceptable safety risk threshold (such as the AET).

PROBLEM:There are circumstances where it is not scientifically or practically possible to accomplish this objective.


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Circumstances where Leachables Testing is not Possible or Practical

1. The drug product cannot be screened for leachables at levels as low as the acceptable safety risk threshold (AET).

2. A packaging system is developed for use with numerous drug products and leachables testing of all the drug products is cost- and time-inefficient.

3. Leachables testing is inherently reactive to potential problems and there is a desire to perform testing that enables problem anticipation and resolution (QbD).

4. Leachables testing may be an inconvenient and costly way to manage change control.


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In situations of analytically challenging Analytical Evaluation Thresholds (AETs) for certain PDPs (e.g., large volume parenterals) and in other situations for ODPs, a specific type of extraction study termed a “Simulation Study,” could be applied (in lieu of or) to supplement and focus drug product leachables studies. These studies can establish an extractables profile representing the worst-case leachables profile of the packaged drug product that the study simulates.

The Concept of the Simulation Study

“since the extractables profile is the same as the leachables profile, then one can safety assess the extractables profile and not perform subsequent leachables testing”. The appropriateness of such an answer rests on the rigor of the simulation and its associated justification.


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The Concept of the Simulation Study

An extractables profile obtained from a properly designed and executed simulation study will be equal to (or greater than) a leachables profile obtained for a drug product over its shelf-life. (meaning that the extractables profile includes all the members of the leachables profile with extractables levels being greater than or equal to the leachables levels).


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Differences between Simulation and Actual Use

1. The drug product formulation has been replaced with one or more simulating solvents.

2. The actual use conditions of contact may have been accelerated.

3. The test article may have been altered (somewhat) to provide an exaggerated and presumably worst case.


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Use of a Simulation Study to Establish a Design Space

Problem Statement: Liquid drug products are packaged in plastic systems. Additives in, and components of, the plastic packaging may leach into the drug product. These leachables may adversely impact the product’s safety and/or efficacy. Thus “leachables present below toxic levels” is a critical quality attribute of packaged drug products.

Current Situation: Each individual drug product that is packaged in a given system is tested for leachables levels. The safety of each individual drug product is established by the toxicological evaluation of the leachables data. The leachables/tox assessment process, along with its associated activities, requires many man-hours and many months to complete.

Desired Situation: Establish safety via parametric analysis (i.e., “if the composition of drug product falls within certain parameters (e.g., a Design Space), then the leachables will be below toxicity thresholds”).


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Establishing the Design Space

1. A specific container/closure system of known and specified composition.

2. Nominal fill volumes of 50 mL to 1000 mL.3. Aqueous SVP and LVP drug products formulated in the pH range

of 2 through 8 with no polarity-impacting agents such as organic solubilizers and stabilizers.

4. Drug products that are terminally sterilized.5. Drug products that are stored (post-sterilization) at ambient

temperature for a period of up to 24 months.

What Situation do we want to Cover?


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1. “Polarity-Neutral” Components (primary function is not drug solubilization, generally components with high aqueous solubility). • Diluents (dextrose, saline)• Buffers (acetate, lactate, bicarbonate, phosphate)• Amino acids• Vitamins

2. “Polarity-Impacting” Components (primary function is to increase the solubility of the drug. Whatever increases the solubility of the drug increases the solubility of the leachables).• Tween 80 (and other commonly employed solubility enhancers)• Cyclodextrins• SDS• Albumin• Liposomes (etc)

The Concept of “Polarity-Impacting” Components


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Establishing the Design Space with a Simulation Study

Test Articles: 50 mL containers filled with one of three extracting solvents (pH 2 solution, unbuffered water and pH 8 buffer). Filled containers subjected to terminal sterilization (autoclaving). Sterilized test articles stored at 40°C for up to 6 months.

Actions: At various times during storage, the fill solutions were characterized for extracted substances via orthogonal analytical methods (reporting threshold = 0.05 mg/L). The maximum concentrations of the extracted substances were toxicologically assessed to establish potential product safety impact.

Design of the Simulation Study:


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Establishing the Design Space with a Simulation Study

Outcome of the Simulation Study:

Outcome of the Toxicological Safety Assessment: The toxicological assessment concluded that the extractables, at their highest measured levels, did not present a meaningful risk of an adverse impact on patient safety.

Conclusion: A Design Space has been established with the boundaries defined previously. Any packaged drug product that falls within the Design Space will have leachables at doses less than or equal to the maximum dose of the extractables (which have been determined to be safe).


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Confirming the Design Space; Targeted Leachables Testing

The Critical Issue:

Are the levels of leachables in drug products less than or equal to the worst case estimates from the simulation

study’s extractables assessment?

Extractables Leachables


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The Leachables Confirmation Study

1. Drug products and a “water-like” simulating solvents were packaged in the packaging system, autoclaved and stored under accelerated conditions up to the anticipated product’s shelf-life.

2. At certain intervals during accelerated storage, the levels of target leachables were measured in the drug product and “water-like” simulating solvents.

3. The levels of the target leachables in the drug product and the “water-like” simulating solvents were compared.

Study Design:


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Table I. Drug Product Formulations Examined in this Study.

Solution Code (1) Container Size (mL) Formulation pH Range Simulating Solvents 50 pH 2, pH unadjusted, pH 8 2 – 8 DP 1 250 10 mg/mL drug, Iso-omotic saline, acetate buffer Not specified DP2 250 (200) (2) 2 mg/mL drug, 0.9% saline 4 - 8 DP3 50 2.5 mg/mL drug, 4.6% dextrose, DL-lactic acid 3.2 – 3.6 DP4 50 0.64 mg/mL drug, Iso-omotic saline, citrate buffer 3.0 – 4.0 DP5 100, 250 (200) (2) 2 mg/mL drug, 5% dextrose 3.5 – 5.5 DP6 100, 250 (200) (2) 2 mg/mL drug, 5% dextrose 3.5 – 4.6 DP7 50 5 mg/mL drug, 5% dextrose 3.8 – 5.8 DP8 100 0.2 mg/mL drug, 5% dextrose, DL-lactic acid 3.4 – 3.8 DP9 100 0.2 mg/mL drug, 5% dextrose, L-lactic acid 3.4 – 3.8 DP10 250 1 mg/mL drug, Iso-omotic saline, acetate buffer 4.9 – 5.1 DP11 100, 250 (200) (2) 1.25 mg/mL drug, 0.9% saline 4.0 – 6.5 DP 12 50 50 mg/mL drug, Iso-omotic saline, acetate buffer 4.0 – 5.5 Notes: (1) DP = drug product with unnamed API. (2) 250 (200) means a 200-mL underfill of a 250-mL container.


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Accumulation Level

Potential Toxicological Safety Risk

Source in the Packaging System

Chemical Nature

Rationale for Targeted Compound Selection:


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Targeted Compounds:


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Targeted Compounds:


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LC/MS methods were developed and validated for measuring the target compounds in the drug products.

A Safety Threshold of 100 ppb (ng/mL) was established for this situation and the LC/MS methods had quantitation limits equal to the safety threshold or lower.

Analytical Considerations:


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Decision Process:


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Desired Outcomes:



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Desired Outcomes:


Result for RC Interpretation Conclusion RC ≤ 1.0 [leachable] ≤ [extractable]

(The Desired Outcome) Verifies the Design Space (leachables are safe because the extractables are safe).

1.0 ≤ RC ≤ 2.0 [leachable] ≤ 2 x [extractable] (An Acceptable Outcome)

Verifies the Design Space (allows for uncertainty in the analytical measurements and the tox assessment).

RC > 2.0 [leachable] > 2 x [extractable] Rejects the design Space (leachables are unsafe).

Relative Concentration (RC) =

[Leachable in drug product]/[Extractable in simulating solvent]


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Confirmation studies have been completed for more than 30 drug products and their associated “water-like” simulating solvents.

These studies have produced more than 4000 individual data points comparing leachables levels in the drug product versus extractables levels in the “water-like” simulating solvent.

Study Status:


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Number of desired outcomes1: > 4000

Number of acceptable outcomes2: 3

Number of unacceptable outcomes3: 0

Study Results:

1A desired outcome is one where either drug product ≤ simulating solvent or both drug product and simulating solvent results were below the safety threshold.

2An acceptable outcome is one in which drug product ≤ 2 x simulating solvent (reflecting typical analytical variation and an acceptable “safety margin”).

3An unacceptable outcome is one in which drug product > 2 x simulating solvent, suggesting that the “water model” was not accurate and the Design Space was flawed.


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The Leachables Confirmation StudyRelative Accumulation of Target Leachable BPAT

Drug Container Relative Concentration of the Target Leachable (1) Product Size (mL) At Time Zero (2) 3 months, 40°C 6 months, 40°C DP1 50 NMT 100 (5) NT (3) NMT 100 (5) DP2 250 (200) 1.15 (4) DP3 50 NMT 100 (5) NMT 100 (5) NMT 100 (5) DP4 50 NMT 100 (5) 0.53 0.56 DP5 100 0.93 0.88 0.83 250 (200) NMT 100 (5) 0.84 0.80 DP6 100 0.74 0.81 0.75 250 (200) NMT 100 (5) NMT 100 (5) NMT 100 (5) DP7 50 NMT 100 (5) NT (3) 0.80 DP8 100 1.00 0.73 0.87 DP9 100 0.91 0.83 0.80 DP10 250 NMT 100 (5) NMT 100 (5) NMT 100 (5) DP11 100 NMT 100 (5) NMT 100 (5) NMT 100 (5) 250 (200) NMT 100 (5) NMT 100 (5) NMT 100 (5) DP12 50 NMT 100 (5) NMT 100 (5) NMT 100 (5) Notes: (1) Relative Concentration = Concentration in drug product/concentration in simulating solvent.

(2) Time Zero is after an autoclave sterilization cycle. (3) NT = Not tested. (4) This drug product was only tested at one time point, representing 24 months storage at 25°C. (5) NMT 100 means the concentration of the target leachable in the drug product was less than the quantitation threshold of 100 ng/mL (ppb).


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Concluding Summary

A Design Space, constructed via simulation extraction studies and related to the safety impact of packaging system leachables, has been established and verified for “water-like” drug products packaged in a specified plastic container-closure system. This Design Space is defined in terms of the drug product’s pH and polarity. Any drug formulation that fits within the Design Space is deemed to be acceptably safe from the perspective of the potential patient safety impact of leachables.


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References

Contact the presenter at: dennisjenke@triadscientificsolutions.comwww.triadscientificsolutions.com

1. D. Jenke. Application of quality by design (QbD) principles to extractables/leachablesassessment. Establishing a design space for terminally sterilized aqueous drug products stored in a plastic packaging system. PDA J Pharm Sci Technol. 64(6): 527-535 (2010).

2. D. Jenke, M. Gill, J. Liu, S. Liao, and X. Huang. Application of quality by design (QbD) principles to extractables/leachables assessment for terminally sterilized aqueous parenteral solutions stored in a plastic packaging system. CNPPA Magazine: Pharmacy & Packaging. 36(6): 4-10 (2014) and 37(1): 5-10 (2015).

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Documents

PQRI PODP Extractables & Leachables Workshop · 4/9/2018 · DP 12 50 50 mg/mL drug, Iso-omotic saline, acetate buffer 4.0 – 5.5 Notes: (1) DP = drug product with unnamed API