Excipient Compatibility

as Predicted by ASAP
A Case Study

Jerusha Thompson
Science of Stability 2015
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October 12-14, 2015 Connecticut, US
Getting To Know
Faster

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Outline
1. Introduction
2. Overview of Traditional Excipient Compatibility Studies
3. Accelerated Stability Assessment Program (ASAP)
4. Case Study
5. Alternate Analytical Technique
6. Comparison of Analytical Techniques
7. Conclusion
8. Acknowledgement

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Introduction
 Provide a rational for excipient selection
 ICH Q8(R2): Pharmaceutical Development
 The compatibility of the drug substance with excipients listed should be evaluated
 Impact on stability of API
 Risk management
 Regulatory Requirement
 QOS: What evidence supports compatibility between the excipients and the drug
substance?

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Traditional Excipient Compatibility Studies

 Binary mixture of active pharmaceutical ingredient (API) and excipient

prepared in a 1:1 ratio

 Excipients showing incompatibility at the 1:1 ratio tested at a ratio more

typical of the final formulation

 Two vial types (duplicate vials for each) prepared for each drug-excipient
blend
 Assay vial (pre-weighed for moisture)
 Composite vial (for additional tests)

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 Traditional Excipient Compatibility Study
 Three controlled conditions
 200 vials prepared for 7 excipients studied open dish

One Excipient
= 25 Vials T=0 T=2 weeks T=4weeks T=8 weeks

Test Conditions Assay Dupl. Comp. Assay Dupl. Comp. Assay Dupl. Comp. Assay Dupl. Comp.

Accelerated - X X X X X X X X X X X X
40ºC / 75% RH
CRT - 25ºC / 60% X X X X X X X X X X X X
RH
Light 2X X X N/A N/A N/A N/A N/A N/A N/A N/A N/A
Total Vial Counts 4 3 3 2 2 2 2 2 2 2 2 2
=
Grand Totals = 10 6 6 6

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Traditional
Excipient Compatibility Studies
 The analytical testing includes:
 Assay
 Impurities
 Description
 Loss on Drying (LOD)
 Results compared to a control (API) across all time points and conditions to
look for any trending
 Any unexplained or unexpected loss in potency, or increase in impurities over
time mandated further investigations
 Excipient ratio screening, at the levels typical of the final formulation.

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Traditional Excipient Compatibility
Studies
 Limitations
 1:1 Binary blends not representative of formulation
 May not pick up on incompatibilities

 Manufacturing
 Processing
 Tableting

 Sample Load
 Resources
 Increased time-line
 Inconclusive results
 Not an indicator of formulation stability

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Accelerated Stability Assessment Plan:
Excipient Compatibility Study
 Rapid approach to determine incompatibilities

 Multiple prototype formulations screened simultaneously

 Provides greater understanding of drug product stability

 Impurity profile
 Allows rapid entry in full formulation development

 Predicts impact of container/closure on product stability

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ASAP: Excipient Compatibility Study
 Sample count depends on study
 21 samples for 3 batches tested
 Amebis Incubation System
 Incubation flask controls temperature/humidity

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Case Study
 aNDA program
 Presence of lactose in reference listed drug (RLD)
 Maillard reaction
 Chemical reaction between amine and sugar

 One known degradation product

 Specification limit defined by ICH Q3B(R2) and monograph
 Drug product: oral tablet
 Strength: 0.5mg, 1mg, and 2mg
 Commercial packaging configuration: 100 and 1000 count HDPE bottle
 Timeline
 12 months to develop final formulation

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Case Study
 API determined to be stable
 Three prototype formulations pressed into tablets
 Manufactured at bench scale
 Formulation 1 approximates RLD formulation

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Case Study
 ASAP design parameters
 7 samples per prototype formulation
 Container closure system selected based on appropriate sized bottle for 100
tablets

Product Type: Tablet

Length: 14 days
Number of Analyses: 7
Specification Limit: 0.2% label claim
Container: 75cc HDPE bottle/HIS cap

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Case Study
 Testing design
 Screening design for excipient selection
 Minimal approach taken comparing three prototypes
 Once prototype formulation selected and optimized then additional more robust ASAP
study conducted

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Case Study
 Stability indicating UHPLC method
 Reporting impurities equal or greater then 0.02% label claim
 2 days for analytical analyses with a developed method

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 Chromatogram

API
0.14

0.12

0.10

0.08

0.06

RRT 3.205
AU

0.04

RRT 3.307
Known 1
0.02

0.00

-0.02

-0.04

-0.06

0.50 1.00 1.50 2.00 2.50 3.00 3.50 4.00 4.50 5.00 5.50 6.00
Minutes

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 Raw Data: % Impurity
Formulation 1: Lactose
Deg Control 50ºC/75%RH 60ºC/50%RH 70ºC/11%RH 70ºC/75%RH 70ºC/75%RH 80ºC/30%RH
Product 14 days 14 days 14 days 1 days 3 days 2 days
Known 1 ND 0.032 0.078 0.076 0.039 0.065 0.099
RRT 3.21 ND 0.141 0.262 0.108 0.150 0.325 0.192
RRT 3.31 ND 0.058 0.256 0.064 0.086 0.059 0.179

Formulation 2: Dicalcium Phosphate

Deg Control 50ºC/75%RH 60ºC/50%RH 70ºC/11%RH 70ºC/75%RH 70ºC/75%RH 80ºC/30%RH
Product 14 days 14 days 14 days 1 days 3 days 2 days
Known 1 0.024 0.392 0.621 0.622 0.314 0.614 0.629

Formulation 3: Starch 1500

Deg Control 50ºC/75%RH 60ºC/50%RH 70ºC/11%RH 70ºC/75%RH 70ºC/75%RH 80ºC/30%RH
Product 14 days 14 days 14 days 1 days 3 days 2 days
Known 1 ND 0.055 0.036 0.043 0.046 0.115 0.040

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Case Study
 Predicted results from ASAP®Prime meeting acceptance criteria of 0.2% label claim
 All degradation products
 Packaging assessed
 With and without desiccant
 ICH accelerated and CRT
 RRT 3.31 poor correlation
 Potential secondary degradation

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 Case Study
Formulation 2-Known-1 40°C/75% RH Formulation 2-Known-1 25°C/60%RH
no desiccant no desiccant

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Case Study
 Formulation 1- RRT 3.31 40°C/75% RH
 Higher error propagation

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Case Study
 Results
 Formulation 1 (RLD)
 Two unique unidentified degradation products observed

 Formulation 2
 Known 1 would have difficulty meeting a shelf-life of 24 months without a desiccant
 Failure at accelerated conditions would require additional testing at an intermediate
condition

 Formulation 3
 Highest probability of passing all conditions without desiccant

 Study results will help justify the excipient and packaging selection in CMC
section of submission

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Alternative Analytical Technique
 Rapid entry into full formulation development with ASAP allows decreased timeline
 Traditional approach to excipient studies ~3-6 months
 ASAP ~ 2-4 weeks
 Rate limiting step can become analytical technology
 Stability indicating HPLC method can take time to develop
 ~1-2 months

 Response of degradation products to parent compound critical

 Quantitative NMR (qNMR)
 One method for all drug products
 No method development required

 No response of degradation product needed

 No quantitative reference standard required

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Alternative Analytical Technique
 qNMR Parameters

1. Pauli, G. F. et al. J. Med Chem. 2014, 57, 9220-9231

2. Weber, M. et al. J. Pharm. Biomed. Anal. 2014, 93, 102-110
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Alternative Analytical Technique

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Alternative Analytical Technique
 Predicted results for meeting acceptance criteria of 0.2%

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Alternative Analytical Technique
 Known 1 data for each prototype formulation analyzed using qNMR
 The results of the analysis predict prototype formulation 3 (Starch 1500)
would have the greatest probability of meeting an acceptance criteria of 0.2%
label claim
 Analysis of unknown degradation products not performed during this analysis
 Further optimization of extraction process necessary
 Both analytical techniques selected prototype formulation 3 as the most
stable formulation

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Conclusion
 The data generated from the excipient compatibility study predicted
prototype formulation 3 would be the best candidate to move forward into
full formulation development
 Analysis of each of the prototype formulation in the ASAP study also provided
an early profile of likely degradation products present in each formulation
 Both analytical techniques investigating selected prototype formulation 3
 qNMR analysis may allow for faster determination of instabilities in a drug product
 The predictions from the ASAP study will be further monitored through the
project, and confirmed through traditional ICH stability studies
 ASAP approach to excipient compatibility testing allows faster entry into full
formulation development ~2-5 month

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Acknowledgement
 Patrick Nelson, Chemist II
 Limin Shi, Scientist II
 Sze Leung, Associate Chemist I
 Tyler Blanke, Associate Chemist I
 Byrant Gay, Ph.D., Scientist I
 Mark Gherke, Ph.D., Associate Director

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