Short-term storage stability ofTriple IT solution

Matthias D’Hondt1, Elien Vangheluwe1, Nadia Lemeire1, Tiene Bauters2, Brigitte

Pelfrene2, Johan Vandenbroucke2, Hugo Robays2, and Bart De Spiegeleer1,*

1 DruQuaR (Drug Quality and Registration) group, Faculty of Pharmaceutical Sciences and 2 Ghent University Hospital, Ghent University, Harelbekestraat 72, B-9000 Ghent,

Belgium (*Bart.DeSpiegeleer@UGent.be)

2011-211b

Triple IT solution

Objective

Stability protocol

Results

Discussion

Conclusion

BGFW - DruQuaR, Fac. Pharm. Sciences, Ghent University

Triple Intrathecal (IT) chemotherapy:

• Cytarabine (CB): pyrimidine antitumor agent

• Methotrexate (MT): synthetic inhibitor

of dihydrofolate reductase

vomiting, fever, paraplegia, meningoencephalopathy

• corticosteroid: reduces complications

Triple IT solution

Objective

Stability protocol

Results

Discussion

Conclusion

BGFW - DruQuaR, Fac. Pharm. Sciences, Ghent University

Hydrocortisone: benzylalcohol (preservative)

Methylprednisolone (21)-sodium succinate (Solu-Medrol®):no preservative

Yet, no in-use stability data available:

logistics and cost issues

Triple IT solution

Objective

Stability protocol

Results

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Conclusion

BGFW - DruQuaR, Fac. Pharm. Sciences, Ghent University

Determination of short-term (in-use) storage stability of Triple IT solution (ex tempore prepared):

(0.385 %m/V CB, 0.154 %m/V MT, 0.051 %m/V MP(21)-SS)

Evaluation of influences:

- Storage temperature- Photometric conditions- Packaging- Batch to batch variability

Triple IT solution

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BGFW - DruQuaR, Fac. Pharm. Sciences, Ghent University

Batch

3 different batches

Packaging material

1. Syringe system (PhaSeal®)

2. Brown glass vial

3. Brown glass vial filled with needles

Triple IT solution

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BGFW - DruQuaR, Fac. Pharm. Sciences, Ghent University

Temperature stability

time points (n=6): 0, 4, 8, 24, 32, 48 hrs.

3 batches, 3 packaging materials (all protected from light)

Temperature (°C) Relative humidity (%)

5 50

25 60

40 75

Triple IT solution

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Controlled conditions

BGFW - DruQuaR, Fac. Pharm. Sciences, Ghent University

Photometric stability

- Triple IT solution quartz cuvette (25°C / 60 % R.H.)

UV light – 2 days

VIS light – 8 days

- (Light protected) control samples

2 batches, in duplo

ICH Q1B compliant (light energy)

Triple IT solution

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BGFW - DruQuaR, Fac. Pharm. Sciences, Ghent University

Fused-core HPLC method

Column (+ guard column) Halo C18 (4.6×150 mm; 2.7 µm)

Column / sample temp. 30°C / 15°C

Mobile phase A: 0.1% V/V glacial acetic acid in H2OB: 0.1% V/V glacial acetic acid in ACN

Gradient programTime (min)

015

%A9010

%B1090

Flow rate 1 ml/min

Injection volume 10 µl

Detection DAD UV @ 240 nm (MP(21)-SS) @ 280 nm (MT and CB)

Triple IT solution

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BGFW - DruQuaR, Fac. Pharm. Sciences, Ghent University

T0hrs. Triple IT

240 nm

280 nm

Triple IT solution

Objective

Stability protocol

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BGFW - DruQuaR, Fac. Pharm. Sciences, Ghent University

Temperature stability – Global results

Triple IT Comp. Degradation Impurity formed Mass balance 1

CB - - 100.39 – 101.31%

MT - - 99.43 – 100.97%

MP(21)-SS 2 stat. significant RRT: 0.88 and 0.90 99.49 – 100.40% 2

Reporting threshold: 0.5%1 relative to T0 hrs.; 95% CI2 Including formed impurities, assuming RRF 1

Triple IT solution

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BGFW - DruQuaR, Fac. Pharm. Sciences, Ghent University

MP(21)-SS degradation kinetics:

assuming (and confirmed) 1st order to determine k

Arrhenius regression:

0.00305000000000001 0.00325000000000001 0.00345000000000001 0.00365000000000001

-7.5

-7

-6.5

-6

-5.5

-5

-4.5

-4

f(x) = − 5472.56704299358 x + 13.1701428843253R² = 0.968557109009822

1/T (K-1)

ln k

Ea: 45.5 kJ/mol(95% CI: 41.6 - 49.4 kJ/mol)

A: 524×103 h-1

(95% CI: 107×103 - 2571×103 h-1)

ln k = ln A – Ea/RT

Triple IT solution

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BGFW - DruQuaR, Fac. Pharm. Sciences, Ghent University

Identification MP(21)-SS related degradants (ESI-MS)

RRT: 0.88 RRT: 0.90[M+H+]+ [M+H+]+

[2M+H+]+[2M+H+]+

Methylprednisolone Methylprednisolone (17)-succinate

BGFW - DruQuaR, Fac. Pharm. Sciences, Ghent University

Batch / packaging material influence on MP(21)-SS degradation

MLR: k batch and packaging material (Temp.

constant)

No stat. sign. (95%) batch / packaging influence

Syr 5°C Syr 25°c Syr 40°C Gl 5°C Gl 25°C Gl 40°C Gl+N 40°C

00.20.40.60.8

11.21.41.6

Batch 1

Batch 2

Batch 3

k (×

10-2

h-1

)

Triple IT solution

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BGFW - DruQuaR, Fac. Pharm. Sciences, Ghent University

Photometric stability – Global results

Triple IT Comp. Degradation (%) 1 Impurity formed Mass balance 1

CBUV - - 101.29

VIS 3.80 RRT 1.12 99.47

MTUV 32.46 - 66.92

VIS 100.00 RRT 0.85; 1.05 28.09

MP(21)-SS 2UV - RRT 0.88; 0.90 98.62

VIS - RRT 0.88; 0.90 90.84

Reporting threshold: 0.5%1 Decrease of API, relative to light protected control samples2 Including formed impurities, assuming RRF=1

Triple IT solution

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BGFW - DruQuaR, Fac. Pharm. Sciences, Ghent University

Photometric stability – MTdegradation

MT: single compound vs Triple IT mixture

Triple IT solution

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0 20 40 60 80 100 120 140 160 180 200

-6

-5

-4

-3

-2

-1

0f(x) = − 0.0252189106582489 xf(x) = − 0.00867469502360543 xf(x) = − 0.107183115418421 x + 0.0541481840581015R² = 0.954331617986911f(x) = − 0.0766560166501102 x + 0.120880473120384R² = 0.963697247158426

MT single UVLinear (MT single UV)MT single VISLinear (MT single VIS)Triple IT UVLinear (Triple IT UV)Triple IT VISLinear (Triple IT VIS)

Time (hrs)

ln(A

ssay

Tx

/ As

say

T0)

BGFW - DruQuaR, Fac. Pharm. Sciences, Ghent University

Related impurities specifications (Ph. Eur.) of MP(21)-SS

MP: 0.5%

MP(17)-SS: 0.5%

Risk: MP (lower solubility) precipitation

Risk: min. (31%

degradation)

Conclusion: some consistent and controlled (MP + MP(17)-SS) degradation

of MP(21)-SS is allowed in FPP (DP) Triple IT (3%).

In API Solu-Medrol® FDP (Triple IT) higher, e.g. 1%

Triple IT solution

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∑impurities < 1%

BGFW - DruQuaR, Fac. Pharm. Sciences, Ghent University

Triple IT solution

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Predicted MP(21)-SS degr. in function of storage condition and time

60 180 360 720 1440 28800.00

1.00

2.00

3.00

4.00

5.00

6.00

7.00

8.00

Refrigerator (5°C)

Time (min)

Pred

icted

MP(

21)-S

S de

grad

ation

(%)

15 30 60 90 120 14400.00

0.20

0.40

0.60

0.80

1.00

1.20

Room temp. (25°C)

Time (min)

5 10 15 300.00

0.10

0.20

0.30

0.40

0.50

0.60Body temp. (37°C)

Time (min)

BGFW - DruQuaR, Fac. Pharm. Sciences, Ghent University

Related impurities specifications (Ph. Eur.) of MT API

0.2% (= IT): H, I

0.3%: (B, E)

0.5% (= QT): C

3%: (F)

6 unspecified 0.05%

∑impurities < 0.5% (excl. imp. B, E and C)

Conclusion:

no significant MT degradation is allowed Triple IT: total imp. <0.5%

Triple IT solution

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6 specified

BGFW - DruQuaR, Fac. Pharm. Sciences, Ghent University

Proposed storage conditions:Storage:

Max. 12 hour refrigerator 1.8% MP(21)-SS degradation

Before administration

Max. 30 min heating cycle (37°C) 0.6% MP(21)-SS degradation

During administration / transport

Max. 2 hours administration (25°C) 1.1% MP(21)-SS degradation

All light protected no MT degradation

Triple IT solution

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Stability protocol

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Conclusion

Thank you for your attention!!!

BGFW - DruQuaR, Fac. Pharm. Sciences, Ghent University