Accelerated Stability Assessment Program in API ...

Accelerated Stability Assessment Program in API development Lovrić M., Posavec R., Sindičić V., Mikulčić V., Runje M.

PLIVA Hrvatska d.o.o., Zagreb, Croatia

Contents – Problem and background – Stability testing – Traditional vs. ASAP stability testing – ASAP approach

– Method development – Test results – Conclusion

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Problem and background – A possible pre-formulation of two synergistic API’s should be tested on stability (API1 & API2) – No pre-knowledge on API2 stability and combination of the two – Needed results immediately (1 month) – Needed analytical method – Impurities known from forced degradation tests

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Stability testing

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Stability testing – ICH = International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use – Guidelines for stability testing

– Shelf Life – how the quality of a drug substance or drug product varies with time – establish a retest period for the drug substance or shelf drug product under storage conditions – assure safety – assure potency/ activity – shelf life set by what hits its limit first 5

Study

Storage condition

Minimum time period

Long term

25°C/60% RH

12 Months

Intermediate

30°C/65% RH

6 Months

Accelerated

40°C/75% RH

6 Months

Traditional vs. ASAP – ASAP = Accelerated Stability Assessment Program – Isoconversion

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ASAP approach Reaction rate

v=

𝑑 𝐴𝑃𝐼 𝑜𝑟 𝐼𝑀𝑃 𝑑𝑡 −𝐸 /

𝑘 = 𝐴 𝑒 𝑎 𝑅𝑇 ln𝑘 = 𝑙𝑛𝐴 − 𝐸𝑎 /𝑅𝑇 k rate constant A collision frequency Ea activation energy

R gass constant T absolute temperature 7

ASAP approach Solids have an added complication: %RH

Ea lnk = lnA– +B RH RT humidity sensitivity factor

Genton and Kesselring, 1977 Waterman et al., 2007 8

ASAP approach – Moisture corrected Arrhenius equation – determination of the isoconversion rate constants at any given condition Table: Basic Screening Protocol

T/°C

%RH

Time (d)

50

75

14

60

40

14

70

5

14

70

75

1

70

40

2

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lnk = lnA–

Ea RT

+B RH

ASAP approach Stage 3

Model Building & Stability Prediction Data Analysis and ASAP model built using data from Stages 1 & 2

2-5 Days Stage 2

Sample Analysis Aged Test Material Analysed Using Stability Indicating Method

1-3 Days Stage 1

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Sample Ageing Test material exposed to range of accelerated environmental conditions 7-21 Days

UHPLC Method Development

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Method development Experimental design (2 API’s + 5 impurities) – Column settings: – Acquity CSH C18, 2.1x100mm, 1.7um – Acquity Phenyl Hexyl, 2.1x100mm, 1.7um – Acquity CSH Fluoro Phenyl, 2.1x100mm, 1.7um – Phosphate Buffer pH settings: – pH = 2.0 – pH = 3.0 – pH = 4.0 – Column temperature settings: 30°C & 60°C – Gradient time: 10 min & 30 min – Organic phase: Acetonitrile 12

Method development Carried out 12 experiments (2tG , 3pH, 2T) → Drylab prediction software Acetonitrile pH 4.0

pH 3.0 pH 2.0 T [°C]

tG [min] 13

http://molnar-institute.com/

Method development pH3/ 30°C/ 10min/ PhH column

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Method development pH4/ 30°C/ 10min/ PhH column

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Method development pH2/ 60°C/ 10min / PhH column

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Method development pH3/ 50 ° C/ 10min/ CSH

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Method development Final → pH3/ 50 ° C/ 10min/ CSH

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Results and discussion

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Test results API2 suspecteded on humidity sensitivity

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Test results – Same conditions – 1. API2 – 2. API1+API2

Upper limit for RH%

Temp ° C RH % Time [d]

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60

25

7,9,15

60

50

4,8,15

70

10

2,4,15

70

20

3,15

70

30

2,15

70

50

1,7,12

70

60

1,3,8

80

5

1,8,13

80

25

1,4,7

80

60

1,2

Test results Test chamber and RH-capsules

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Test results API2 → conditions T=80°C/ RH=60%/ t=2 days -4 degradants

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Test results API1 + API2 → conditions T=80°C/ RH=60%/ t=2 days

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Test results → low chance API2 will reach 0.5% of any impurity at 25°C/60% RH in 1.5 years

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Test results → 50% chance API2 will reach 0.50% of each impurity at 45°C/70% RH in 1.5 years

45°C/70% RH

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Conclusion – API2 is stable at 25°C/60% RH for 3+ years – starts degradation at 60% RH, shown also by DVS plot (high water uptake) – The 2-component formulation is more stable at all tested conditions – ASAP is a fast and easy method for single- and multi-component stability testing

– Only work intensive part is analytics (UHPLC)

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