The Value of Digital Photography By Louise Rutherford and Dean Hatt.

The Value of Digital PhotographyBy Louise Rutherford and Dean Hatt

Agenda

–Introduction–Case Study A–Case Study B–Case Study C–Case Study D–Case Study E–Conclusions–Questions

Presentation title 2

Introduction

– Digital photography was introduced into the Dispensary in 2008 to primarily assess potential colour changes on GLP DMSO stability studies

– Over the last 6 years we have managed to capture digital images on over 150 stability studies

– Approximately 20% of these have demonstrated a colour change over time

– The set up and use of digital photography on stability studies has previously been presented to the CHAOTIC group

– The use of digital photography has now been extended beyond stability assessments


Case Study A

– Compound A was tested within Pharmaceutical Development on a small scale and shown to have high aqueous solubility

– A formulation in saline was required for continuous infusion to support in-vivo studies

– Dispensary were responsible for the development of in-vitro formulations in DMSO/Water/hERG PSS

– Initiated a solubility assessment on an early batch of compound

Solubility Assessment


Compound A – Early BatchSolubility in Water


Compound A – Formulations in Saline


Compound A. Batch Colour Differences

– Early Batch

– New Batch

Compound A

– To summarise:

– Problem 1 – Formulation changing form over time producing ‘worm cast’

– Problem 2 – Dramatic colour difference between batches

– Problem 3 – Extraordinary differences in formulations of the SAME batch prepared in the same conditions but using compound from different containers


Multiple Problems

Pharmaceutical Development Container – New Batch

Dispensary Container – New Batch

Case Study A

– Pictures were sent to the project team which immediately allowed escalation of the issue and meetings were set up to discuss.

– Lab investigations started in collaboration between SA and Pharmaceutical Development

– Likelihood this is related to the formation of a trihydrate

– Continuous infusion studies were delayed as a result of the finding

– Formulation work is ongoing

Conclusions – Where Are We Now


Case Study B

– DRF’s had successfully been completed on early batches

– Standard suspension in 1% MC at reasonably low concentration – up to 10 mg/mL.

– GLP batch was received and stability study was initiated

Oral Stability Study


Compound B


‘Gumming’

Compound B

– Formulation was stable at up to 1 mg/mL in 1% MC

– Formulation not suitable at 10 mg/mL

– In-vivo studies potentially required up to 10 mg/mL

– SA dispensary conducted a vehicle assessment study

– Use of surfactants and intermittent sonnication/stirring were identified as the likely route to take

– The addition of 0.2% SLS was selected with the following result........


Unsuitable vehicle

Case Study B

– Digital photography was utilised to demonstrate the formulation issue to both SA project team member and Pharmaceutical Development

– Agreed that the formulation was unsuitable

– This was taken forward to successful stability study with this new vehicle

– Both stable and homogenous

– This was successfully used in GLP studies

– This has also been used with a new salt form of the same drug and this information was also used in developing a further formulation for MNT study

Conclusion


Case Study C

– Stability studies in Water, hERG PSS and an aqueous buffer were successfully conducted up to 100 mg/mL– Solubility assessment demonstrated up to approx 400 mg/mL in all

three vehicles

– Conducted on an early DRF batch that was made to GxP

– All GLP studies scheduled to start at CRO including one month nebulised inhalation studies

– A haemolysis assay was conducted in house using the new GLP batch

Starting GLP studies


Compound C

5 mg/mL in Buffer Vehicle


Compound C 12 mg/mL in Buffer Vehicle


Compound C

New Batch v Old Batch New Batch – Water V DMSO


Compound C


50 mg/mL in buffer vehicle

– Dark Deposits on glass

Case Study C

– Digital photography was able to demonstrate a clear difference in solubility of the new batch

– < 5 mg/mL compared with approx 400 mg/mL

– Dramatic colour difference between the two batches

– Pictures clearly showed the appearance of a dark red substance throughout the formulations

– Meetings were held between SA and Pharmaceutical Development

– Samples of all formulations sent to Pharmaceutical Development for analysis

– Pharm Dev could not identify the dark red substance but analysis results were close to nominal

– CRO studies were postponed to allow clean up and formulation re-work to be performed

– This was high profile as it was one of the first outsourced packages using the new SA strategy.

Conclusions


Case Study D

– Carcinogenicity study at CRO about to begin

– Formulation in 0.5% MC

– Compound was a sodium salt

– pH was at the top end of the acceptable range pH 12 at 200 mg/mL

– Potential reverse solubility but the dark colours made this difficult to assess

– Trial formulations at the CRO demonstrated poor physical stability and crystallisation of formulations which failed to re-suspend

– SA Dispensary conducted a further stability study looking at the physical stability and how we could advise the CRO on how they could prepare it

Physical Instability


Compound D

200 mg/mL Day 0 20 mg/mL Day 0


Reverse Solubility

Compound D

Day 7 200 mg/mL not stirred Day 7 60 mg/mL not stirred


Colour Differences

Compound D

20 mg/mL 60 mg/mL


Day 15 stirred v non stirred

Compound D

200 mg/mL


Stirred v Non Stirred

Case Study D

– Digital photography was used to demonstrate a time course of physical stability at a range of concentrations and the effect of continuous stirring

– Crystallisation was not seen on the scale performed in this stability study

– Project team were happy for us to make recommendations as to the frequency and scale / detail of preparation to allow consistent formulations on study

– At 200 mg/mL the recommendation was to prepare the day prior to dosing and store without continuous stirring

– At concentrations between 0.1 and 60 mg/mL the recommendation was to prepare at least 3 days prior to dosing to ensure that a suspension was dose

Conclusions


Case Study E

– Current formulation contained 2-hydroxypropyl beta cyclodextrin

– FDA rejected CAC proposal for use in a 2 year carc study due to link with cyclodextrins and pancreatic tumours in rats

– Had low and variable exposure

– SA conducted a vehicle assessment study

– Vehicle selected was 50:50 (v/v) PEG 400: Saline

– Formulation a solution

– Solution at high levels potentially required heat to maintain

– Stability study conducted to assess chemical and physical stability

Temperature Effect on Oral Stability Study


Compound E


Temperature Related Colour Change

– 10 mg/mL Day 0 – 10 mg/mL Day 7 37°C

– 10 mg/mL Day 15 37°C

– 10 mg/mL Day 15 4°C

Compound E


– Day 0 100 mg/mL – Day 7 100 mg/mL 37°C

– Day 15 100 mg/mL 37°C

– Day 15 100 mg/mL 4°C

Stability Results

Day 0 Day 7 (approx 37°C)

Day 15 (approx 37°C)


Determined Sample Concentration (mg/mL)

9.041 8.72 8.711 9.171

% of Nominal Concentration 90.4 87.2 87.1 91.7


– 10 mg/mL Stability Results





94.61 98.9 98.51 98.71

% of Nominal Concentration 94.6 98.9 98.5 98.7

– 200 mg/mL Stability Results

Compound E

Day 0 0.1 mg/mL Day 15 0.1 mg/mL – 37°C






0.11 0.0943 0.08321 0.09861

% of Nominal Concentration

100 94.3 83.2 98.6

Case Study E

– Formulation provided increased and non variable exposure in in-vivo studies

– Formulations were chemically stable for up to 15 days at 0.1-100 mg/mL when stored at approximately 4°C

– At 100 mg/mL the formulation failed to stay in solution at both tested temperatures, but was re-solubilised when minimal heat applied and/or maintained

– Formulations were chemically stable for up to 15 days at 10-100 mg/mL when stored at approximately 37°C but unstable at 0.1 mg/mL at this storage condition

– Digital photography was used to assess colour change throughout all phases

– Colour changes at 10 and 100 mg/mL and chemical instability at 0.1 mg/mL following storage at 37°C, preclude maintenance of these solutions at this temperature

– Solutions at 100 mg/mL to be stored at 4°C and re-solubilised for dosing period only

Conclusions


Overall Conclusions

– Digital photography can be used beyond the original remit of assessing instability

– It is a useful tool for assessing:

– Batch variation

– Insolubility

– Physical instability

– It can therefore aid in:

– Proactive formulation assessment

– Reactive formulation issues

– Fast, non subjective communication of formulation issues to the relevant people

– This is of greater importance with the SA strategy of outsourcing GLP studies where formulations are prepared at a greater scale and on batches manufactured using different synthetic routes


Questions?

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The Value of Digital Photography By Louise Rutherford and Dean Hatt.

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