29-Apr Outline. Automation in dissolution testing. Mumbai , May 4 Samir Haddouchi

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1 Automation in dissolution testing Mumbai , May 4 Samir Haddouchi samir.haddouchi@sps-pharma.com 1 Outline - Introduction about automation - Automation for dissolution testing - Validation of automated methods - Case studies 2 Automation is already present everywhere in a pharmaceutical laboratory! Who is injecting manually samples onto the HPLC? Compared to all other techniques used, HPLC is still considered as a major and noble technique. However, several other automated systems are available and widely used: Automated physical testing Automated dissolution systems Automated sample preparation systems Mainly for labor savings!! 3 1

2 Why using automated systems? - Productivity - Time to market - Quality - Operator safety 4 Productivity (1) Most obvious reason to invest on automated systems! Automated systems can operate a defined process without any interaction of the analyst. This releases time for other added-value activities (ie paperwork ). Few full time equivalents may be gained in this manner. 5 Productivity (2) The return of investment is usually quite easy to evaluate based on the salary. However, the savings can be considered as "static". The only way to improve continuously the situation is to make additional investments. However, the objective of such investment is rarely to reduce the headcount! 6 2

3 Why using automated systems? - Productivity - Time to market - Quality - Operator safety 7 Time to market Instead of the previous situation where the aim was to carry out more analyses throughout the year, automation can also help to dicrease the impact of time-consuming steps. In production, the time needed to release a batch is reduced and therefore the following steps can be done with no risk (ie packaging, shipment, etc ). In development, automated systems (especially dissolution) can support the formulation development by analyzing different variants overnight and giving the opportunity to improve the formula the day after 8 Why using automated systems? - Productivity - Time to market - Quality - Operator safety 9 3

4 Analytical quality (1) Be careful to the difference between: - Quality - Quality Assurance!! What is the goal when developing a characterization method for a product? To ensure that the data generated reflect the quality of the product and are not related to the quality of the method! 10 Analytical quality (2) Recently, USP published several papers on the influence of different factors and parameters on the results of Prednisone calibration!! One of the main reason identified to be a root cause on non compliant results was the operator. By using automated systems, one can eliminates this variable and therefore ensure having an overall better method. 11 Quality Assurance Rough estimation of the cost for an OOS report : 1'500 $ (lost time, paper work, etc ) Some companies handle hundreds of such reports!! Using automated systems can also help minimizing the risk of analytical errors or mix-ups. This is an area of concern for the FDA. It is easier to audit a secured database than a lab book and what about auditing any human brain!! FDA officials say: «If you didn t document it, it didn t happen. In God we trust, for everyone else we require documentation». 12 4

5 Why using automated systems? - Productivity - Time to market - Quality - Operator safety 13 Safety Some active ingredients used in the pharmaceutical domain are extremely dangerous: - cytotoxics - cytostatics - nanoparticles - highly potent drug, etc The mass opinions are no more accepting the idea of risk. Automated systems can help avoiding employees exposure to such products. 14 Outline - Introduction about automation - Automation for dissolution testing - Validation of automated methods - Case studies 15 5

6 Automated sampling This is the first step in automation. Allows to perform sampling automatically i.e. over night. Samples can be stored in tubes or vials for a further quantification (also called off-line) Or measurements can be done online (UV-Visible photometry) and then the results are available "on the fly" (more cost effective) 16 USP2 instrument online 17 Fully automated systems Allow to automate: - the preparation of the test (heating, degassing and filling the dissolution media in the vessels) - the dissolution test itself (with offline collection or online readings) - The cleaning of the system to be able to start another test All these steps should be done without user interaction. These systems are more expensive than a semi automated system but they allow to have one single operator producing 10 to 15 dissolution tests per day and moreover, tests could be done during week ends 18 6

7 Fully automated systems 19 Outline - Introduction about automation - Automation for dissolution testing - Validation of automated methods - Case studies 20 Filtration Filtration Aim: Confirms that the drug tested does not adsorb onto the filter. Procedure: Manually filtered samples and automated filtered samples are compared. 21 7

8 Cleaning Cleaning verification Aim: Confirms that automated cleaning cycle is sufficient to prevent carryover. Procedure: Run a normal dissolution, followed by a blank run. 22 Cross validation Cross validation Aim: Confirms that automated results are not significantly different than manual results. Procedure: Run dissolution on your current systems, then on the automated (minimum n=3 batches) Possible issue: Is the variability observed due to the product or to the method? 23 Outline - Introduction about automation - Automation for dissolution testing - Validation of automated methods - Case studies 24 8

9 Acknowledgements Sean Space Pfizer US Emmanuel Scheubel Roche CH Krystyna Pobloka Teva Canada 25 Pfizer Case Studies Varenicline Film-Coated Tablets Approved nicotinic receptor partial agonist smoking cessation. Approved in over 60 countries BCS Classification 1 Lasofoxifene Lasofoxifene (high potency compound) is an estrogen receptor agonist Feasibility and validation of the use of SOTAX for dissolution testing Cetirizine HCl Cetirizine hydrochloride (Zyrtec) is an orally administered selective H 1 receptor antagonist approved for treatment of seasonal and perennial allergic rhinitis and chronic idiopathic urticaria. Query response 26 Varenicline Tartrate 2 dosage strengths subjected to SUPAC screen Aberrant and variant dosage forms evaluated with selected conditions Apparatus USP <711> Dissolution Apparatus I (baskets) and Apparatus II (paddles) Media 500 ml of water 500 ml of 0.01N HCl 500 ml of 0.1N HCl 500 ml of ph 4.5 buffer 500 ml of ph 6.8 buffer Basket Speed 50 and 100 rpm Paddles speed 50, 75 and 100 rpm Total number of dissolution runs 340 in 3 months 27 9

10 Varenicline: Why automation? SOTAX system used to: Evaluate effects of agitation, media, and apparatus type on the release characteristics of 0.5 and 1.0 mg tablets 5 media, 2 paddle speeds, 2 basket speeds Evaluate release characteristics of aberrant/variant tablets Used to analyze ICH and Site Validation stability studies (4 lots of each strength in 3 packaging configurations each) Over 600 analyses in one quarter Approved in 71 countries Launched in 48 countries 28 Validation Protocol for Lasofoxifene Validation Parameters Linearity/Recovery Reproducibility/Carryover Filter validation Dissolved oxygen SUPAC media screen Paddle type Dissolution Conditions USP Apparatus 2 Temperature: 37 C ± 0.5 C Rotation Speed: 75 RPM Dissolution Media: 0.01N HCl 500 ml of media/vessel 5, 10, 20, 30 min. sample pulls Over 25 analyses were performed at the various validation conditions. 29 Summary of Validation Results Linearity met acceptance criteria (R 2 = ) Reproducibility met acceptance criteria (% RSD of the average % 20 minutes of 6 consecutive runs = 3.3%) Carryover met acceptance criteria (< 2% carryover after 6 consecutive runs) Filter validation demonstrated by successful recovery Dissolved oxygen results reported and plotted (no differences between fully aerated media and deaerated media) SUPAC media screen has not been assessed QC wishes to use a SOTAX AT-70 for automated dissolution testing for commercial lots of lasofoxifene tablets. Due to this feasibility and validation work, this is possible

11 Cetirizine Chewable Tablet Hardness Study 96 Lots x 2 Time points / Lot = 192 Disso Runs 3 Runs / Day = 64 Days (This is an optimistic estimate!) Using Automated Disso = 28 days Actual = 36 day Savings* * Sotax AT70 initially running 4 Lots / day as learning curve leveled we were able to run 9 Lots / day for a potential saving of 43 days 31 Metric analysis Varenicline Cetirizine 20 0 Automation(dissolution runs per month with analysis) Manual (Estimate 12 runs per week)) 32 Roche Case Studies Case Study #1 : Ileum release enteric coated tablets Case Study #2 : HPLC On-line 33 11

12 Ileum enteric coated tablets % dissolved time (min) GTS 0073/03 S100/Talcum 100/50-7 mg in 2 media P50 GTS 0073/03 S100/Talcum 100/50-13 mg in 2 media P50 Different enteric coating thickness for Ileum release GTS 0073/03 S100/Talcum 100/50-4 mg in 2 media P50 GTS 0073/03 S100/Talcum 100/50-10 mg in 2 media P50 According to USP <711> resp. P.E 2.9 : no release 2 ph 1.1 and neutral ph 34 Ileum enteric coated tablets 35 Ileum enteric coated tablets Preprandial = fasted state ph and residence times in various segments of the GI tract Segment ph MRT (tablets) 1 Dissolution Method Design: stomach 1.8 (1-3) 60 min HCl - 1 h duodenum 6.0 (4-7) < 10 min upper jejunum 6.5 (5.5-7) 30 min ph 6.0-1h lower jejunum 6.8 (6-7.2) 30 min upper ileum 7.2 ( ) 60 min lower ileum 7.5 (7-8) 120 min proximal colon hours 1 non-disintegrating tablets ph 7.0-2h ph and mean residence time in various segments of the of fasted GI tract: (Source J.B. Dressman et al., University Frankfurt 2005) enteric coating 36 12

13 Ileum enteric coated tablets 1 ph change 2 ph change s ph level method ph level method ph ph 3 2 ph residence time (min) 3 2 ph residence time (min) 37 Ileum enteric coated tablets: Set up of the system for 2 ph changes Product name 38 Ileum enteric coated tablets % dissolved time (min) GTS 0073/03 S100/Talcum 100/50 P 4 mg 3 media GTS 0073/03 S100/Talcum 100/50 P 7 mg 3 media Different enteric coating thickness for Ileum release Conclusion: One coating was clearly not tight enough for the ileum release purpose. Automation was the only solution for this highly complex 2 ph changes method with full change. The method can be easily implemented in routine and provides potential for IVIVR/C investigations

14 Ileum enteric coated tablets Enhancement of capacity has to be calculated with all activities: preparation and cleaning of system as well as documentation and archiving Benefit of fully automated process No. of run Manual Sotax AT-70 1 ph change Sotax AT-70 2 ph changes 1 1 day 1 day 1 day 4 4 days 2 days 2 days 8 8 days 4 days 4 days At least a factor 2 can be reached & a heavy manual handling can be overcome 40 Dissolution & HPLC On-line HPLC measurement is the main limiting time factor in dissolution testing. Typical dissolution profile time for IR : 1 H with 5 sampling = 30 samples Typical HPLC run time for dissolution = 5 Typical HPLC sequence with SST = 40 injections = 200 = 3.3 hours Manual Off line process 2-3 dissolution testing /day measurements over night (with maxi capacity of auto sampler) = 10 hours of analysis (can be critical for non stable solutions) First enhancement step = HPLC Online 41 Dissolution & HPLC On-line Sotax AT70smart fitted with TS70 Option and Kloen Typical dissolution run time with LC on line = 3.5 hours HPLC on line process 3-4 dissolution testing /day sequential runs = 15 hours of analysis (can be critical for non stable std solutions) 2nd enhancement step = Fast HPLC 42 14

15 Dissolution & HPLC On-line 4.6*50 mm, 3.5 µm, 1.5 ml/min, 40 C; 70 bars Retention time: 3.4 min LC run time 4` 43 Dissolution & HPLC On-line 2.1*50 mm, 1.8 µm, 1.0 ml/min, 70 C ; 400 bars Retention time: 0.6 min LC run time 0.8` 44 Dissolution & HPLC On-line HPLC measurements time decreased up to 30 / run Typical dissolution profile time for IR : 1 H with 5 sampling points Fast HPLC measurement time for 40 samples = 25 Typical dissolution run time with LC on line & 40 runs = 1.6 H (dissolution time + cleaning) On- line with fast HPLC 10 dissolution testing /day measurement over night Limitation = AT70 capacity!!!!!! (10 runs) 45 15

16 Dissolution & HPLC On-line Benefit of fully automated process No. of run Manual Off line Sotax AT-70 On-line HPLC Sotax AT-70 On-line + Fast HPLC day 1 day 1 day days 2 days 1 days days 3-4 days 2-3 days At least a factor 3 can be reached. Comparable to UV-on line with better selectivity (early phase API is not so well known and change frequency is high, that can be hazardous with UV) ideal choice for early phase 46 Cost Saving Evaluation Cost Saving in $CND/Batch Cost Saving in $CND/Year Product I $ $140,625 Product II $ $87,500 Product III $ $25, Conclusions Validation has been focused on high volume products. As a result of transfer to automated methods, time of release of the finish product decreased due to the overnight and weekend runs. Significant cost saving per batch (runs unattended - available resources for other tasks). Reduced number of the investigations due to lab errors (locked methods)

17 Thank you for your attention. SPS Pharma Services Orleans - France 49 17