Implementation of an Online UV monitoring system in Tinzaparin Sodium Manufacture

Size: px

Start display at page:

Download "Implementation of an Online UV monitoring system in Tinzaparin Sodium Manufacture"

Sharyl Lane
6 years ago
Views:

1 Implementation of an Online UV monitoring system in Tinzaparin Sodium Manufacture 1

2 LEO Pharma Corporate presentation We help people achieve healthy skin 2

3 For decades LEO Pharma was a very diversified business But as a part of our growth journey, we sharpened our focus on dermatology 3

4 We help people suffering from Thrombosis The appearance of blood clots is also called thrombosis it can be difficult to detect however, once detected, the blood clots are highly treatable Many of us are at risk from blood clots that develop in the deep veins of our legs due to inherited risk factors, such as genetic disposition, or acquired conditions, such as major surgery or cancer treatment Thrombosis is one of LEO Pharma s non-derma offerings and we have more than 70 years of experience in helping patients avoid or recover from blood clots At LEO Pharma, we offer treatments in the shape of innohep and Protamine Sulphate LEO Pharma

5 5

6 THE CLOTTING CASCADE Ant it H

7 CLOTTING FACTORS THROMBIN (IIA) XA ANTI CLOTTING FACTORS ANTI-THROMBIN

8 H E P A R I N ANTI-THROMBIN HEPARIN MODE OF ACTION H E P A R I N ANTI-THROMBIN H E P A R I N ANTI-THROMBIN THROMBIN (IIA) H E P A R I N ANTI-THROMBIN XA

9 L M W H TINZAPARIN (LMWH) MODE OF ACTION ANTI-THROMBIN L M W H ANTI-THROMBIN L M W H ANTI-THROMBIN THROMBIN (IIA) L M W H ANTI-THROMBIN XA

10 Assay of Heparin Ph.Eur H E P A R I N ANTI-THROMBIN THROMBIN (IIA) THROMBIN (IIA) THROMBIN (IIA) 405 nm Substrate Peptide Pna

11 MAST CELL

12 MUCOSA IS REMOVED FROM INTESTINAL CASING THROUGH ROLLERS MUCOSA

13 There is selective binding to the resin. This is a the key impurity removal step

14 LEO Pharma Cork 14

15 Heparin is a complex molecule 15

16 Tinzaparin sodium (LMWH) Heparinase Specific MWD specifications 16

17 Tinzaparin Manufacture The degree of depolymerisation directly affects the potency and yield of the product It is important to have a reliable method of monitoring the reaction in order to ensure a consistent and optimised process. The reaction is currently monitored by taking advantage of the formation of an unsaturated iduronic acid derivative during the depolymerisation which absorbs ultraviolet light. The change in ultraviolet light at 235 nm (delta A) is used as a measure of the number of bonds cleaved and therefore a measure of the degree of depolymerisation of Heparin Sodium. 17

18 Tinzaparin Manufacture Current method of Offline sampling Advantages Simple (Analytically) Reproducible Disadvantages Laborious Not real time Potential yield implications Typically offline readings obtained over the course of the reaction. Aim is to get the Delta A within 1 AU 18

19 Tinzaparin Online Monitoring System The ideal situation is to implement an online method of monitoring the reaction, which would eliminate the requirement for sampling and the delay in obtaining data used to terminate the reaction. 19

20 Tinzaparin Online Monitoring System Options considered; Lab scale experiments Univariate Online UV method Multivariate Online UV method Raman Spectroscopy NIR FIPA (Flow Injection Polymer Analysis) 20

21 Tinzaparin Online Monitoring System Raman and multi-spectrum UV gave the best response Multi-spectrum UV was chosen as the most suitable technology for an onsite trial. 21

22 Development Challenges It can be seen that as the peak moves the absorbance at 235nm is at a different point on the curve and so the correlation with reaction progression is not linear. The advantage of collecting data for a range of spectra means that issues like this can be dealt with, but it also means that the mathematical methods used to analyse the data are nearly as important as the raw data. 22

23 Tinzaparin Online Monitoring System Pilot plant (10L) trials performed Flowcell UV Spectrophotometer Recirculation Pump Computer Tinzaparin Reaction vessel 23

24 Tinzaparin Online Monitoring System Optimisation of the system; Pilot Scale Concentration Effects to determine if the product concentration in the solution has an effect on the UV signal. Temperature Effects a reaction was ran at a different temperatures to determine the effects of temperature on the UV signal. ph Effects- Reaction 2012-UV-013 This trial was to determine if the UV signal was affected by varying ph levels. Flow cell width 24

25 Online Tinzaparin Reaction: Full Batch Scale 25

26 Tinzaparin Online Monitoring System Further Optimization of the data: Batch scale (8 batches) Peak Analysis Peak Height Analysis Peak Centre Analysis Peak Area Analysis PLS (Partial least squares) Model 26

27 Tinzaparin Online Monitoring System PLS is a multivariate technique which assesses all the data available and then assigns weightings (or loadings) to each variable (wavelengths in our case) according to how much each variable changes with regard to the response variable in question. In effect the first factor calculated (or principal component ) is simply a weighted average of the raw absorbance values. This component is then analysed to determine how much of the variation this new composite variable explains another component calculated. More components can be calculated until all the variation in the data is explained, ideally with as few components as possible. Therefore it is possible to reduce the information collected by dozens of variables down to two or three principal components. 27

28 Tinzaparin Online Monitoring System Predicted A235 measurements compared to reported offline measurements 28

29 Regulatory strategy Change type 1b other Introduction on Online UV as an alternative option for monitoring reaction progression. UV analysis already used in production (Offline) No quality attributes were potentially impacted by change e.g. Assay and MWD not impacted by introduction of the online method. Current controls for the reaction (Offline Measurement) remain in place 29

30 Key Learnings Selection of Data and Data processing Identification of data that provide the best results Engineering Challenges Operation of UV instrument in production rooms Recirculation loop cleaning and maintenance Validation Challenges Moving UV instrument into ATEX area Regulatory Strategy Meeting commitments. 30

31 Special Thanks Alison Winger PhD - MSAT Development Scientist Jason Murtagh - Development Process Engineer Liam Ryan - MSAT Development Scientist Karen Colgan Regulatory/Quality Specialist Sandra Patricia Auguste-Bowler Principal Scientist Clariet Scientific 31

32 Thank You 32

HEPARIN CALCIUM. Heparinum calcicum

HEPARIN CALCIUM. Heparinum calcicum Pharmeuropa 25.1 1 Reference: PA/PH/Exp. 6/T (12) 38 ANP NOTE ON THE MONOGRAPH Definition. It is proposed to restrict the scope to heparin material of porcine origin since some of the latest requirements