Surfactants: Raw Material and Drug Product Control Strategy

Transcription

1 Pharma&Biotech Surfactants: Raw Material and Drug Product Control Strategy Atanas Koulov Lonza Drug Product Services NBC Boston PHARMA & BIOT ECH PROT EIN T HERAPEUT ICS MANUFACT URING MAY 20 22, 2015

2 Forward-Looking Statements Certain matters discussed in this presentation may constitute forward-looking statements. These statements are based on current expectations and estimates of Lonza Group Ltd, although Lonza Group Ltd can give no assurance that these expectations and estimates will be achieved. Investors are cautioned that all forward-looking statements involve risks and uncertainty and are qualified in their entirety. The actual results may differ materially in the future from the forwardlooking statements included in this presentation due to various factors. Furthermore, except as otherwise required by law, Lonza Group Ltd disclaims any intention or obligation to update the statements contained in this presentation. 2 PHARMA & BIOT ECH PROT EIN T HERAPEUT ICS MANUFACT URING MAY 20 22, 2015

3 A good control strategy comprises of Raw materials testing/ qualification Product characterization throughout development Adherence to GMP Manufacturing process validation In-process control Specifications (release, stability) Stability testing 3 PHARMA & BIOT ECH PROT EIN T HERAPEUT ICS MANUFACT URING MAY 20 22, 2015 Based on ICH Q8 (R2), Q10, Q11

4 Role of surfactants in protein therapeutics 0 % % 0.01 % 0.02 % 0.05 % PS20 Khan, Mahler, Kishore (2015) EJPB 97, ; Kiese, Pappenberger, Friess, Mahler (2008) J Pharm Sci 97, Non-ionic surfactants likely stabilize proteins by competitive interaction with interfaces The required concentrations are typically derived from formulation studies with (artificially) induced interfaces (e.g. shaking & freeze/thaw); thermal studies cannot demonstrate the need to use surfactants for protein stabilization In certain cases, interaction and colloidal stabilization of the protein by the surfactant is also found to occur 4 PHARMA & BIOT ECH PROT EIN T HERAPEUT ICS MANUFACT URING MAY 20 22, 2015

5 Surfactants (in general) Types Ionic (e.g. SDS, CTAB) Non-ionic (e.g. polysorbates, n-octyl-b-d-glucopyranoside, Triton X-100) Zwitterionic (e.g. CHAPS) Important properties: CMC (critical micelle concentration) HLB (hydrophilic/ lipophilic balance) Aggregation number Cloud point Kraft point Most of these are not used in parenteral formulations due to safety-related limitations or concerns 5 PHARMA & BIOT ECH PROT EIN T HERAPEUT ICS MANUFACT URING MAY 20 22, 2015

6 Surfactants used in parenteral formulations Polysorbates Poloxamer Avg mol wt: 8350; CMC = 0.064M; HLB = 29 MW av : 1310; CMC = 0.002% (w/v) (0.013 mm); HLB = 15 x= 98, y= 67, z= 98 w+x+y+z=20 MW av : 1228; CMC = 0.007% (w/v) (0.06 mm); HLB = PHARMA & BIOT ECH PROT EIN T HERAPEUT ICS MANUFACT URING MAY 20 22, 2015

7 Polysorbate as a pharmaceutical excipient Fatty acid ester PS20 PS80 Caproic CH 3 (CH 2 ) 4 COOH Caprylic CH 3 (CH 2 ) 6 COOH Capric CH 3 (CH 2 ) 8 COOH Lauric CH 3 (CH 2 ) 10 COOH Myristic CH 3 (CH 2 ) 12 COOH Palmitic CH 3 (CH 2 ) 14 COOH Palmitoleic CH 3 (CH 2 ) 5 CH=CH(CH 2 ) 7 COOH Stearic CH 3 (CH 2 ) 16 COOH Oleic CH 3 (CH 2 ) 7 CH=CH(CH 2 ) 7 COOH Linoleic CH 3 (CH 2 ) 3 (CH 2 CH=CH) 2 (CH 2 ) 7 COOH Linolenic CH3(CH2CH=CH)3(CH2)7COOH 1% - 10% - 10% % % 5% 7-15% 16% - 8% 7% 6% 11% 58-85% 3% 18% - 4% European Pharmacopoeia, :0426 and : PHARMA & BIOT ECH PROT EIN T HERAPEUT ICS MANUFACT URING MAY 20 22, 2015 PS are complex and heterogeneous mixtures (synthesis uses some precursors from natural products) Manufacturing processes may vary/ change

8 Polysorbate as a pharmaceutical excipient Borisov et al., J Pharm Sci, 104(3), PS are complex and heterogeneous mixtures PS raw materials recommended storage ambient, but, DP typically stored at 2-8C 8 PHARMA & BIOT ECH PROT EIN T HERAPEUT ICS MANUFACT URING MAY 20 22, 2015

9 Polysorbates may degrade via different mechanisms Hydrolytic Non-enzymatic Bates et al., J Pharm Pharmacol 25: Kishore et al., J Pharm Sci, 2011, 100:2, Enzymatic? LaBrenz, 2014, J Pharm Sci,103: Hall et al., J Pharm Sci. 2016,105(5): Dixit et al., J Pharm Sci. 2016,105(5): Oxidative Donbrow et al., 1978, J Pharm Sci 67: Borisov et al., J Pharm Sci, 104(3), ; Porter et al., 1995, Lipids 30: ; Yin and Porter, 2005, Antioxid Redox Signal 7: ; Kerwin BA J Pharm Sci 97(8): Kishore et al., J Pharm Sci, 2011, 100:2, PHARMA & BIOT ECH PROT EIN T HERAPEUT ICS MANUFACT URING MAY 20 22, 2015

10 Mechanisms of PS degradation Oxidation Auto oxidation via radical mechanism Initiation (hydrogen abstraction produces free radicals) Formation of peroxy radicals (reaction with molecular oxigen) Propagation intra- or intermolecular hydrogen abstraction Light or transition metals may accelerate these reactions Temperature dependent, though significant degradation can happen at 2-8 C as well Can happen in formulation (during storage)! Can happen in placebo Likely concomitant protein oxidation May be mitigated by antioxidants, radical scavenger or chelating agents in the formulation (pat. # WO A2) 10 PHARMA & BIOT ECH PROT EIN T HERAPEUT ICS MANUFACT URIN G MAY 20 22, 2015

11 Mechanisms of PS degradation Hydrolysis Polysorbates (esters) are susceptible to hydrolysis (proteins have aqueous formulations) However, reaction seemingly slow under protein DP storage conditions (2-8 C) Enzyme-catalyzed hydrolysis Assumed by esterase (<ppm) that is carried over (HCP) If enzyme-based, should have ph and temperature optima Data for enzyme-mediated PS hydrolysis are limited Large variety of degradation products Kishore et al., Pharm Res, 2011, 28: PHARMA & BIOT ECH PROT EIN T HERAPEUT ICS MANUFACT URING MAY 20 22, 2015

12 Analytical methods for characterization of polysorbates A number of analytical tools are available for PS quantification & PS degradant characterization: RP-HPLC/ mixed mode-hplc assays (often used in conjunction with FMA) Detection: MS ELSD CAD Various gradients depending on the purpose PDAM assay Fluorescence micelle assays in various formats Microspectroscopic methods FTIR Raman GC-MS 12 PHARMA & BIOT ECH PROT EIN T HERAPEUT ICS MANUFACT URIN G MAY 20 22, 2015

13 Analytical methods for characterization of polysorbates Availability of a sophisticated analytical toolbox is key to understanding surfactant degradation: Raw material testing Monitoring of surfactant content and stability in formulations Understanding of degradation pathways degradation products are diagnostic of the root cause(s) 13 PHARMA & BIOT ECH PROT EIN T HERAPEUT ICS MANUFACT URIN G MAY 20 22, 2015

14 Content assays Fluorescence micelle assay depends on micelle formation HPLC or e.g. plate reader format HPLC assays RP or mixed mode CAD, ELSD or MS detection non-linear calibration curves; different LOD NMR Kishore et al., J Pharm Sci 2011, 100: 2 Different measurements different results! All content assays are impacted differently by surfactant degradation Hvattum et al. J Pharm Biomed Anal 2012, PHARMA & BIOT ECH PROT EIN T HERAPEUT ICS MANUFACT URIN G MAY 20 22, 2015

15 Composition assays Degradation products of polysorbates Siska et al., 2015, J Pharm Sci, 104: Li et al., Anal. Chem. 2014, 86, Borisov et al., J Pharm Sci, 104(3), Hvattum et al. J Pharm Biomed Anal 2012, PHARMA & BIOT ECH PROT EIN T HERAPEUT ICS MANUFACT URIN G MAY 20 22, 2015

16 Methods to characterize PS degradation products Polysorbate degradation products e.g. particles (FFAs and FA esters) FTIR microspectroscopy Raman microspectroscopy Cao et al., J Pharm Sci, 2015, 104: Saggu et al, Pharm Res, 2015,32: PHARMA & BIOT ECH PROT EIN T HERAPEUT ICS MANUFACT URIN G MAY 20 22, 2015

17 A good control strategy comprises of Raw materials testing/ qualification Product characterization throughout development Adherence to GMP Manufacturing process validation In-process control Specifications (release, stability) Stability testing 17 PHARMA & BIOT ECH PROT EIN T HERAPEUT ICS MANUFACT URIN G MAY 20 22, 2015

18 PS are complex and heterogeneous mixtures POE POE sorbitan di- and tri-esters Isosorbide polyethoxylates (IPE) Hewitt D et al., J Chromatogr A PHARMA & BIOT ECH PROT EIN T HERAPEUT ICS MANUFACT URIN G MAY 20 22, 2015

19 Importance of raw material testing and storage Batch-to-batch and supplier variability Impact of impurities present in the raw material Free fatty acids present in PS presumably unreacted starting material (Siska et al., 2015, J Pharm Sci, 104: ) Presence of peroxides in PS Singh et al., AAPS PharmSciTech, Vol. 13, No. 2, June 2012 Wasylaschuk et al., 2007, J Pharm Sci, 96(1) Ha et al., J Pharm Sci Oct;91(10): Improper storage and handling can result in oxidative degradation of PS. Proteins can be oxidized too, with potential impairment of binding/efficacy Trp oxidation as a result of improper storage and handling of PS (Lam et al., Pharm Res. 2011, 28(10): ) 19 PHARMA & BIOT ECH PROT EIN T HERAPEUT ICS MANUFACT URIN G MAY 20 22, 2015

20 Importance of raw material testing and storage Sourcing Supplier qualification Batch control Handling and storage recommendations Kishore et al., 2011, Pharm Res., 28:1194 Store at 2-8 C Protect from air Protect from light Single-use containers (avoid re-use after opening) 20 PHARMA & BIOT ECH PROT EIN T HERAPEUT ICS MANUFACT URIN G MAY 20 22, 2015

21 A good control strategy comprises of Raw materials testing/ qualification Product characterization throughout development Adherence to GMP Manufacturing process validation In-process control Specifications (release, stability) Stability testing 21 PHARMA & BIOT ECH PROT EIN T HERAPEUT ICS MANUFACT URIN G MAY 20 22, 2015

22 What could happen? A lot! Decrease in surfactant content during storage Loss of protection against interfacial stress Not necessarily major impact on protein stability some degradation products also surface active Effect of surfactant degradation products on the protein Protein oxidation the presence of oxidative species may result in oxidation of e.g. Met, Trp Possible impact on protein stability by e.g. free fatty acids 22 PHARMA & BIOT ECH PROT EIN T HERAPEUT ICS MANUFACT URIN G MAY 20 22, 2015

23 Impact of PS degradation on protein formulations Kishore et al., 2011, Pharm Res., 28:1194 Degradation products of PS still show surface activity even after 60% loss of content by micelle assay 23 PHARMA & BIOT ECH PROT EIN T HERAPEUT ICS MANUFACT URIN G MAY 20 22, 2015

24 What could happen? Particles! Poorly soluble degradation products (e.g. fatty acids) may form particles Kishore et al., 2011, Pharm Res., 28:1194 >3 ppm lauric acid triggered Protein Particle formation and increase in soluble aggregates 24 PHARMA & BIOT ECH PROT EIN T HERAPEUT ICS MANUFACT URIN G MAY 20 22, 2015

25 A good control strategy comprises of Raw materials testing/ qualification Product characterization throughout development Adherence to GMP Manufacturing process validation In-process control Specifications (release, stability) Stability testing 25 PHARMA & BIOT ECH PROT EIN T HERAPEUT ICS MANUFACT URIN G MAY 20 22, 2015

26 Process development, validation and in-process control Surfactants can adsorb to contact surfaces e.g. manufacturing equipment (filters, tubing, etc.), leading to significant losses Importance of process development and IPC testing Mahler et al., (2010) J. Pharm. Sci. 26 PHARMA & BIOT ECH PROT EIN T HERAPEUT ICS MANUFACT URIN G MAY 20 22, 2015

27 A good control strategy comprises of Raw materials testing/ qualification Product characterization throughout development Adherence to GMP Manufacturing process validation In-process control Specifications (release, stability) Stability testing 27 PHARMA & BIOT ECH PROT EIN T HERAPEUT ICS MANUFACT URIN G MAY 20 22, 2015

28 Specifications, release and stability testing Quality should be built into the product, and testing alone cannot be relied on to ensure product quality (FDA Guidance for Industry: Quality Systems Approach to Pharmaceutical CGMP Regulations) Know your product! Surfactant testing for release and stability typically done in the extended characterization assay panel provided that: Raw material qualification and control is performed Raw material has been properly stored and handled Careful and sound drug product and manufacturing process development has been done mitigate the risks! Careful and sound drug product and manufacturing process characterization has been done In order to support all of the above 28 PHARMA & BIOT ECH PROT EIN T HERAPEUT ICS MANUFACT URIN G MAY 20 22, 2015

29 extensive analytical toolbox and expertise are needed 29 PHARMA & BIOT ECH PROT EIN T HERAPEUT ICS MANUFACT URIN G MAY 20 22, 2015

30 Thank you Acknowledgements Roman Mathäs, Dorothee Lay, Susanne Jörg, Monika Geiger, Dorota Roberts, Stephanie Ferrell, Karen Fallen, Hanns-Christian Mahler URL PHARMA & BIOT ECH PROT EIN T HERAPEUT ICS MANUFACT URIN G MAY 20 22, 2015