EXTRACTABLES & LEACHABLES Standard Protocols in Single Uses Technology

Transcription

1 EXTRACTABLES & LEACHABLES Standard Protocols in Single Uses Technology USP and BPOG Approaches; a discussion in brief Dr. Andreas Nixdorf SGS Life Sciences 2017 CPHI Frankfurt

2 RISK FACTORS ASSOCIATED WITH E&L General quality consideration with leachables Product stability Aggregation, increase in particulates, Interfere with analytical methods or diagnostic tests Negatively impact on process performance cell growth, rate of drug release, drug solubility, ph, product yield Product safety (toxicological risk) The leachable may be toxic and poses a health risk to the consumer Efficacy consideration The leachable interacts with the drug product formulation or API so as to alter its stability and potency 2

3 THE CHALLENGES OF END USER interpretation Sustain a Qualified Status Suppliers data (complete?) Patient Safety Product Impacts Functionality by compatibility Input End User Risk Mitigation Regulatory acceptance Warning letters from authorities Economic Impacts Regulatory requirements Supply Chain Keep under your Controls 3

4 LITERATURE SOURCES STANDARD PROTOCOL DISCUSSIONS Some key publications PDA, Application of Single-Use Systems in Pharmaceutical Manufacturing, Technical Report No. 66 Parenteral Drug Association, Inc Biophorum operations Group (BPOG): Best Practices guide for evaluating Leachables risk from polymeric Single Use Sytems used in biopharmaceutical manufacturing. (2017) Ding W, Madsen G, Mahajan E, O Connor S, Wong K, Standardized Extractable Testing Protocol for Single- Use Systems in Biomanufacturing, Pharmaceutical Engineering, 2014; 34(6), Drafted USP <1665> and <665> USP forum (2017) 4

5 PROS OF THE USE OF STANDAD PROTOCOLS If extractables testing data provided by a supplier are not sufficient, the end user has to perform own studies; these results in the same components being tested multiple times and delay in application of SUS in biomanufacturing. It would ensure, that a comprehensive and consistent set of extractables testing data are readily available to the endusers. Assures comparability of chemical profiles from SUS components from same functionality but delivered from different vendors. It would assist SUS suppliers in more efficiently selecting materials in line with end-user needs. BPOG Standardized Extractables Testing Protocol for SUS in Biomanufacturing, Pharm. Eng

6 USP <1665/665> - RISK BASED APPROACH Classify your disposables in different risk classes: A: Baseline assessment B: Expanded Baseline assessment C: Full Testing assessment Please compare with risk assessment procedure as proposed by BPOG group: Biophorum operations Group (BPOG): Best Practices guide for evaluating Leachables risk from polymeric Single Use Sytems used in biopharmaceutical manufacturing. (2017) 6

7 ESTABLISH LEVEL A OF CHARACTIZATION Level A (Baseline assessment): The requirement is that all materials of construction must comply with USP <661.1>: Identity; Physicochemical characteristics; Biological reactivity test, USP <87>; Additives (by proper reference to 21 CFR Indirect Food Additives Used in Food Contact Substances); Levels of extractable metals. 7

8 ESTABLISH LEVEL B OF CHARACTERIZATION Level B (Expanded Baseline assessment): One requirement is that all materials of construction must comply with USP <661.1> and, The materials of construction must meet the requirements for Plastic Class VI designation, In Vivo <88>; Additives by proper testing (list of containing additives and levels). 8

9 FOOD CERTIFICATE INFORMATION Example (Polyurethane) of Food Proper Testing List (EU): CAS Substance Restriction Hexamethylene diisocyanate QM*(T) = 1 mg/kg ,4-tolylene diisocyanate QM*(T) = 1 mg/kg Octadecyl-3-(3,5-di-tert-butyl-4- hydroxyphenyl) propionate.... *QM max. conc. of residual in the plastic. ** SML restriction of specific migration limit. SML = 6 mg/kg Leaching Residue Potential Hazard 9

10 ESTABLISH LEVEL C OF CHARACTERIZATION Level C (Full Testing assessment): One requirement is that all materials of construction must comply with USP <661.1> and specification for Level B met; Materials extractable profile has fully established relevant to situation. 10

11 Components HOW MANY STANDARDIZATION WOULD BE USEFUL? STANDARDIZED EXTRACTABLES TESTING USP <665> Short term (Extraction?) Extraction (solutions C1, C2, C3) Extraction at 40 C Long term (Use Study?) Extraction Duration 1 day 7 days 21 days Storage container X X X Mixing bag X X X X Bioreactor bag X X X Tubing connector and disconnector X X Aseptic/sterile connector and disconnector X X Sensor/valve X X X Molded parts of mixers X X X Polymer pump surfaces X X X Tubing X X X Gasket, O-ring X X X Sterilizating filter X X X Process filter X X X Tangential flow filtration X X X Chromatographic column X X X Filling needle X X X C1: acidic extraction at ph 3; C2: alkaline extraction at ph 10; organic extraction 1/1 ethanol/water (v/v) 11

12 DIFFERENT PROTOCOLS EXTRACTION CONDITIONS BPOG Extraction temperature 25 C (=< 30 min contact); 40 C USP Extraction time depending on SUS component: 24h, 7d, 21d, 70d Material to surface ratio 6 cm2/ml Extraction temperature: 40 C Extraction time depending on SUS component: 24h, 7d, 21d Material to surface ratio 6 cm 2 /ml Solvents: BPOG: 50% ethanol, 1%PS-80, 0.1M H 3 PO 4, 0.5N NaOH, 5M NaCl, WFI USP: 50% ethanol, HCl/NaCl at ph 3, Phosphate buffer ph 10 12

13 CONS OF THE USE OF STANDAD PROTOCOLS In general, standard extractable protocols do not take into account the different chemical nature of polymers or coated materials. Not all polymeric materials will show chemical resistance under certain conditions. The chemical profiles may be overestimated, that could lead to a disqualification of a beneficial material. By protocol multiple orthogonal methods are used to chemically profile materials extractables. Particular critical substances may require target analysis, thus they run out of analytical window by using screening methods. 13

14 INADEQUATE CHEMICAL RESISTANCE SANITIZATION WITH 1M NaOH EXAMPLE Delamination flakes SEM image of damaged area. Degradation mechanism 600 cm 2 / 150 cm Pt cured Silicone Tubes Simulated use study: 40 C&50 C 7d, 1M NaOH TOC: µg/cm 2 ; mg/150 cm ICP-MS: Si element; saturated detector after 1:1000 dilution. Delamination of tube inner surface (SEM: scanning electron microscope). High risk of particle formation. Oligomeric substances. Mosammad Shamsun Nahar*, Jing Zhang Analysis of Damaged Silicon Rubber Hose, American Journal of Analytical Chemistry, 2011, 2,

15 INADEQUATE RESISTANCE - AQUEOUS ALCOHOL SOLVENTS EXAMPLE Virus filter with PES membrane Exaggerated Extraction: PBS buffer ph % (v/v) iproh, 28d 40 C Amount of embedded membrane polymer found: > 350 mg/filter! ESI + MS (QToF) Ion Trace Under real use conditions only minor quantities are released below toxicological relevant limit. The filter membrane was demonstrated incompatible to aqueous alcohol solutions. 15

16 INADEQUATE RESISTANCE - PARTICLE FILTER SYSTEM - 50% ETHANOL EXAMPLE Extraction conditions: 50% ethanol at 40 C for 48h: A b u n d a n c e S i g n a l : S c r e e n i n g _ E x t r a c t a b l e s _ _ _ 2 4. D \ F I D 1 A. c h T i m e - - > Advanced disintegration of polymeric material: high amounts of low mass oligomers. 16

17 EXAMPLE CUSTOMIZE REALISTIC EXTRACTION CONDITIONS -5M NaCl 5M NaCl, high salt concentrations are not appropriate! Salt effect will lower solubility of Leachables. There will be no chemical interaction between lipophilic polymer (surface) and 5M NaCl. So, why this extraction? 17

18 CUSTOMIZE REALISTIC EXTRACTION CONDITIONS - POLYSORBATE EXAMPLE PS-80 generates high analytical background noise. It also suppress detectability of Extractables. PS-80 can be simulated by ethanol or IPA/water mixtures!* Tween could contain carry over leachables that are sourced by storage conditions and chemical decomposition of PS-80. *Dennis Jenke, Ph.D. A Means of Establishing and Justifying Binary Ethanol/Water Mixtures as Simulating Solvents in Extractables Studies, Smithers/Rapra E&L USA 2015: Bethesda, MD; May 13,

19 CUSTOMIZE REALISTIC EXTRACTION CONDITIONS POLYSORBATE RELATED IMPURITIES EXAMPLE PS-80 is a polymeric mixture consisting from lipophilic monoesters condensed with ethylene oxide. Class Examples Source Alcohols C4-8 PS-80 Breakdown Aldehydes C6-10 PS-80 Breakdown Ketones C5-C8 PS-80 Breakdown Carbonic acids C4-8, C18, C16 PS-80 Breakdown others Glycols-ethers PS-80 Breakdown Leachables Antioxidant, fatty acids, fatty alcohols,. Interaction with storage container 19

20 RADIATION RESISTANCE EXAMPLE Validation of radiation regarding impact on extractable conc. level was missed! Dose: approx. 32 kgy Extraction of Pt cured silicone tube at 50 C for 24 h with WFI Analyte Blank µg/ml µg/cm 2 Compared to Blank (LOQ) an increase by factor of Formaldehyde < LOQ Formiate < LOQ Acetate < LOQ µg/cm µg/cm 2 20

21 STANDARD EXTRACTION PROTOCOLS - SELECTION OF EXTRACTION CONDITIONS Misapplied use of plastic could cause chemical attack; it may occur in several ways: Disintegration or degradation of physical nature due to absorption, permeation, solvent action, swelling Oxidation, where chemical bonds are attacked, Hydrolysis, were e.g. ester bonds are attacked, Radiation, were chemical reaction are triggered, Thermal degradation, Delamination, due to chemical attack. In E&L studies those substances must be assessed that could migrate into DP or process steam. 21

22 STANDARD EXTRACTION PROTOCOLS - RISK ASSOCIATED WITH SEP Misconceptions increases the risk of faulty decisions. Extraction conditions are too harsh: Decomposition of the polymeric network, high levels of oligomers are expected, Generation of high conc. levels of breakdown products. Extraction conditions are too harsh: Screening methods do not discover all relevant substances combine with target analysis. Material qualification can become not longer valid: Under real use condition there is probably no risk on leaching into the drug product. 22

23 IMPROVEMENTS TO DISCUSS SOME CUSTOMIZATION NEEDED Simulated migration studies with conditions that are selected close to real process conditions would be the best practice to asses risk from SUS such as bags, tubes, connectors and filters. Extractables studies conditions should be selected to avoid materials damage! Extraction conditions selection must based on damage mode studies and/or chemical resistance studies. SGS is offering: Chemical characterization (Extractables studies), Simulated Use Studies (Leachables studies), and Damage Mode Studies to support end-user materials qualification process. 23

24 THANK YOU FOR YOUR ATTENTION Visit us at our booth Hall 4.2 B30 LIFE INSPIRED Dr. Andreas Nixdorf Life Sciences Senior Scientist / Business Development Manager SGS INSTITUT FRESENIUS GmbH Extractables & Leachables Impurity Profiling H578 Kasteler Str. 45 D Wiesbaden Phone: andreas.nixdorf@sgs.com Web : 24