FIOLAX Academy. Training Module II Drug-Container Interaction

Transcription

1 Training Module II Drug-Container Interaction

2 Glass Advanced Seminar Training

3 16 : Training Module II Hydrolytic Resistance Surface Alkalinity ph Shift Extractables & Leachables Delamination Protein Adsorption Surface Treatments Lyophilization Light Protection

4 17 Definitions: Neutral Glass, Hydrolytic Resistance, Alkalinity, Extractables & Leachables European Pharmacopoeia (Ph. Eur. 7.0) Glass Containers for Pharmaceutical Use Glass containers for pharmaceutical use are glass articles intended to come into direct contact with pharmaceutical preparations. Colourless glass is highly transparent in the visible spectrum. Coloured glass is obtained by the addition of small amounts of metal oxides, chosen according to the desired spectral absorbance. Neutral glass is a borosilicate glass containing significant amounts of boric oxide, aluminium oxide alkali and/or alkaline earth oxides. Due to its composition neutral glass has a high hydrolytic resistance and a high thermal shock resistance. Soda-lime-silica glass is a silica glass containing alkali metal oxides, mainly sodium oxide and alkaline earth oxides, mainly calcium oxide. Due to its composition soda-lime-silica glass has only a moderate hydrolytic resistance. The hydrolytic stability of glass containers for pharmaceutical use is expressed by the resistance to the release of soluble mineral substances into water under the prescribed conditions of contact between the inner surface of the container or glass grains and water. Alkalinity, Alkali Release The release of soluble alkali components from the glass into water, usually tested acc. to Ph. Eur., USP, ISO 719, ISO 4802 Type I Is in accordance with the limits described in the current pharmacopeias concerning consumption of acid by titration Extractables Components of a certain packaging material (e.g. glass or rubber stopper) that are released during a certain test procedure Leachables Components of the container closure system that are released under the usual storage conditions

5 18 Hydrolytic resistance Water and acid attack cause an ion exchange Na + Hydrolytic attack H + + OH - O H H Na + Acid attack H + + CI - H CI Schematic picture of the exchange of protons and sodium ions Ions from the glass are exchanging with the hydrogen ion from the water. These cations from the glass can be Na +, K +, Ca 2+, Ba 2+, Mg 2+, depending on what is present in the glass structure.

6 19 Hydrolytic resistance Titration and flame AAS can be used to measure ion release Na + Na + OH - OH - Titration With HCl Determination of OH - ions Indirect determination of sodium ions Quite unprecise method Flame AAS With spectrometer Determination of Na +, K +, Ca 2+, directly Much more precise measurement Measurement of individual containers possible

7 20 Hydrolytic resistance Glass grain test and surface test to determine the glass quality Initial Material Test Measurement Result Quality of the whole bulk glass Glass Grain H 2 O or 121 C Alkali ions in solution measured by Titration or Flame AAS Quality of the inner surface of the glass Tubing / Container surface

8 21 Hydrolytic resistance Comparison of different Pharmacopeias Glass grain test Europe Ph. Eur M HCl 50 ml test liquid Surface test 0.01 M HCl / 100 ml test liquid USA USP 0.02 M HCl 50 ml test liquid 0.01 M HCl / 100 ml test liquid Japan JP vials: 2 ml 0.01 M H 2 SO 4 / 5 g glass not described Extraction method autoclaving autoclaving boiling 2 hours Measurement method glass grain: titration surface: titration and flame AAS titration titration Limit Type I acc. surface test the same depending on the filling volume ISO 719 and ISO 720 describe the glass grain test ISO and ISO describe the container surface test

9 22 Hydrolytic resistance Comparison of different Pharmacopeias describing the surface test Ph. Eur. Maximum volume of 0.01 M HCI per 100 ml of test liquid (ml) Glass containers Filling volume (ml) Types I and II Type III Up to Above 1 and up to Above 2 and up to Above 5 and up to Above 10 and up to USP Maximum volume of 0.01 M HCI per 100 ml of test liquid (ml) Test Liquid (ml) Filling volume (ml) Types I and II Type III Up to Above 1 and up to Above 2 and up to Above 5 and up to Above 10 and up to ISO Capacity of container (volume corresponding to the filling volume) [ml] Maximum values for the consumption of hydrochloride acid solution [c(hcl)= 0.01 mol/l] (5.2) per 100 ml of the extraction solution, mol/100 ml Classes HCT 1 and HCT 2 Class HCT 3 Class HCTB Class HCT D Up to Above 1 and up to Above 2 and up to Above 3 and up to Above 5 and up to Above 10 and up to

10 23 Hydrolytic resistance Different tests to evaluate the quality of the glass container surface Method Target Information Glass grain test (Ph. Eur., USP, JP, ISO 719, ISO 720) Alkali release of the container surface (Ph. Eur., USP, ISO 4802) ph value after filling/autoclaving (Ph. Eur. / USP) Electric conductivity after filling/autoclaving (Ph. Eur.) Modern trace analysis: AAS, AES, ICP-MS, quick tests All ions influencing the ph value All ions influencing the ph value All ions influencing the ph value Extractables/Leachables Extractables/Leachables Glass type, composition Glass type, container quality Container quality, surface reactions Container quality, surface reactions Container quality, surface reactions

11 24 Hydrolytic resistance Different kinds of Type I glasses There are 3 groups of Type I glass tubing 3.3 glass is mainly used in the USA. 5.0 glass ( FIOLAX type, neutral glass) is the most widely used pharmaceutical glass worldwide. 7.0 glass is mainly used in India, China, Russia. Europe 5.0 glass China / Russia 7.0 glass 5.0 glass 3.3 glass USA 3.3 glass 5.0 glass India 7.0 glass 5.0 glass

12 25 Hydrolytic resistance Differences in Type I Glass Tubing Glass Type Borosilicate 3.3 Borosilicate 5.0 Borosilicate 7.0 Composition SiO B 2 O Al 2 O Na 2 O/K 2 O MgO/CaO/BaO Physical Data Working Point Transformation Temperature (Tg) Mean Coefficient of Thermal Expansion (CTE) 1,260 C 1,145-1,170 C 1,030-1,100 C 525 C C C

13 26 Hydrolytic resistance Glass Types according to the glass grain test USP Consumption 0.02 M HCl/1 g Glass 0.1 ml up to 0.85 ml Type I Type III Ph. Eur. Consumption 0.02 M HCI/1 g Glass 1.0 ml up to 8.5 ml Type I Type III ISO 720 Consumption 0.02 N HCI/1 g Glass 0.1 ml up to 0.85 ml up to 1.5 ml HGA 1 HGA 2 HGA 3 ISO 719 Consumption 0.01 N HCI/1 g Glass 0.1 ml up to 0.2 ml up to 0.85 ml up to 1.5 ml up to 3.5 ml HGB 1 HGB 2 HGB 3 HGB 4 HGB 5 BORO-8330 TM FIOLAX clear FIOLAX amber ILLAX AR-GLAS

14 27 Hydrolytic resistance Relation between glass grain test and container surface test Container Surface Test Limit Type I Container BORO-8330 container FIOLAX container 7.0 container Other glass container Influence of conversion Glass Grain Test for Tubing Limit Type I Tubing Other glass tubing 7.0 Tubing BORO-8330 TM FIOLAX

15 28 Hydrolytic resistance Relation between glass grain test and container surface test Container Surface Test Type I USP Type I Ph. Eur. Class 1 ISO 4802 Type III USP Type III Ph. Eur. Class 3 ISO 4802 Glass Grain Test for Tubing Converting hot Converting Converting Type I USP Type I Ph. Eur. HGB 1 ISO 719 Type III USP Type III Ph. Eur. HGB 3 ISO 719

16 29 : Training Module II Hydrolytic Resistance Surface Alkalinity ph Shift Extractables & Leachables Delamination Protein Adsorption Surface Treatments Lyophilization Light Protection

17 30 Surface Alkalinity Alkali Borates are released during hot forming Na + O B O - When applying too much heat to the glass Sodium Borates are evaporating and condensate at cooler areas.

18 31 Surface Alkalinity Alkali Borates are released during hot forming Boiling temp./ C NaBO Na 2 B 4 O NaOH 1388 NaCl 1465 Optical fibre to spectrometer FIOLAX clear sample holder Pyrometer Gas burner Measurement of the alkali evaporation with a spectrometer Sodium intensity [counts] 20,000 17,500 15,000 12,500 10,000 7,500 5,000 2, temperature Time [s] Sodium signal 1,800 1,600 1,400 1,200 1, Temperature [ C]

19 32 Surface Alkalinity During vial manufacturing, the glass is heated up to 1,600 C. Especially the bottom forming process contributes to the enrichment of alkali components at the glass surface. Pre-heating and pre-forming Final neck forming Bottom forming Temperature [ C] 1,600 1,400 1,200 1, :36 09:37 09:38 09:39 09:40 09:41 Time [min:s] Vial machine RP 16

20 33 Surface Alkalinity SIMS analysis: Sodium profile of a vial after different production steps 10 3 Wall 10 3 Bottom Tubing tube wall Hot-forming Sodium Sodium Annealing after annealing 15 nm Storage after storage Sputter time [sec] Sputter time [sec] Data by SCHOTT Pharma Services

21 34 Surface Alkalinity The production of ampoules is similar to the vial manufacturing process. Alkali components are enriched at the container surface MM 30 (Moderne Mecanique)

22 35 Surface Alkalinity Formation of Alkali Borates Alkali borates condensate at cooler areas of the container They are highly water soluble Alkali borate crystals In the annealing lehr Washing cannot remove the alkali completely

23 36 Surface Alkalinity The alkalinity of containers can be influenced by forming temperatures, machine output, the annealing process,... Containers with a Type I composition result usually also in Type I based on the surface test. But the test result is not as constant as the glass grain test. The converting has a significant influence. Hot converting leads to high container alkalinity. mg Na2O / l Limit ISO SCHOTT study: Collection of vials from different converters volume vial [ml] 8412 FIOLAX clear 8414 FIOLAX amber BORO-8330

24 37 : Training Module II Hydrolytic Resistance Surface Alkalinity ph Shift Extractables & Leachables Delamination Protein Adsorption Surface Treatments Lyophilization Light Protection

25 38 ph Shift A low ph is defined by a high concentration of H + ions A high ph is defined by a high concentration of OH - ions acidic neutral basic H + H + OH - OH - H + H + H + H + OH - OH - OH - lemon juice vinegar cola milk blood soap washing powder

26 39 ph Shift What can influence the ph value of water (WFI) in an ampoule? FIOLAX Glass Tubing Ampoule Manufacturing Washing Dry Heat Sterilisation Filling, Autoclaving Inspection, Packaging Storage Glass: Composition Alkali content Chem./Phys. properties In some cases, sulphate treated ampoules lead to a lower ph Shift. Washing at higher temperatures or with additives (acetic acid) can bring an improvement. Initial ph of the WFI: As low as possible Burner gases can lower the ph value. Storage temperatures: The lower, the better Open ampoules should be preferred against closed ampoules (Form D). Alkalinity of the empty ampoules: Low alkalinity low ph Shift The ampoule size must be adjusted to the injection volume: Worst case example: 2 ml ampoules filled with 0,5 ml drug solution The ampoules should be sealed smoothly. Too hot flames will increase alkali release and ph value. Does the autoclave times work well? Longer autoclave times and higher temperatures will increase the ph shift.

27 40 ph Shift What can influence the ph value of water (WFI) in a vial or a syringe? FIOLAX Glass Tubing Container Manufacturing Washing Dry Heat Sterilisation Filling, Autoclaving Inspection, Packaging Storage Glass: Composition Alkali content Chem./Phys. properties In some cases, sulphate treatment leads to a lower ph Shift Washing at higher temperatures or with additives (acetic acid) can bring an improvement. Initial ph of the WFI: As low as possible Rubber stoppers can release alkali ions ( ph increase) and also acidic components ( ph drop). Storage temperatures: The lower, the better Alkalinity of the empty containers: Low alkalinity low ph Shift The vial size must be adjusted to the injection volume: Worst case example: 10 ml vials filled with 2 ml drug solution Does the autoclave work well? Longer autoclave times and higher temperatures will increase the ph shift.

28 41 Surface Alkalinity SCHOTT Study ( ) 10 ml BORO-8330 vials Type I with low alkalinity 18 months storage at room temperature after autoclaving 1 day 1 week 1 month 3 months 6 months 12 months 18 months [t] limit ISO limit ph value limit conductivity mg Na 2 O/l (ISO ) ph value conductivity [μs/cm]

29 42 Surface Alkalinity SCHOTT Study ( ) 10 ml FIOLAX clear vials Type I with low alkalinity 18 months storage at room temperature after autoclaving 1 day 1 week 1 month 3 months 6 months 12 months 18 months [t] limit ISO limit ph value limit conductivity mg Na 2 O/l (ISO ) ph value conductivity [μs/cm]

30 43 Surface Alkalinity SCHOTT Study ( ) 10 ml FIOLAX clear vials Type I with higher alkalinity 18 months storage at room temperature after autoclaving ph and conductivity exceeding the limits after autoclaving 1 day 1 week 1 month 3 months 6 months 12 months 18 months [t] limit ISO limit ph value limit conductivity mg Na 2 O/l (ISO ) ph value conductivity [μs/cm]

31 44 Surface Alkalinity SCHOTT Study ( ) 10 ml SCHOTT Type I plus vials 18 months storage at room temperature after autoclaving 1 day 1 week 1 month 3 months 6 months 12 months 18 months [t] limit ISO limit ph value limit conductivity mg Na 2 O/l (ISO ) ph value conductivity [μs/cm]

32 45 : Training Module II Hydrolytic Resistance Surface Alkalinity ph Shift Extractables & Leachables Delamination Protein Adsorption Surface Treatments Lyophilization Light Protection

33 46 Extractables & Leachables Definition Extractables: Components of a certain packaging material that are released during a certain stress test procedure (e.g. aggressive solvents, exaggerated conditions of time and temperature) Leachables: Components of the container closure system that are migrating into the drug formulation during usual production process and storage Belief some years ago Belief nowadays Extractables Extractables Leachables Leachables Some years ago it was believed that all Leachables were a subset of Extractables. So all potential substances could have been measured by just doing an Extractables study. Now it is known that Leachables can be formed over a longer time period that cannot be found in an Extractables study. This can e.g. happen if a Leachable from a certain material reacts very slowly with another Leachable from another material forming a new substance with unknown effect.

34 47 Extractables & Leachables Planning of an Extractables & Leachables study EU and the US regulations state that: Equipment shall be constructed so that surfaces that contact components, in-process materials, or drug products shall not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements Risk assessment Risk assessment: Of all process parameters Dose-related Factor Low risk High risk Dosage volume 1 ml 1000 ml Extractables study Leachables study Controlled extractables study: Extraction conditions, toxicological evaluation of extracted substances, (Accelerated) leachables study or migration study: Planned based on the results received from the extractables study Process-related method Dosage frequency Contact area per volume of drug product Contact time Once per incident (acute) Large bag, filter or connector Minutes (transfer tubing or connector) Daily (chronic condition) Small bag Months (storage bag) Example extract of a risk assessment

35 48 Extractables & Leachables Potential Extractables & Leachables from glass Potential E & L from glass: Silicon Oxygen Sodium, Potassium Aluminum Boron Calcium, Magnesium, Barium FIOLAX clear FIOLAX amber BORO- ILLAX AR-GLAS 8330 TM Si Si Si Si Si O O O O O Na Na Na Na Na Al Al Al Al Al B B B B B Ca Ca K Ca Ca Fe K K Ti Mn Mg K Fe Ba Ba Ba Oxygen Silicon Boron Sodium Aluminum

36 49 Extractables & Leachables Concentration of Extractables & Leachables also depends on hot forming process Surface alkalinity measurement of FIOLAX clear ampoules (2 ml) after 60 minutes autoclaving Extraction medium: Water ppm Na 1.4 Si 1.3 Na Lot A Smooth/slow converting lower alkalinity Al Lot C Hot/fast converting higher alkalinity Si Ca Al Ca B Mg Lot A B Mg Lot C

37 50 Extractables & Leachables Concentration of Extractables & Leachables also depends on ph value of solution 10 ml Tubing Vials Type I Borosilicate Glass 60 minutes Autoclave Extraction Medium: Water Different ph Values ppm Si Na ppm ppm Si Na ppm ppm Si Na Al ppm ppm ppm All glass components could be found in different concentrations Al Rubber components could be identified as well (Na, Ca, Mg, Zn, Ti) Ba K Ba K 0.4 Ba S.J.Borchert, M.M.Ryan, R.L.Davison, W.Speed; Journal of Parenteral Science & Technology 1989; 43 (2); 67-79: Accelerated Extractable Studies of Borosilicate Glass Containers Ca K Al Mg ph 4 ph 6 ph 8-10 Ca Ca Al Aluminum Ba Barium Ca Calcium K Potassium Mg Magnesium Na Sodium Si Silicium

38 51 Extractables & Leachables Concentration of Extractables & Leachables also depends on the filling volume Main Leachables according to USP <660> Relative concentration [%] B Na Al Si Ca FIOLAX 2 ml FIOLAX 10 ml FIOLAX 50 ml Measurement by SCHOTT Pharma Services

39 52 Extractables & Leachables SCHOTT Pharma Services Identification and quantification of released contaminants from closure system into the drug Syringe system has at least five components critical for E&L studies Extraction Separation and Identification Tipcap Glue Plunger / Stopper volatile semi-volatile non-volatile Gas chromatograph Tungsten Glass barrel Silicone sample Liquid chromatograph

40 53 Extractables & Leachables Main influencing factors Glass container Drug and formulation Processing Glass composition Ammonium sulphate treatment Container size/shape Testing method Closure (Na, Ca, Mg, Zn, Ti) Filling level Buffers ph value of solution Converting temperatures Speed of transformation process Annealing of containers Autoclaving after filling (time, temperature) Sterilization process Storage conditions

41 54 Extractables & Leachables Regulatory guidelines & further literature 1. European Commission. Good Manufacturing Practices. Medicinal Products for Human and Veterinary Use, 2010; Vol 4 2. US Government Printing Office. Equipment Construction. Code of Federal Regulations, Food and Drugs 2010; Title 21, Part European Pharmacopoeia 7.0, chapter Plastic containers for aqueous solutions for parenteral infusion 4. US Food and Drug Administration. Pharmaceutical cgmps for the 21st Century A Risk-Based Approach, Final Report 5. Bestwick D., Colton R., Extractables and Leachables from Single-use Disposables; Bioprocess Int. 2009; 7(S1): BPSA Extractables and Leachables Subcommittee. Recommendations for Extractables and Leachables Testing, Part One: Introduction, regulatory Issues and Risk Assessment. BioProcess Int. 2007; 5(11): BPSA Extractables and Leachables Subcommittee. Recommendations for Extractables and Leachables Testing, Part Two: Executing a Program. BioProcess Int (1): Guidance for Industry: Container Closure Systems for Packaging Human Drugs and Biologics. III. Qualification and Qulatiy Control of packaging Components. US FDA, 1999

42 55 : Training Module II Hydrolytic Resistance Surface Alkalinity ph Shift Extractables & Leachables Delamination Protein Adsorption Surface Treatments Lyophilization Light Protection

43 56 Delamination Upper surface layer of glass detaches from the bulk glass Resulting in the appearance of flakes in solution Leaving pits on the surface

44 57 Delamination Mechanism of glass attack and delamination risk Drug solution Glass surface Oxygen Silicon Boron Sodium Aluminum Drug 1. Dissolution 2. Selective Dissolution 3. Dissolution + Reaction Erosion No risk for flakes (possible precipitates) According to SCHOTT Pharma Services Erosion + Weak porous Layer Risk for siliate flakes Erosion + Compound Layer Risk for compound flakes

45 58 Delamination Some recalls within the past years Company Product Container Date Fresenius Kabi Nexus, APP, Benztropine Mesylate Injection Vial 06/30/2013 Bedford Laboratories Acetylcysteine solution Vial 12/20/2011 American Regent Methyldopate HCI Injection Vial 06/06/2011 American Regent Dexamethasone Vial 03/16/2011 American Regent Bacteriostatic Sodium Chloride for Injection Vial 03/15/2011 American Regent Potassium Phosphates Injection Vial 02/04/2011 American Regent Sodium Thiosulfate Vial 02/03/2011 Cumberland Pharma Acetadote Injection Vial 12/30/2010 American Regent Dexamethasone sodium phosphate Vial 12/20/2010 Amgen Epogen & Procrit Vial 09/24/2010, 11/30/2010 & 12/17/2010 Sandoz/EBEWE Pharma Methotrexate Solution for Injection Vial 10/29/2010 & 11/29/2010 EBEWE Pharma Fluorouracil and Methotrexate Injection Vial 11/18/2010 Leo Pharma Sodium fusidate for injection Vial 07/26/2010 Baxter Hylenex Pediatric Rehydration Product Vial 05/17/2010 Sandoz Fentanyl Citrate Injection Vial US Food and Drug Administration Web Site ( MHRA Web Site (

46 59 Delamination Independant of specific formulation Product ph Buffer Chelator Salt Methyldopate HCI (50 mg/ml) Citric acid (5 mg/ml) Dexamethasone sodium phosphate (4 mg/ml) Sodium citrate (19.4 mg/ml) EDTA (0.5 mg/ml) Sodium bicarbonate (7.4 and 8.4 %) Sodium bicarbonate (74 or 84 mg/ml) Concentrated sodium Chloride (23.4 %) NaCI (23.4 %) Bact. Sodium chloride (0.9 %) NaCI (0.9 %) Potassium phosphate ~6.7 KH 2 PO 3 (23.6 %) K 2 HPO 3 (22.4 %) Sodium thiosulfate (100 mg/ml) Soidum borate for ph adjustment Acetadote (200 mg/ml) EDTA (0.5 mg/ml) Fluorouracil (50 mg/l) 9.2 Methotrexate (25 mg/ml) NaCI (0.49 %) Epogen/Procrit (2k-10k units) 6.1 or 6.9 Sodium citrate NaCI (5.9 or 8.2 mg/ml) (5.8/1.3 mg/ml) citric acid (0/0.06 mg/ml) Hylenex (150 units) ~7.4 K 2 HPO 3 (1.4 mg/ml) EDTA (0.9 mg/ml) NaCL (8.5 mg/ml) CaCI 2 (0.3 mg/ml)

47 60 Delamination Influencing factors Glass container Drug and formulation Processing Ammonium sulphate treatment Coating Glass composition Surface alkalinity Complexing components (EDTA) Organic acid buffers (phosphate, citrate) ph value and ionic strength Properties of the drug itself Converting temperatures Speed of transformation process Annealing of containers Autoclaving after filling (time, temperature) Sterilization process Storage conditions

48 61 Delamination Wall morphology of the reaction zone Delamination is most pronounced in the transition zone between wall and bottom Delamination is linked with a porous reaction layer, in this case, with B, Na depletion - the depletion is not observed right after production Data by SCHOTT Pharma Services

49 63 Delamination Flake morphology Flake on a filter Reaction zone before flakes start peeling off 100 μm

50 64 Delamination Flake morphology Vials with delamination contain flakes The flakes show a thickness of < 500 nm but lateral dimensions up to 1000 µm. The composition is often silicate-like but could also be a compound build of glass and drug elements SEM-micrographs of flakes after filtration Compound flake EDS-spectra revealing composition Intensity 1e4 C 1000 O 100 Na Al P Si [kev] Intensity 1e C O Na Al Si 10 Data by SCHOTT Pharma Services Silicate flake [kev]

51 65 Delamination SCHOTT Pharma Services Particle analyses (e.g. delamination) 1. Filtration Accelerated aging test Step 1 Characterize problematic sample Step 2 Develop tailored accelerated test: Simulate the problem within days Step 3 Perform accelerated test: Apply tailored test to a set of different containers Step 4 Characterize and interpret result 2. Analyses by SEM/EDX Results Morphology Composition Size Indication for the origin Customer benefit: Decrease risk within stability cycle (months)

52 79 : Training Module II Hydrolytic Resistance Surface Alkalinity ph Shift Extractables & Leachables Delamination Protein Adsorption Surface Treatments Lyophilization Light Protection

53 80 Surface treatment Inner surface treatment Ammonium sulfate treatment Siliconisation of containers Hydrophilic / hydrophobic coatings Outer surface treatment Anti scratch coating for tubing (polyethylene based) Siliconisation of vials and ampoules

54 81 Surface treatment Ammonium sulfate treatment Type II glass NH 3 Na Na Ammonium sulfate SO 4 NH SO 4 4 NH 4 Na Na NH 3 Na Na SO 4 Na This treatment is mainly used for molded vials Type III to produce a (very) thin Type I like inner surface. Presently it is also used for Type I glasses.

55 82 Surface treatment Siliconisation of containers Liquid Lubricants Silicone oil standard Mineral & vegetable oils have been previously used Loosely bound to surface Liquid + Solid Lubricants Baked-on silicone Silicone oil cocktail Reduced amount of free silicone Can be used for all types of containers Types of silicone oil usually used: DC360 and DC365 But: Silicone oil is known to generate particles, shows migration and coalescence, and can induce protein aggregation, also can generate sub visible particles below 100 µm

56 83 Surface treatment Hydrophilic Coating SCHOTT Type I plus Washing process Activation of the inner surface by pure oxygen Introduction of the coating gas Start of the plasma reaction Formation of the layer PICVD procedure Microwave Microwave Layer water pure oxygen Quartz-like surface Chemical bond to the vial surface Chemically uniform Density coating (i.e. non-porous) Layer thickness: µm

57 84 Surface treatment Hydrophobic Coating SCHOTT TopYield TM Si-O-C-H layer Chemical bond to the vial surface PICVD procedure Density coating (i.e. non-porous) Layer thickness: ~ 40 nm Facilitation of an elegant Lyophilization cake Easy emptying of residual volume after reconstitution CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 H 3 C CH 2

58 85 : Training Module II Hydrolytic Resistance Surface Alkalinity ph Shift Extractables & Leachables Delamination Protein Adsorption Surface Treatments Lyophilization Light Protection

59 86 Lyophilization Freeze drying Definition: Procedure where the water is taken away from the solution to form a dry powder Application: Drugs that are sensitiv to heat, highly water insoluble, instable in aqueous solution, e.g. some antibiotics, hormones, enzymes, vaccines, blood plasma, sera, DNA-recombinant material and antibodies Statement from the FDA: [ ] products are manufactured in the lyophilized form due to their instability when in solution. Many of the antibiotics, such as [ ] are made by the lyophilization process [ ]

60 87 Lyophilization State of matter diagram of water Water exists in its three states depending on temperature and pressure At the Triple point (6 mbar and 0 C) water in its gaseous, liquid and solid state is coexisting. Pressure [mbar] 1, solid freezing liquid By changing the pressure or the temperature the state can be influenced start of sublimation Tr gaseous (vapour) primary drying secondary drying Temperature [ C]

61 88 Lyophilization General procedure with maximum parameters like temperature and time Temperature [ C] freezing primary drying secondary drying temperature Time [days] pressure Pressure [ C] Freezing of product under ambient pressure Decrease in pressure Increase in temperature as energy supply for sublimation Further decrease in pressure and increase in temperature to finalize sublimation

62 89 Light Protection Lyophilization oven Courtesy of GEA Lyophil GmbH

63 90 Lyophilization General mechanism Energy supply by heat transfer through conduction, convection and radiation radiation vapour freezing nucleus (-30 C) sublimation zone product convection conduction

64 91 Lyophilization Requirements for the primary packaging Temperature shock resistance of glass For the development of lyophilized products there are needed: Solvents: e.g. water, ethanol, DMSO Network formers: e.g. mannitol, sucrose, sorbit, urea, dextran, PVP Stabilizers: e.g. amino acids, HSA, calcium chloride buffer substances Bulking agents if necessary: e.g. mannitol, glycine The temperature shock resistance depends on both the coefficient of thermal expansion and the wall thickness of the glass container. Ph. Eur. [ ] Type III glass containers are in general suitable for [ ] parenteral use (except for freeze-dried preparations) [ ] Typical values for coefficient of thermal expansion (CTE) Type I glasses Type III glasses

65 92 Lyophilization Requirements for the primary packaging Temperature shock resistance of glass Largest wall thickness of a hollow glass vessel that is only shocked from the outside Largest wall thickness of a hollow glass vessel or a massive glass that is shocked from both sides simultaneously Temperature difference [ C] CTE Temperature difference [ C] CTE wall thickness [mm] borosilicate glasses 3.3 (BORO-8330 ) borosilicate glasses 5.0 (FIOLAX ) borosilicate glasses 7.0 soda lime glasses (AR-GLAS ) wall thickness [mm] borosilicate glasses 3.3 (BORO-8330 ) borosilicate glasses 5.0 (FIOLAX ) borosilicate glasses 7.0 soda lime glasses (AR-GLAS )

66 93 Lyophilization Requirements of the primary packaging Geometry 5 1. Wall thickness Temperature shock resistance increases with decreasing wall thickness For proper capping a certain wall thickness is required 2. Bottom flatness The flater the bottom the better the temperature conduction 3 and 4. Bottom corner angle Should be minium of 1.8 mm strong Vial neck Constant diameter for stopper fitting Freezing start Freezing start Mannitol is increasing the effective volume expansion of the water-ice-transition which means bigger stress on glass The smaller the filling volume the less stress is on the glass

67 94 : Training Module II Hydrolytic Resistance Surface Alkalinity ph Shift Extractables & Leachables Delamination Protein Adsorption Surface Treatments Lyophilization Light Protection

68 95 Light Protection Ultraviolet light can damage organic molecules Critical wavelength: nm FIOLAX amber tubing, 0.5 mm wall thickness Transmission [%] ,000 1,100 Wavelength [nm] UV range visible light infrared light

69 96 Light Protection Light sensitive drugs need a special light protection FIOLAX amber borosilicate glass provides protection against UV light Chemical Composition main components in approx. weight % FIOLAX clear FIOLAX amber SiO B 2 O Al 2 O Na 2 O 7 7 K 2 O - 1 BaO <<1 2 CaO 1.5 <1 TiO 2-5 Fe 2 O 3-1

70 97 Light Protection Comparison of different pharmacopeia Europe / USA Ph. Eur. / USP Japan JP Russia GOST nm Volume [ml] Transmission max. [%] Volume [ml] Transmission max. [%] Wall [mm] Transmission max. [%] Ampoules up to 1 > 1-2 > 2-5 > 5-10 > more than For the whole range of wall thicknes > > > > > Vials up to 1 > 1-2 > 2-5 > 5-10 > more than For the whole range of wall thickness > > > > > nm not specified not specified WT 1.00 mm WT > 1.00 mm min. 60 % min. 45 % not specified not specified

71 98 Light Protection The annealing process improves the light protection Transmission of FIOLAX amber, wall 1.00 mm Transmission [%] ,000 1,100 Wavelength [nm] tubing vial annealed

72 99 Light Protection Influence of Wall Thickness Higher wall thickness better light protection Transmission of FIOLAX amber Glass Tubing Transmission [%] ,000 1,100 wall 0.50 mm Wavelength [nm] wall 0.60 mm wall 1.20 mm

73 100 Light Protection Influence of Heat Treatment Limit value 35 % and Transmission 450 nm Transmission of FIOLAX amber annealing at different temperatures Wall 0.55 mm Transmission [%] tubing (34.6 %) annealed 590 C (30.1 %) annealed 630 C (28.7 %) 475 Wavelength [nm]

74 101 Light Protection FIOLAX Pallet Certificate If FIOLAX tubing is converted properly into containers according to ISO standards light protection requirements are all fulfilled. UV light protection of SCHOTT FIOLAX amber Constant content of Fe 2 O 3 and TiO 2 Reliable UV light protection (certified on every FIOLAX amber tubing pallet) FIOLAX ampoules (ISO 9187) and vials (ISO 8362) acc. to USP and Ph. Eur. Long term stability of light sensitive drugs glass type outside diameter wall thickness tubing length pallet weight procution date SAP material number transmission pallet number contained in code 128 mean value and standard deviation of OD mean value and standard deviation of WT siding mean and max. out-of-round value mean and max. straightness value control number of the tubing lot RS article number code EAN 13

75 102 Light Protection FIOLAX Certificate ISO st Hydrolytic Class Light Protection Heavy metals SCHOTT guarantees: Constant Type I glass composition (glass grain tests: Type I) Constant light protection Heavy metal impurities comply with all relevant regulatories

76 Tubing SCHOTT AG Scientific Services Dr. Folker Steden Erich-Schott-Strasse Mitterteich Germany Phone +49 (0)9633/ Fax +49 (0)9633/ Egb KR/Printed in Germany