The MDI project in Mexico a V.A.R.I & Co. perspective. Gabriele Marchetti

Transcription

1 The MDI project in Mexico a V.A.R.I & Co. perspective. Gabriele Marchetti

2 A GAP in the market For the budget made available from the Multilateral fund, none of the traditional inhaler development companies were interested, partly due to the cost and partly due to the terms of reference.

3 V.A.R.I. S.p.A recognised an opportunity To integrate specialist service providers to create a highly responsive synergistic group, drawing on industry leading expertise, without incurring the overheads of a larger organization. And so was born V.A.R.I & Co.

4 VARI VARI, part of the LINDAL Group, is one of the world s leading manufacturer of valves and actuators for pharmaceutical aerosol systems. VARI have manufactured 20mm metering valves for CFC propellants for a wide range of pharmaceuticals applications for over 25 years, supplying pharmaceutical companies all around the world. VARI has an extensive experience in a range of territories including South America, Cuba, Africa, Europe, Russia and Asia and is the leading supplier with more than 90% of the pmdi valve market share in some of these regions.

5 VARI VARI facility is located in Oggiono (LC), in the North of Italy. The manufacturing area has 6000 square meters: 1500 Square metre cleanroom 300 Square metre laboratories 900 Square metre offices VARI services provided: Pharma components moulding (ISO8) pmdis valves assembling (ISO7) Other valves production (Nasal, Oral, Topical) Analytical support Engineering and technical support pmdi Formulation support (i2c partnership)

6 VARI FACILITY VARI new facility has been built from greenfield in 2009 with a state of the art positively pressurized cleanroom. VARI s cleanrooms are equipped with HEPA filters that allows both moulding and assembly of products in a tightly controlled environment, which with our associated procedures greatly reduces risks associated with product contamination The cleanroom injection moulding equipment are fully electric machines with clamping forces up to 110 tonnes. These machines include a dedicated clean air module above the clamping unit with HEPA filter (H14). All servomotors are fanless and ecapsulated. Full encasement of the discharge area in stainless steel. VARI assembling lines make in-process controls of 100% of the valves produced (components presence, dimensions, functionality, and dose checks). All valves are laser coded on the ferrule to allow full traceability of each valve.

7 VARI QUALITY SYSTEM VARI operates its systems to ensure full compliance of external regulatory expectations, although not a manufacturer of finished product VARI s approaches and procedures are consistent with the aims of cgmp. VARI maintains full traceable records of all inputs and outputs throughout the manufacturing process. VARI have implemented and maintains a quality system in compliance with ISO 9001:2008 and ISO 13485:2004. ISO 13485:2004 specifies requirements for a quality management system where an organisation needs to demonstrate its ability to provide medical devices and related services that consistently meet customer and regulatory requirements

8 VARI MARKET PRESENCE United Kingdom Poland Russia Mexico Cuba Italy Iran Syria Iraq Egypt Pakistan Bangladesh India Taiwan Brasil Argentina

9 i 2 C UK Location London Heathrow and Birmingham Airports are ~ 2 hours by rail or car from Cardiff. Cardiff London London Birmingham Bristol Bristol Airport is ~ 1 hour from Cardiff. i2c history 9

10 i 2 C : History 1980 s Pharmaceutics research group at Welsh School of Pharmacy, Cardiff University, pioneer uses of gamma scintigraphy to investigate lung deposition and gastrointestinal transit of novel dosage forms 1992 Cardiff Scintigraphics Limited (CSL) formed as an independent spin-off company from Cardiff University 2001: Simbec Scintigraphics (SS) joint venture formed between CSL and Simbec Research Limited (SRL) to promote clinical scintigraphy services 2005: SS included in Wales top 100 most enterprising new companies present: CSL relocated in Cardiff to promote in vitro evaluation of inhaled pharmaceuticals trading as i2c Pharmaceutical Services SS continues with clinical scintigraphy trials provided via an alliance between i 2 C and SRL i2c history 10

11 i 2 C : Facilities Unit 8 11

12 i2c: Facilities Projected Plan Unit 6 i2c history 12

13 i2c Pharm Aerosol Testing Equipment 13

14 Scintigraphic Analysis: Comparators Kr Vent DPI MDI MDI + Spacer Spacer 14

15 Who or What is PharmaDelivery Solutions Ltd? An independent consultancy (Founded July 2003) service focusing on Drug Delivery Device Technology. It draws actively, both on an extensive experience base and ongoing links to the drug delivery market. It has formed strategic associations that will allow us to offer an even broader compliment of inputs to accelerate the development process of products relying on device technology.

16 VARI HFA VALVE The VARI HFA valve is a new generation product based on a tried and tested design used in pharmaceuticals aerosol application worldwide for over twenty five years. It has been specifically developed for use with HydroFluoro Alkane propellants systems and incorporates the latest innovations and thinking in materials engineering to offer reliability, performance and clean product profile. The VARI HFA valve components are: FERRULE: Aluminum Silver Anodized INNER GASKET: Chlorobutyle STEM PBT / POM METERING CHAMBER TPE SPRING AISI 316 Stainless steel HOUSING PBT / POM OUTER GASKET Chlorobutyle OUTER RING LDPE Standard dosages are 25µl, 40µl, 50µl, 55µl, 63µl, other dosages available upon requests The valve is NOW commercially available in two versions: 3.00 mm stem (VARI Standard stem size) The new 3.16 mm stem diameter Detailed Type III DMF lodged with FDA (Nr April 2008)

17 Metering chamber refills following valve operation

18 Metering chamber empties to atmosphere PROPELLANT BOILS AND EXPANDS

19 Existing supplier Enhanced performance Coated Make and fill Time Temperature Homogenization Many considerations when Own CFC Brand CFC Brand HFA Other None None Water Acetic Acid Citric Acid Other Stabilizer Predicate product Packaging components Number of actuations Canister size Dose Volume developing an MDI Formulation preparation Product Profile Replacement HFA product Basic Approach Purging Filling approach Post fill clean Surfactant Solution Suspension None Vacuum Propellant in can Propellant through valve Single stage Two stage Cold Fill None Vacuum Propellant fill None Oleic acid Sorbitan tri-oleate Lecithin PEG Novel

20 Simplified outline of the programme

21 Original agreed products Salbutamol 200 dose, 100 µg/ dose label claim of Salbutamol Base (equivalent) from the valve (may be formulated using Salbutamol Sulphate and/ or specified in an acceptable manner as the Dose ex mouthpiece if agreed). Unless otherwise agreed the reference product for determination of equivalence shall be, Laboratorios Salus, ASSAL Beclamethasone dipropionate (High strength ) 200 Dose, 250 µg/ dose label claim ex valve of Beclamethasone dipropionate( in the form of a recognised, salt, solvate etc. If required) and/ or specified in an acceptable manner as the Dose ex mouthpiece if agreed) Unless otherwise agreed the reference product for determination of equivalence shall be, Laboratorios Salus DOBIPRO 250

22 Basic outline for provided technology Formulation Development Pilot Batches Pilot Stability Tech Transfer Validation M anufacture Industrial Stability Batches Equipment M anufacture Factory Acceptance Test Shipping, Site Acceptance Tests 24 M onths Stability 6 Months Accelerated Stability Regulatory Submission

23 General Objectives To develop HFA MDIs which as a minimum may not be considered inferior to the current local marketed HFA and CFC products. To develop HFA MDIs which (where appropriate) may not be considered inferior to equivalent international HFA MDIs which are (or may become) available in the local market. To develop HFA MDIs applying quality standards equivalent to international regulatory expectations.

24 General Objectives (continued) Draw upon formulation approaches which have been approved by multiple regulatory bodies with experience of inhaled therapeutics. Avoid the use of novel excipients where possible. Specification of commercially advantageous products through the avoidance of proprietary and/ or prohibitively expansive packaging components.

25 General Objectives (continued) Wherever possible draw on international clinical opinion on products to reduce the risk of generating clinical concerns. Reduce the Risk of IP infringement as far as is possible.

26 An example of the development process

27 Step 1 Literature review/ commercial products Ventolin Evohaler ProAir HFA Airomir/ Proventil HFA

28 Which reference product Current CFC product OR

29 Don t have to look the same to be equivalent

30 Risks of referencing a current CFC product May differ in specification to internationally approved HFA brands, which are the current competitor products. Significant clinical review of the internationally approved HFA brands has been undertaken, a different therapeutic profile would need to be considered locally. May un-necessarily and unfairly expose historic CFC products to scrutiny, using more current analytical techniques than were in place during original approval.

31 Ventolin Evohaler

32 Proair HFA

33 Airomir/ Proventil HFA

34 Overview All three of the international products are suspension of Salbutamol (as sulphate) Ventolin HFA only uses HFA 134a propellant Proair and Airomir contain Ethanol

35 Ethanol widely used Trade Name API No. Doses Label Claim mcg Dose of Active* mcg Dose of Salt* mcg Metered Volume mcl Alvesco Ciclesonide Alvesco Ciclesonide Alvesco Ciclesonide Atrovent HFA Ipratropium Bromide Combivent Ipratropium Bromide/ Salbutamol Sulphate /100 21/100 21/120 Flixotide 50 Fluticasone Propionate Flixotide 125 Fluticasone Propionate Flixotide 250 Fluticasone Propionate Ventolin EVOhaler Salbutamol Sulphate Seretide 50 EVOhaler Salmeterol xinafoate/ Fluticasone Propionate /50 25/50 25/50 63 Salmeterol xinafoate/ Seretide 125 EVOhaler Fluticasone Propionate /100 25/100 25/ Salmeterol xinafoate/ Fluticasone Propionate /250 25/250 25/ Seretide 250 EVOhaler Serevent Evohaler Salmeterol xinafoate Tilade CFC free nedocromil sodium Proventil HFA Salbutamol Sulphate QVAR 50 Beclomethasone dipropionate QVAR 100 Beclomethasone dipropionate Those shaded in green contain ethanol

36 Solubility aspects OK API WATER ETHANOL Salbutamol Sulphate Freely Soluble Practically Insoluble Salbutamol Base Sparingly soluble Soluble (96%) Levalbuterol HCL 180 mg/ml (Freely) Practically Insoluble Formoterol fumarate Slightly soluble Sparingly soluble Fluticasone Propionate practically insoluble slightly soluble 95% ethanol Ipratropium Bromide freely soluble Slightly soluble Mometasone furoate monohydrate practically insoluble Slightly soluble Beclamethosone Dipropianate Very slightly soluble Freely soluble/ Sparingly soluble (96%) Salmeterol Xinofoate sparingly soluble slightly soluble Salmeterol Base Slightly soluble Sparingly soluble Fenoterol hydrobromide Soluble Soluble Tiotropium Bromide sparingly soluble Soluble Nedocromil sodium Soluble Triamcinolone Acetonide practically insoluble Sparingly soluble SCG Soluble Practically Insoluble Bambuterol hydrochloride Freely Soluble Soluble Budesonide practically insoluble Sparingly soluble Terbutaline Sulphate 1 g / 1-5 ml (Freely) 1 g / 250 ml (Slightly)

37 Step 2 patent literature review The following patents were reviewed amongst many others MX A US 5,225,183 EP EP US 5,439,670 US 5,695,743 US 5,776,434

38 Step 3 SWOT analysis conducted on formulation approaches

39 Ethanol Containing Lower cost of goods (plain cans) Lower cost of goods higher outputs Lower GWP than propellant only formulations Improved moisture stability Simplified processing steps Contains ethanol More competitive for export markets S W O T Flammability in manufacturing

40 Ethanol Free No Ethanol More expensive Coated Cans More Expensive Lower output rate More complex to manufacture Higher GWP than ethanol containing formulation. Batch size may be limited at benificiary by equipment available. Closer to GSK product S W O T Known Stability issues at high humidity Closer to GSK patents May require Foil overwrap.

41 Impact of choosing the Propellant only approach Vs. ethanol containing Coated cans Foil overwrap Cost of goods as much as 50% greater

42 Orifice size 0,25 0,30 0,30 0,35 Vent Airomir Metering vol µl

43 Step 4 Tentative development specification Based on literature and product review ethanol contents in the range 5 to 10% appear to give acceptable performance. To achieve acceptable particle size distributions with HFA/ ethanol formulations spray orifii in the range 0,25 to 0,35 preferred. 25 or 50µl metering valves used.

44 Step 5 preliminary screening A number of trial formulations were prepared and evaluated against commercial innovator products.

45 Issue Ventolin and Airomir do not have equivalent performance, a balance between actual performance and most probable registered specification was developed.

46 Orifice size 0,25 0,30 0,30 0,35 Metering vol µl

47 Active % Deposition Active % Deposition NGI Distribution of Ventolin Ventolin 1 Ventolin 2 Ventolin 3 NGI NGI Distribution using 50 µl valve & 0.25 mm Nemo Actuator 7.35 % EtOH 8 % EtOH 10 % EtOH NGI

48 Active % Deposition Active % Deposition NGI Distribution of Airomir Airomir Airomir 2 Airomir 3 NGI NGI Distribution using 50 µl valve & 0.25 mm Nemo Actuator 7.35 % EtOH 8 % EtOH 10 % EtOH NGI

49 Step 6 Product specification based on optimum overall performance selected.

50 AGREE THE SPECIFICATION BASED ON THE Terms Of Reference (with a reality check)

51 The sensible approach To agree a target specification(s) based on published data (reviewed) and in-vitro assessment of internationally launched HFA products (where in existence). Where an internationally launched HFA products does not exist. To agree a target specification based on published data (reviewed) and in-vitro assessment of both the local and international CFC products.

52 Proposed approach Label claim Containing 108 µg per actuation (ex actuator) of Salbutamol sulphate (Equivalent to 90µg Salbutamol base) from the mouthpiece. Formulation contents containing HFA 134a ethanol and oleic acid. Reference product: 3M Qvar (Or an equivalent Brand Name) Justification: This is an internationally approved HFA MDI version of this product approved in over 55 countries, including UK, USA, Australia, New Zealand, France, Germany and Japan.

53 Ventolin/ Airomir as declared In can Salb Sulp Salb base μg/ puff μg/ puff From valve No loss Salb Sulp Salb base μg/ puff μg/ puff From Act 10% loss Salb Sulp Salb base μg/ puff μg/ puff

54 Typical published actuator loss Declared Ex Company Product Declared Ex- Valve µg/ puff Mouthpiece µg/ puff Loss % GSK Ventolin M Airomir Boehringer Ingelheim M Qvar M Qvar GSK Flovent GSK Flovent GSK Flovent GSK Serevent AstraZeneca *1 Symbicort 80/ AstraZeneca *1 Symbicort 160/ GSK Seretide As per the individual losses above 12 and 16

55 Stability at pilot scale was primarily to demonstrate the robustness of the formulation filled at pilot scale, not for registration.

56 Basic outline for provided technology Formulation Development Pilot Batches Pilot Stability Tech Transfer Validation M anufacture Industrial Stability Batches Equipment M anufacture Factory Acceptance Test Shipping, Site Acceptance Tests 24 M onths Stability 6 Months Accelerated Stability Regulatory Submission

57 A significant undertaking

58 The output 1075 pages of data 1620 pages of data

59 A mammoth undertaking

60 The story now becomes that of the industrialization Thank You