QbD Applications for Lipid-Based Pharmaceutical Products. Alyn McNaughton

Transcription

1 QbD Applications for Lipid-Based Pharmaceutical Products Alyn McNaughton

2 Capsugel Technology Platforms Bioavailability Enhancement Targeted Release Capsule Technologies / Encapsulation Specialized Applications Salt Screening / Selection Micronization Spray-Dried Dispersions Hot-Melt Extrusion Lipid-Based Formulations Liquid / Solvent-Based Formulations Nanotechnologies Nano-milling Nano-crystals Enteric / DR Capsule Technologies Multi-particulate Technologies Fluid-bed layering Extrusion/Spheronization Lipid Multiparticulates (LMP) Mini-tabs Fixed Dose Combinations Bi/Tri Layer Matrix Capsule-in-Capsule Multiparticulates Extended / Controlled Release Osmotic / zero order release Matrix and MP / 1st order release Colonic Delivery using LFHC Gelatin Capsules (Coni-Snap) Specialty Polymer Capsules Vcaps Plus (HPMC) PlantCaps and OceanCaps Enteric Capsules DRcaps Vcaps Enteric entrinsic DDT DPI Capsules (inhalation) Sprinkle Capsules Encapsulation Technologies Specialized Clinical Trial Capsules Taste-Masking Approaches Pediatric Applications MP formulations Sprinkle Capsules Biotherapeutics Bio-processing Bio-formulations Inhalation SD-based formulations DPI capsules Abuse Deterrent Forms Key Services API Characterization / Preformulation Studies API-in-Capsule / Micro-dosing Evaluations Technology Selection Models / Methodologies Clinical Trial Material (CTM) Manufacture CTM Primary / Secondary Packaging & Distribution Commercial Manufacturing Specialized Handling (highly potent API, controlled substances, cold chain, hormones, probiotics, other) Product Range Drug Product Intermediate Hard Capsules Powder / Multiparticulate Filled Capsules Osmotic, Matrix, Orally Dissolving Tablets Liquid-filled Hard Capsules Soft Gelatin Capsules Sachet Alyn McNaughton 2

3 Agenda for Today Why Liquid Filled Dosage Forms QbD Concepts Formulation Development Case Study Liquid Filled Soft Gel Capsules Case Study Liquid Filled Hard Capsules Case Study Conclusions Questions & Answers Alyn McNaughton 3

4 Lipid / Liquid Filled Dosage Forms Versatile Applications Targeted & Modified Release Lipid & Co-solvent based formulations In-line milling -Particle size reduction Low Dose Content Uniformity Lipid/Liquid Fill Technologies Combination Therapies Abuse Deterrence High Potency Manufacture Alyn McNaughton 4

5 Lipid / Liquid Filled Dosage Forms Fewer Process Steps Granulated tablet process vs Liquid Filled Hard Capsules & Softgel Capsules Tablets Dry Blend Wet Mass Sieve Dry Screen Granulate Compress Fewer process steps Versatile solutions SGC LFHC Mix Fill & Seal Dry Mix Fill Seal Reach the market faster Alyn McNaughton 5

6 Quality By Design Concepts

7 Quality by Design Principles Two important ideas in the Quality by Design Targeted Quality: a shared objective on the project outcomes and product specifications Design: QbD already starts in early phase and intensifies throughout the project scale-up Core principles Must be acknowledged by Top Management as a way of conducting projects QbD is performed as a teamwork Diverse group, including the client Breaking the silos With process experts and fresh eyes (!) QbD is an investment at the startup Generating valuable knowledge on the product Reducing risks and global timelines Alyn McNaughton 7

8 Rationale: Regulatory expectation Reproducibly manufacture medicines that are safe and effective The concept and definition of Quality Target Product Profile (TPP), Critical Quality Attribute (CQA), Critical Process parameters (CPPs), Design space and Control strategy are described in: ICH Q8 Pharmaceutical Development ICH Q9 Quality Risk Management ICH Q10 Pharmaceutical Quality System FDA Guidance for Industry: Process validation EMA Guideline on process validation for finished products Alyn McNaughton 8

9 High Level Roadmap Quality by Design: begins with end in mind Define Target Product Profile Define Critical Quality Attributes CQA f (Materials attributes, Process parameters) Establish Control Strategy RMS, CPP, IPC, FPS Alyn McNaughton 9

10 Development to Commercialization Roadmap Quality by Design: begins with end in mind SCALING UP QTPP Product definition CQA definition GAP Analysis GAP identification pcpp Risk Assessment Evaluation of the pcpp IPCs and Action plan Engineering batch (es) Formulation development Process exploration through DoE Definition of the PAR RISK ASSESSMENT UPDATE REGISTRATION BATCHES Validation batches Validation within the PAR Definition of the NOR RISK PROFILE Commercial batches Continuous Process Verification CPP: Critical Process Parameters CQA: Critical Quality Attribute DoE: Design of Experiments IPC: In-Process Controls NOR: Normal Operating Ranges PAR: Proven Acceptable Ranges (Design Space) pcpp: potential CPP which variation could influence a CQA QTPP: Quality Target Product Profile Iterative process Exploration to find the edges of failure; definition of the Design Space (PAR) Validation within the PAR; definition of the NOR NOR Alyn McNaughton 10

11 Lipid-Based Formulation Development Case Study

12 Biological Factors Physical Factors Drug Candidate Qualification Technology Selection API Attributes TPP Design Space Dose (mg) Maximise formulation capacity Supersaturation SR M <2.5 Structure Available NA NA MW (g/mol) ~500 NA NA Solubility in water (μg/ml) <1 Increase & Sustain Solubility Maximise Solubility in Dipsersion and Digestion Log P ~6 Lymphatic Absorption Possible NA Permeability P app High NA NA Efflux Yes Inhibit Efflux mechanisms Select excipients for Efflux inhibition Pre-systemic metabolism Yes Promote Lymphatic Absorption Select Long Chain Triglycerides Food Effects Yes Induce Fed State Maximise Lipid Content Exposure (%) Aqueous suspension, fasted dogs 3 Promote Bioavailability through lipid solubilisation Optimise Pre and post digestion Alyn McNaughton 12

13 Lipid Technology Selection Generated from: Deep knowledge of technology / formulation benefits and limitations 2-dimensional physicochemical assessment of technology applicability Past experience: compounds Understanding of the barriers to BA Fundamental physical relationships Used to: Guide technology selection for BA enhancement Identify technology optimal performance areas Alyn McNaughton 13

14 Excipient effects on efflux transporters BCRP inhibition Span 40 Span 80 Propylene glycol Glyceryl triacetate Ethyl oleate Tween 20 Span 20 Cremophor EL Brij 30 Pluronic P85 Tween 80 Cremophor RH40 Myrj 52 Vitamin E TPGS Gelucire 44/14 No significant changes in intracellular ATP levels P-gp inhibition Yamagata et al., Int J Pharm 2009, 370, Yamagata et al., J Cont Release 2007, 124, 1-5 Alyn McNaughton 14

15 Bioavailability Enhancement Lipid Formulations SOLUBILIZATION ABSORPTION Pre-formulation solubility findings Lipidex TM Christopher J. H. Porter et al., Nature Reviews 2007 Increasing solubilization and drug disposition in the intestinal lumen Impacting the absorption pathway of drug transport to the systemic circulation Interacting with natural enterocytebased transport and metabolic processes Scientifically rationalised formulation design: Formulation development techniques from experienced developers and aided by software Design space determined through solubility of API in excipients selected for functional properties Laboratory evaluation of design space based on Placebo phase diagrams Dispersion testing and digestion testing prior to optimisation Alyn McNaughton 15

16 Aqueous API Concentration [%] Digestive modelling study Data Digestion Testing of 5 Selected Formulations: Digestion testing on 50mg dose equivalents Formulation based on central points from theoretical models ph stat Digestion Modelling 1 2 Formulations 1 and 3 show good performance based on selected composition Time [min] Alyn McNaughton 16

17 Optimisation Drug loading through DoE testing Optimisation of Drug loading for Formulation 3 Supersaturation Ratio SRM determined for compositions lipid (30 60%), Surfactant (25 60%) and co-surfactant (10 25%) through DoE for a 50mg dose An optimal zone is achieved for this formulation where the SRm < 2.5 (achieved < 2.0) Formulations 3 composition selected from within ideal control space Alyn McNaughton 17

18 Soft Gelatin Scale-Up Case Study

19 Process scale-up overview Context Major Challenges Timing (7 Months) Transfer of the manufacturing process for a registered ophthalmic soft gelatin capsule to one Capsugel site including scale-up and optimization of the process Get Critical Quality Attributes within specifications, especially by limiting API migration into the shell to obtain fill formulation assay within specifications Mid Apr 2016 May-Jun 2016 Project Start-up Process design and Risk Management Evaluate an alternative excipient in the fill formulation Mid Jul st full-scale Engineering batch with DoE execution, need for broader exploration Execute the process optimization within a short timeframe Mid Aug nd full-scale and 3rd 1/10 scale Engineering batches with DoE execution Nov validation / registration batches Alyn McNaughton 19

20 Design of Experiments for the Second Engineering Batch A 19 levels DoE, engineered to: Generate fine knowledge around expected golden runs Parameter Unit Parameter a / Parameter b / Parameter c / e f1g1 f1g1 f1 g1 g2 f1g1 f1g1 f1g1 f2g2 a f1 g1 g2 f2g1 f1g1 g2 f2g1 Broader explore the edges of failure Parameter d / Parameter e / f1g1 f1g1 f1g1 f1g1 f1g1 Parameter f / Parameter g / Parameter h / Alternate excipient Specific runs Expected golden runs Specific runs Alyn McNaughton 20

21 Process scale-up outcomes Wide process exploration through optimal design using only 3 technical batches of fill formulation API migration vs parameters a & b Identification of the process edges of failure Improvement of Critical Quality Attributes Assay accuracy: Average assay is closer to the target value Assay precision: Lower assay variations Parameter B Parameter a Validation batches successfully manufactured for a future Robust commercial process Example of contour plot analysis on process parameters influence on a CQA Alyn McNaughton 21

22 Liquid Filled Hard Capsule QBD Case Study

23 Compounding Vessel charged with excipients API transferred by vacuum The mixed using high and low shear elements The agitator is typically in continuous operation to maintain suspension uniformity and maintain even temperature distribution Temperature controlled via vessel jacket Product and Process Attributes Uniformity of suspension/solution Uniformity of particle size (aggregate free) Even viscosity Moisture content Minimal thermal degradation products Potential CPP Homogenisation speed and time Agitator speed Bulk mix temperature Alyn McNaughton 23

24 Capsule filling At the core of the high speed capsule machine, there are a set of high speed precision pumps Pumps capable of precision dosing down to approximately 120mg (lower weights possible but are formulation dependent) The hoppers can be stirrer to maintain suspension stability (if required) Both the hoppers and the pump assembly are jacketed for temperature control Product and Process Attributes Weight uniformity Dripping, tailing at filling nozzles Uniformity of content Potential CPP Nozzle sizes exit velocity Pump timing/drawback Filling speed viscosity limited Pump and hopper temperature Stirrer speed Fill volume Dripping and splashing: if it happens in LFHC, you will see it! Alyn McNaughton 24

25 Banding Capsules rectifies into carriers then sealing solution is applied to the joins by roller applicators Band dried in a drying chamber The banding operation applies 4-10mg of film at joins at up to 100,000 caps/hour Banding is relatively formulation independent but can be influenced by internal capsule pressure Capsule carriers Banding formulation Disc Product and Process Attributes Capsules Visual assessment uniform bubble free application Leak free vacuum testing challenges band integrity Doctor blade Potential CPP Banding solution composition/viscosity Banding speed Disc format and speed Disc height Band weight Drying chamber temperature Alyn McNaughton 25

26 Filling & Banding of Product A Product A is formulated in a blend of thermal softening and low melting excipients and filled into size 00 gelatin capsules The formulation was developed by the client and transferred to Capsugel for Phase III and commercial manufacture Filling temperature was established at 61 C Filling and banding trials were conducted to define optimum processing conditions for high volume manufacture Banding speed 50,000 Capsules / hr 30,000 Capsules / hr Observation Capsules opening on exit from filling machine and on bander Regular sticking of capsules in the banding rectification mechanism Trial abandoned Capsules opening on exit from filling machine and on banding Regular sticking of capsules in the banding rectification mechanism Runs continually interrupted It is worth of noting that these capsules meet all other acceptance criteria including assay, RS, uniformity of contents, weight uniformity and dissolution. However, process capability severely curtailed Alyn McNaughton 26

27 % Weight Loss Investigation into the Filling & Banding Issues with Product A Root cause analysis investigation pointed to over-pressurisation Observation of capsules popping open on exit from filling machine and on the bander Elongated capsules A simple experiment: internal pressure will expel liquid on piercing of the capsules proportional to internal pressure. Sealed capsules were heated to manufacturing temperature for consistency Weight loss recorded before and after piercing and data shows significant weight loss due to internal pressure within the capsules Internal pressure Capsule Number (50k/hr) (30k/hr) Standard Elongated Alyn McNaughton 27

28 Considerations for Optimisation of the Filling Process Evaluation of CPP Pressurisation occurs when the capsule is closed at commercial filling speed In addition, the air density will reduce at elevated filling temperatures further increasing pressure The target fill volume was set too high during small scale development This was a late stage programme, too late to modify formulation or capsule size Control Options Control options were to reduce filling speed, rapidly reduce local temperature post filling, to improve capsule venting through capsule design or local vacuum depressurisation. QbD through the development process would have identified this as a risk and the target fill volume was the CPP that should have been controlled Reduction of the filling speed was evaluated at a range of speeds, measuring the internal pressure of the produced capsules through piercing and weight loss. Products & Process Attributes Weight uniformity Dripping, tailing at filling nozzles Uniformity of content General Potential CPPs at Commercial Manufacturing Stages Nozzle sizes exit velocity Pump timing/drawback Filling speed viscosity limited Pump and hopper temperature Stirrer speed Fill Volume Alyn McNaughton 28

29 % Weight Loss Solution Simple and effective solution Speed reduction sufficiently reduced internal pressure A control space was established around 20, 000capsules/hour Successful process validation completed Over 20 commercial batches have now been manufactured. Products & Process Attributes General Potential CPPs at Commercial Manufacturing Stages 20,000 Capsules/hr Uninterrupted runs Internal Pressure Capsule Number (50k/hr) (30k/hr) (20k/hr) Alyn McNaughton 29

30 Conclusions

31 Conclusions Lipid / liquid filled technologies offer versatile solutions to a number of key problem statements, including Addressing poor solubility (BCS II / IV compounds) Safe and effective handling of high potency API applications Rapid screening and advancement of drug candidates Manufacturing is a simple process with fewer process steps than other solid oral technologies which makes it straightforward for QbD applications QbD principles are readily applicable to liquid filled product concepts, starting with the project and iterating all along the project life-cycle Projects can be received at any stage of development and progressed with a risk based approach Key challenges to QbD application include: Identify genuine risks based on a scientific approach Sincere application of QbD execution of action plans Finding the right balance between classic approach and QbD with respect to commercial viability Valuable Knowledge generated alive how to share it and keep it Alyn McNaughton 31

32 Thank You Contact us : solutions@capsugel.com