Excipient Considerations for Continuous Manufacturing Implementation FDA-PQRI Conference March 22-24, 2017 David R. Schoneker Director of Global Regulatory Affairs Email: dschoneker@colorcon.com 1
Continuous Manufacture of Tablets Important Excipient Properties Particle Size Cohesiveness Non-uniform Blending Density Particle Size & Shape Moisture Content Material strength to withstand shear Particle Size & Shape Density (avoid separation/segregation) Surface properties (carrying capacity) Moisture Content Compressibility (elastic or plastic deformation) Fragmentation Relaxation post compression Thermo responsiveness and Disintegration Disintegration to granules Disintegration to powder particles Dissolution of the API 2
Special Excipient Properties Needed Impact of Excipient Material Attributes on Product Quality for Continuous Manufacturing of Tablets Special excipient properties needed for CM Key properties which impact: Material Feeding Process Dynamics related to type of process Powder Flow influence of process variables and particle properties
Role of Key CM Material Properties Material feeding Q1: Can we feed each ingredient at the required flow rate? Q2: Can we feed each ingredient with variability below certain threshold? Q3: What is the impact of excipient variability from batch to batch on material feeding? Process dynamics Q3: Can we achieve blend or coating homogeneity? Understanding determines material characterization and control considerations Ref: T. O Connor, Y. Wang OPQ, FDA 4
Continuous Powder Flow Ref: T. O Connor, Y. Wang OPQ, FDA 5
Material Feeding Failure Modes Potential failure modes Clogging and obstructions due to cohesion, electrostatics Fluctuations due to compressibility Low feed rates are typically more challenging to deliver consistently Strategies to address this challenge include: Pre-blending of minor formulation components Utilization of novel materials designed for easier feeding Need Designed for Purpose Excipients Ref: T. O Connor, Y. Wang OPQ, FDA 6
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Material Characterization Characterization of input materials Evaluate raw material attributes (e.g., particle size distribution and density) affecting the formulation flow behavior, segregation potential, etc. Powder characterization can include: Particle size distribution; Shear cell test measurements; Compressibility; Permeability; Dynamic flow; and Electrostatics Multivariate analysis of material attributes can be helpful as multiple test methods can characterize various aspects of material flowability Ref: T. O Connor, Y. Wang OPQ, FDA 8
Raw Material Control Considerations Appropriate material specifications Impact of drug substance or excipient lot-to-lot variations on feeding Impact of variation of material attributes on process dynamics (i.e. RTD) what is known about the true variability of these attributes? If legacy product, appropriateness of the existing drug substance specifications for CM Appropriateness of the compendial specification for excipients Compendial specifications may not address all the physiochemical properties that can affect manufacturability and final product quality Appropriate material characterization required for each individual process and product based on the risks to product quality Existing vendor and compendial specifications may be sufficient in some cases but not in others Ref: T. O Connor, Y. Wang OPQ, FDA 9
The Need for Designed for Purpose Excipients 10
Designed for Purpose Excipients Existing Excipients will only be able to meet certain CM process needs There is a significant need for formulated or co-processed systems and various types of novel excipients that are Designed for Purpose in CM processes. A new process is needed for FDA to independently qualify novel excipient safety IPEC/IQ proposal For CM Blending and Tableting Processes: Materials designed to address feeder flow consistency and improve content uniformity throughout the batch Enhanced properties needed to improve flow Number of feeders may be limited, therefore pre-mixed excipient blends can help reduce the need for many feeders For CM Coating Processes: Coating systems need to be formulated with ingredients that provide properties that can coat faster and which are very robust to slight variations in the coating process conditions 11
Example -Continuous Film Coating of Tablets Tablets can be film coated in the ConsiGma semicontinuous coater. Custom designed film coatings are applied at 3% weight gain. 12
Design and Testing Objectives Assess the performance of a new coating system*, specifically designed for application at high solids concentration. Understand how increased solids concentration can impact coated tablet quality and process throughput in the GEA Consigma coating process. * Opadry QX
Coating System Formulation Formulation uses a relatively new polymer with unique properties that provide a strong flexible film with good moisture barrier properties The formulation was designed using this polymer and other components that help to optimize the film properties for use in semi-continuous film coating as well as in certain other types of coating processes Designed for higher solids content coating which can significantly increase productivity and take advantage of CM speed while assuring good tablet appearance 14
Initial Coating Trials to Verify Design Trial # Solids conc. % Theor. WG (%) Spray rate (g/min) Coating susp. To apply (g) Coating time (min) *Load / discharge / preheat / dry (min) Total throughp ut rate (kg/hr) Total system (twin wheel) output (kg/hr) 1 25 3 50 400 8.5 21 42 2 25 3 80 400 5.5 33 66 3 30 3 50 333 6.7.5 27 54 4 30 3 80 333 4.2.5 43 86 * 90 seconds / 15 seconds / 15 seconds Trials showed increased output with increased spray rate and solids content
Results of Initial Trials - Appearance All trials resulted in coated tablets with no visible defects. Coating was smooth and uniform with visually consistent color. Results created interest in further studies to assess the design and gain process understanding 30% solids concentration
DOE Study Performed - Additional Understanding A Design of Experiment (DOE) strategy was used to vary inlet temperature, spray rate and coating solids concentrations over a wide range. Trial no. Solids concentration (w/w %) Inlet temp ( C) Spray rate (g/min) Total spray time (min) 1 27.5 90 60 5.5 2 27.5 75 80 4.1 3 35.0 90 80 3.2 4 20.0 60 80 5.6 5 20.0 75 60 7.5 6 35.0 60 40 6.4 7 27.5 75 All 19 40 Trials 8.2 8 27.5 60 60 5.5 9 20.0 90 were 80 5.6 10 27.5 75 60 5.5 completed in 11 27.5 75 60 5.5 12 27.5 75 one day 60 for the 5.5 13 35.0 60 80 3.2 DOE 14 20.0 90 40 11.3 15 35.0 75 60 4.3 16 35.0 90 40 6.4 17 20.0 60 40 11.3 18 30.0 75 60 5.0 19 30.0 90 80 3.8
Results Color Uniformity 7 6 Total color difference (ΔE) (n=20) 5 4 3 2 1 Color variability not visually discernable below instrumental value of 3 ΔE for this yellow color. 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Trial number 1% WG 2% WG 3% WG
Results Gloss and Roughness Coatings were visually smooth and glossy, with instrumental surface roughness averaging < 5.5 Sa and gloss between 70 and 85 GU, for all but the wettest conditions (trials at the lowest solids and fastest application rates), where some increase in roughness was seen (up to 7.0 Sa).
Study Conclusions The special designed coating system was successfully applied in the semi-continuous ConsiGma coater under many conditions. The flexibility and robustness of this coating system, to be applied over a wide range of solids concentrations (up to 35%), along with fast attainment of coating uniformity in the ConsiGma process, allows wide adaptability to meet continuous tableting line throughput requirements. Due to the novel design of the ConsiGma process and speed of coating, the entire 19 trial DOE was completed in one day, in effect at production scale. The use of On-line Raman spectroscopy successfully allowed for real-time monitoring of coating build rates and was used to quickly identify any process deviations.
PQRI CM Workshop - 2018 There are a number of workshops and conferences being held to discuss various aspects of CM Most speakers at these conferences have recognized the significant importance of excipient and API properties and material variability in CM processes However, most of these conferences have focused most of the discussion on the CM process itself from an equipment perspective in terms of the proposed solutions for variability Equipment and process solutions may be limited IPEC and PQRI are currently developing a plan for a workshop in 2018 which will focus completely on the Impact of Excipients and APIs on Continuous Manufacturing. 21
Objectives of the PQRI CM Workshop To bring together both industry and regulatory experts to discuss the impact of excipients and APIs in Continuous Manufacturing of Oral Dosage Form Pharmaceutical Products (Benefits & Challenges). Identify and evaluate excipient and API properties (possibly new) which could impact the continuous manufacturing process Mitigation of failure modes in Continuous Manufacturing related to excipients and APIs. How to design for excipient and API variability in Continuous Manufacturing. Apply experience from decades of Continuous Manufacture of Excipients, APIs and other industries. Developing new excipients and grades designed for Continuous Manufacture Implications for Continuous Manufacture of API Composites.
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