M | MANUF LEC L3

Cards (62)

  • In Ointment & Cream, Ingredients, formulation and product viscosity differ widely, however, a typical manufacturing process breaks down into four individual operations:
    • Preparation of the oil phase
    • Hydration of aqueous phase ingredients
    • Forming the Emulsion
    • Dispersion of the Active Ingredient
  • Typical manufacturing process
    1. Preparation of the oil phase
    2. Hydration of aqueous phase ingredients
    3. Forming the Emulsion
    4. Dispersion of the Active Ingredient
  • Methods
    • Trituration method
    • Levigation
    • Fusion method
    • Mechanical addition
  • Equipment
    • High Shear Batch Mixer
    • High Shear In-line Mixer
    • Flashmix Powder/ Liquid Mixer
    • Bottom Entry Mixer
  • High Shear Batch Mixer
    • Process from 1 to 8000 gallons
    • Eliminate agglomerates and fish eyes
    • Create stable emulsions and suspensions
    • Reduce particle size
    • Rapidly dissolve solids
    • Accelerate reactions
  • High Shear Batch Mixer (How it works?)
    1. Stage 1: High-speed rotation of rotor blades exerts suction, drawing materials upwards
    2. Stage 2: Centrifugal force drives materials towards periphery, milling action
    3. Stage 3: Intense hydraulic shear as materials forced out through stator perforations
    4. Stage 4: Materials expelled at high speed, circulation pattern minimizes aeration
  • High Shear In-line Mixer
    • Aeration free
    • Self-pumping
    • No bypassing
    • Interchangeable workheads
    • Sanitary construction
    • Easy maintenance
    • Lower power requirements
    • Eliminates agglomerates and fish eyes
    • Creates stable emulsions and suspensions
    • Reduces particle size
    • Rapidly dissolves solids
    • Accelerates reactions
  • High Shear In-line Mixer (How it works?)
    1. Stage 1: High-speed rotation of rotor blades exerts suction, drawing materials into rotor/stator
    2. Stage 2: Centrifugal force drives materials towards periphery, milling action
    3. Stage 3: Intense hydraulic shear as materials forced out through stator, along pipework
  • Flashmix Powder/ Liquid Mixer
    • Fast powder incorporation rates up to 500 lbs/min
    • Agglomerate-free, consistent product
    • Suitable for higher temperature and higher concentrations
    • Minimum aeration
    • Sanitary, modular construction
    • Low power requirement, no additional pump
    • Low level, ergonomic design
    • Simple to install, operate and clean
  • Flashmix Powder/ Liquid Mixer (How it works?)
    1. Stage 1: In-Line mixer recirculates liquid from vessel through Flashmix
    2. Stage 2: Powder feed valve opens, powder forced into liquid stream
    3. Stage 3: Powder and liquid combined with intense shear in mixer, passed back to vessel
  • Bottom Entry Mixers
    • Designed to fit into bottom or side of vessel
    • Used with slow speed anchor stirrer or scraper for high viscosity
    • Gives high shear homogenization, stirrer distributes output
    • Ideal for high viscosity cosmetic, pharmaceutical and food products
    • Can also be used on low viscosity products and to wet out powders
  • Bottom Entry Mixers (How it works?)
    1. Stage 1: High speed rotor blades exert suction, drawing materials downwards
    2. Stage 2: Centrifugal force drives materials towards periphery, milling action
    3. Stage 3: Intense hydraulic shear as materials forced out through stator, projected radially
  • QC Tests for Creams and Ointments
    • Physical Appearance
    • Particle Size Determination
    • Weight Variation Test
    • Solubility Test
    • Viscosity Determination
    • Assay of Active Ingredient
    • Sterility Test
    • Metal Particles in Opthalmic Ointments
  • Physical Appearance
    Cracking of emulsion, development of granular/lumpy appearance, marked viscosity changes, crystal growth, gross microbial contamination
  • Particle Size Determination
    Dilute sample, mount on slide, examine under microscope, count particles above/below specified limit, compare to official limits
  • Weight Variation Test
    1. Select 10 filled containers, remove labels, weigh each unit, calculate average weight
    2. Average net weight must not be less than labelled amount
    3. Net weight of any single container must not be less than 90% (for 60g or less) or 95% (for more than 60g but not more than 150g) of labelled amount
    4. If requirements not met, weigh 20 more containers, average of 30 must meet limits
  • Solubility Test
    Contents should be soluble in 9 parts water and 1.7 parts hot water, miscible with alcohol, ether and chloroform
  • Viscosity Determination
    Viscosity determined as specified in monograph
  • Assay of Active Contents
    Assay performed according to monograph, percentage within official limits
  • Sterility Test for Opthalmic Ointments
    Performed by membrane filtration or direct inoculation method
  • Metal Particles in Opthalmic Ointments
    Melt contents of 10 tubes, heat at 85°C for 2 hours, allow to cool and solidify, examine under 30x microscope
  • Solubility
    Soluble in 9 parts of water and in 1.7 parts of hot water
  • Miscibility
    Contents should be miscible with alcohol, ether and chloroform
  • Viscosity determination
    Viscosity shall be determined as specified in the individual monograph
  • Assay of active contents
    Assay of active contents should be performed according to official monograph and percentage should be within the official limits
  • Sterility test for ophthalmic ointments
    1. Membrane filtration method
    2. Direct inoculation method
  • Metal particles in ophthalmic ointments
    1. Melt the contents of 10 tubes individually/separately in 60mm petri dishes
    2. Cover the dishes and heat at 85 degree celcius for 2 hours; if needed slightly increase the temperature to achieve full fluidity
    3. Allow each to cool at room temperature and solidify
    4. Invert the Petri dish on the stage of microscope furnishing 30 times magnification and equipped with calibrate eye piece micrometer
    5. In addition to usual light source, direct an illuminator from the above at an angle of 45 degree
    6. Examine the bottom of the entire Petri dish for metal particles
  • Count the particles greater than 50 nanometer in any dimension
  • Not more than one tube should contain 8 such particles and total number of such particles in all 10 tubes should not exceed 50
  • If the requirements are not met, perform the test on 20 additional containers
  • Not more than 3 out of 30 tubes should contain more than 8 particles and the total number of such particles in all 30 tubes should not exceed 150
  • Use process-control tools
    • Manufacturing vessels with programmable logic controllers (PLCs) can provide more reliable and accurate control of the pressure/temperature and mixing speed and times
  • Add ingredients in the optimal phase and order
    • Adding ingredients in the correct phase contributes to overall stability
  • Protect API from degradation
    • APIs can be protected by using yellow or amber light that is free from harmful low-wavelength UV rays and by using nitrogen, argon, or another inert gas to purge the product of oxygen
  • Identify equipment constraints
    • The manufacturer must be able to perform all processes using its current equipment capabilities
  • Consider regulatory requirements
    • To scale up a process used for clinical batch manufacturing or transfer a commercial process to a new manufacturing site, the equipment must at least be of the same materials of construction and employ the same type of mixing, as defined in the SUPAC-SS guidance
  • Consider an outsourcing partner
    • Outsourcing formulation development and manufacturing to a contract development and manufacturing organization (CDMO) allows technology transfer, scale-up, and manufacturing to take place at one location, which ensures project continuity
  • Understand critical process parameters - temperature
    • Too much heating during processing can result in chemical degradation. Insufficient heat can lead to batch failures, and excess cooling can result in the precipitation of solubilized ingredients
  • Understand critical process parameters - heating and cooling rates
    • Heating too slowly can result in poor yields from evaporative loss. Heating too rapidly may burn areas of the batch in contact with the heating surface, which raises the potential for burnt material in the batch. Rapid cooling can result in precipitation/crystallization or increased viscosity
  • Understand critical process parameters - mixing methods and speeds
    • Proper mixing speeds must be obtained for each phase at every batch scale. Optimal hydration depends on the amount of shear imparted to initially disperse the polymer into the medium. Emulsification typically requires high shear or homogenization to obtain the optimal droplet size and dispersion, while the mixing of a gel may require low shear in order to preserve certain physical characteristics, such as viscosity