PILOT PLANT SCALE UP FOR LIQUID ORALS
PILOT PLANT SCALE UP FOR LIQUID ORALS
• Simple solutions are the easiest to scale up but requires tanks of adequate size and mixing capability
• The equipment can have heating/ cooling capabilities for rapid dissolution of ingredients
• Filtration equipment are required for removal of unwanted particles
• The material used in the construction of equipment is important
• Should be non-reactive and facilitate easy cleaning
• Fabricated stainless steel is most suitable as it is non-reactive (expect for some acidic substances)
• This can be overcome by Passivation (pre-treating the stainless steel with acetic acid or nitric acid solution to remove the surface alkalinity)
• Passivation has to carried out periodic intervals
• If the batch involves preparations containing alkaline substances, then passivation needs to be repeated before the next batch
Importance of Pilot Plant Scale-Up
Efficient pilot plant scale-up offers several benefits, including:
Cost Efficiency: Producing larger batches reduces manufacturing costs per unit.
Product Consistency: Ensures the product maintains consistent quality and characteristics.
Regulatory Compliance: Helps meet regulatory requirements for commercial production.
Market Availability: Enables the timely release of medications to the market.
Key Considerations in Scaling Up
Formulation Optimization
Optimizing the formulation is critical during scale-up. Factors such as ingredient compatibility, solubility, and stability must be evaluated and adjusted as needed to maintain product integrity.
Equipment Selection
Selecting the appropriate manufacturing equipment is essential. Equipment should be capable of handling larger volumes and maintaining precise process control.
Process Validation
Thorough process validation is necessary to ensure that the scale-up process consistently produces high-quality liquid oral pharmaceuticals.
Challenges in Liquid Oral Scale-Up
Scaling up liquid oral formulations can present various challenges, including:
Homogeneity: Ensuring uniform mixing of ingredients in larger batches.
Equipment Scaling: Adapting laboratory processes to larger equipment.
Quality Control: Maintaining rigorous quality control throughout the scale-up process.
Key Considerations in Scaling Up
Formulation Optimization
Optimizing the formulation is critical during scale-up. Factors such as ingredient compatibility, solubility, and stability must be evaluated and adjusted as needed to maintain product integrity.
Equipment Selection
Selecting the appropriate manufacturing equipment is essential. Equipment should be capable of handling larger volumes and maintaining precise process control.
Process Validation
Thorough process validation is necessary to ensure that the scale-up process consistently produces high-quality liquid oral pharmaceuticals.
Challenges in Liquid Oral Scale-Up
Scaling up liquid oral formulations can present various challenges, including:
Homogeneity: Ensuring uniform mixing of ingredients in larger batches.
Equipment Scaling: Adapting laboratory processes to larger equipment.
Quality Control: Maintaining rigorous quality control throughout the scale-up process.
Best Practices for Successful Scale-Up
Comprehensive Planning
Detailed planning is essential. A well-structured scale-up plan should address formulation adjustments, equipment requirements, and quality control protocols.
Risk Assessment
Identify potential risks and develop mitigation strategies. This proactive approach helps minimize unexpected issues during scale-up.
Monitoring and Testing
Continuously monitor critical process parameters and conduct in-process testing to ensure product consistency.
Regulatory Compliance
Adherence to regulatory guidelines is non-negotiable in the pharmaceutical industry. Pilot plant scale-up must meet regulatory requirements to ensure product safety and efficacy.
Mixing vessels
SCALE UP CONSIDERATIONS- Solutions
1. Tank size (diameter)
2. Impeller type and number
3. Impeller diameter
4. Rotational speed of the impeller
5. Mixing capability of impeller
6. Clearance between Impeller Blades and wall of the mixing tank
7. Height of the filled volume in the tank
8. Filtration equipment (should not remove active or adjuvant ingredients)
9. Transfer system
Pilot Plant design for Suspensions
• Suspensions require more attention during scale up because of additional processing needs
• The addition and dispersion of suspending agents require a vibrating feed system
• A powder eductor can facilitate the addition of a material that tends to clump during the process or that is difficult to disperse
• Or they can be made into a slurry with a portion of the vehicle before addition
Powder eductor
• If the suspending agents are difficult to disperse, then it can be made into a slurry with a portion of the vehicle and completely dispersed using a high shear mixer
• Helps in rapid and complete hydration of the suspending agent when added to a larger portion of the vehicle
• The time and temperature required to hydrate suspending agents is critical.
• If the hydration process is incomplete before the other ingredients are added, the quality of the suspension is adversely affected
High Shear Mixer
For uniform dispersion of active ingredients; prevent wetting difficulties and eliminate formation of dry agglomerates
1. Prepare a slurry with a wetting agent using a high shear mixer
2. Pre-treat the hard to wet material by blending it in a high shear powder blender with the liquid ingredients and a surfactant
• The type of mixers, pumps, mills and horse power of the motors should be carefully selected based on the scale up performance
• The equipment should be selected according to size of the batch and maximum viscosity of the product during the manufacturing process
E.g Size of mixer is important
• Undersized mixers- inadequate distribution or excessive production time
E.g Speed of mixing
• Mixing at high speed- incorporation of excessive amount of air into the entrapped air is difficult to remove and if left behind – can affect the physical and chemical stability of the product and the reproducibility of the filling operation
• The entrapped air can be removed using a vacuum unit called Versator
Versator
• The finished suspension needs to be filtered in order to remove any unwanted particulate matter
• The mesh size of the filter should be such that it removes only unwanted foreign particulates and not the active ingredient (since suspension has particulate matter)
• Filters with screens of 150 mesh having aperture size of 100 microns can be used to remove unwanted suspended materials that are below the easily visible range without retaining the suspended active ingredients
Filter Press
SCALE UP CONSIDERATIONS- Suspensions
1. Addition and dispersion of suspending agents
2. Hydration/Wetting of suspending agent
3. Time and temperature required for hydration of suspending agent
4. Mixing speeds (High speed leads to air entrapment)
5. Selection of the equipment according to batch size
6. Versator (to avoid air entrapment)
7. Mesh size (the one which is chosen must be capable of removing the unwanted foreign particulates but should not filter out any of the active ingredients)
Pilot Plant design for Emulsions
• Manufacturing of liquid emulsion products entails specialized procedures and scale up into production equipment involves extensive process development and validation
• The globule size of the internal phase affects the physical properties of the emulsion- appearance, viscosity and physical stability
Homogenizer
SCALE UP CONSIDERATIONS-Emulsions
1. Temperature
2. Mixing equipment
3. Homogenizing equipment
4. In process or final product filters
5. Screens, pumps and filling equipment
6. Phase volumes, viscosities and densities
Use of high shear mixers à causes à Air entrapment
Use of high shear mixers à Prevented by à Use of vessels that operate under controlled vacuum
Filtration in the final stage à causes à Affects quality of the emulsion
Filtration in the final stage à Prevented by à Filtration of oil and water phases separately before emulsification
Filling equipment
Liquid orals filling, sealing and labeling
FAQ
What is pilot plant scale-up in the context of liquid oral pharmaceuticals?
Pilot plant scale-up is the process of transitioning from laboratory-scale development and testing of liquid oral medications to producing larger quantities that are suitable for commercial distribution.
Why is pilot plant scale-up important in the pharmaceutical industry?
Pilot plant scale-up is vital because it ensures that pharmaceutical companies can efficiently produce high-quality liquid oral medications at a scale that meets market demand while adhering to regulatory standards.
What are the key considerations when scaling up liquid oral pharmaceuticals?
Key considerations include formulation optimization, equipment selection, process validation, and maintaining product quality and consistency during the scaling process.
What are the challenges associated with scaling up liquid oral formulations?
Challenges include achieving homogeneity in larger batches, adapting laboratory processes to larger equipment, and maintaining stringent quality control throughout the scale-up process.
What are some best practices for a successful pilot plant scale-up?
Best practices include comprehensive planning, risk assessment, continuous monitoring and testing, and strict adherence to regulatory guidelines.
How does pilot plant scale-up impact the cost efficiency of liquid oral pharmaceutical production?
Scaling up allows for the production of larger batches, which typically results in reduced manufacturing costs per unit, making the process more cost-efficient.
What is the role of equipment selection in pilot plant scale-up?
Equipment selection is critical to ensure that the chosen machinery can handle larger volumes and maintain precise control over the manufacturing process.
Why is regulatory compliance crucial during pilot plant scale-up?
Regulatory compliance is essential to ensure that the final product meets safety and efficacy standards, allowing for its approval and distribution in the market.
How can pharmaceutical companies mitigate risks during the scale-up process?
Mitigation strategies involve identifying potential risks in advance and implementing measures to minimize or eliminate them, reducing the likelihood of unexpected issues during scale-up.
What are the benefits of successful pilot plant scale-up for liquid oral pharmaceuticals?
Benefits include cost-efficient production, consistent product quality, compliance with regulatory requirements, and timely availability of medications in the market.
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