Scaleup for capsules
- 1. 1 SCALE UP AND TECHNOLOGY TRANSFER PCE-MIP 202 T Topic: PILOT PLANT SCALE UP FOR CAPSULES UNDER THE GUIDANCE OF: Dr. Mahalaxmi Rathnanand Associate Professor Dept. Of Pharmaceutics MCOPS, MAHE SUBMITTED BY: Seema Kamath 190617004 MPharm (Semester-2) Industrial pharmacy
- 2. 2 CAPSULES : It is a solid unit dosage form in which the drug is enclosed with either hard or soft soluble shell generally made of gelatin intended to be swallowed whole. STAGES OF CAPSULE PRODUCTION: 1. Material Handling 2. Mixing of ingredients 3. Granulation 4. Drying 5. Lubrication 6. Making of capsules 7. Filling of capsules 8. Finishing Unit operations: - 1. MATERIAL HANDLING SYSTEM: In laboratory the materials are simple scooped or poured by the hands, but in intermediate or large scale operations, handling of these materials often becomes necessary. If a system is used to transfer materials for more than one product, care must be taken to prevent cross contamination. Any material handling system must deliver the accurate amount of the ingredient to the destination. The type of system selected also depends on the characteristics of the materials. More sophisticated methods of material handling materials such as vacuum loading systems, metering pumps, and screw feeds systems are used. 2. DRY BLENDING: Powders to be used for encapsulation or to be granulated must be well blended to ensure good drug distribution. Inadequate blending at this stage could result in discrete portion of the batch being either high or low in potency. Steps should also be taken to ensure that all the ingredients are free of lumps and
- 3. 3 agglomerates. For these reasons screening/mixing of ingredients usually makes the process more reliable and reproducible. The equipment’s used for blending are: - V blender Double cone blender Ribbon blender Slant cone blender Bin blender Orbiting screw blenders vertical and horizontal high intensity mixer Scale up consideration in dry blending a. Variations of the blender geometry between scales acceptable: Mixing action is determined by the mechanics of the mixer and can only be changed by converting from one to another or by modifying the blender through addition of baffles or plates. b. The order of addition of components to the blender: A low-dose active ingredient may be sandwiched between two portions of directly compressible excipient in the blender to improve dispersion and/or avoid loss to the surface of the blender. c. The blender load (load level or fill level): The amount of material volume to the total mixer volume affects the efficiency of the blender. Each blender has an optimum working volume and a normal working range. Overloading a blender retards the free flow of the granulation and reduces the efficiency of the blender. Conversely, if the load is too small, the powders slide rather than roll in a blender and proper mixing does not occur, or time of mixing increases. d. Rate of rotation (rpm) or mixing rate: Mixing speed differs for different type of mixers example- blade rotation speed of planetary type mixer, and mixer tumbling or rotational speed for a twin shell, cone type, or similar type of mixer.
- 4. 4 e. Time of Mixing: the mixing time can be decreased if available data show the materials to be consistently and uniformly mixed in less time than originally directed. Alternatively, the time may need to be increased if the mixing time is shown to produce material with borderline uniformity. Mixing time also affects the compressibility of the finished blend. Excessive mixing time may fracture fragile excipient and ruin their compressibility. In Process Quality Control test: Content uniformity test. 3. GRANULATION: The most common reasons given to justify granulation are: - a) To impart good flow properties to the material b) To increase the apparent density of the powder c) To change the particle size distribution d) Uniform dispersion of active ingredients Traditionally, wet granulation has been carried out using, Sigma blade mixer, and Heavy-duty planetary mixer. Wet granulation can also be prepared using tumble blenders equipped with high- speed chopper blades. More recently, the use of multifunctional “processors” that are capable of performing all functions required to prepare a finished granulation, such as dry blending, wet granulation, drying, sizing and lubrication in a continuous process in a single equipment. Scale-up considerations for Fluidized Bed Granulations: i. Process Inlet Air Temperature ii. Atomization Air Pressure iii. Air Volume iv. Liquid Spray Rate v. Nozzle Position and Number of Spray Heads vi. Product and Exhaust Air Temperature
- 5. 5 vii. Filter Porosity viii. Cleaning Frequency ix. Bowl Capacity. IPQC Test: hardness of granules, flow properties, moisture content. 4.DRYING: The most common conventional method of drying a granulation continues to be the circulating hot air oven, which is heated by either steam or electricity. The important factor to consider as part of scale-up of an oven drying operation are: i. airflow ii. air temperature iii. depth of the granulation on the trays. If the granulation bed is too deep or too dense, the drying process willbe inefficient, and if soluble dyes are involved, migration of the dye to the surface of the granules. Drying times at specified temperatures and airflow rates must be established for each product, and for each particular oven load. The importantfactor to consideras partof scale up of fluidized bed drying operation include: i. Optimum load ii. Air flow rate iii. Inlet air temperature iv. Humidity of incoming air Fluidized bed dryeris an attractivealternative to thecirculating hot air ovens. Their main advantage. Their main advantage is reduction in drying time. Fluidized bed drying times are usually less than 1 hour. First, optimum loads must be established then, rate of airflow and inlet air temperature as well as the humidity of the incoming air mustbe established, sincetheseall affectthe dryingtime. Iftheair is drawnfromoutsidethe plant without being conditioned, the large-scale seasonal variation in terms of temperature and humidity that may exist can alter the drying process. IPQC TEST: moisture content
- 6. 6 5.LUBRICATION Lubricants are added to enhance the powder flow by reducing the inter particle friction. Equipments used are: Octagonal blender Ribbon blender Factors affecting Lubrication: Amount of lubricant added Grade of lubricant used Compatibility with other ingredients Mixing time. IPQC Test for Lubrication: • Angle of Repose: The angle between the surface of the pile and the horizontal surface. 𝜃 = 𝑇𝑎𝑛−1 ℎ 𝑟 At a higher angle of repose- powder may not have sufficient mobility to distribute. At lower angle of repose powder has sufficient mobility to maintain uniform bed. • Carr’s Compressibility Index & Hausner Ratio: Both are determined by measuring bulk volume and the tapped volume of a powder.
- 7. 7 6.Capsule-filling: In contrast, there are several types of capsule-filling equipment, each with its own operations. The fill material is treated in different ways in each case, and hence the challenges of fitting instrumentation also differ. i. Dosing Disc Machine: • Contains dosing disc which has got a number of holes similar to that of die cavity of tablet press. • Below the dosing disc there is a sealing pate that closes the holes. • Above the dosing disc a constant level of powder is maintained. • Five sets of pistons compress the powder into cavities to form plugs. i.e. each powder plug is compressed five times per cycle • Any excess powder is scrapped off and plugs are ejected into capsule body by transfer piston. ii. Dosator machine : • This machine contains a cylindrical tube filled with a movable piston known as dosator. • The end of the tube is open and the height of the piston is adjusted depending upon the amount of the powder to be filled. • The tube is brought down into the powder bed • The powder enters the open end and slightly gets compressed against the piston • Then the pressure is applied to the piston pushing the powder bed forming a powder plug due to compression • The dosator holding the powder plugs is then withdrawn from the powder hopper and moved over empty capsule body • Finally the piston is pushed downwards to eject plug into the capsule body.
- 8. 8 Filling Scale Up Techniques In the production of capsules, the powder blend (simple/granulated) is converted into plugs, either by single stroke or multi stroke. Plugs are soft and having breaking strength less than 1N, but retains sufficient mechanical integrity until it is delivered into the capsules. The scale up of capsule filling operation considers the operating principles and designing principles. The machinery produces plugs by compression and ejects into the capsule body. A few factors are relevant. Plug height to diameter ratio >1 Compression force range: 50-200N Piston or tamping pin compression speed range: about 100-500m/sec According to SUPAC IR Level 1 change: batch sizes 10 times of the pilot batch Level 2 change: batch size is beyond 10times of pilot Level 2 changes could significantly impact the formulation quality and performance. Supplement of changes effected is to filed to USFDA. If the in vivo equivalence data remains same, then the changes are accepted. The CGMP procedures are followed and full description of the change is documented and reported to FDA. Processing conditions During pilot plant scale up, the following factors are considered for gelatin capsules. These conditions are applicable to both the systems, dosator machine and dosing disc machine. Mixing load, mixing speed, mixing time: As per CGMP, blending/mixing is an important process, which ensures the drug content uniformity in capsules. Material load, mixing speed and mixing time are critical parameters and the blend uniformity is tested.
- 9. 9 Moisture content: it is a critical factor for granules to become compact as well as to maintain physical stability (sticking and picking) and chemical stability (degradation). Plug formation: the tamping pressure on the pins affects the dissolution rate. Hence minimum tamping pressure is required in case of dosing disc machine. In case of dosator machine the stable powder arch is needed to prevent loss of material ejection and quantitative transfer of powder into the capsule shell. Scale up considerations: Multiple tamp principle (in dosing disc machine) is more efficient than the single stroke dosator machine (without vacuum densification). A dosator machine requires a high degree of compatibility, because the open of the dosator is exposed, while lifting the dosator. Higher weight variation is reported. Free flowing powders often do not form plugs well enough to be transferred by the dosator. In this case, dosing disc machine is preferred. The dosing disc machine requires about half of the amount of magnesium stearate for plug formation and ejectibility. In this machine, shearing of lubricant (mg stearate) is high. During tampering step, the formulation is coated excessively with the lubricant. In dosing disc machines high shearing of lubricant (Mg stearate) is achieved due to multiple tamping. Accordingly dissolution may be slow. 7. FINISHING: Finished capsules from the filling equipment’s require some sort of dusting /polishing operation before the remaining operations of the inspection, bottling, and labeling are completed. Dusting and polishing operations vary according to the type of filling equipment used, the type of powder used for filling and the individual desires for the finished appearance of the completed capsules. The following are the methods most
- 10. 10 commonly used, based on the desired output, formulation, required final appearance, etc. Pan polishing: - Because of its unique design the Acceta Cota pan may be used to dust and polish the capsules. A polyurethane or cheese cloth liner is placed in the pan, and the liner is used to trap the removed dust as well as to impart the gloss to the capsules. Cloth dusting: - In this method, the bulk filled capsules are rubbed with a cloth that, may or may not be impregnated with an inert oil. This procedure is a hand operated, but one that can handle reasonable volumes, and that results in a positive method for removal of resistant materials. In addition, it imparts an improved gloss to the capsules. Brushing: - In this procedure, capsules are fed under the rotating soft brushes, which serves as to remove the dust from the capsule shell. This operation must be accompanied by the application of the vacuum for dust removal. Some materials are extremely difficult to remove by brushing, even to the point of impregnating the brushes and causing scratches or deformation of the capsules. Equipments for sorting of the capsules and polishing are as follows: i. Rotosort ii. Erweka KEA iii. PM 60 Scale up considerations for finishing: In cloth dusting- number of capsules to be rubbed with a cloth. In polishing- type and quality of polishing agent, pan rotation speed. In brushing- types of brush, brush rotation speed, extent of vacuum required. IPQC test- Appearance, disintegration, dissolution, microbial test.
- 11. 11 LAYOUT OF CAPSULE MANUFACTURING PLANT It refers to the allocation of space and the arrangement of machines and necessary services needed in a production process within a factory building in other to perform the various unit operations involved in the manufacturing process of dosage forms. A proper layout increased productivity and helps in proper utilization of man, money, material and machines. Process areas require high quality finishes maintaining CGMP standards. Traditionally pharmaceuticalmanufacturingfacilities havebeen designed on the basis of single rooms or cubicles for each stage of the manufacturing process. Environmental Conditions: The storage of filled capsules is closely controlled and monitored Humidity has a significant effect on moisture content The processing room is controlled within 45 to 55 % RH
- 12. 12 REFERENCES The Theory & Practice of Industrial Pharmacy by Leon Lachman, Herbert A. Lieberman, Joseph L. kenig, 3rd edition, published by Varghese Publishing house. CVS Subrahmanyam and J Thimmasetty, “Industrial Pharmacy Selected Topics” 1st edition Nash, R. A. Process validation for solid dosage forms. Pharm Tech June (1979). Larry L. Augsburger, Stephen W. Hoag; Pharmaceutical Dosage Forms Capsules, CRS Press. B.Venkateswara Reddy, A.Deepthi, P.Ujwala. CAPSULE PRODUCTION – INDUSTRIAL VIEW. Journal of Global Trends in Pharmaceutical Sciences Vol.3, Issue 4, pp -887-909, October–December 2012