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Manufacturing of Quality Oral Drug Products
Processing and Safe Handling of Active Pharmaceutical Ingredients (API)
Sam A. Hout
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eBook - ePub
Manufacturing of Quality Oral Drug Products
Processing and Safe Handling of Active Pharmaceutical Ingredients (API)
Sam A. Hout
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About This Book
This book provides an understanding of what is required to engineer and manufacture drug products. It bridges established concepts and provides for a new outlook by concentrating and creating new linkages in the implementation of manufacturing, quality assurance, and business practices related to drug manufacturing and healthcare products.
This book fills a gap by providing a connection between drug production and regulated applications. It focuses on drug manufacturing, quality techniques in oral solid dosage, and capsule filling including equipment and critical systems, to control production and the finished products. The book offers a correlation between design strategies and a step-by-step process to ensure the reliability, safety, and efficacy of healthcare products. Fundamentals of techniques, quality by design, risk assessment, and management are covered along with a scientific method approach to continuous improvement in the usage of computerized manufacturing and dependence on information technology and control operations through data and metrics.
Manufacturing and Quality Assurance of Oral Pharmaceutical Products: Processing and Safe Handling of Active Pharmaceutical Ingredients (API) is of interest to professionals and engineers in the fields of manufacturing engineering, quality assurance, reliability, business management, process, and continuous improvement, life cycle management, healthcare products manufacturing, pharmaceutical processing, and computerized manufacturing.
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1 Milling and Charging
DOI: 10.1201/9781003224716-1
Raw materials are received by the warehouse and placed in quarantine until released. To be released an item must:
- be from an approved vendor
- meet Quality Standards (AQS), which might require examination/testing by materials lab
- be entered in manufacturing planning and control database. Powdered materials used in granulation are dispensed from the warehouse’s pharmacy and staged near milling and charging area.
The first step is to mill materials specified in the Master Formula (MF), usually only sodium chloride and ferric oxide require milling. However, other components can be milled if required. In the milling process, materials are ground by, e.g., Quadro Comil (conical mill) equipment, or possibly by a fluid air-mill, and passed through a sieving screen to break up lumps and to ensure a reduced and uniform particle size for proper blending and granulation. Materials that require milling tend to clump, so they must be protected from moisture by sealing them in poly bags and keeping them away from moisture. They must be charged/mixed with the rest of the powdered materials within a specified time, typically within 72 hours of milling.
Charging involves loading pre-weighed materials received from the pharmacy into tote bins or directly into blender, e.g., Patterson-Kelley (PK). All components are charged using sifting screens, e.g., Porta-Sifter with a screen
- break up clumps
- ensure a uniform consistency
- identify and remove possible foreign material.
Tote charging is accomplished in the designated milling-and-charging room. A lift (e.g., Meto) is used to empty barrels into the Porta-Sifter, which is on an elevated platform above the totes. If the blender is manually charged directly from barrels, then the portable Porta-Sifter screens the material directly to the blender.
Milling
Materials, such as sodium chloride and ferric oxide, require milling per the MF. They are milled using the Quadro Comil. Quadro Comil is fitted with a 20-mesh screen per MF (mesh number stands for the number of openings per inch in the screen). Powders are passed through the mill and collected in poly bags.
Based on common practice, the pharmacy dispenses slightly more materials than required, since some loss is expected during milling. The operators divide and weigh the milled powders based on MF-specified quantities for each bowl (tote) being prepared. A bowl represents the quantity that will fit into the agglomeration equipment (e.g., Glatt fluidized bed).
Charging
Materials that do not require milling are received from the pharmacy pre-weighed and divided into quantities required for a bowl. After charging to totes, the net weight of the totes is determined to ensure that the bowl weight falls within the validated loads and that all ingredients were charged.
If required, the lot is split into bowls, usually due to the size/weight limitations of the Glatt fluid bed granulator (FBG). Materials for each bowl are placed in totes in the MF-specified order.
Meto-Lift is designed to lift and invert barrels over the Porta-Sifter. It has a funnel-like top that clamps over the open barrel. The flow of material is controlled by a gate valve in the funnel opening. After the barrel has been inverted and attached to the Porta-Sifter using a rubber collar, the valve is opened allowing the granulation to flow from the barrel.
The Porta-Sifter is on an elevated platform that allows totes to be rolled under it. It is fitted with a six-mesh screen (six openings per inch). The granulation flows through the Porta-Sifter into the tote. This screening helps break up any clumps that may have formed in the granulation and helps to ensure that foreign materials are not included in the granulation.
If blender cannot be charged from totes, it is possible to charge it directly from barrels through a portable Porta-Sifter. In this case, attention must be paid to the oxygen level as the powders can be explosive. Anytime the blender is opened while processing materials, it must be purged with nitrogen. When loading from barrels, the oxygen level should be checked after each barrel, and purging should be done whenever the oxygen level reaches or exceeds 8%.
Milled sodium chloride and ferric oxide (if required) must be added to totes/blender within 72 hours (3 days) of milling. Typically, raw materials may be stored in totes for a maximum of 120 hours (5 days) before the start of granulation. Net weight of the tote must be determined and compared to the specified values in MF. Work in progress (WIP) totes must be labeled with in-process labels showing weights, lot numbers, and dates. Totes are moved to staging area for granulation.
If components are received, already granulated, in barrels from client/supplier, it is put into totes using the Meto-Lift and Porta-Sifter, has the lubricant added/blended, and then goes directly to compression process. Totes are labeled with a WIP label showing weights, lot number, and dates. After tote charging of both drug and osmotic granulation, totes are taken to blending, then to the staging area for core compression. Critical elements of the process are:
- Failure to mill and screen powders could result in poor distribution of materials throughout granulation. This could have an impact on both core compression and drug dosage levels.
- Even dispersal of sodium chloride is critical to the osmotic properties of granulation since it is used to regulate the solute levels of granulation.
- Even distribution of ferric oxide is important in getting a consistent coloring in the core OSD.
Totes should be thoroughly checked before charging to ensure that they are clean, dry, and contain no foreign materials. Dump valve seal check by opening and closing the valve should reveal condition of the seal. Operators should always check the screen after charging each barrel for the presence of foreign material. The barrels, poly bags, ties, and seals should be kept away from the charging area. The use of razor blades in dispensing can create problems as they can easily fall into the materials or shred plastic bags.
An easy way to cross-check what is in the tote is to take the total weight of all components given on the MF and compare it to the net weight of the tote. If the weights differ, it could indicate that either not all or extra material were charged, or that there is a problem with pre-weighed materials from the pharmacy.
2 Granulation
DOI: 10.1201/9781003224716-2
Granulation is a process of agglomeration, whereby smaller particles are brought together into an aggregate with increased void space in the larger aggregate free-flowing state to allow for breakdown into dissolution when hydrated. The process of granulating is one of the most versatile and important precompression process steps in drug product solid dosage manufacturing. By granulating, powders can be mixed, and cling together to increase free-flowing characteristic, instantize dissolution, and become nearly dust free.
Granulating involves the blending of powdered components, the introduction of a binding agent, drying the resulting mixture, and milling to obtain a uniform granule size. Dry powders are moistened with a solvent during granulation. Some of the powdered material dissolves at least partially. A process aid binder is added to the dry mix to improve adhesion when in solution. Pendular bridges are formed between the particles during granulation. The open compressible structure allows the granule to hold moisture internally yet still be free flowing. Granules can be formed as a dry mix, pendular, funicular, capillary, kneaded capillary, and coated. The tensile strength increases about three times from pendular to the capillary state.
Dry granulating applications require added pressure and/or heat to form slugs, which are then milled to a uniform size. Wet granulating of dry mixtures, whereby they are mixed with a solvent to dough consistency and then dried and milled to achieve a uniform granule. Many of these processes involve moving the product between various vessels as it moves from blending, to agglomerating, to drying, and to milling. This approach is inefficient in terms of process times and labor costs, and it exposes the product to potential contamination.
There are two different methods to prepare powdered materials by using fluid-bed granulator or a twin-shell liquid-solid blender. The first three steps – mixing, agglomerating, and drying – in both processes are accomplished in a single vessel.
A fluid-bed granulator (e.g., Glatt) suspends the powder particles in a stream of air, a fluidized bed, while atomized binder solution is sprayed. It uses heated air to dry the granulation throughout the process. A blender (e.g., PK) mixes the powders with an organic solvent, ethanol using a tumbling (rotating) motion. It then uses heat and a vacuum to remove ethanol from the granulation at the end of the process. In both methods, the granulation is milled for size uniformity at the end.
Granulation allows for instantized particle size and weight for increased dissolution and reduction of dust levels, which improves powder explosion risk. This allows safer, cleaner, and easier handling with less loss of product due to airborne or electrostatic bonding to manufacturing surfaces.
Agglomeration (granulation) fuses particles of different size, shape, and density permits easier mechanical handling without a substantial loss of mix quality due to segregation. The fusing of particles has little or no effect on the chemical structure of the components; it helps to ensure a consistent blend of all components. Agglomerates facilitate mixing by improving homogeneity of low dosage level products by evenly mixing and adhering the active drug to fillers and diluents. In addition, it improves dosage uniformity by improving the uniformity of components that reach the compression machine by decreasing segregation, which is due to differences in density and size.
PK Blender Manufacturing Process
The blender intensifier bar is used to enhance the spray pattern homogeneity during the spraying cycle. It rotates at approximately 3,000 rpm. Dispersion blades keep the granulation from sticking to the spray discs. The entire intensifier bar assembly is removed and disassembled for cleaning. The blending process uses an organic solvent, anhydrous ethyl alcohol, and a binding agent, HPMC, which is added to dry ingredients before spraying. The process forms pendular bridged granules. During spraying, ethyl alcohol dissolves HPMC, which allows it to form the bridges between particles through surface tension/capillary action. The bridges then recrystallize during drying. The API drug substance and other excipients are not soluble in ethyl alcohol. At the end of spraying, the mixture has a moist loose granular consistency, which easily compacts much like a snowball. It has a moisture level of 18%–24% by weight depending on the product. The granulation is then dried by heating the jacketed vessel to a temperature between 70°F and 100°F per MF and creating a vacuum within the vessel. The vacuum applied is normally 100 mm Hg (standard ambient atmospheric pressure is 760 mm Hg). Drying times can take as long as 24 hours. The vacuum pumps and alcohol condenser are usually located outside the blender building.
Fluidized-bed granules are relatively uniform in size, even before milling. Blender granulation can be lumpy. As a result, milling to a uniform size granule is critical. The blender vessel is inverted with the charge/discharge hatch down, and a fluid air mill is attached. As the granulation is milled, it is moved to a tote with a spiral feeder. The portable fluid air mill is continuously purged with nitrogen and is supplied with chilled water. The maximum allowable temperature is 100°F. After milling, the granulation is pre-blended on the tote tumbler and then the lubricant, magnesium stearate, is added to the tote and finely blended.
Charging
Materials are received, and the anhydrous ethyl alcohol is dispensed into pressure vessel through a 3-μm filter. Air is then used to pressurize the vessel and push the alcohol through the lines to the blender spray discs. The blender can be charged directly from drums by using a portable Porta-Sifter. Powders are sifted directly into the blender in the order specified in MF. While charging the blender, attention must be paid to the oxygen level as the powders can be explosive. Anytime the blender is opened during processing, it must be purged with nitrogen. When charging from barrels, the oxygen level should be checked after each barrel; if the oxygen level reaches or exceeds 8%, blender must be purged.
To charge from totes, the blender is rotated so the neck is aligned with the opening in the ceiling. It is purged with nitrogen and the charging collar is attached to the top of PK blender. The tote is positioned in the charge station over the PK and the tote is grounded. The inflatable seal on top of the collar is inflated to form a seal between the PK collar and the tote. The tote is then purged with nitrogen and the valve on the bottom of the tote is opened. To ensure that all the powders fall into the PK, the operators can use a slight vacuum and/or they can tap on the sides of the tote using rubber mallets. The same procedures are repeated for the second tote. After charging, components are blended by rotating the PK at 6 rpm for 30 minutes with intensifier bar off.
Granulating
The intensifier bar is turned on and a specified quantity of ethyl alcohol is sprayed while blending for a specified time. Most products call for the spraying to occur in several increments, normally with the bulk of the alcohol being sprayed during the first one. Spraying is complete when the wet sample shows a moisture level within range for that product (normally 18%–24%) per MF. When the required moisture level is reached, the hot water circulation pumps are started, and the MF-specified temperature is set. Normally the filter in the vacuum line is changed. However, in some cases, the pressure differential across the filter is monitored, and the filter is changed only when it reaches a given limit. A new circle chart is installed to monitor the vacuum, and the vacuum pumps are started. The vacuum is taken down slowly to 100 mm Hg.
With the intensifier bar off, the first 2 hours of drying involves cycling the blender rotation between 1.5 rpm for 5 minutes and 0 rpm for 10 minutes. After the first two hours, the PK is set at 1.5 rpm, and the granulation can dry for 8–10 hours depending on the product. After the second drying cycle, samples are taken (normally from each side of the PK), and the average moisture loss on drying (LOD) is checked against the target. Drying continues until the LOD values are within range. Some products require up to 40 hours to dry. When the desired LOD is reached, the water heater and circulating pumps are turned off.
Milling
The relative humidity of the process room should be maintained below 55%. Blender is positioned with the charge/discharge opening straight down and a portable fluid air mill is connected to it by a cloth boot. The mill and PK are continuously purged with N2, and the mill has chilled water circulating through it to keep it below 100°F. A ten-mesh screen (ten openings per inch) is used on the mill per MF. The walls of the PK should be scraped, and that material is also milled. The outlet of the fluid air mill relates to a cloth boot to the feed hopp...