Pharmaceutical manufacturing is the process of industrial-scale synthesis of pharmaceutical drugs as part of the pharmaceutical industry. The process of drug manufacturing can be broken down into a series of unit operations, such as milling, granulation, coating, tablet pressing, and others.
While a laboratory may use dry ice as a cooling agent for reaction selectivity, this process gets complicated on an industrial scale. The cost to cool a typical reactor to this temperature is large, and the viscosity of the reagents typically also increases as the temperature lowers, leading to difficult mixing. This results in added costs to stir harder and replace parts more often, or it results in a non-homogeneous reaction. Finally, lower temperatures can result in crusting of reagents, intermediates, and byproducts to the reaction vessel over time, which will impact the purity of the product. [1]
Different stoichiometric ratios of reagents can result in different ratios of products formed. On the industrial scale, adding a large amount of reagent A to reagent B may take time. During this, the reagent A that is added is exposed to a much higher stoichiometric amount of reagent B until it is all added, and this imbalance can lead to reagent A prematurely reacting, and subsequent products to also react with the huge excess of reagent B. [1]
Whether to add organic solvent into aqueous solvent, or vice versa, becomes important on the industrial scale. Depending on the solvents used, emulsions can form, and the time needed for the layers to separate can be extended if the mixing between solvents is not optimal. When adding organic solvent to aqueous, stoichiometry must be considered again, as the excess of water could hydrolyze organic compounds in only mildly acidic or basic conditions. In an even wider scope, the location of the chemical plant can play a role in the ambient temperature of the reaction vessel. A difference of even a couple of degrees can yield much different levels of extractions between plants located across countries. [1]
In continuous manufacturing, input raw materials and energy are fed into the system at a constant rate, and at the same time, a constant extraction of output products is achieved. The process's performance is heavily dependent on the stability of the material flowrate. For powder-based continuous processes, it is critical to feed powders consistently and accurately into subsequent unit operations of the process line, as feeding is typically the first unit operation. [2] Feeders have been designed to achieve performance reliability, feed rate accuracy, and minimal disturbances. Accurate and consistent delivery of materials by well-designed feeders ensures overall process stability. Loss-in-weight (LIW) feeders are selected for pharmaceutical manufacturing. Loss-in-weight (LIW) feeders control material dispensing by weight at a precise rate and are often selected to minimize the flowrate variability that is caused by change of fill level and material bulk density. Importantly, feeding performance is strongly dependent on powder flow properties. [3] [4]
In the pharmaceutical industry, a wide range of excipients may be blended together with the active pharmaceutical ingredient to create the final blend used to manufacture the solid dosage form. The range of materials that may be blended (excipients, API), presents a number of variables which must be addressed to achieve target product quality attributes. These variables may include the particle size distribution (including aggregates or lumps of material), particle shape (spheres, rods, cubes, plates, and irregular), presence of moisture (or other volatile compounds), particle surface properties (roughness, cohesion), and powder flow properties. [5] [ pages needed ]
During the drug manufacturing process, milling is often required in order to reduce the average particle size in a drug powder. There are a number of reasons for this, including increasing homogeneity and dosage uniformity, increasing bioavailability, and increasing the solubility of the drug compound. [6] In some cases, repeated powder blending followed by milling is conducted to improve the manufacturability of the blends.
In general, there are two types of granulation: wet granulation and dry granulation. Granulation can be thought of as the opposite of milling; it is the process by which small particles are bound together to form larger particles, called granules. Granulation is used for several reasons. Granulation prevents the "demixing" of components in the mixture, by creating a granule which contains all of the components in their required proportions, improves flow characteristics of powders (because small particles do not flow well), and improves compaction properties for tablet formation. [7]
Hot melt extrusion is utilized in pharmaceutical solid oral dose processing to enable delivery of drugs with poor solubility and bioavailability. Hot melt extrusion has been shown to molecularly disperse poorly soluble drugs in a polymer carrier increasing dissolution rates and bioavailability. The process involves the application of heat, pressure and agitation to mix materials together and 'extrude' them through a die. Twin-screw high shear extruders blend materials and simultaneously break up particles. The resulting particles can be blended and compressed into tablets or filled into capsules. [8]
The documentation of activities by pharmaceutical manufacturers is a license-to-operate endeavor, supporting both the quality of the product produced and satisfaction of regulators who oversee manufacturing operations and determine whether a manufacturing process may continue or must be terminated and remediated.
A Site Master File is a document in the pharmaceutical industry which provides information about the production and control of manufacturing operations. The document is created by a manufacturer. [9] The Site Master file contains specific and factual GMP information about the production and control of pharmaceutical manufacturing operations carried out at the named site and any closely integrated operations at adjacent and nearby buildings. If only part of a pharmaceutical operation is carried out on the site, the site master file needs to describe only those operations, e.g., analysis, packaging. [10]
A tablet is a pharmaceutical oral dosage form or solid unit dosage form. Tablets may be defined as the solid unit dosage form of medication with suitable excipients. It comprises a mixture of active substances and excipients, usually in powder form, that are pressed or compacted into a solid dose. The main advantages of tablets are that they ensure a consistent dose of medicine that is easy to consume.
Spray drying is a method of forming a dry powder from a liquid or slurry by rapidly drying with a hot gas. This is the preferred method of drying of many thermally-sensitive materials such as foods and pharmaceuticals, or materials which may require extremely consistent, fine particle size. Air is the heated drying medium; however, if the liquid is a flammable solvent such as ethanol or the product is oxygen-sensitive then nitrogen is used.
In industrial process engineering, mixing is a unit operation that involves manipulation of a heterogeneous physical system with the intent to make it more homogeneous. Familiar examples include pumping of the water in a swimming pool to homogenize the water temperature, and the stirring of pancake batter to eliminate lumps (deagglomeration).
Extrusion is a process used to create objects of a fixed cross-sectional profile by pushing material through a die of the desired cross-section. Its two main advantages over other manufacturing processes are its ability to create very complex cross-sections; and to work materials that are brittle, because the material encounters only compressive and shear stresses. It also creates excellent surface finish and gives considerable freedom of form in the design process.
Excipient is a substance formulated alongside the active ingredient of a medication. Excipients serve various purposes, including long-term stabilization, bulking up solid formulations containing potent active ingredients in small amounts, or enhancing the therapeutic properties of the active ingredient in the final dosage form. They can facilitate drug absorption, reduce viscosity, or enhance solubility. Excipients can also aid in the manufacturing process by improving the handling of active substances, facilitating powder flowability, or preventing denaturation and aggregation during the expected shelf life. The selection of excipients depends on factors such as the route of administration, dosage form, and active ingredient.
Fluidization is a process similar to liquefaction whereby a granular material is converted from a static solid-like state to a dynamic fluid-like state. This process occurs when a fluid is passed up through the granular material.
In the manufacture of pharmaceuticals, encapsulation refers to a range of dosage forms—techniques used to enclose medicines—in a relatively stable shell known as a capsule, allowing them to, for example, be taken orally or be used as suppositories. The two main types of capsules are:
Plastics extrusion is a high-volume manufacturing process in which raw plastic is melted and formed into a continuous profile. Extrusion produces items such as pipe/tubing, weatherstripping, fencing, deck railings, window frames, plastic films and sheeting, thermoplastic coatings, and wire insulation.
Pharmaceutical formulation, in pharmaceutics, is the process in which different chemical substances, including the active drug, are combined to produce a final medicinal product. The word formulation is often used in a way that includes dosage form.
A high-shear mixer disperses, or transports, one phase or ingredient into a main continuous phase (liquid), with which it would normally be immiscible. A rotor or impeller, together with a stationary component known as a stator, or an array of rotors and stators, is used either in a tank containing the solution to be mixed, or in a pipe through which the solution passes, to create shear. A high-shear mixer can be used to create emulsions, suspensions, lyosols, and granular products. It is used in the adhesives, chemical, cosmetic, food, pharmaceutical, and plastics industries for emulsification, homogenization, particle size reduction, and dispersion.
A tablet press is a mechanical device that compresses powder into tablets of uniform size and weight. A tablet press can be used to manufacture tablets of a wide variety of materials, including pharmaceuticals, nutraceuticals, cleaning products, industrial pellets and cosmetics. To form a tablet, the granulated powder material must be metered into a cavity formed by two punches and a die, and then the punches must be pressed together with great force to fuse the material together.
A powder is an assembly of dry particles dispersed in air. If two different powders are mixed perfectly, theoretically, three types of powder mixtures can be obtained: the random mixture, the ordered mixture or the interactive mixture.
A conical mill is a machine used to reduce the size of material in a uniform manner. It is an alternative to the hammermill or other forms of grinding mills. As the name implies, the conical mill varies in diameter from where the feed enters to where the product exits.
Granulation is the process of forming grains or granules from a powdery or solid substance, producing a granular material. It is applied in several technological processes in the chemical and pharmaceutical industries. Typically, granulation involves agglomeration of fine particles into larger granules, typically of size range between 0.2 and 4.0 mm depending on their subsequent use. Less commonly, it involves shredding or grinding solid material into finer granules or pellets.
Tableting is a method of pressing medicine or candy into tablets. Confectionery manufacture shares many similarities with pharmaceutical production.
Micro-compounding refers to the mixing or processing of polymer formulations in the melt on a very small scale, typically several ml. The advantage of the use of a micro-compounder for R&D are significant: it gives faster, yet reliable results with much smaller samples and at much less investment costs, thus speeding up the innovation process in R&D of polymer materials, pharmaceutical, biomedical and nutritional applications.
Agglomerated food powder is a unit operation during which native particles are assembled to form bigger agglomerates, in which the original particle can still be distinguished. Agglomeration can be achieved through processes that use liquid as a binder or methods that do not involve any binder.
Material extrusion-based additive manufacturing (EAM) represents one of the seven categories of 3d printing processes, defined by the ISO international standard 17296-2. While it is mostly used for plastics, under the name of FDM or FFF, it can also be used for metals and ceramics. In this AM process category, the feedstock materials are mixtures of a polymeric binder and a fine grain solid powder of metal or ceramic materials. Similar type of feedstock is also used in the Metal Injection Molding (MIM) and in the Ceramic Injection Molding (CIM) processes. The extruder pushes the material towards a heated nozzle thanks to
Topical gels are a topical drug delivery dosage form commonly used in cosmetics and treatments for skin diseases because of their advantages over cream and ointment. They are formed from a mixture of gelator, solvent, active drug, and other excipients, and can be classified into organogels and hydrogels. Drug formulation and preparation methods depend on the properties of the gelators, solvents, drug and excipients used.
3D drug printing or 3D printing of pharmaceuticals is a technology that uses three-dimensional printing techniques to create customized pharmaceuticals, such as 3D printed tablets. It allows for precise control over the composition and dosage of drugs, enabling the production of personalized medicine tailored to an individual's specific needs, such as age, weight, and medical condition. This approach can be used to improve the effectiveness of drug therapies and to reduce side effects.