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‌Pharmaceutical manufacturing

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‌ harmaceutical manufacturing is the process of industrial-scale synthesis of pharmaceutical drugs as

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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.

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‌Toledo Pharmacal Company from Toledo, Ohio seen in 1905

‌Scale-up considerations Edit

‌Cooling Edit

‌ hile a laboratory may use dry ice as a cooling agent for reaction selectivity, this process gets
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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]
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‌Stoichiometry Edit

‌ ifferent stoichiometric ratios of reagents can result in different ratios of products formed. On the
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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]

‌Solvent extractions Edit

‌ hether to add organic solvent into aqueous solvent, or vice versa, becomes important on the industrial
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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]

‌Unit operations

‌Formulation and pre-formulation development

‌Powder feeding in continuous manufacturing

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 performance is
heavily dependent on stability of the material flow rate. 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 flow rate 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]

‌Powder blending

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]

‌Milling

‌ uring the drug manufacturing process,milling is often required in order to reduce the average particle
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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.

‌Granulation

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

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‌ ot melt extrusion is utilized in pharmaceutical solid oral dose processing to enable delivery of drugs
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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]

‌Documentation

T‌ he 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.

‌Site Master File (SMF)

‌ Site Master File is a document in the pharmaceutical industry which provides information about the
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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]

‌See also

‌References

^‌ a b c Laird, Trevor (July 2010). "How to Minimize Scale Up Difficulties" (PDF).Chemical Industry Digest.
Maharashtra, India: Blockdale Media. pp. 51–56. Archived from the original (PDF) on 22 May 2015.^
Blackshields, Caroline A.; Crean, Abina M. (3 July 2018). "Continuous powder feeding for pharmaceutical
solid dosage form manufacture: a short review". Pharmaceutical Development and Technology (Review).
23 (6): 554–560.doi:10.1080/10837450.2017.1339197.ISSN 1083-7450. PMID 28590824.S2CID
205750263.^ Wang, Yifan; Li, Tianyi; Muzzio, Fernando J.; Glasser, Benjamin J. (15 February
2017)."Predicting feeder performance based on material flow properties". Powder Technology. 308:
135–148.doi:10.1016/j.powtec.2016.12.010.ISSN 0032-5910.^ Cartwright, James J.; Robertson, John;
D'Haene, Dorie; Burke, Matthew D.; Hennenkamp, Jeffrey R. (1 April 2013). "Twin screw wet granulation:
Loss in weight feeding of a poorly flowing active pharmaceutical ingredient". Powder Technology.
Special Issue: 5th International Granulation Workshop Granulation across the length scale 2011. 238:
116–121. doi:10.1016/j.powtec.2012.04.034.ISSN 0032-5910.^ Baxter, Thomas; Prescott, James (2
January 2009). Developing Solid Oral Dosage Forms. Academic Press. ISBN 978-0-444-53242-8.^
"Pharmaceutical Drug Formulation, Development & Drug Delivery". Particle Sciences Drug Development
Services. Lubrizol. Archived from the original on 10 October 2015. Retrieved 24 October 2015.^ Aulton,
Michael; Malcolm,

‌Plant manufactured pharmaceuticals

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‌This article needs additional citations for verification. (July 2013)

‌ lant manufactured Pharmaceuticals are pharmaceuticals derived from genetically modified plants used
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as therapeutic compounds. This can be used as the replacement for the traditional method of
inoculating animals for Cell Culture production. We can use plants to cure and prevent diseases that may
have once been deemed incurable. Through biotechnological advancements, we are able to produce
complex therapeutic proteins from plant cells.[1] Such Therapeutic Proteins are seen in brands like
Enevrel and Remicade for rheumatoid arthritis, Herceptin, a breast cancer treatment. Plants like tobacco
are hosts for protein production for applications such as; anemia, hepatitis C & B, hypertension,
antimicrobial, and liver disease.[1][2]

‌Impact on business and industry

‌
‌ ith the advancement of Plant Manufactured Pharmaceuticals, comes the advancements of a new type
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production in industry. Companies such as ZEA Biosciences are developing cost-effective and scalable
pharmaceutical ingredients using plants instead of cell culture. Unlike cell culture, plants can have a
much larger production capacity, a mass quantity of plant hosts on site, and the ability to make specific
antibodies that is used as a bio-reactor for specific patient needs.[1] Indirectly, the need to grow plants
that are being used as Plant Manufactured Pharmaceuticals will increase in geographic areas where
certain plants naturally grow, for instance in developing countries. Increasing the need for agricultural
societies in developing countries will help certain countries to export and make trade alliance with other
countries and with the development of the therapies that can control diseases like Cholera and
HIV/AIDS.[1]

‌Ideas of enhanced recovery

L‌ andscape Gardens that must be grown for the production of the therapeutic proteins brings a new time
of recovery for certain patients. Professor Roger Ulrich of Texas A&M University believes that
Therapeutic Gardens can help the spiritual needs of patients and enhance stress recovery. This relieves
the patient of stress and gives the patient a feeling of tranquility during their recovery.

‌Criticism and awareness

‌ any corporations are allowed to create genetically modified organisms and secure them through
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intellectual property rights creating monopolies, a fact that continues to evoke criticism . Awareness and
education is needed for the public to understand how even GM plants have helped medical research.
For instance, in 1992, a group of American students produced a Hepatitis B vaccine from a genetically
modified tobacco plant showing the ability of produce pharmaceutical compounds.

‌References

^‌ a b c d e f Horton, Susannah (2012).RETHINKING THE INDUSTRIAL LANDSCAPE - REVEALING THE

CURATIVE POTENTIAL OF GENETICALLY MODIFIED PLANTS. Clemson University: ProQuest LLC. pp. 1–
18.^ THOMAS, BRUCE. "Production of Therapeutic Proteins in Plants" (PDF). UNIVERSITY OF CALIFORNIA
Division of Agriculture and Natural Resources. Retrieved 2 May 2013.

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