Question

A project requires weighing and dispensing of multiple hi-potent (ECL>3) pharmaceutical compounds in powder form for a blockbuster, commercially marketed drug, it’s a sterile processing plant. Provide your conceptual HVAC design description that include primary enclosures (only HVAC for handling and transfer devices) and secondary (room/HVAC) containments to protect product attributes (integrity, efficacy, purity), personnel from environmental exposures. Elegant, energy efficient, and least cost design URS solution are required criteria. A project requires weighing and dispensing of multiple hi-potent (ECL>3) pharmaceutical compounds in powder form for a blockbuster, commercially marketed drug, it’s a sterile processing plant. Provide your conceptual HVAC design description that include primary enclosures (only HVAC for handling and transfer devices) and secondary (room/HVAC) containments to protect product attributes (integrity, efficacy, purity), personnel from environmental exposures. Elegant, energy efficient, and least cost design URS solution are required criteria.

Answer 1

What can HVAC do?
HVAC system performs four basic functions:
1. Control airborne particles, dust and micro-organisms – Thru air filtration using high efficiency particulate air (HEPA) filters.
2. Maintain room pressure (delta P) – Areas that must remain “cleaner” than surrounding areas must be kept under a “positive” pressurization, meaning that air flow must be from the “cleaner” area towards the adjoining space (through doors or other openings) to reduce the chance of airborne contamination. This is achieved by the HVAC system providing more air into the “cleaner” space than is mechanically removed from that same space.
3. Maintain space moisture (Relative Humidity) – Humidity is controlled by cooling air to dew point temperatures or by using desiccant dehumidifiers. Humidity can affect the efficacy and stability of drugs and is sometimes important to effectively mould the tablets.
4. Maintain space temperature - Temperature can affect production directly or indirectly by fostering the growth of microbial contaminants on workers.
Each of above parameter is controlled and evaluated in light of its potential to impact product quality.
What HVAC can’t do?
1. HVAC can not clean up the surfaces of a contaminated surfaces, room or equipment
2. HVAC can not compensate for workers who do not follow procedures
We will learn about the specific design aspects later in this course, but first we will briefly discuss the generic pharmaceutical process.

Pharmaceutical Process
The task of the pharmaceutical manufacturer is to combine the medicinally active agents provided by a fine chemicals plant, or by extraction from vegetable, animal or other source, with suitable inactive ingredients so that the end product may be used in the correct dosage to produce the effect needed.
Simplified Process
Figure below illustrates a simplified diagram of the chemical synthesis process for pharmaceuticals. There are five primary stages in chemical synthesis: (1) reaction, (2) separation, (3) crystallization, (4) purification, and (5) drying. Each of these five stages is described below.

Reaction(s) –
In the reaction process, raw materials are fed into a reactor vessel, where reactions such as alkylations, hydrogenations, or brominations are performed. The most common type of reactor vessel is the kettle-type reactor generally made of stainless steel or glasslined carbon steel, range from 50 to several thousand gallons in capacity. The reactors may be heated or cooled, and reactions may be performed at atmospheric pressure, at elevated pressure, or in a vacuum. Generally, both reaction temperature and pressure are monitored and controlled. Nitrogen may be required for purging the reactor, and some intermediates may be recycled back into the feed. Some reactions are aided via mixing action provided by an agitator. A condenser system may be required to control vent losses. Reactors are often attached to pollution control devices to remove volatile organics or other compounds from vented gases.
Separation –
The main types of separation processes are extraction, decanting, centrifugation, and filtration. The extraction process is used to separate liquid mixtures.
• Extraction process is used to separate liquid mixtures. It takes advantage of the differences in the solubility of mixture components i.e. a solvent that preferentially combines with only one of the mixture components is added to the mixture. Two
streams result from this process: the extract, which is the solvent-rich solution containing the desired mixture component, and the raffinate, which is the residual feed solution containing the non-desired mixture component(s).
• Decanting is a simple process that removes liquids from insoluble solids that have settled to the bottom of a reactor or settling vessel. The liquid is either pumped out of the vessel or poured from the vessel, leaving only the solid and a small amount of liquid in the vessel.
• Centrifugation is a process that removes solids from a liquid stream using the principle of centrifugal force. A liquid-solid mixture is added to a rotating vessel— or centrifuge—and an outward force pushes the liquid through a filter that retains the solid phase. The solids are manually scraped off the sides of the vessel or with an internal scraper. To avoid air infiltration, centrifuges are usually operated under a nitrogen atmosphere and kept sealed during operation.
• Filtration separates fluid/solid mixtures by flowing fluid through a porous media, which filters out the solid particulates. Batch filtration systems widely used by the pharmaceutical industry include plate and frame filters, cartridge filters, nutsche filters, and filter/dryer combinations.
Crystallization -
Crystallization is a widely used separation technique that is often used alone or in combination with one or more of the separation processes described above. Crystallization refers to the formation of solid crystals from a supersaturated solution. The most common methods of super saturation in practice are cooling, solvent evaporation, and chemical reaction. The solute that has crystallized is subsequently removed from the solution by centrifugation or filtration.
Purification -
Purification follows separation, and typically uses the separation methods described above. Several steps are often required to achieve the desired purity level.
Re-crystallization is a common technique employed in purification. Another common approach is washing with additional solvents, followed by filtration.
Drying -
The final step in chemical synthesis is drying the product (or intermediates). Drying is done by evaporating solvents from solids. Solvents are then condensed for reuse or disposal. The pharmaceutical industry uses several different types of dryers, including tray dryers, rotary dryers, drum or tumble dryers, or pressure filter dryers. Prior to 1980, the most common type of dryer used by the pharmaceutical industry was the vacuum tray dryer.
Today, however, the most common dryers are tumble dryers or combination filter/dryers. In the combination filter/dryer, input slurry is first filtered into a cake, after which a hot gaseous medium is blown up through the filter cake until the desired level of dryness is achieved. Tumble dryers typically range in capacity from 20 to 100 gallons. In tumble dryers, a rotating conical shell enhances solvent evaporation while blending the contents of the dryer. Tumble dryers utilize hot air circulation or a vacuum combined with conduction from heated surfaces.
Product Extraction
Active ingredients that are extracted from natural sources are often present in very low concentrations. The volume of finished product is often an order of magnitude smaller than the raw materials, making product extraction an inherently expensive process.
Precipitation, purification, and solvent extraction methods are used to recover active ingredients in the extraction process. Solubility can be changed by pH adjustment, by salt formation, or by the addition of an anti-solvent to isolate desired components in precipitation.
Solvents can be used to remove active ingredients from solid components like plant or animal tissues, or to remove fats and oils from the desired product. Ammonia is often used in natural extraction as a means of controlling pH.
Fermentation -
In fermentation, microorganisms are typically introduced into a liquid to produce pharmaceuticals as by-products of normal microorganism metabolism. The fermentation process is typically controlled at a particular temperature and pH level under a set of
aerobic or anaerobic conditions that are conducive to rapid microorganism growth. The process involves three main steps: (i) seed preparation, (ii) fermentation, and (iii) product recovery.
Seed preparation -
The fermentation process begins with seed preparation, where inoculum (medium containing microorganisms) is produced in small batches within seed tanks. Seed tanks are typically 1-10% of the size of production fermentation tanks (U.S. EPA 1997).
Fermentation -
After creating the inoculum at the seed preparation stage, the inoculum is introduced into production fermentors. In general, the fermentor is agitated, aerated, and controlled for pH, temperature, and dissolved oxygen levels to optimize the fermentation process. The fermentation process lasts from hours to weeks, depending on the product and process.
Product Recovery -
When fermentation is complete, the desired pharmaceutical byproducts need to be recovered from the fermented liquid mixture. Solvent extraction, direct precipitation, and ion exchange may be used to recover the product. Additionally, if the product is contained within the microorganism used in fermentation, heating or ultrasound may be required to break the microorganism’s cell wall. In solvent extraction, organic solvents are employed to separate the product from the aqueous solution. The product can then be removed from the solvent by crystallization. In direct precipitation, products are precipitated out of solution using precipitating agents like metal salts. In ion exchange, the product adsorbs onto an ion exchange resin and is later recovered from the resin using solvents, acids, or bases.
Formulation of Final Products
The final stage of pharmaceutical manufacturing is the conversion of manufactured bulk substances into final, usable forms. Common forms of pharmaceutical products include tablets, capsules, liquids, creams and ointments, aerosols, patches, and injectable dosages. Tablets account for the majority of pharmaceutical solids.
To prepare a tablet, the active ingredient is combined with a filler (such as sugar or starch), a binder (such as corn syrup or starch), and sometimes a lubricant (such as magnesium state or polyethylene glycol). The filler ensures the proper concentration of the active ingredient; the purpose of the binder is to bond tablet particles together. The lubricant may facilitate equipment operation during tablet manufacture and can also help to slow the disintegration of active ingredients.
Tablets are produced via the compression of powders. Wet granulation or dry granulation processes may be used. In wet granulation, the active ingredient is powdered and mixed with the filler, wetted and blended with the binder in solution, mixed with lubricants, and finally compressed into tablets. Dry granulation is used when tablet ingredients are sensitive to moisture or drying temperatures. Coatings, if used, are applied to tablets in a rotary drum, into which the coating solution is poured. Once coated, the tablets are dried in the rotary drum; they may also be sent to another drum for polishing.
Capsules are the second most common solid oral pharmaceutical product in the United States after tablets (U.S. EPA 1997). Capsules are first constructed using a mold to form the outer shell of the capsule, which is typically made of gelatin. Temperature controls during the molding process control the viscosity of the gelatin, which in turn determines the thickness of the capsule walls. The capsule’s ingredients are then poured (hard capsules) or injected (soft capsules) into the mold.
For liquid pharmaceutical formulations, the active ingredients are weighed and dissolved into a liquid base. The resulting solutions are then mixed in glass-lined or stainless steel vessels and tanks. Preservatives may be added to the solution to prevent mold and bacterial growth.
If the liquid is to be used orally or for injection, sterilization is required.
Ointments are made by blending active ingredients with a petroleum derivative or wax base