IV Production Center Introduction

The IV Production Center (IVPC) is a manufacturing facility for the production of solutions for parenteral (intravenous or intramuscular administration) medical requirements. The facility produces IV solutions from local water sources using blow/fill/seal (BFS) aseptic packaging, which eliminates the ordering, shipping, storing, handling, cleaning and sterilization of pre-made containers. With its design incorporating a unique single-operation BFS machine, the facility exceeds U.S. and international quality standards, while producing product at unit costs of $0.15 to $0.25 per unit depending on labor, electric, water rates and the type of end cap desired, (puncture port or EuroCap). For the first time high quality IV solutions manufactured on a local basis will be available to almost any country and locale.

Turn-key Program

SBT Technology can provide an integrated, turn-key program for the IVPC, including site engineering, building structure, build-out, systems equipment, computer hardware, systems software, complete erection and installation, and operational training. In addition, SBT personnel provide on-going quality assurance, technical and maintenance assistance as part of the comprehensive program. In some cases it is possible to use an existing building.

Facility

If a structure is required it would be a pre-engineered and completely pre-fabricated for shipment to and erection at the selected site. SBT engineers visit the site to determine infrastructure capability, local resource availability and site-specific requirements. Modifications dictated by local conditions are thus made at the earliest possible stage to avoid duplication of effort, unnecessary engineering and the associated increases in cost. The same process is followed if an existing building is to be used. SBT will develop the list of renovations required that the owner can either do or contract with SBT to accomplish.

All segments of the manufacturing process are addressed in facility operations, including sterilizing, labeling, mixing, packaging, warehousing, inventory control, shipping and receiving. The patented, state-of-the-art production equipment integrates new automation, barrier isolation technologies, digital control systems to guarantee the most effective and validatable method of filling and packaging sterile pharmaceutical, biological solutions.

Standard IVPC facility designs are available in production capacities of 10 to 40 million units per year. The use of two BFS machines has the added advantage of incorporating two completely independent systems providing total production redundancy and virtually eliminating downtime due to testing, maintenance, or product line changes. Custom sizes are also available. A unit is considered to be a 500 mL bag of solution.

Product Diversity

Using state-of-the-art technology, the IVPC facility can produce virtually any IV solution product in virtually any size aseptically-filled and terminally-sterilized medical grade plastic container. Standard molds that are based on international criteria and uses are supplied with the initial facility equipment. Custom and specialty admixtures can be produced but they are generally produced in small production runs that may reduce the total number of units produced in a year.

Product expansion and diversification is simple and convenient. Any product expansion must be based on the needs of the customers. If there is a market the solutions can be produced.

Cost and Profitability

The complete cost for an IVPC project varies from country to country, the number of machines, what the owner want included, type of building and local fees or permits. Costs and associated initial operating capital requirements allow for an extremely quick return on investment (ROI) of only 3-5 years, depending on location and market variables, and the number of production lines per facility. ROI is projected using very conservative figures and a realistic operational model of three 8-hour shifts per day. With profitability typically being established at only 30%-35% production capacity, IVPC purchasers have great latitude in adjusting both profitability and ROI by adjusting both product mix and operational modes.

The facility is capable of producing one unit of an IV solution, (500 mL), for approximately $0.15 - $0.25 (weighted average production cost for 8 most common solutions).

Secondary product lines with significantly higher profit margins (compounded, specialty and custom IV solutions and drugs with market prices of $5 to $20 per unit) can be introduced at any time to greatly enhance profitability while long distance shipping costs and import duties are eliminated within the target market area. Local permitting for these products may be costly and should be not considered until after the facility is making money.

Background

The term "large volume parenteral" (LVP) solutions, is the technologically accepted nomenclature of the U.S. Food and Drug Administration for intravenous (IV) solutions. LVPs or IV solutions consist of water for injection, low concentrate solutions of pure saline, dextrose, carbohydrates, electrolytes, lipids, vitamins, proteins, etc., intended for intravenous administration to patients who require maintenance therapy or total parenteral nutrition (TPN) because of inability to eat or digest.

IV solutions are either administered alone, or as a vehicle for administering medications, which are mixed into the solutions for a wide variety of therapies: antibiotic, anti-inflammatory, anesthetics, critical care, chemotherapy, etc.

IV solutions are packaged in aseptically filled, terminally sterilized, pyrogen-free medical grade plastic bags from 100 ml to 1000 ml in volume.

All solutions are administered with the aid of administration sets consisting of various lengths of tubing and configurations of connecting apparatus and needles. Some solutions are injected through gravity drip systems, but the modern trend, indeed a requirement in some countries, is administration through the use of various types of mechanical pumps. If the owner is interested SBT can arrange for private labeling of both administration sets and pumps. Both are expensive to produce in small quantities but by combining the SBT purchasing power economies of scale can be achieved for the owner.

SBT IVPC Concept

The IVPC facility was especially created for international markets to provide countries with an indigenous capacity to produce the basic components for their own high quality medical care (alleviating the costs associated with shipping and inventory maintenance), as well as high-valued products for export.

Based on past experience in international markets, SBT committed itself to providing a comprehensive, turnkey program with 4 essential components:

• State-of-the-art water-for-injection and blow-fill-seal equipment
• Complete facility engineering, equipment installation and computer systems
• Product formulae and process validations
• Training for management, production, marketing and sales personnel

The building can either be an existing building, modified to meet the needs of the plant or a new building designed specifically for this application by Neal Mitchell and Associates of Northbridge MA.

In addition, SBT offers on-going technical and operational assistance to ensure that the products continue to maintain international quality standards.

Design, Manufacturing and Management

The IVPC concept is an innovative entry in the field of advanced aseptic manufacturing. SBT engineers and technical staff are constantly enhancing IVPC technology to create more effective and validatable methods of filling and packaging sterile pharmaceutical, biological and medical products. Engineers and designers with extensive knowledge, background, and direct, day-to-day experience with blow-fill-seal and conventional sterile manufacturing facilities, provide customers with extensive project support, from product development, protocol implementation and manufacturing through regulatory guidance and assistance, including process validation.

Project managers and project engineers are multi-disciplined professionals experienced in dealing with the business, cultural and political aspects of executing international projects. Senior project managers' experiences include design, engineering and construction of high-tech bio-medical research facilities, bio-medical manufacturing facilities, medical clinics, hospitals, and health and science facilities. These professionals are fully versed in state-of-the-art engineering standards, regulatory compliance, government relations, finance and administration.

Technology

Current USFDA standards in the U.S. permit an undetected contamination variable of one-in-one million production units. In other words, the 1 billion plus IV units used in the U.S. annually permit the probability that 1,000 contaminated IV units may enter use undetected. The unique, state-of-the-art technology of the IVPC facility improves upon this factor by 1,000 times. The chance of having undetected contamination in an IV unit produced by an IVPC facility is reduced to a probability of one-in-one billion. This also exceeds the current international standards.

IVPC technology provides a major improvement over the traditional manufacturing methodology and resultant product quality for IV solutions. Traditional factory environments permitting many airborne particles and contagion are replaced with a modified clean room at the filling point and only achievable in the IVPC facility.

De-ionization and pre-treatment of the feed water occurs prior to distillation, eliminating the possible contribution of particulate matter from the de-ionizing process itself. The capacity of the pre-treatment system is 150% of the projected production capacity. This allows for longer life of the filters, which reduces the cost of running the plant.

Furthermore, distilling water that is relatively free of dissolved mineral content prevents superheating of the feed water and the resulting entrainment of solute particles into the downstream water stock. The still is a multi-stage unit that also has a capacity of 150 times the projected production requirements. In addition the still supplies sterile water to the steam boiler that supplies the steam to the autoclave and for use by the clean in place system for cleaning tanks, pipes and machinery. The downstream implications of minimizing particulates in the mixing tank and filter are essential to achieving a superior-quality product. A secondary benefit is that no mineral deposits are left during the cleaning process, which promotes longer life.

The air quality of the filling zone is critical for aseptic filling processes. The traditional rotary filling of containers is replaced by an innovative machine that blows a plastic container, fills it, and seals it all in one operation. Bottles or bags produced separately from the filling operation must be examined for bacterial and particulate contaminants. The IVPC blow-fill-seal machine, by producing a seamless container from plastic resin at temperatures in excess of 300 degrees centigrade and injecting water or other solutions into the sterile container before sealing, greatly reduces both the chance of contamination and the need for secondary inspection and testing.

The IVPC machinery includes a custom-engineered PLC control system, with customized screens and available SCADA capabilities. Plastic temperature control is integral to the control system. Enhanced documentation accumulation is also built into the system. Operator interface software accumulates data in real time from numerous modules, including particle counters, differential pressure monitors, and filter integrity testers. Data is communicated back to the PLC control system and electronically filed for the critical control factors, which relate to the batch's processing. Parameter monitoring can be customized according to the requirements of a customer. The computer system is on an NT-2000 platform and can be either in English or the local language.

The program continuously monitors machine parameters and operating interventions. The system is capable of performing statistical process control on the sampled data as well as recipe batch control, historical trending, alarm management and multi-level security. A firewall is placed between the data that is related to production and quality systems and any other data on the system used for business reasons to provide for security of all data.

Labeling of the completed product is performed after cascade sterilization by packaging equipment in the production line. The container is fully identified by a code embossed into the plastic when it is filled on the BFS. At no time is the product without identification.

Finally, the process is further improved with terminal sterilization via autoclaves. This is a 10 cubic meter autoclave that operates at both higher pressures and temperatures then conventional autoclaves. The resulting reduction in the variability of temperatures within the chamber reduces the probability that a bacterium can escape destruction by heat, sustaining the production improvements in the previous steps.

After leaving the autoclave the containers are labeled with a paper/plastic label with all the required information of the local country, plus any ISO certifications. This includes description, expiration dates, production date, formulary and batch numbers.

Primary Product Line

This is a listing of the most common IV solutions that can be produced by the manufacturing facility designed by SBT Technology Inc. This is not an all-inclusive listing of possible solutions but the most common ones that will make up the vast majority of solutions produced. SBT encourages the owner of the facility to conduct a formal market study, of which solutions should be produced, others than those listed. When that list has been developed SBT will supply the formulary for those additional solutions and assist the owners in gaining approvals of them from the governing agency within that country.

Primary Product Line

• Dextrose 2.5% and water
• Dextrose 5% and water
• Dextrose 10% and water
• Dextrose 20% and water
• 0.9% saline and water
• 0.45% saline and water
• 0.22% saline and water
• 5% Sodium Bicarbonate and water
• Water for injection
• 5% dextrose/0.22% saline and water
• 2.5% dextrose/0.45% saline and water
• 5% dextrose/0.45% saline and water
• 10% dextrose/0.45% saline and water
• 5% dextrose/0.9% saline and water
• 10% dextrose/0.9% saline and water
• Ringer’s solution
• Lactated Ringer’s solution
• Half strength lactated Ringer’s/5% dextrose
• Ringer’s solutions/5% dextrose
• Lactated Ringer’s solution/5% dextrose

Typical Collapsible Bag

Based on local market requirements the following solutions may be considered

Potassium Chloride and Dextrose in similar mixtures to saline and dextrose
Potassium Chloride with Ringer’s or lactated Ringer’s
Multi vitamins in Dextrose or saline
Electrolytes

Additional Product Lines

Additional products include specialty solutions commonly required in specialty/tertiary care facilities or in advanced stages of disease, including cardioplegic solutions for heart surgery, medical-grade water solutions for burn victim treatment, and peritoneal dialysates for the care of advanced kidney disease. Other uses include treating infantile diarrhea, malaria and dengue fever.

These higher profit margin products take advantage of the regional production capability of and are unique to the IVPC facility. The profit potential outperforms that of the primary product line and, while these markets require cultivation and development within local areas, the early engagement of these markets provides the means to expand production facilities and profit margins at little risk.

Product Material Requirements

Product materials are procured within the local economy, if available, and if they meet USFDA standards. The principal raw materials required for the production of IV solutions are the following:

1. Potable water

2. Pharmaceutical grade chemicals

3. Plastic/container fittings

4. Package finishing

• label material to be printed on location
• cardboard shipping containers

Costs Per Unit

The major expense are plastic, electricity, labor ,the raw materials and water. The depreciation on the equipment, loan payments and taxes vary and must be included into the final unit cost..

Utility Requirements

Water

Plan on 1,200,000 liters of water for each 1,000,000 liters produced.

Electricity

The electric power requirements for overall operations at full annual plant capacity is approximately 226,000 kWh. The blow-fill-seal machine is the major consumer of electric power. In regions where electricity supply is questionable or unreliable, diesel or gas generators could be installed as part of the facility for continuous and uninterrupted operation of the production equipment. As part of the initial site investigation, SBT will prepare a site survey report and analysis of power resources to determine the need and cost of alternate power source supply.

Telecommunications

A reliable telephone system for regional communication is necessary. Internet access is required since it provides a direct link to SBT support systems, including data computer systems support.

Environmental Considerations

The production of IV solutions is an "ultra-clean" industry and poses no environmental threat whatsoever. The production and disposal of waste involves both liquid and solid wastes, none of which rises to the level of "industrial" waste.

Solid Waste

Solid waste from the IVPC facility is minimal, comprising mostly scrap from material packing cartons and accumulated amounts of raw materials from the production process. These wastes are mostly biodegradable and may be recycled, landfilled or incinerated. Since no PVC material is used the waste products can be incinerated without the release of dioxin into the air. It is strongly suggested that consideration be given to “regrinding” any plastic wastes and either reusing them or selling them to other manufacturers in the area.

Liquid Waste

Wastewater generated from the facility is less concentrated and dangerous than standard sanitary waste. The low concentrations of sugars and salts in the IV solutions results in low concentrations of these chemicals in the wastewater. Sugars and salts are also biological products, and in such low concentrations, are less detrimental to the environment than municipal sanitary waste.

Air Quality

There is negligible impact on air quality from the exhaust hoods used in the cleanroom manufacturing process. Where local electricity supply is not reliable, fumes generated by diesel combustion or gas-fired generators, if required, are minimal.

Market

Although the U.S. market comprises almost 70% of the total world market for IV solutions, the market in emerging nations is growing much faster, and presents a tremendous opportunity for the SBT IVPC facility. This growth is due to the building of better and higher quality health care institutions and other health care infrastructures in areas once deemed dormant.

World market growth is driven by population increases and constant up scaling and sophistication of health care delivery. As part of this up-scaling, IV infusion therapy is becoming increasingly important in overall health care treatment regimens as new developments in antibiotics and other medications used in areas such as chemotherapy, burn centers, and renal/peritoneal dialysis centers favor intravenous use and application.

Many countries continue to rely on imported product, up to 40% of the solutions were imported in 1999, which is often too expensive for the general population to afford. Frequently, where product is made locally, the quality is poor and inconsistent, and the costs are still high. In addition, the lack of inexpensive and readily available supplies of IV solutions in many developing nations has lead to a high incidence of death from nonmortal injuries and nonterminal diseases. The SBT IVPC provides an immediate, safe and relatively low cost remedy to this situation. Since both US and International Standards, for IV solutions are met with this plant the export to surrounding countries.

Personnel Requirements

Often one of the most expensive budgetary items for a business is personnel, the extreme efficiency of the SBT IVPC design provides for significant cost savings in this area. There needs to be one machine operator per shift, who has good mechanical skills. This person can run up to 5 machines. Support personnel to move products from the BFS machine to the autoclave and on to the final packaging line is no more then 4 per BFS machine. The boxing the products is 2 people and moving the product into the warehouse is an additional person. This requirement is per shift.

A pharmacist or chemist is needed to perform the quality assurance testing.

All staff are thoroughly trained by SBT on the use, maintenance and operation of the production equipment. Training occurs at the facility before production starts and continues for a set period of time after production startup.

Additional office staff, managers and other support personnel are to be determined by the owner/operator.

Economic Profile

The economic advantages of producing International quality IV solutions can result in an extremely short return on initial investment. Profitability can be established at only 30% to 35% production capacity.

• Direct production costs using U.S. cost figures are 45% - 65% lower than current market pricing for USFDA quality primary product lines. Under the U.S. calculation, direct and indirect labor costs comprise the largest single cost element. In emerging nations, where the cost of labor is much less and the cost of high quality IV solutions often is much higher, the actual production cost figures can be 60% - 90% lower than the current market pricing of imported solutions.
• Secondary product lines with significantly higher profit margins can be introduced at any time to greatly enhance profitability.
• Long distance shipping costs are not incurred with the regional target market creating significant savings on distribution costs.
• Demand for IV solutions is so great that should production exceed local demand, opportunities for national and export sales are unlimited in the foreseeable future.
• Local labor is trained in the technology and employed by the facility. The efficiency of the technology allows for a small staff of personnel to maintain rated production capacity.

In general, IVPC facility variable production costs (direct labor, supplies, utilities, etc.) are similar to those of competitors, while overhead and fixed costs (management and administrative salaries, rent, distribution, marketing, and amortization) are considerably less. Substantial savings alone are realized in the area of transportation and distribution.

For additional information contact SBT at info@sbttech.com