The pharmaceutical industry is an important component of health care systems throughout the world; it is comprised of many public and private organizations that discover, develop, manufacture and market medicines for human and animal health (Gennaro 1990). The pharmaceutical industry is based primarily upon the scientific research and development (R&D) of medicines that prevent or treat diseases and disorders. Drug substances exhibit a wide range of pharmacological activity and toxicological properties (Hardman, Gilman and Limbird 1996; Reynolds 1989). Modern scientific and technological advances are accelerating the discovery and development of innovative pharmaceuticals with improved therapeutic activity and reduced side effects. Molecular biologists, medicinal chemists and pharmacists are improving the benefits of drugs through increased potency and specificity. These advances create new concerns for protecting the health and safety of workers within the pharmaceutical industry (Agius 1989; Naumann et al. 1996; Sargent and Kirk 1988; Teichman, Fallon and Brandt-Rauf 1988).
Many dynamic scientific, social and economic factors affect the pharmaceutical industry. Some pharmaceutical companies operate in both national and multinational markets. Therefore, their activities are subject to legislation, regulation and policies relating to drug development and approval, manufacturing and quality control, marketing and sales (Spilker 1994). Academic, government and industry scientists, practising physicians and pharmacists, as well as the public, influence the pharmaceutical industry. Health care providers (e.g., physicians, dentists, nurses, pharmacists and veterinarians) in hospitals, clinics, pharmacies and private practice may prescribe drugs or recommend how they should be dispensed. Government regulations and health care policies on pharmaceuticals are influenced by the public, advocacy groups and private interests. These complex factors interact to influence the discovery and development, manufacturing, marketing and sales of drugs.
Many countries have specific legal protections for proprietary drugs and manufacturing processes, known as intellectual property rights. In instances when legal protections are limited or do not exist, some companies specialize in manufacturing and marketing generic drugs (Medical Economics Co. 1995). The pharmaceutical industry requires large amounts of capital investment due to the high expenses associated with R&D, regulatory approval, manufacturing, quality assurance and control, marketing and sales (Spilker 1994). Many countries have extensive government regulations affecting the development and approval of drugs for commercial sale. These countries have strict requirements for good manufacturing practices to ensure the integrity of drug manufacturing operations and the quality, safety and efficacy of pharmaceutical products (Gennaro 1990).
International and domestic trade, as well as tax and finance policies and practices, affect how the pharmaceutical industry operates within a country (Swarbick and Boylan 1996). Significant differences exist between developed and developing countries, regarding their needs for pharmaceutical substances. In developing countries, where malnutrition and infectious diseases are prevalent, nutritional supplements, vitamins and anti-infective drugs are most needed. In developed countries, where the diseases associated with ageing and specific ailments are primary health concerns, cardiovascular, central nervous system, gastrointestinal, anti-infective, diabetes and chemotherapy drugs are in the greatest demand.
Human and animal health drugs share similar R&D activities and manufacturing processes; however, they have unique therapeutic benefits and mechanisms for their approval, distribution, marketing and sales (Swarbick and Boylan 1996). Veterinarians administer drugs to control infectious diseases and parasitic organisms in agricultural and companion animals. Vaccines and anti-infective and antiparasitic drugs are commonly used for this purpose. Nutritional supplements, antibiotics and hormones are widely employed by modern agriculture to promote the growth and health of farm animals. The R&D of pharmaceuticals for human and animal health are often allied, due to concurrent needs to control infectious agents and disease.
Aseptic processing in positive pressure cleanrooms utilizing HEPA filters was the norm in the 1980s. The gown, mask, goggles, gloves and booties were the “barrier” between the operators and the product and container critical zone. It has been noted that the faster processing reduces open time and thereby reduces contamination risk. Machines may generate particles but far the most contaminants came from people and that the particles also contained viable microorganisms.
It is a common knowledge that people were still the largest contributor to cleanroom contamination. More people, more movement, more speed and more talking all increased the total generated bioburden. Terminal sterilization is the best when the products can tolerate the process. Products up to this point in time were mainly chemical based and change was coming with more vaccines and the blossoming of the biotech industry, where the products were heat labile and were also growth media for any contamination.
Isolators were used for sterility tests, weighing, blending and transferring but the step of using isolators for fill finish equipment was the last to be considered.
Aseptic filling of sterile drug remains one of the most challenging processes in biopharmaceutical manufacturing. It requires coordination and interaction between personnel, product, equipment and support facilities. At the same time, the formulation of highly potent active pharmaceutical ingredients (HAPIs) is growing due to significant advances in clinical pharmacology and oncology research.
Higher potency APIs have greater effect at a lower concentration than traditional APIs, and the trend towards higher potency is reflected within the biopharmaceutical area too. The increased potency of sterile products requires evaluating the manufacturing process from two different angles: the high containment requirements for operator and environmental safety; and the aseptic process regulations for the protection of the integrity of the finished sterile product.
Following the ISPE Risk-Mapp guidelines, an isolator is defined as a leak-tight enclosure designed to protect operators from hazardous or potent processes, or product processes from people or detrimental external environments, or both.
The level of containment is defined by the manufacturer or consulting agents who will define the occupational exposure limit (OEL) required for specific drug manufacturing. For highly potent compounds, the isolator should ensure an OEL of 1-10 µm/m3 or lower over the sampling period.
A high containment isolator is generally operated under negative pressure to ensure maximum operator and environmental safety. Should the containment envelope be breached, the outside are will be pulled inside avoiding product exposure for the operator.
The negative pressure is typically -100 Pa and must be electronically controlled. For the same reason, the air in the isolator must not exchange with that of the surrounding environment. HEPA filters are used to circulate the room air with a ‘push-push’ system for safe remote change. High containment glove boxes are usually purged with nitrogen for higher safety or for air-sensitive product requirements.
Safety features should be integrated: for example, interlocked doors and windows with safe guard glove ports after start of operation. All levels should be displayed to indicate in real time the status of the isolator (pressure, nitrogen, etc.)
This type of isolator is typically classified as ISO 7 (Class 10,000 at rest, Grade C) and as part of the recommended use, all materials exiting the isolator must be cleaned or contained using rapid transfer ports (RTP) or airlocks.
The entire isolator must be cleanable in a reproducible and quantifiable manner to avoid cross-contamination. Swab tests and tracer substances should be used during qualification. Ergonomics are therefore an important part of the design to allow operators to reach and wipe and every part of the cabinet.
To qualify the containment isolator, a series of tests needs to be performed during the Factory Acceptance Test (FAT) and Installation and Operation Qualifications on site. It is highly recommended to test the OEL level during the FAT, or once installed on site, to verify that it meets the specified design OEL. A third part usually performs all the operations in the isolator using a placebo, allowing airborne particle concentrations on the operator and in the room to be measured to certify that the OEL level has been achieved.
The requirements for the isolators used with aseptic processing differ from the containment isolator technology. They must not exchange air with the surrounding environment, but work under positive pressure. The philosophy here is to protect the product from the outside, which means, that in case of containment breaching, the positive pressure will ‘push’ the cabinet air out to protect the product from the environment, but exposing the operator to the product. The positive pressure is typically of 50 Pa and must be electronically controlled.
Extensive sterilization procedures have to be applied prior to production and nitrogen purge is not required. Air from the room is typically recirculated in the isolator via a HEPA filter. Uni-directional Air Flow (UDAF) circulated the air with a required minimum 0.45 m/s airflow inside the isolator. A uniform and efficient airflow system is critical for a proper aseptic environment.
For Grade A, the airborne particle classification of this of isolator is ISO 4.8, dictated by the limit for particles ≥ 5.0 µm (with minimum sample volume of 1m3 taken per sample location). The design and construction of cleanrooms and controlled environments are covered in ISO 14644. This standard stipulates the total particulate counts required for a clean environment needed to meet the defined air quality classifications.
Instead of strict cleaning procedures and contained transfer of materials, the aseptic isolator must be sterilized in a reproducible manner using vaporized hydrogen peroxide (VHP). All materials that enter the isolator must be sterilized and must enter either directly through a decontaminating or sterilizing system, or via an RTP.
A series of test should also be performed during a Factory Acceptance Test (FAT) and Installation and Operation Qualifications carried out on site. The isolator integrity is verified by leak testing, consisting of several pressure tests, such as the pressure hold test (twice the operating pressure with a loss of less than 0.5% of the total volume of the isolator per hour being acceptable), or glove pressure test, supported by physical and microbial qualifications and trend analysis.
Cleanroom Technology, 2014. Cleanroom Technology: Containment. Retrieved from http://www.powdersystems.com/pdf/pub/CT-Feb2014-Dual-Isolator-Editorial.pdf