Manufacturing High-Potency Drugs Using Isolators

Isotechniques, or techniques of adjacent volumes, are a processing method for pharmaceutical preparations containing high-potency active pharmaceutical ingredients (APIs) (e.g., cytostatics, hormones, and antibiotics) in absolute secure conditions to ensure the safety of the operator and the quality of the finished product. Manufacturing using isotechniques takes place in isolators.

Isotechniques offer certain advantages for aseptic production of injectable, high-potency drugs. In the sanitized areas of cleanrooms, the operator brings in contamination in a limited manner. A completely biodecontaminated environment exists inside the isolator, where only the drug and material for manufacturing come in direct contact with the processing system. In such operative circumstances, contamination by microbes is more limited than in cleanroom conditions because the absence of direct human intervention allows for better cleaning and complete biodecontamination of the entire working environment. Complete biodecontamination with vaporized hydrogen peroxide of the working area inside isolators allows for operation in a biodecontaminated environment. Cleanrooms, however, are exclusively sanitized and operate under conditions of controlled contamination.

A biodecontaminated environment

The automatic cycle of biodecontamination guarantees the reproducibility of the process. Manual disinfection is a time-consuming activity that may not be consistently performed and is dangerous because of the continuous exposure of operators to sanitizing agents. Biodecontaminating agents such as vaporized hydrogen peroxide achieve sterilization by the dispersion of gas. The gas can reach all surfaces exposed to its contact, even the hidden ones. Its products are oxygen and water, which are harmless. Isotechniques also exceed the onerous barrier created by the modality of clothing and microbiological control. The US Food and Drug Administration has expressed a favorable opinion for increasing the use of isotechniques for drug production in asepsis, especially for the production of high-potency APIs.

Isolators for high-potency drugs

Some aspects to consider when using isolators while processing injectable, high-potency drugs are:

• Containment of contamination, particularly airborne contamination

• Individual protection of personnel

• Management of cross-contamination

• Aseptic processing and sterility of handled material and product

• Efficiency of biodecontamination cycles

• Efficiency of barriers and their integrity

• Management of the environmental impact as a result of the process (i.e., refluent, industrial waste, liquids, gas, and air).

A practical demonstration of the productions of liquids or lyophilized injectables in glass vials is shown in Figure 1. The operating line is set up by several isolators partly connected in a row, where all manufacturing operations are done. These operations are: weighing of raw materials, their volatilization in tanks, transfer of the solution to the dosage systems, washing and depyrogenation of vials, filling of vials, capping (complete if liquid; partially, if liquids are to lyophilize), eventual freeze-drying, sealing, external washing, and drying of filled and sealed vials.

Figure 1: Production flow for liquids in vials. (ALL FIGURES AND IMAGES ARE COURTESY OF THE AUTHOR.)

The process is made in a production line with isolators. The following are phases of the main production process:

• Phase I: Preparation of the distribution circuit (distributor, needles, and tubes)

• Phase II: Preparation of isolators (cleaning and biodecontamination)

• Phase III: Preparation of various materials (vials, stoppers, and seals)

• Phase IV: Preparation of the solution and its filtration.

Phase II is typically for a production process using isotechniques. Phase IV is strongly affected by the kind of API (i.e., high-potency) used in the solution preparation, and this aspect considerably changes the manipulation modalities of the API.

Risks in high-potency manufacturing

The use of a production line for manufacturing injectable, high-potency drugs in asepsis has risks. It is important to determine the risk levels of the critical aspects of the processing. The principal areas that should be taken into consideration when evaluating risk areas and modalities to control are as follows:

• Management of chemical contamination

• Management of cross-contamination

• Management of aseptic processing

• Management of the environmental impact

• Comparison of different aseptic techniques used in manufacturing high-potency drugs.

Isolators are an up-to-date and suitable solution for manufacturing injectable high-potency drugs as they guarantee elevated risk control. Isolators have two unique features that make them suited to this type of manufacturing: containment of contamination, particularly airborne contamination, and protection of personnel. These features avoid dispersion of high active material to the environment and guarantee the protection of operators to exposure from these materials.

Isolators (ALL FIGURES AND IMAGES ARE COURTESY OF THE AUTHOR.)

Management of chemical contamination

The intermediate phases of the production process do not pose significant risk because the liquid product is confined inside the isolators or the distributor system (tanks, transfer tubes, and needles). From a containment perspective, it is much easier to manage liquid solutions than powder because of the following:

• Liquids have more limited characteristics of dispersion and diffusion

• Solutions are significantly more diluted than an active principle in powder

• The principal risks to diffuse contamination are tied to dispersion in air and are present when liquids are in an aerosol phase.

The risky points of the production process are:

• Preparation of the solution (i.e., the handling of high-active powders)

• Product vials (i.e., the potential that a solution drops on the surface of sealed vials or vials break inside the freeze-dryer)

• Washing of soiled process components (e.g., tanks, tubes, needles, and the freeze-dryer)

• Transfer of various materials potentially contaminated on their surface.

The approaches to mitigate risk in each of these areas are detailed below.

Preparation of the solution. Adoption of isolators that operate with negative-pressure conditions and the integrity control of the isolators, particularly the gloves, shield operators from exposure to powders. The direct transfer of the powders to the predissolution tank, integrated in the isolator, avoids any risk of environmental dispersion. The cleaning of the closed isolator and the gathering of washing water in such a tank guarantee that the product of manufacturing remains confined, in liquid form, inside the tank. The periodical substitution of the filters, mainly exhaust ones, is executed by a trained staff, which is aware of the risks, and through a system of high containment (i.e., bag-in/bag-out).

Product vials. The last phase of the production process involves the external washing and drying of the sealed vials, which eliminate eventual traces of contamination by the product solution. The unloading of the vials from the freeze-dryer is another extremely risky point for the operators' exposure to the powder because the product is turning to its solid state. Because of the high incidence of vials breaking in the freeze-dryer, this phase is conducted within isolators both during loading and unloading. These operations further use an automatic system (i.e., pusher) and an adequate condition of loading (i.e., "pizza door"), which noticeably reduce human intervention during the process and favor the maintenance of aseptic conditions.

Washing of soiled process components. The cleaning procedures are mainly handled automatically. Where manual intervention is necessary, however, gloves are used. All manual washing activities are conducted on soiled solution components and never on powder ones.

Transfer of various materials. Because of previous handling (e.g., the supplier's container that holds the API, the container holding the API that is returned from production to the warehouse, and samples of material), all materials potentially contaminated by traces of high-active powders on their surfaces are handled with protective gloves and individual protective equipment such as masks and glasses. As a precautionary measure, all containers are wrapped in new plastic covers that collect traces of powder and avoid dispersion into the environment. All critical manipulations are performed under the safety hood or inside the isolators by trained personnel who are aware of and trained to control the risk.

Management of cross-contamination

Processing schemes help to individualize and graphically identify the main areas of risk for cross-contamination and the related precautions that need to be taken. Adopting dedicated components is the principal precaution needed to avoid cross-contamination.

During solution preparation, gloves, containers, equipment for pouring, transfer tubes, and filters are dedicated to the product, which limits common use to only the tanks. This dedication reduces to a minimum the cleaning-validation studies that show the absence of cross-contamination between different products. The use of disposable tanks completely eliminates the risk of cross-contamination, which allows related studies to be avoided.

During the repartition phase of the solution, gloves, transfer tubes, distributors, connections, filters and needles are completely dedicated to the product. The adoption of push systems for the liquids such as peristaltic pumps with harmless gas or with pressure through harmless gas mitigates the risk of cross-contamination in all production steps where these push systems are used (e.g., from tank to tank or from tank to needles).

During post-lyophilization, cross-contamination has to be evaluated by studies that verify the efficiency of automatic processing of cleaning in place.

Management of aseptic processing

Aseptic processing and sterility assurance is essential when producing injectable drugs with isolators. This process is connected with the efficiency of the biodecontamination cycles of isolators and barriers and their integrity. The risky points for the sterility assurance are as follows:

• Sterilization of material in contact with solution to fill

• Sterilization (i.e., biodecontamination) of areas with Class ISO 5, degree 100 preservation of aseptic conditions and integrity of the interested areas

• All manufacturing phases where the possibility of contact between sterilized material and classified areas of Class ISO 8, degree 100,000 exists.

The precautions needed to guarantee against these risks in aseptic processing are detailed below.

Sterilization of material in contact with the solution to fill. All materials in contact are sterilized with clean steam and protected with adequate wrappings. At the end of the biocontamination process, it must be ensured that the concentration of the oxidant agent should be less than 1 ppm in the environment and the same environment (under the isolators) needs to be maintained for the entire duration of the production and in overpressure with respect to the surrounding area. The solution to fill is filtered at 0.2 µm, collected, and transferred to sterile surfaces.

Biodecontamination of areas with degree 100 maintenance of aseptic conditions and integrity of interested areas. Isolators are comparable to a classified degree 100 area with the difference of having smaller volumes liable to total biodecontamination with vaporized hydrogen peroxide. At the end of the biodecontamination process, the concentration of the oxidant agents should be less than 1 ppm in the environment, and the same environment (under the isolators) needs to be maintained for the entire duration of the production and in overpressure with respect to the surrounding area. The preliminary cleaning made inside the isolators serves not only to remove residuals but also controls the microbic contamination of the environment before biodecontamination. The framework of the isolators is essentially made of steel and windows of glass. The only critical point for the maintenance of the integrity is represented by the gloves used to operate inside the box. Therefore, the main control is verifying the integrity of the gloves before and after their use. The sterility of the freeze-dryer is granted through automatic sterilization cycles in place and through the running of the structural integrity test for the chamber made by vacuum done at the end of each cycle.

All production phases where the possibility of contact between sterilized material and classified areas with degree 100,000 exists. Various sterilized material protected by wrappings is transferred to the autoclave. Because the area of the isolators is classified degree 100,000 the wrapping may potentially be contaminated. Biodecontamination of the surface of the wrappings inside the isolators necessitates that all material inside the isolators and all surfaces are appropriated. The sterilized stoppers are transferred by the isolator to the loading hopper made of stainless steel endowed with a a/ valve that protects the stoppers and in general the content of the hopper from the area with degree 100,000 and allows the stoppering phase in the capping section of the filling line.

Management of environmental impact

When manufacturing high-potency drugs, managing the environmental impact of the process (i.e., refluent, industrial waste, liquids, gas, and air) is important. Critical points in managing environmental impact are:

• Collecting and treating the water used to wash the components that come in contact with the product, and the external surfaces of the final containers (i.e., vials) that may be potentially contaminated by the product and the freeze-dryer

• Treating circulating air in rooms and chambers. potentially contaminated (isolators).

The principal precautions that should be made to manage these risks are outlined below.

Collecting and treating the used water. Water from washing processes that may be polluted are channeled and collected in a single system. The waters, gathered in a storage tank, are submitted to a concentration process through distillation (see Figure 2). The distilled water has to be tested and validated by high-performance liquid chromatography for the absence of active principles. The water is sent to the sewer system while the concentrate is subject to the elimination of special waste. The concentration of refluent can be substituted or supported with a chemical demolition process of the active principle through the use of oxidizing or denaturizing agents.

Figure 2: The concentration of a refluent-scheme of the system. (ALL FIGURES AND IMAGES ARE COURTESY OF THE AUTHOR.)

Treating circulating air. Depending on the phase of the manufacturing process, the surroundings of isolators may be in depression (i.e., when the drug is a powder, but not yet sterile, and is highly dangerous because of its aerosol dispersion) or in overpressure (i.e., when the aseptic processing becomes the most critical element).

The air that is poured into the isolators of degree 100 is subject to absolute filtering. The air taken by isolators is partly expelled in the environment and partly recycled with an input of fresh air from the ambient environment. The amount of air subject to recirculation is treated by filtration using high-efficiency particulate air (HEPA) filters, HEPA filter efficiency classification H13 (i.e., recovery), and afterward by a H13 filter (expulsion). In these isolators, the product can be present only in liquid form and only because of accidental reversal or vials that are not well closed. Therefore, the aerosol contamination is near to zero.

In case of isolator compounding, the exhaust air is treated by a H14 filter (i.e., HEPA filter efficiency classification H14). The retaken one is a totally recycled previous filtration by a H14 filter with the use of a further intermediate H13 filter.

Pros and cons of aseptic techniques

Particular attention should be given to the different aseptic techniques used in manufacturing high-potency drugs. Containment and guarantee of sterility constitute the principal technical elements in evaluating isotechniques. Isotechniques offer the possibility of working with solvent products and inflammables and to render the working place inert.

Economic considerations. Taking into account economic considerations, traditional cleanrooms require lower investment than isolators, but cleanrooms do not guarantee the same sterility assurance level as the isolators. Cleanrooms are especially tied to extensive monitoring of microbiological contamination and particles, the dressing and its control, the extended surfaces to condition, the extensive use of cleaning agents, and the disinfection of the environment.

Although isotechniques require high installation costs, they guarantee elevated asepsis, a higher level of containment, and lower operating costs. Figure 3 compares the different features of traditional cleanrooms, restricted access barrier systems, and isolators.

Figure 3: Comparison of cleanrooms, restricted access barrier systems, and isolators. (ALL FIGURES AND IMAGES ARE COURTESY OF THE AUTHOR.)

Regulatory considerations. The opinions expressed by the US Food and Drug Administration and the European Medicines Agency regarding isolators have an important role in the above comparison of isolators and cleanrooms (1–7). FDA mentions isolators 55 times in its latest guideline of manufacturing in asepsis (1). This guideline (1) states:

A well-designed positive pressure isolator, supported by adequate procedures for its maintenance, monitoring, and controls, offers tangible advantages over traditional aseptic processing, including fewer opportunities for microbial contamination during processing.

Moreover, FDA acknowledges removal of operators in critical areas may have the effect of increasing the asepsis conditions. It states in the guidance (1):

In contrast, a process conducted in an isolator ... can have a low risk of contamination because of the lack of direct human intervention and can be simulated with a lower number of units as a proportion of the overall operation.

Richard Friedman, director of the Division of Manufacturing and Product Quality of the Office of Compliance at FDA's Center for Drug Evaluation, recently affirmed that he would not use cleanrooms for a new pharmaceutical facility. This position is in line with the positive trend of using isolators, especially for manufacturing high-active drugs.

The incentive of using innovative technologies when producing drugs, in this case isolators, is consistent with the philosophy expressed by FDA in its report, Pharmaceutical CGMPs for the 21st Century—A Risk-Based Approach (2).

EMEA is less explicit than FDA in expressing its opinion on the most appropriate technology of aseptic production, especially of high-potency drugs. FDA was the first regulatory authority identifying isolators in its guidance in 2004 (1).

There are more isotechniques used in Europe than in the United States. The growing number of pharmaceutical facilities using isolator technology approved by EMEA in Europe seems to indicate a favorable point of view of the European regulatory authorities to isolator technology.

A trend analysis shows an increasing number of facilities using isolator technology. In 1998, 84 facilities provided aseptic filling in isolators. This number increased to 174 facilities in 2000, 201 in 2002, and to 258 facilities in 2004 (3).

The growth in the number of facilities offering aseptic processing is related to the growth in high-potency drugs. In 1995, only 5% of APIs were regarded as high-potency, compared with 50% in 2005. There are also higher numbers of high-potency pharmaceuticals coming off patent between 2010 and 2011. Also, there is an increase of high active principles as a result of reduction in dosages.

Conclusion

Isolators are the sole future of high-potency drug processing in the pharmaceutical industry. Isolators represent the only existing technology that guarantees the best protection for operators and the high sterility-assurance level of injectable products. The fully isolated system provides total containment for all material handling with the highest capital costs offset by lower operating cost.

Use of isolators has grown with the correspondent increase in the discovery and use of high-potency drugs. The industry is understanding the advantages of isolators even if regulations do not officially require their use. The isolator will be the only technology allowed by regulatory authorities for manufacturing high- potency drugs under safe conditions. The advantages offered by isolators compared with traditional cleanrooms is pushing the industry to choose isolator technology for future investments in high-potency manufacturing (1–10).

Maurizio Battistini is a general manager and the qualified person with Abraxis BioScience, via Cadepiano, 24–6917, Lugano Barbengo, Switzerland, tel. +41 91 9852640, Fax +41 91 9852641, MaurizioBattistini@abraxisbio.ch.

Note: A "qualified person" is a designation in European pharmaceutical regulations (Article, 51 EU Directive 2001/83/EC for Medicinal Products for Human Use).

References

1. FDA, Guidance for Industry—Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practice Appendix 1: Aseptic Processing Isolators (Rockville, MD), Sept. 2004, available at www.fda.gov/CbER/gdlns/steraseptic.pdf, accessed Oct. 13, 2008.

2. FDA, Pharmaceutical CGMPS for the 21st Century—A Risk-based Approach (Rockville, MD), available at www.fda.gov/Cder/gmp2004/GMP_finalreport2004.htm, accessed Oct. 13, 2008.

3. J. Lysford and M. Porter, "Barrier Isolation History and Trends," presented at the International Society for Pharmaceutical Engineering Washington Conference: Barrier Isolation Technology, Washington DC, June 2004.

4. ISO, ISO 14644-7 Cleanrooms and Associated Controlled Environments: Part Z: Separative Devices (Clean Air Hoods, Gloveboxes, Isolators and Mini Environments) (Geneva, Switzerland) Oct. 2004.

5. PDA, Technical Report No. 34 Design and Validation Of Isolator System for Manufacturing and Testing of Health Care Products, June 2001.

6. PIC/S, PI 014-1: Recommendation—Isolator Used for Aseptic Processing and Sterility Testing (Geneva, Switzerland), June 2002.

7. EUDRA, EU GMP: Eudra I: Medicinal Products for Human and Veterinary Use: Good Manufacturing Practices Vol. 4, Annex 1, p. 66.

8. "FDA Q&A on Barrier Isolation—The FDA Answers Your Questions on Barrier Isolator Technology," Pharm. Eng. 27 (2), 2007.

9. L. Francis, "Containment Considerations for Toxic and Potent Aseptic Liquid Filling," Pharm. Eng. 27 (3), 2007.

10. J. Agalloco, J. Akers, and R. Madsen, "Choosing Technologies for Aseptic Filling: Back to the Future, Forward to the Past, Pharm. Eng, 27 (1), 2007.

For a comparison of conventional cleanrooms, restricted access barrier systems, and isolators, see the online exclusive, "A Comparison of Conventional Cleanrooms, Restricted Access Barrier Systems and Isolators".