Maurizio Battistini is the general manager of APP Pharmaceutical Partners in Switzerland.

Maurizio Battistini

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.   

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.  

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

Containment of contamination, particularly airborne contamination 

Aseptic processing and sterility of handled material and product

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.   

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:  

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.) 

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.  

 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). 

 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.   

 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.    

 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.     

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.  

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 

Articles

The author discusses the key issues to consider when using isolators such as containment, protection of personnel, the efficiency of biodecontamination cycles, sterility assurance levels, barriers and their integrity, and environmental impact.

Manufacturing High-Potency Drugs Using Isolators

The use of isolators has grown with the correspondent increase in the discovery and use of high-potency drugs. Isolators provide 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 costs. The advantages offered by isolators compared with traditional or conventional cleanrooms is pushing the industry to choose isolator technology for future investments in high-potency manufacturing. Outlined below are different features of conventional or traditional cleanrooms, restricted access barrier systems (RABS), and isolators. 

The costs for conventional cleanrooms are well-defined, and costs for engineering and heat, ventilation, and air-systems conditioning systems can be substantial. RABS have higher costs compared with cleanrooms and have more equipment-related costs. Isolators typically have more costs for the principal installation (1). 

The time for qualification for cleanrooms, RABS, and isolators is typically six to nine months. There are no particular problems in qualifying cleanrooms. Qualification of RABS may theoretically avoid some of the issues relating to qualification of isolators. Longer periods for qualifying isolators are reflective of additional requirements rather than technical hurdles (1). 

Operating costs for RABS are higher than those for cleanrooms. Isolators also have higher operating costs than cleanrooms, but there can be cost-savings in gowns, supplies, and environmental monitoring. Isolators, however, may have additional costs for vaporized hydrogen peroxide and the time used for biodecontamination (1). 

Isolators are basically much smaller environments than traditional cleanrooms. The airflow inside an isolator for aseptic production has to be filtered in an absolute manner. The expelled or retaken air inside isolators for containment has to be filtered for dust and airborne aerosols. 

The absence of personnel and consequently the microbiological contamination brought in by those operators suggest that the air speed and scheduled exchanges in an isolator may be lower than in a cleanroom. A minimum of 20 exchanges per hour inside isolators is suggested. 

Thermohygrometric conditions also have to be considered in the impact of biodecontamination and its efficiency. The choice of these parameters inside isolators for aseptic production is influenced by such qualification and by the fact that inside biodecontaminated isolators, there are not conditions that favor the growth of microorganisms on substratum used for production and process control. 

In cleanrooms, there are classified and only-sanitized areas, where the operator intervenes physically, and therefore, in a limited manner brings in contamination. 

A completely biodecontaminated environment exists inside an isolator. Only the drug and the material for manufacturing come in direct contact with the processing system. In such operating conditions, microbial contamination is less than under cleanroom conditions because of the absence of direct human intervention, thereby ensuring higher cleaning and the complete biodecontamination of the whole working environment. In contrast to cleanroom processing, the complete biodecontamination with vaporized hydrogen peroxide for the working area inside isolators creates a biodecontaminated environment. Cleanrooms are exclusively sanitized and therefore have "controlled contamination." 

 is a general manager and the qualified person with Abraxis BioScience, 

Cadepiano, 24–6917, Lugano Barbengo, Switzerland, tel. +41 91 9852640, Fax +41 91 9852641, 

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

1. J. Agalloco, J. Akers, R. Madsen, "Choosing Technologies for Aseptic Filling: Back to the Future, Forward to the Past," 

Manufacturing High-Potentcy Drugs Using Isolators

A comparison of conventional cleanrooms, restricted access barrier systems, and isolators, shows the benefits of using isolators in high-potency drug manufacturing.

Comparison of Conventional Cleanrooms, Restricted Access Barrier Systems, and Isolators

Selecting the right partner is the key factor in every outsourcing relationship. Risk analysis can be the ideal instrument for obtaining preliminary information when evaluating a potential contract service provider and can become an integral part of the sponsor's supply chain. This article describes the main factors in risk analysis when transferring drug-manufacturing activities to a third party. 

When evaluating a potential partner, the following factors should be taken into account: 					

Partner's knowledge, experience, professionalism, and technology

Cost analysis; verification that requirements are met (e.g., regulatory, qualitative, technological, safety and environment, backup, and disaster recovery) 

Clear definition of the critical steps of the process and allocation of responsibilities (e.g., supply and analysis of raw materials, in-process controls, analytical controls on the finished product and release, preservation and shipment of the finished product)

Activities planning and intermediate testing

Formalization of the relationships (e.g., legal supply contract, secrecy agreement, quality agreement)

Collaboration between the customer and the partner during risk analysis allows an integrated and shared evaluation of risks and benefits. The key element of this process is to identify and understand risk and to determine how much investment is needed to reduce each existing risk. 

The acceptance level of risk and the margin of control must be determined. In addition to risk understanding, the main factors are identification, management, and weight-up.  

 Risk analysis is a continuous process that begins with the identification of all risks. During the first phase of analysis, opportunities and threats should be identified (see Figure 1). The probability of each opportunity and threat is determined, as well its their consequences, to assess the effect and benefit of each item.  

 The results of the identification phase determine the level of risk management (see Figure 1). First, one should plan activities by taking into account the availability of various resources (e.g., economic, number of personnel, experience, knowledge). Risk-management planning must be continuously monitored and documented, and a periodic follow-up of the status should be performed. The management-reviewing step can be a learning process because it provides an opportunity for partners to share knowledge and experiences and exchange analytical data. 

				The last phase of the continuous review process—understanding—is the most important because it involves shareholders in the activity, uses the analysis performed in the previous phases, and helps set the boundary conditions of subsequent steps in the process (see Figure 1).			

 An important instrument in risk analysis is the protocol of the preliminary evaluation. To analyze the risk of the suppliers and contract service providers, it is necessary to resort to a predefined instrument, adaptable to the demands of each partner, in which it is possible to include all the activities in the preliminary evaluation. The protocol document should include the following chapters: technical aspects; qualitative aspects (prerequirements); logistical aspects; organizational aspects and communication; vulnerability; safety; and environment. Elaboration of this protocol document is up to the contract provider. The compilation of various questions to be answered is up to the contract acceptor. 

Another important instrument is the inspection audit and the checklist of risk analysis. These documents are prepared by the sponsor, using the evaluation's protocol as a basis. They help the contract service provider verify all the risk elements and their weight. 

The final instrument is the evaluation's report, including the risk's weight-up and the action plan. The final report preparation is submitted to the sponsor. The report's basic chapters are the risk assessment, formulated starting from the compilation of the checklist indicated above, and the remediation and action plan that describes the interventions necessary to reduce the risk factors in the exposed analysis areas. 

				The assessment must differentiate the areas of higher risk (threats) from those that represent chances for improvement (opportunities). The operative tools necessary to identify risk areas are then finally presented to define the value (risk analysis) and to attribute the level of gravity and acceptance for business (risk assessment), the possible need for remedial actions, and the resolution time and responsibilities (action–remediation plan).			

 Risk weight-up considers the effect and probability of threats and opportunities enumerated in the risk identification phase; these can be weighted using the different levels shown in each quadrant in Figure 2. The levels are defined as follows: very high (VH), high (H), medium (M), low (L), and very low (VL). Because the defined levels are five in the ordinate and five in the abscissa of each quadrant, the worst-case risk is associated with the couple VH–VH (5 × 5 = 25). Similarly, the best-case risk is associated with the couple VL–VL (1 × 1 = 1). 

The quadrants are highlighted in colors corresponding to probability and impact-level combination. The yellow areas are where the risk is acceptable for threats and opportunities. The red and pink areas are associated with the unacceptable risk for threats and opportunities. 

For example, if you must transfer an industrial process in an emerging country in which partner knowledge (or experience, 

) may be very low and the cost is very low, then the evaluation of the risk is: 

 threat: impact VH(5) × probability VH(5) = risk 25  

opportunity:impact VL(1) × probability VL(1) = risk 1 

Therefore, there is a big threat to transfer the industrial process, with a very low confidence level and a very big economic opportunity. In this case, management must decide whether the economic opportunity is acceptable while considering the risk associated with the partner's inexperience or whether it is better to partner with another more knowledgeable service provider for an acceptable increase of cost. In this alternative case, the threat risk may be considerably less, and the opportunity could be less interesting. 

Example of a supplier evaluation questionnaire			

Essential elements of a preliminary evaluation protocol

The evaluation of a selected partner may involve several financial and industrial aspects (see sidebar, "Example of a supplier's evaluation questionnaire"). The evaluation should also contain information about the following: 					

Identification of the designated contact person

Company turnover during the past three years and turnover percentage connected to exportation(availability of the company's financial statements)

Number of employees, their turnover and distribution on the basis of the competence areas (e.g., logistics, administration, production, control)

Organization chart, roles, and responsibilities

Analysis of the processes and activities performed internally and externally

Main products and customers and their percentage division 

Problems from natural disasters (earthquakes, typhoons) in the contract manufacturing areas and protective actions

Dimension and layout of the property (covered and open warehouses, production, offices, 

), including their building standards, age, and possibility of expansion

Management of main energy resources (electricity, water, 

Protection of the area against damages and fire

Protection and backup of critical and reserved information

Production organization (e.g., number of shifts)

Costs for developing starting materials into the finished product

Saturation level of the most important systems (free capacity) and their age

Activities automation and information-technology levels 

Existence of management procedures for major good manufacturing practice processes (e.g., review and release of the batches, complaints, market's traceability and recall, deviations, changes, staff education, and training)

Manufacturing management and product control (e.g., written specifications defined for each product and its components, equipment, and critical validated processes; written analytical methods; batch documentation; and functions dedicated to the planning of productive activities and to materials stocks)

Main customers, their qualification, and reliability

Risk management is essential in any successful outsourcing partnership. The author outlines the steps toward identifying, understanding, and controlling risk in key manufacturing areas.