odern research labs and production facilities may look a little bit claustrophobic as they are often segregated in closed box, the so-called isolators, in order to keep workers out of the contact with high potency active pharmaceutical ingredient (HPAPI). Workers themselves may look like Ebola’s doctors, as they are completely dressed with protective suits and masks. Glove boxes and ports are the only possibility to access the production compartments. Isolators represent the last frontier in the application of risk containment to pharmaceutical production as a safety measure (figure 1).
High potency active ingredients are a market segment showing a strong growth at the global level (+10% per year), being many new medicines anti-tumoral and anti-proliferative agents. The regulatory framework is rapidly evolving and increasingly asks for great attention toward the integration of GMP, quality and safety procedures.
The need to avoid cross-contamination between different medicinal products, one of which may be based on an HPAPI, is another driver force toward the adoption of containment measures.
Typical high potency active ingredients are hormones or cytostatic drugs: they may have a carcinogenic or mutagenic effect or cause genetic mutations if handled in relatively high quantities without suitable protection.
Each production phase has to be carefully evaluated as for its related risk; initial planning of production facilities should take into consideration all the measures needed to remove this risk. The analysis not limited just to the production plant, but it may concern also the warehouse management, cleaning processes and the maintenance of the equipment.
Guia Bertuzzi, member of the Board of ISPE Italia (the Italian affiliate of the International society of pharmaceutical engineering) and product manager at IMA Active, tells about latest trends in risk containment.
The level of containment
As we said, careful planning of all operations is the first step toward a good containment’s strategy. «The needed level of containment should be decided right from the beginning of the planning, in order to avoid too radical measures that may result inconvenient for workers to operate», tells Bertuzzi.
To help the decision, the containment’s pyramid graphically resumes the different levels of danger to be used for risk analysis (figure 2). These have to be correlated to time exposure and operative layout. The occupational exposure level (OEL) is the parameter upon which the decision is taken: an OEL value minor or equal to 10 mg/m3 calls for the implementation of more rigid risk containment measures.
OEL is just one among several different parameters available as international standards in order to measure and classify the toxicity of the active ingredients and of other chemical substances. Operational exposure limit usually refers to inhalation exposure and it is used as an indication of the maximal concentration of the substance in the air at working places that allows no risks for the health. OEL levels change for oral or parenteral exposure. Exposition time is calculated on the basis of eight hours per day (40/h per week) over the entire life span. International guidelines do not indicate a precise requisite as for exposure levels during production.
«There are several tables of operational exposure levels available, prepared by different international institutions. The limit of exposure may differ according to the layout of the production. – tells Guia Bertuzzi – Production plant companies prefer to use the occupational exposure band (OEB), as in its definition the toxicity of the pure substance is considered. This is a useful information to start risk analysis and to select procedures and plants that are the more suited for the specific case».
What needs to be contained
The working environment is the sum of the room, the equipment and the people working in it. «According to regulatory guidelines, it is necessary to adopt suitable protections for the working space and the equipment, in order to facilitate as far as possible the free movements of the workers – adds Bertuzzi (see also box 1). – Starting from an OEB level of 3, protective measures have to be directly applied on the machines: they start to look different. The planning is aimed to keep separated the process area and the technical area containing the auxiliary apparatus needed to run the machines. Manual operations should be limited as far as possible. Glove ports and isolation barriers are used if it is necessary to allow access for the operator. High level of automatic control is also put in place. Cleaning systems are also completely automatized. Absolute air filtration is used to manage air movements between the external and interior of the isolator, a procedure that is involved at various degrees with all operations on powdered high potency ingredients».
Air flow control
Air flow is one of the more critical points that need to be considered in risk analysis. The bigger the scale of the operation, the greater is the quantity of air involved, thus requiring more stringent safety measures. The solution more widely used is the filtration of suspended particles using absolute filters, a highly complex technique to be put in place. «A pressing machine, for example, moves a very small quantity of air as the pill is created: a simple aspiration system, with a limited filtering surface, is enough. Fluid belt machines, used for powder granulation and drying, are the more difficult to be managed, as they work with thousands of air cubic meters each hour. The air that could have become in contact with the HPAPI needs to be filtered before it can be eliminated. These filters have a surface of hundreds of thousands of square meters and they too need to be handled under containment», explains Bertuzzi.
The monitoring of the efficacy of containment is possible thanks to detection devices located close to critical points of the equipment or on the workers’ dressing.
Unknown toxicity substances
New substances coming from the research labs often have a still incomplete toxicity profile. It is thus more difficult to establish definitive levels of exposure to be used for risk analysis. According to Guia Bertuzzi, there are two opposite behaviours to face this issue: «Big multinational companies can invest great sums for the production facilities: they ask for the maximal containment. Other companies, often working at preliminary R&D on small quantities of substance (max 1 Kilogram) and without 24H production needs, consider the risk level to be lower, as time exposure is shorter. There are still some manual operations difficult to make safe as for the equipment is concerned: the choice is thus to protect the workers with an appropriate dressing».
The risk analysis
The attention of pharma industry toward the adoption of containment measures has increased in parallel to the increasing regulatory requirements. «A first phase, some years ago, saw an initial rush: any solution was suitable regardless to the type of the production. Many companies invested a lot of money without reaching the goal, time and costs of production also increased. A later phase saw a greater attention to risk analysis and a better planning of the containment strategy», further explains ISPE Italia representative.
In the production of solid pharmaceutical products, for example, the critical steps are the manipulation of the pure active ingredient and the mixing phase coming before the definition of the final pharmaceutical form. «Steps where the manipulation of the active ingredient is higher or it takes a longer time are the more critical ones, as well as weighting procedures. For small quantities, the operation is completely segregated inside the isolator. Completely automated weighing machines are available for bigger quantities. The risk level progressively decreases as the active ingredient is diluted upon mixing with the excipients», tells the expert.
Simple solutions are also available, as for example disposable flexible isolators; they get wet and are discharged at the end of the production. «This type of solution is suitable for production facilities already in place, that were not built in order to facilitate containment of the product», adds Bertuzzi.
The so-called make-a-batch is a theoretical simulation of the entire production process that can help running a good risk analysis. (box 2) The simulation considers in deep detail each single step of the process, even the more “forgettable” ones, in order to better value their potential impact.
The Standardized Measurement of Equipment Particulate Containment guideline (SMEPAC) may help in the periodic monitoring of the efficacy of the containment measures adopted.
The type of production may also condition the modalities of containment, as Guia Bertuzzi tells: «There is no need for separation of production areas if the plant is fully dedicated just to one product; there is a greater tolerance also for the flows of materials and workers. In the case of a multi-product plant, there is need to consider the risk of cross-contamination: working environment should be partitioned in different areas, one for each process. Cleaning, too, becomes a critical operation to pay a great attention to».
A new containment-based production plant has to be validated using the standard validation procedures. There is still a debate open on the reliability of containment measures, after validation and over a long period of time. «Two are the key elements of a production chain, not only valid for the pharmaceutical industry. In my opinion, the future challenge shall combine high standard levels for production, plant’s flexibility and cost containment. An approach more aware toward containment is now available. The multi-disciplinar risk analysis asks for the participation of all internal functions, and even of suppliers of equipment and materials. Technical solutions are thus the most appropriate ones without being overestimated», remarks Bertuzzi.
Personal protection equipment
Personal protection equipment is used to reduce the risk to enter in contact with dangerous substances. Personal protection equipment shall be used each time it is impossible to avoid the risk, or to reduce it, using preventive technical measures, collective protection equipment or different modalities of work organisation.
Production and risk analysis
The Baseline® Guide: Risk-Based Manufacture of Pharmaceutical Products (Risk-MaPP) has been released by ISPE; it is based on the provisions of the ICH Q9 Quality Risk Management. The guideline helps in the management of the cross-contamination risk, so to reach a good compromise between product quality and safety for workers. (source ISPE)