Pharmaceutical production has deeply changed since the last two decades, and highly potent active pharmaceutical ingredients (HPAPIs) play now a increasing central role in the fight against many diseases, i.e. cancer. The flip side of the game is represented by the need to protect workers who handle HPAPIs along the entire life cycle of the drug product manufacturing, from synthesis of the pharmaceutical active ingredient to distribution of the finished medicinal product. A further degree of complexity is represented by the fact that highly toxic substances are often available in the physical form of combustible powders. As explained by Sonia Ricci, past president of Ispe Italy Chapter, «there is need to integrate the good manufacturing practices (GMP) – at the base of quality requests for medicinal products and of their safety and efficacy – with the protection of the workers’ and environmental health, according to applicable laws. Many HPAPIs’ containing drugs are, for example, oncology products. There is an increasing demand of these medicines especially from emerging countries such as India or China, where a great part of the population asks to access advanced therapies made available by research».
The first Manual on HPAPIs’ containment
Based on these considerations, in 2010 the Containment Community of practice (CoP) of the Ispe DACH Chapter (Germany-Austria and Switzerland) started to draft a Containment Manual, the first of its kind at the international level. «We had never thought it would have become an Ispe’s best seller, with more than seven hundred copies sold in one year and a half – tells the coordinator of the initiative, Richard Denk –. The motivation to draft the Manual has been that there was quite nothing available on the topic of containment, and the pipelines of pharmaceutical companies indicated that many highly active products would have entered the market. Together with the Containment Manual, the Ispe Smepac Good practice guide is also available on the measurement of containment and the RiskMaPP guideline on the risk-based manufacturing of medicinal products».The manual explains the basis of containment and risk analysis, to then discuss in deeper detail containment measures along the entire life cycle of the product, as well as those for oral solid dosage forms and for active pharmaceutical ingredients (API). The document gives also an overview of the primary and secondary technical solutions available to contain HPAPIs, on validation procedures for occupational hygiene and for cleaning and waste management. «The Manual offers many useful information that should be included into every user requirements specification (URS)», adds Richard Denk. He also explains how the drafting of the document followed a different procedure than the normal one used by Ispe to develop new guidelines. At the beginning the document was thought for the German market only, thus it was drafted in German without involvement of the Ispe’s Guidance document committee (GDC),that is usually the responsible for the development of the guidelines of the Association. «We followed the procedure in any case, and after finalisation the document was sent to experts from the industry for their revision and comments – tells Denk -. The introduction of the Manual on the German market went very well, thus we have been asked for an English translation just after the publication of the German text. The English version has been sent to the Ispe’s GDC Committee for a revision, but without implementation of the comments we received. This because the English translation had to be identical to the German one already published». The Ispe DACH group coordinator also explains how – after the generally very good comments received by the GDC – the second edition of the Manual should become a true Ispe’s Good practice guide. «The document is now available also in the library of the European Directorate for the Quality of Medicines and Health (EDQM) of the European Council. EDQM is the editor of the European Pharmacopeia and the responsible for the release of the Certificate of Conformity. We are thus very proud of this, because it reflects the importance of the Ispe DACH’s Containment Manual», further tells Denk.
The critical points for a correct containment
The life cycle of a medicinal product is very complex, and there are many issues to be considered to develop containment measures specific for each single case, which have to be based on a preliminary risk assessment. The analysis should always proceed in parallel from three different points of view: the safety of workers, the evaluation of exposure limits and those of the risk of explosion for HPAPIs’ powders. «The base for a correct risk assessment is always the knowledge of the process and of how to manipulate substances that might determine a potential exposure of the operator: only so it is possible to identify really effective protective measures – explains Sonia Ricci, who coordinated Ispe Italy’s working group on the safety of pharmaceutical processes using combustible and highly active powders -.The identification of the strategy for protection and risk control, in particular, requires to consider the quantities of the manipulated substances, the length of exposure and the characteristics of the product, especially the capacity of the substance to disperse into the environment».
Containment measures start from the primary ones, related to the characteristics of the equipment used to manipulate the substance. Secondary containment measures are those related to the characteristics of the buildings (i.e. HVAC systems). «The application of operative procedures (which can be subject to human errors) or the use of DPI (i.e. protective clothing or rebreathers) must always be considered as additional protection measures – never as the only one – because they force to work under difficult conditions», adds the Ispe Italy’s past-president.
The validation of the entire approach
According to the current legislation, the employer is called to demonstrate the efficacy of the chosen containment systems by mean of periodical measurements of the concentration of airborne substances into the environment. «The frequency should be determined by the categorisation defined for the specific risk. The mode for execution of the measurements are defined by the SMEPAC guideline (Standardized measurement of equipment particulate airborne concentration)», Sonia Ricci explains.
The more widely used parameters to determine the exposure risk to HPAPIs for the operators are the occupational exposure limit (OEL) or the occupational exposure band (OEB). OEL’s values depend upon the route of administration of the HPAPI (oral, parenteral or by inhalation) and represents the maximum concentration in air at the working place to which the worker can be exposed during a time interval defined as the work shift (8 hours TWA) or the short term exposure (15 minutes, STEL limit). OEL may vary upon the specific manufacturing situation (including buildings, equipments and workers). OEB is based on the toxicity of the pure substance and classify the highly active ingredient into a specific category (tabella 1) according to its potency and the outcomes for the health of workers. «To determine the hazard of a particular substance some methods refer to the OEL, while others are based on the categorisation of risk phrases. Risk analysis methodologies generally refers to the exposure to the substance by inhalation, and differentiate among solid substances (airborne powders) or in the liquid form (that might generate vapours). Specific methods are available for the risk assessment in case of exposure by contact», explains Ricci.
How to contain the risk
A good risk analysis allows to design the production plant taking into consideration containment systems suitable to provide and adequate level of exposure, lower to the ones known to be dangerous for workers’ health. Containment strategies (i.e general ventilation, localised vacuum systems, manipulation into isolators with open or closed systems) are ranked according to their efficacy level. In the case of multi-product plants, it should be also considered the risk of contamination between different production campaigns, according to the guidelines published by the European medicines agency. «Guidelines ask to run a risk analysis to identify protection measures suitable to provide a certain level of segregation between different productions (if they are run simultaneously) and to provide effective cleaning of the production plant between different batches», further explains Ispe Italy’s representative. In some instances, the containment strategy has to be applied to already existing plants, or it should be evaluated since the first steps of the design of a new one. Pharmaceutical production is continuously evolving, and it might occur to manage changes of production on existing plants which had not been designed to manipulate HPAPIs. «Should this be the case, specific solutions should be considered, also taking into consideration the number of batches per year. The use of single use containment systems is a possible example suitable for already existing plants. The design of a new plant requires to think to flexible solutions to manage future productions», tells the expert. But the first solution to be always considered, also suggests Sonia Ricci, should be the possibility to use a less toxic substance for the process instead of the HPAPI. An alternative to containment might also be represented by a process modification to avoid exposure of workers, for example by use of pre-dosed substances or lower concentrations to minimise the risk. Cleaning of the plant should also be managed appropriately. «A closed process eliminates the risk of exposure to the dangerous substance for workers only when an efficient and automatic cleaning process (CIP) of the plant is put in place at the end of each production batch. It is essential to validate the cleaning process to ensure that the system had been cleaned, to avoid exposure of the operator to traces of dangerous/toxic substances during the following phases of the plant’s maintenance», explains Ricci. The employer is also responsible to inform workers about the risks connected to the manipulation of chemical substances and to provide training on the procedures that should be applied to manage it.
The containment pyramid
|> 100 mg/die||1000-5000 mg/m3||1 – scarcely dangerous|
|10-100 mg/die||100-1000 mg/m3||2 – moderately dangerous|
|1-10 mg/die||10-100 mg/m3||3 – dangerous|
|0,1-1 mg/die||1-10 mg/m3||4 – highly dangerous|
|< 0,1 mg/die||< 1 mg/m3||5 – extremely dangerous|