Pharmaceuticals hold enormous potential to do good, yet Active Pharmaceutical Ingredients (APIs) are also inherently dangerous and can damage the health of employees and the environment. If a pharmaceutical worker is injured or exposed to a toxic substance, or if a major environmental breach occurs, there will be a cascade of consequences which can extend far beyond the originating event. As well as penalties, there may be impacts on business continuity and reputation, even when harm was caused by an event elsewhere in the supply chain.
Because many of the chemicals involved are unique, regulatory requirements to control worker and environmental exposure to APIs tend to be generic. Without the driving force of regulatory compliance, some Contractor Research or Manufacturing Organisations (CRO/CMO) may not be compelled to fully assess the dangers posed by APIs and may not have the knowledge or resources to deal with API-related risks. This makes it essential to conduct audits and provide support so that API exposure is understood, addressed, and well managed by CRO/CMOs.
This is a complex area in which practices change rapidly, so it is highly recommended that you seek out reputable specialist expertise to help you navigate through the requirements and expectations of local regulations as well as internationally acceptable practice, and that you communicate these requirements and expectations effectively with your suppliers.
Investigating the following questions, with the support of specialists, will position you to help your partners increase their API-related industrial hygiene and safety. It will also give you greater confidence that your partners aren’t putting themselves or you at risk.
What should the API exposure limits be?
One of the main clues as to your partner’s management of industrial hygiene risks is whether they have obtained the appropriate hazard evaluation data.
This should apply not only to the APIs and associated raw materials that they handle, but also the solvents and other chemicals used in the production process. While Material Safety Data Sheets (MSDS) with Occupational Exposure Limits (OELs) are readily available for common chemicals and solvents, OELs for APIs may be less readily available due to limited toxicological data.
It is not uncommon for the industry to use occupational exposure bands (OEBs) for APIs, where conservative, order-of-magnitude ranges of OELs are presented. These OEBs vary between OEB1 (least toxic) and OEB5 (most toxic) and are used to guide the necessary exposure control practices typically required to manage such substances. In any event, a legal limit or guideline (such as an OEL) should never be viewed as a line between ‘safe’ and ‘unsafe’. The best approach is to always keep exposures or the risk of a hazard as low as possible.
How exposed are workers?
Where exposure and process safety risks are high, the facility should consider using closed-loop production processes wherever possible. Restrictions on open handling and/or limitation to the scale of operation could also be used to control the risks.
Each activity – including non-production activities such as cleaning – should be assessed in detail, such that all major hazards can be identified and adequately addressed with appropriate control measures.
What containment plans and controls are in place?
Based on the OELs/OEBs of the substances and the risk of exposure to workers, one should initially consider risk management using the hierarchy of controls. While it may be difficult to use alternative raw starting materials for a product, one should always try to eliminate the use of hazardous solvents or substitute them with less hazardous substances.
Facility design and engineering controls are also critical elements in managing exposure risks. The facility should carefully consider the selection, use and maintenance of appropriate devices and systems as part of a containment strategy that is consistent with the associated OEL/OEB of the chemical being handled.
For example, isolation can be achieved through rigid or flexible isolators, contained powder transferring system, mobile curtains, doors, or negative-pressure airlocks depending on the risk level the chemical may represent. Directional airflow, HVAC recirculation or single-pass operation, exhaust air filtration and safe filter replacement procedures, use of capture devices and overall inspection and maintenance of associated equipment should all be considered in an effective containment strategy.
Furthermore, administrative controls such as a robust staff training, exposure monitoring and a medical surveillance program will help the factory and its workers correctly implement the strategy and monitor the effectiveness of the occupational hygiene program. Last, but not least, personal protective equipment (PPE) must be appropriately used and maintained.
Although implementation of the higher-level hierarchical controls is clearly preferable, such changes are generally more disruptive in the short term and are likely to be more costly compared with the lower-level hierarchical controls. Therefore, it may be necessary to prioritize improvement works based on the severity of the risks and develop a practical corrective action plan leading to a sustainable outcome.
What systems and procedures are in place?
In demonstrating the applicability of the control measures used in managing exposure risks, the facility should ideally have performed risk assessments for the specific worker activities and implemented the necessary control measures and work procedures (where required) to reduce risks to acceptable levels.
Besides knowledge of the specific OELs/OEBs of APIs, it is very important to measure actual worker exposure concentrations of the APIs for compliance. This is generally easier said than done however, as measurement of API exposure concentrations are very rarely a regulatory requirement, and analytical testing of APIs can often be limited to a small pool of specialty laboratories charging significantly higher unit prices.
Maintenance and verification of equipment operation specification (such as fume-hoods and local exhaust ventilators) are also rarely performed to validate adequacy of exposure control. Such checks and measurements should be made periodically to support safe operations.
Where training as part of regulatory requirements for local health and safety professionals is considered inadequate, suppliers may seek additional forms of training from reputable organizations, such as those provided under the Occupational Hygiene Training Association framework.
Are your partners just complying with regulations/standards?
In many jurisdictions, especially in developing countries where a large proportion of the world’s pharmaceutical manufacturing activities are taking place, local regulatory compliance typically is not sufficiently detailed to safely manage specialty chemicals. Therefore, the appetite for improved industrial hygiene at your supplier’s facility may be limited. If immediate improvements cannot be achieved, continuous dialogue to develop longer term goals with interim progress milestones may be a more effective step towards a sustainable business partnership.
In the quest to rapidly discover, develop, produce, and distribute increasingly advanced diagnostic tests and sophisticated medications, we can’t afford to risk workers’ health. Industrial hygiene, worker safety and responsible management of APIs must be prioritized at all stages of the supply chain for a safe and sustainable pharmaceutical industry.
