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Safety in API Manufacturing
The pharmaceutical companies around the world manufacture medicines that cure, and save, and protect the human lives on this planet and at the same time, the manufacturing of medicines itself involves risks that undergoing or causing hurt, injury, or loss, especially, the manufacturing of Active Pharmaceutical Ingredients (API). The author delves into details of hazards & risks posed and the safety measures that should be taken during the manufacturing of APIs.

As we all know that the definition of safety is "The condition of being safe from undergoing or causing hurt, injury, or loss." Thus, pharmaceutical companies have to set controls for safe working and take into account the human and financial cost of accidents. There is a duty of care to all employees, contractors and visitors.

The Scientific Background of Manufacturing API
In a very broader way, an API may be a Synthetic or natural material. Manufacturing synthetic API involves more hazards to Health, safety and Environment in comparison to the manufacturing of natural API which also do involve hazards like bio-hazards but the former is more critical with respect to safety and this article details safety in synthetic API manufacturing. In synthetic API manufacturing, all are chemicals and it involves fire, blast, hazardous wastes, and emission poisonous and non-poisonous gases which forces a very safe environment and good safety practices.

Safety Hazards
The most significant occupational health and safety hazards occur during the Dr Sivakumar Chief Scientific Officer (CSO) Enaltec Labs operational phase of API industry primarily include the following:

• Thermal Hazards Heat The use of large volumes of pressurised steam and hot water are with compounding operations presenting potential for burns due to exposure to steam or direct contact with hot surfaces as well as heat exhaustion. Recommended management practices includes insulation, labeling and regular inspection of steam and thermal fluid pipelines, design of steam vents, pressure release valves away from areas where workers have access.

• Chemical Hazards Exposure to Chemicals
The risks of occupational exposure to chemicals in manufacturing activities are potentially complex. Among the most common types of chemicals and exposure routes is the inhalation of Volatile Organic Compounds (VOCs) from recovery, isolation, and extraction activities; from handling of wet cakes in drying operations; and from fugitive emissions for leaking pumps, valves, and manifold stations (eg, during extraction and purification steps). In API manufacturing, employees may be exposed to airborne dusts during the handling of the product as well as during the processing of various stages like dispensing, drying, milling, and mixing operations. A potential inhalation exposure to chemical emissions during routine plant operations is also a risk where the employee inhales the product at an unacceptable range.
The use of Personal Protective Equipments (PPE) like, nose masks, hand gloves, gas detections systems and alarms, and well segregated and designated work areas for various activities which includes unidirectional air flow systems, HVAC (Heating Ventilation and Air Conditioning Systems, and Forced Vapour Exhaust) systems. The use of gravity charging from enclosed containers by vacuum, pressure, and pumping systems during charging and discharging operations minimise fugitive emissions and mitigates the exposure to staff. Though there are well equipped systems, awareness on safety is very important and it should be impacted by regular training procedures which involves the reading of MSDS (Material Safety Data Sheet).

• Fire and Explosions API manufacturing involves use of pyrophoric reagents like Organolithiums, such as n-Butyl lithium; Organomagnesiums (Grignard reagents); Metallic hydrides, such as sodium hydride, potassium hydride, lithium aluminum hydride and some boranes. Pyrophoric reagents are extremely reactive to oxygen and moisture, and precautions must always be taken to prevent their exposure to air, which usually leads to spontaneous ignition.
A trained and knowledgeable team only can avoid fire and explosions in an API manufacturing facility. For example, an employee should know what the chemical he is handling, whether it is flammable and what if it catches fire. In such cases, the concerned staff performing such operation should involve the safety guards and experts.

• Process Safety
Process safety programmes which explains complex chemical reactions, use of hazardous materials (eg, toxic and reactive materials, and flammable or explosive compounds) and multistep reactions should be in place and trained at defined intervals will create awareness on the safety.
Physical safety can be managed by appropriate preventive maintenance and mechanical integrity of the processing equipments and utilities.
The use of hazardous chemicals, nevertheless is unavoidable in the API manufacturing, the companies should perform and risk assessment, training programmes, and should create awareness on the properties of various chemicals, reactions and an emergency plan to safeguard themselves in an emergency situation.

• Laboratory Safety
As testing of the products is a integral part of the manufacturing, there are potential safety issues involved in the testing of active pharmaceutical ingredients which involves the use of various chemicals and its disposal. The use of various chemicals in a variety of qualitative and quantitative analysis produces majorly spillages as it emits gases and effervescence. The microbiological testing involves the use of various microorganisms also needs to be disposed in a manner that it is killed completely before disposal. Otherwise, it creates chance of infection and contamination in the laboratory. The use of PPE, water showers near the laboratory can aid in minimising and controlling the safety hazards that arises from the laboratory. The microbiology lab should have adequate air controls, sterilisation aids/equipments, and safety cabinets mitigate the risk of infection and contamination.

The Law
Companies are legally bound to create safe and healthy working conditions, good safety practices and buildings.
• The Employer is responsible for the health and safety of the workforce (staff and contractors), guests and the general public who may come into contact with the workplace, its products and the local environment.
• Employees are responsible for their own health and safety and that of their colleagues. Major points of the law are covered by the Health and Safety at Work Act 1974.

The Regulations and Compliance
As there is a risk to human life in the manufacturing of API, there are a number of rules and regulations laid down by the Indian Government as well as international organisation of standards like ISO. The first and foremost of all is that the API factory should be constructed and maintained as per the Factory Act of India and the compliance for the same is surveyed by Factory Inspectors. The ISO 14000 family addresses various aspects of environmental management. It provides practical tools for companies and organisations looking to identify and control their environmental impact and constantly improve their environmental performance. ISO 14001:2004 and ISO 14004:2004 focus on environmental management systems.
The other standards in the family focus on specific environmental aspects such as life cycle analysis, communication and auditing. Apart from ISO 14001, every state has a pollution control board which seeks Consent-to-Operate various hazardous chemicals and their effluents and is being monitored regularly by the concerned authorities.
ISO 18001, the OHSAS specification is applicable to any organisation and it establishes an OH&S management system to eliminate or minimise risk to employees and other interested parties who may be exposed to OH&S risks associated with its activities.
• Assure itself of its conformance with its stated OH&S policy
• Demonstrate such conformance to others
• Implement, maintain and continually improve an OH&S management system
• Make a self-determination and declaration of conformance with this OHSAS specification.
• Seek certification/registration of its OH&S management system by an external organisation

On the other hand, international organisations like US EPA (Environmental Protection Agency of United States), EEA (European Environmental Agency) also emphasise on the various environment, health and safety aspects of the pharmaceutical companies.

Risk Assessments
Pharmaceuticals are a business that uses practical science as a basis to most of its work especially the synthetic API manufacturing companies. Almost every day very dangerous chemicals are used, whilst on the other hand radioactive substances and biological hazards such as bacteria and viruses are of concern in radioactive active pharmaceutical ingredient manufactures and biological API manufacturers respectively.
A formal risk assessment program involves risk identification, risk evaluation, risk mitigation, risk control, corrective and preventive action. The risk is identified as low, moderate and high and further evaluation is done according to the risk category.

It is clear that the use of hazardous chemicals in indispensable in the manufacturing of active pharmaceuticals especially of synthetic origin. On the other hand, natural active ingredients like plant extracts and animal tissues possess a different kind of biological hazard. While working on the safety aspects, a concept called Green chemistry, also known as sustainable chemistry, is a philosophy of chemical research and engineering that encourages the design of products and processes that minimise the use and generation of hazardous substances which reduces the thermal, fire and explosive hazards.
The use of water instead of organic solvents for chemical reaction and employing solid state chemistry as an alternate of chemical synthesis in organic solvents minimise the chemical effluent and avoids the generation of hazardous substances in the process of manufacturing pharmaceutical substance. These concepts are majorly playing role in the risk mitigation and creating more safe working environments. Therefore, safety in the manufacturing of active pharmaceutical ingredient is an integral part of the manufacturing activity and it should be equally treated as that of the quality concerns.