Expert Article: Considering the Safety of Medicines from Concept to the End User
For pharmaceutical and medical device manufacturers, ensuring safety at every stage is not only a regulatory requirement but also a critical factor in maintaining product quality, brand reputation, and business continuity.
Cormica partner with clients across the product lifecycle, offering end-to-end testing solutions that encompass analytical chemistry, microbiology, and physical testing. With GMP, GLP, and ISO 17025 accreditations and facilities across the UK, EU, and US, we provide global regulatory support and expert guidance to help our clients develop, validate, and release safe, effective products with confidence.
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Michael Arthur
Michael Arthur is QEHS / Quality Assurance Lead at Cormica's Wickham Micro laboratory in Gosport, UK.
Introduction: Ensuring Safety Across the Product Lifecycle
The safety of medicines and the people around it must be considered paramount throughout the supply chain, from the concept to the end user. During drug development, many models are used to identify modes of action for the Active Pharmaceutical Ingredients (APIs) and the impact that those and the other components may have on the end user. Will the API or medical device target only the intended organ, system, or microorganism (the final product), or will it have a wider effect upon the body of the end user. We must also consider what the component materials may do to those who come into contact with those producing or handling the final product before reaching the end user.
Identifying Hazards During Development and Manufacture
Some components may have deleterious effects on the people handling the product either in their raw form (e.g., corrosive, or toxic properties of the chemicals, or risks of damage from physical properties such as sharp edges), or these risks may take form from the processing of the materials during the manufacture (combining materials to make active compounds, or the creation of physical hazards during the shaping or manipulation processes). Sometimes the development of the product must be stopped at the research and development stage due to the perceived risks, but at other times, the perceived benefits are sufficient to outweigh those risks and development will continue. Development of the product will proceed through physical, chemical, and microbiological analysis to confirm or deny suitability while simultaneously, the manufacturers will be looking into the processes required for the manufacture.
Use of Equipment and Process Controls in Manufacturing
For the manufacture of the product, it may be that the companies involved are able to use complete off the shelf (COTS) equipment such as blenders, micronizers, or CNC lathes and milling machines. If this is the case this will lessen the risk to personnel involved with the manufacture of the product due to many of the risks associated with the equipment having been evaluated, with appropriate controls already built into the systems. The systems that may be in place include, but are not limited to emergency shutdown buttons, restricted access barrier systems (RABS), remote operating systems or full automation, which should reduce the risk to personnel as far as practicable. One of the few pitfalls of the manufacturing process though is that it involves the most dangerous creature on earth. PEOPLE, who will be discussed in more detail further on. If the manufacturer needs a novel manufacturing system, they will be required to include all of the control systems into the plans from the start and will possibly be required to adapt the designs throughout the use as new risks become apparent such as new guard systems where risk of unrestricted access is discovered or exposure of the product to the environment and / or personnel.
Managing Product Transfer and Environmental Exposure Risks
Even if the manufacturer is able to use a COTS system, there will be a need to be a system for moving the product between manufacturing stages. The movement may be contained within a carrier system such as a conveyor or pump system or may involve using an intermediate bulk container (IBC). Whichever system is chosen, the manufacturer must consider the exposure of the product to personnel or the environment as the risks can go both ways. Exposure of the product to the environment or personnel could introduce contaminants such as viable or non-viable particulates, moisture, or temperatures outside the requisite levels. Contamination of the product can then lead to spoilage through degradation or render it unsafe for the end user due to the presence of bacteria, moulds, yeasts, fungi, deleterious chemicals or damaging foreign bodies. Exposing the product to personnel or the environment can similarly cause deleterious consequences to them. Many chemicals can be found that are harmful to the environment, damaging plants, water courses, or animals. Such chemicals actively used in medicines may include hydrochloric acid, which is commonly used to control and adjust pH levels, or penicillin, used to make medicines such ampicillin or amoxicillin (both very commonly prescribed for infections), which can cause sensitivity over prolonged exposure and anaphylaxis on exposure to the wrong person.
Scaling Up: From R&D to Live Trials
Once given approval to begin live trials, many of the machines or processes may need to be scaled up, bringing increased hazards such as using greater volumes of hazardous chemicals, moving greater volumes of intermediate product between manufacturing processes, and using larger, more powerful machinery. As a result of this, the hazard controls must be scaled up or even entirely rethought.
The Role of Animal Testing in Early Trials
Some of the first live trial stages involve the use of animals. Although this is heavily campaigned against, it is a necessary process to find out what effect the product will have against living tissue, which cannot be accurately mapped in a normal laboratory. There may be additional interactions of the chemical with the body, amplified by the presence of hormones, and chemicals naturally released by living creatures under stimulation (exercise, stress, pleasure), or similarly there may be inhibition of the API by those hormones or chemicals, which could not have been predicted by chemical or in-vitro testing. Laboratory testing also cannot always determine the maximum safe amount to take before the product does more harm than good. It may also be possible to identify whether the product has any addictive properties which again may risk the end user due to the people hazard to be discussed shortly.
First-in-Human Trials and the Complexity of Human Behaviour
When it is determined safe to progress trials, small numbers of people are selected to undergo stage one human trials. It is possible for the in-vivo laboratories to control and map the environments and oral intake of the animals that are used for the testing, however humans present the people problem. People can actively choose to take risks. No other sentient creature on earth would actively choose to partake in activities that have the opportunity to kill them, from forcing open the bars on a rollercoaster seat while the ride is in motion or riding a motorbike at excessive speeds in the rain, in high traffic areas, right down to activities such as simply drinking energy drinks with all of the various stimulants and chemicals in them (caffeine is lethal if you have concentrations of as little as 80µg/mL of blood, which can be achieved by ingesting approximately 10 grams). Individuals may also react differently to the product depending upon how they have developed, or due to the lifestyle choices that have been made previously.
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Assessing Safety, Effectiveness and Post-Trial Monitoring
After the stage one trials have completed, the activity of the product and any complications are reviewed to determine whether it is safe or suitable to continue with trials. Does it work sufficiently on enough people? Does it cause serious complications to the people using it? Does it have lasting effects, good or bad? Sometimes the product may leave the end user with no energy, an inability to talk or even swallow, and bed bound being pumped with food and water through an intravenous drip, but if it is for a short time while the drug destroys the carcinoma, without killing the user, the decision will probably be made to progress with trials and put plans together for rehabilitation of the user once they have finished the course of treatment. Further trials will continue to gather data via pharmacovigilance to develop the leaflet that goes into the packaging. Each and every stage of the trials and each event for the trial user has to be monitored, recorded, evaluated and then reported to demonstrate that the product is as safe as it possible to be for the user.
Ongoing Vigilance: Post-Approval Safety and Contamination Risks
Even after the product has been approved for release to market, safety for the personnel manufacturing it and the end user must remain a priority. All equipment must be cleaned serviced and maintained to ensure that it is producing the product consistently in the same way, without causing contamination or damage to the manufacturing equipment may lead to contamination of the product by bacteria or particulates gaining entry to the product. Parts of the equipment may shave off, depositing anything from microscopic to clearly visible particulates into the product. Damaged or degraded seals may allow the influx of oil, for example. All of these may not be visible during final inspection or analysis but often have a deleterious effect on the product and / or the user. Should moving parts of the machinery or the electronics used to power them become exposed, this can cause serious or even fatal injuries to the personnel operating the equipment.
Managing Product Transfer and Environmental Exposure Risks
If the product is able to undergo terminal sterilisation, the presence of viable contaminants, although still needing to be controlled, is not as critical as for products that are unable to be sterilised after manufacture. The reason some products may be unable to be terminally sterilised can be varied but often comes down to three primary reasons: degradation, inactivation or not being viable for the product (prohibitively expensive or too unsafe).
Terminal sterilisation methods include the use of dry heat, moist heat, membrane filtration or ionising irradiation. The heat methods may partially or fully degrade sensitive APIs, and moisture from wet heat sterilisation can react with compounds, altering concentrations of the API in solution or initiating the degradation of dry powders (which are reconstituted at the point of use and then have a shortened shelf life). Membrane filtration is only possible for products that are fully soluble, therefore solid, dry powder or gelatinous/viscous products would be retained along with any of the viable particulates that the manufacturer is trying to remove. The last method, sterilisation by Gamma-radiation, requires dedicated facilities to contain the radiation-emitting substance, which may significantly change biomechanical properties of products, alter physio-chemical properties or, through the degradation of the viable organism, lead to toxic by-products such as bacterial endotoxins. With sterilisation by irradiation, other significant controls are required to be followed to control the release of emissions, which, dependent upon the facility, may include COMAH regulations 2015 R3(2b).
Due to the inability to terminally sterilise some products, aseptic manufacture must be used, with environmental monitoring performed throughout production and with minimal intervention into the production line to prevent contamination of the product. Additional precautions are required for the manufacturing area, which include, but are in no way limited to, full gowning of the personnel to prevent exposure of skin and clothing to the environment, full sanitisation of the manufacturing environment using agents such as Hydrogen Peroxide Vapor prior to the initiation of the batch manufacture, and physical separation of the personnel from the production line by isolation. The raw material is required to be tested for microbiological and chemical quality before use and then, as with all products, the intermediate and final product as well.