Avoiding HPAPI Contamination
By Olindo Lazzaro, Director, Global EHS Technical Operations & Max Brescia, Global Drug Product Account Director at AbbVie
Drug products are typically formulated of several components, the most significant of which is the active pharmaceutical ingredient (API). According to the FDA definition, the intended function of an API is to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or function of the body1.
Efficacious at much lower doses than APIs, high potency active pharmaceutical ingredients (HPAPI) represent a rapidly growing market, driven mainly by their utility within cancer treatment and efficacy as antibody drug conjugates (ADC). However, along with high potency, HPAPIs often exhibit high cytotoxicity, therefore efforts to prevent cross-contamination are essential to a safe manufacturing process which guarantees the wellbeing of employees, the environment and the patient.
Strict regulations regarding the manufacture of HPAPIs require that pharmaceutical companies and contract manufacturing organizations (CMO) carefully select equipment, outline processes and deploy appropriate containment strategies. With extensive expertise in HPAPI manufacturing, scientists at AbbVie Contract Manufacturing, a division of AbbVie, adhere to stringent guidelines to ensure that safety remains of paramount importance.
What are high potency active pharmaceutical ingredients (HPAPI)?
The definition of an HPAPI has not yet been standardized, however an API that is considered highly potent can be placed into one of the following four categories2:
- A pharmacologically active ingredient or intermediate with biological activity at approximately 150 μg/kg of body weight or below in humans (therapeutic daily dose at or below 10 mg)
- An active pharmaceutical ingredient or intermediate with an occupational exposure limit (OEL) at or below 10 μg/m3 of air as an 8-h time-weighted average
- A pharmacologically active ingredient or intermediate with high selectivity (i.e., ability to bind to specific receptors or inhibit specific enzymes) and/or with the potential to cause cancer, mutations, developmental effects, or reproductive toxicity at low doses
- Or, by default, a novel compound of unknown potency and toxicity
To minimize the risks associated with manufacturing and handling these substances, it is vital that procedures are put in place to mitigate any hazards.
Engineering controls within HPAPI manufacturing
Inadequate containment of HPAPIs and the various materials involved in their manufacture can endanger employees and the environment, as well as decreasing product yields or causing cross-contamination of the drug product. By applying rigorous engineering controls within the manufacturing process and implementing standards to guide the selection of equipment, technologies and procedures, high-quality HPAPIs can be produced to exacting specifications without adverse effects.
At AbbVie Contract Manufacturing, the implementation of engineering controls requires firstly that the exposure potential be determined. Following this, a containment band is identified and used to select a containment strategy. Next, a suitable manufacturing process is determined, with due consideration given to factors which include material handling, choice of equipment, environmental protection and GMP requirements. With extensive expertise in the manufacture of HPAPIs, AbbVie scientists can provide clear guidance through each stage of this process to minimize risk while reducing cost and shortening timelines.
Determine the exposure potential
To identify the exposure potential (EP) incurred during manufacture of an HPAPI, factors including the quantity of material to be handled, the percentage of this that is active (i.e. the relative proportions of the HPAPI and any excipient components), the dustiness of the material, and the task duration should all be considered.
For example, the rapid production of small (g) or medium (kg) quantities of a substance with low dust potential, such as a tablet, would be associated with a low exposure potential. In contrast, the exposure potential of an extended production process resulting in large (ton) quantities of a powder would be high.
Identify the containment strategy
Once the exposure potential has been assessed, the Performance Based Level of Exposure Control (PBLEC) band should be identified, since this will be used to determine the containment strategy. A categorization system used to classify chemical hazards and risks, PBLEC banding is designed to control employee occupational exposure and establish residual cleaning limits for equipment used in manufacturing.
Historically consisting of four categories, with a value of four representing the highest level of containment, PBLEC banding has recently been re-evaluated by AbbVie Occupational Toxicology and Environmental Health and Safety (EHS) to accommodate the increasing potency of AbbVie’s chemical library. The addition of a fifth band for compounds with a potency of <0.01 mg/day and high potential for severe toxicity allows for alignment of the banding thresholds closer to numerical limits for similar agents that have sufficient in vitro, animal and/or human data to support using health-based criteria to establish the formal employee exposure limit (EEL) and patient residual dose level (RDL).
Select a control approach
Following identification of the PBLEC band, a containment strategy can be chosen. Ranging from level 1, the least restrictive, through to level 5, which includes the use of glovebox isolators with rapid transit ports (RTP) and closed/dust tight systems with closed transfer, the purpose of the containment strategy is to minimize any occupational and patient risks related to the chemicals used in manufacturing the HPAPI.
Step 3 - Select Control Approach
Containment Strategy 1
- Open Transfer
- General ventilation, consider LEV
Containment Strategy 2
- Limited open handling allowable for low dust generating operations
- Use specifically designed and engineered LEV and/or certified enclosure at dust generating points and for high dust generating operations
- Emphasis is placed on closed material transfer through direct connections
Containment Strategy 3
- No Open Transfers outside of certified enclosures (e.g. downflow booth, VBE, hoods)
- Dust-tight connections with specifically designed and engineered LEV
- Directional Airflow
- WIP or CIP included with process operations
- Flexible Containment should be considered (e.g. continuous liners, Hicoflex® bags)
- Split butterfly valve should be considered
Containment Strategy 4
- No Open handling
- Processes in general should be closed and where potential risk of breach is present, the equipment should be placed within a directional airflow enclosure
- Directional airflow with additional powder containment technology is allowed
- Transfers are Closed and utilizing high containment technologies for make/break connections (e.g. SBV, Hicoflex®, continuous liners)
- Split butterfly valve with extraction
- WIP or CIP included with process operations
- Open handling within an isolator is allowed in this strategy
Containment Strategy 5
- No open handling
- Processes should be Closed and handled within an isolator, when possible
- Split butterfly valve with liquid rinse, standalone or with dust extraction within enclosure
- WIP or CIP included with process operations
LEV - ; WIP – wash in place; CIP – clean in place; RTP – rapid transit port; VBE - ; SBV -
Verification of the chosen containment strategy with AbbVie EHS personnel is required prior to selection of the equipment and technologies that will be used for manufacturing, however it should be noted that a reduction in respiratory personal protective equipment cannot be assumed until all occupational hygiene exposure assessment studies have been completed.
Decide on the manufacturing process
There are a multitude of factors to consider when selecting an HPAPI manufacturing process. Not only should each step of the overall procedure be subjected to a risk-based approach as previously described, but the characteristics of the materials or compounds involved and the nature of the equipment that will be used should also be thoroughly reviewed. Environmental considerations and GMP requirements should also be given due thought.
- The process
A key point to consider when deciding on the manufacturing process for an HPAPI is the type of handling that will be necessary. This includes a thorough evaluation of the quantity of material that will be handled, as well as the number of transfer steps which will be involved. It is also important to determine whether handling will be direct or indirect, or limited versus repeated. By designing processes which restrict the amount of handling and the number of transfer points to the lowest levels possible, operator exposure is minimized.
Further considerations include product sampling requirements such as size, quantity, location and container type, in addition to any limitations of the receiving laboratory. HPAPI manufacturers should also anticipate and account for any in-process adjustments such as tooling changeovers, equipment malfunctions, inspections, or line clearances.
- The materials
The physical characteristics of an HPAPI and the materials involved in its manufacture can have a significant impact on its risk of affecting the operator and the environment. For example, a granular, dense compound that is prone to clumping may be much easier to contain than a compound that is light and fluffy.
Another factor that should be considered is the form of the compound - whether liquid, solid, vapor or gas. Particulate size, adhesion and viscosity are also of note since nanomaterials, high adhesion compounds and dusty materials are notoriously difficult to contain. Other chemical characteristics which require evaluation include flammability, combustibility, reactivity and explosivity.
- The equipment
Considerations regarding equipment for HPAPI manufacturing are many and varied. Standardization of valves and containers, and compatibility with upstream and downstream processing can contribute significantly to the selection of a suitable containment strategy, while equipment cleaning and maintenance should also be assessed.
For cleaning purposes, decisions should be made regarding whether a process is dedicated or not, which cleaning materials will be used for deactivation, and the types of cleaning methods that will be employed. While clean-in-place methods rely on automatic procedures which require no manual intervention, wash-in-place techniques necessitate some manual involvement. Ergonomics is yet another factor to consider, with accessibility, the capacity to make any necessary equipment adjustments, and the ease of equipment cleaning and maintenance all requiring evaluation.
- Environmental considerations
Environmental control of HPAPI manufacturing processes is essential to safety, as well as being critical to the production of a high-quality compound. By using data generated from environmental risk assessments and studies of predicted no-effect concentrations (PNEC), strategies can be put in place for controlling factors such as atmospheric emissions, effluent treatment and waste disposal.
To prevent particle release into the atmosphere, it may be necessary to implement cleanroom systems, fogging showers, or dedicated, security access-controlled laboratories, or to incorporate high efficiency particulate air (HEPA) filters into work areas. Waste water may require containment until concentrations and the potential for environmental impact have been evaluated. The cost implications of holding large volumes can be offset by adhering to processes that minimize the generation of effluent. Solid waste may also necessitate containment prior to disposal, yet while hazardous waste is typically sent for incineration, any waste deemed non-hazardous should be subject to rigorous monitoring before leaving the manufacturing site.
Thought should also be applied to green manufacturing processes, since the pharmaceutical industry has a key role to play in tackling global environmental challenges. To ensure effective environmental stewardship, many of AbbVie’s sites have achieved ISO 50001, ISO 14001 or EMAS certifications, while one of the company’s goals is to maintain site effluents at ten-fold below PNEC.
With a commitment to operational monitoring to ensure that use and disposal of the company’s products do not adversely affect human health or the environment, AbbVie supports continuing research in order to further understand issues surrounding pharmaceuticals in the environment (PIE). This guides efforts to minimize the potential for environmental impact, and is achieved by:
- Completion and submission of environmental risk assessments to regulatory authorities which are used to evaluate potential environmental risks associated with patient use of medications
- Completion of environmental effect (toxicology) studies to allow calculation of predicted no-effect concentrations (PNECs) for APIs
- Evaluation of the potential environmental risks of pharmaceuticals currently in development or exempted from environmental assessments by regulatory agencies
- Partnering with industry organizations such as the Pharmaceutical Research and Manufacturers of America (PhRMA) and the European Federation of Pharmaceutical Industries and Associations (EFPIA) in order to improve methods to identify and quantify environmental risks
- Avoidance of direct disposal of excess or expired pharmaceuticals in wastewater treatment and to landfill
- Identification of water-quality control technology to limit the Predict Environmental Concentration (PEC) in the vicinity of the manufacturing facilities, implementation of effective segregation of concentrated streams and, where needed, state–of-the-art design of specific waste water treatment
- Monitoring of manufacturing site effluents, implementation of appropriate control mechanisms, and utilization of best in class technologies to manage and reduce API concentrations in effluents and air emissions
AbbVie aims that by 2025 the concentration of company APIs does not exceed the PNEC in the receiving water bodies and is tenfold below the PNEC for APIs with potential environmental risk. A further intention is for company facilities to achieve zero pharmaceutical waste to landfill.
- GMP requirements
Good manufacturing practice (GMP) ensures that HPAPIs meet designated requirements for quality and purity, as well as providing guidance for manufacture under an appropriate quality management system. Including activities that range from receipt of materials, production, packaging, re-packaging, labelling, re-labelling, quality control, release, storage, distribution and cleaning, GMP minimizes the risks involved in HPAPI production3, 4. AbbVie’s contract manufacturing facilities are run under current good manufacturing practice (cGMP) regulations to produce HPAPIs that are safe, effective and demonstrate batch-to-batch consistency.
AbbVie for HPAPI manufacturing
Although some major pharmaceutical companies have the capacity to perform HPAPI manufacturing in-house, it can be wise to partner with a knowledgeable and experienced CMO for this important stage of a drug’s life cycle. This reduces costs and timelines, and ensures the safety of employees, the environment and the patient.
While the expense of manufacturing rises substantially with requirements for specialized facilities, additional PPE, medical surveillance for workers, pollution controls and specialized housekeeping, a CMO will already have equipment and procedures in place. Furthermore, having successfully accomplished HPAPI manufacturing previously, a CMO can offer a well-established platform employing robust systems throughout the entire HPAPI handling program to thoroughly minimize risk.
Contact AbbVie Contract Manufacturing (www.abbviecontractmfg.com) to discuss the manufacture of your high potency API. With an outstanding track record of quality and safety compliance, we manufacture many of the HPAPIs within our own pipeline as well as delivering successful manufacturing projects for third parties. We also offer wide-ranging expertise in biologics manufacturing, cold chain, and packaging.