Keywords: Containment; Engineering; Pharmaceutical Manufacturing; Risk Assessment
Key Takeaways:
- In the event of conflicting criteria, personnel safety must always take precedence over GMP requirements.
- The most appropriate containment solution for each facility should be based on a holistic assessment.
Specific Characteristics of Highly Potent Substances
Highly potent substances, or HPAPIs, are pharmaceutical ingredients that exert a biological or therapeutic effect at very low doses and may cause significant adverse effects. The definition of an HPAPI varies depending on the literature consulted. WHO [1] and ISPE [2] define potent APIs as substances that pose a substantial risk of harm to human health, other organisms, or the environment, even at very low exposure levels.
Some of the conditions that define an HPAPI based on the substantial risk it poses include the following [3]:
- They exhibit biological activity at approximately 150 μg/kg body weight or less in humans.
- They require a therapeutic daily dose (DDD) of 10 mg or less.
- They have an occupational exposure limit (OEL) of 10 μg/m³ of air or less, based on an 8-hour time-weighted average (TWA).
- They exhibit high selectivity (the ability to bind to specific receptors or inhibit specific enzymes) and/or have the potential, at low doses, to cause cancer, mutations, developmental effects or reproductive toxicity.
- Any novel compound of unknown potency and/or toxicity.
The harmful toxicological effects on health [2] that HPAPIs may cause are related to:
Figure 1. Hazard pictograms
Source: Prepared by the authors
The relationship between the specific potency and toxicity values of the substances [4] establishes a risk gradient associated with each substance:
Figure 2. Risk matrix associated with a substance
Source: Prepared by the authors
Additionally, substances may present other hazards associated with their physical properties (explosivity, flammability, corrosivity, etc.) or with the risks they pose to the environment.
Given the wide variety of HPAPIs and their associated hazards and effects, these substances need to be categorized in order to assign an appropriate risk level and define suitable containment solutions. This is particularly important because both the economic impact and the operational complexity of the plant can vary significantly depending on the technical solution selected.
Global Overview of Pharmaceutical Manufacturing with HPAPIs
The importance of highly potent substances in the pharmaceutical market continues to grow year after year. The increasing focus on more targeted and personalized treatments is driving the development and use of highly potent substances that require only very small quantities to achieve therapeutic effects.
Currently, approximately one quarter of pharmaceutical manufacturing involves products containing HPAPIs [5]. Likewise, around one quarter of new drugs are HPAPI-based formulations [6], while 60% of drugs currently in development incorporate these substances [5].
Figure 3. Share of HPAPIs in global pharmaceutical production
Source: Prepared by the authors based on data from [5] and [6]
When looking at current pharmaceutical manufacturing involving highly potent substances, most HPAPIs are produced through chemical synthesis, although a significant proportion are of biotechnological origin [7]. Most HPAPI-containing formulations are intended for oncology treatments, followed by hormonal therapies [6]. In terms of dosage forms, HPAPI-containing medicines are predominantly solids (capsules, tablets, and granules), followed by liquids/injectables, with semisolids and other dosage forms representing only a small proportion [8].
Figure 4. HPAPI types and production breakdown
Source: Prepared by the authors based on data from [6], [7] and [8]
Risk Assessment Methodology
Containment risk assessment can be approached using a variety of methodologies. One approach follows principles similar to those established by ICH [9] for quality risk management in pharmaceutical products. These principles were subsequently adapted by ISPE for its Risk-MaPP methodology [10] and later incorporated into its containment guidance [2]:
Figure 5. Containment risk assessment methodology
Source: ISPE [2]
The risk associated with an operation is linked to the hazard posed by the substance being used, as well as the way in which it is handled:
Figure 6. Risk Function
Source: ISPE [2]
To control a risk, the first step is to consider whether the substance causing the hazard can be substituted or eliminated. If this is not possible, technical and operational measures should be implemented to reduce exposure to the hazard, with the aim of reducing the risk to acceptable levels.
Therefore, the first step is to identify both the significant characteristics of the hazardous substances and the details of the process being assessed. The main variables to be collected during the risk identification phase are the physical characteristics of the substances and their exposure limit values, as well as the quantity of substance involved and the significant stages of the process, including their associated durations and the technology used in the operation:
Figure 7. Key Concepts Associated with Risk
Source: Prepared by the authors
Several systems are available for assessing the risks associated with the products and processes involved. Most of these systems are based on establishing categories linked to specific containment measures. One of the most widely used methods for categorizing product risk is the OEB (Occupational Exposure Band) system [2] [11]:
Figure 8. OEB Exposure Bands
Source: ISPE [2]
Following the methodology established by ISPE [2], once the characteristics of the substances are known, they are classified according to their Spread Potential (SP). This value is then combined with the quantity and exposure time to determine the Exposure Potential (EP) involved. The EP is subsequently compared against the assigned Occupational Exposure Band (OEB) in a risk matrix, with the aim of determining the Primary Containment Strategy (PCS). This strategy defines the first level of containment required to protect the operator from the product.
Figure 9. Methodology for Assessing Primary Containment Risk
Source: ISPE [2]
Similarly, the Migration Potential (MP) will be determined by considering the likelihood of residual material from the substance dispersing after cleaning and decontamination, together with the potential quantity that could be dispersed. This value is then assessed in another risk matrix against the assigned Occupational Exposure Band (OEB) to determine the Secondary Containment Strategy (SCS). This strategy defines the second level of containment required to protect the facility from the product.
Figure 10. Methodology for Assessing Secondary Containment Risk
Source: ISPE [2]
The boundary of the secondary containment system defines the perimeter of the containment area.
Figure 11. Primary and Secondary Containment Concepts
Source: Prepared by the authors
The strategy for directly protecting operators within the containment area through the use of personal protective equipment (PPE) will be determined once the quantity of hazardous substance present in the room has been calculated, taking into account the leakage rate of the primary containment equipment, the dilution capacity of the room’s HVAC (Heating, Ventilation and Air Conditioning) system, and the operator’s exposure over the defined period. The objective is to ensure that the applicable exposure limits are not exceeded, including NOEL values, daily/shift exposure limits (OEL, TWA, PDE, HBEL, etc.), and short-term exposure limits (STEL).
Design Process for a High-Containment Facility
Once the risks present in the plant have been identified, assessed, and characterized, the most appropriate solutions for the facility must be defined. The layout should comply both with GMP criteria for pharmaceutical manufacturing areas, aimed at preventing contamination of the product by the surrounding environment, and with occupational health and safety and environmental protection requirements. In the event of a conflict, HSE criteria should always take precedence over GMP requirements, while maintaining the protection of the general population as the highest priority.
Once the containment area has been defined, the first step is to establish the most appropriate pressure regime and airlock configuration to ensure that contaminants cannot escape from the containment area. Negative pressure is therefore maintained in the highest-risk areas, with pressure cascades, bubbles, sinks, or combinations of these established in adjacent airlocks, depending on the required gowning steps and the criticality of the containment strategy to be achieved.
Figure 12. Example of personnel airlock layout for a containment area
Source: Prepared by the authors
With regard to room classifications, all applicable GMP requirements will be complied with, depending on the type of facility and manufacturing process under consideration. Annexes 1 and 2 of the European GMP guidelines for the manufacture of sterile medicinal products and biological medicinal products, respectively [12] [13], are the main reference documents.
Technologies and Equipment Associated with Containment Strategies
Once the primary (PCS) and secondary (SCS) containment strategies identified through the risk assessment have been established, the most appropriate solutions must be defined to ensure the required level of containment for the processes to be carried out. Some of the most commonly used technologies are described below [2][14][15][16][17]:
Figure 13. Primary Containment Strategies and Associated Equipment. References: ISPE [2 y 14], EMA [15] y INSHT [16 y 17]
Sources: ISPE [2] [14] EMA [15] y INSHT [16][17]
Figure 14 – Secondary Containment Strategies and Associated Operational Considerations
Fuentes: ISPE [2] [14] EMA [15] y INSHT [16][17]
The selection of the most appropriate containment solution for each facility should be based on a holistic assessment that considers all the factors involved and the specific characteristics of the process, such as the particular requirements of multiproduct facilities, the desired production intensity, the available budget, the impact on personnel availability and operational flexibility, the level of redundancy defined for critical utilities, etc.
All these factors will influence and determine the selection of certain solutions over others. This selection and elimination process should be carried out by a multidisciplinary working group together with the Client, in order to ensure that the facility’s containment design is fully aligned with the expected operational requirements and capabilities.
Conclusions
The design of pharmaceutical manufacturing facilities handling products that pose a certain level of risk and require containment measures is becoming increasingly standardised, largely due to the growing use of HPAPIs in pharmaceutical formulations.
Only through a systematic risk assessment during the engineering phase, based on reliable data on the substances and formulations involved and tailored to the parameters of the intended manufacturing process, can the containment area and its appropriate treatment be properly determined.
The main objective is to adopt a global approach that takes into account all the operational particularities of the facility, enabling the successful completion of the design process for a high-containment facility with appropriate technical and operational solutions that ensure both the safety of personnel involved in production and the quality of the pharmaceutical products manufactured.
The success of a facility design incorporating containment solutions lies in identifying the precise solution that meets the needs of the process, addressing the safety requirements of this type of facility while also ensuring the economic and operational sustainability of the project.
List of Abbreviations
(listed in order of appearance)
HPAPI: High-Potency Active Pharmaceutical Ingredient
WHO: World Health Organization
ISPE: International Society for Pharmaceutical Engineering
API: Active Pharmaceutical Ingredient
DDD: Defined Daily Dose
OEL: Occupational Exposure Limit
TWA: Time-Weighted Average
ICH: International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
Risk-MaPP: Risk-Based Manufacture of Pharmaceutical Products
STEL: Short-Term Exposure Limit
NOEL: No Observed Effect Level
PDE: Permitted Daily Exposure
HBEL: Health-Based Exposure Limit
OEB: Occupational Exposure Band
SP: Spread Potential
EP: Exposure Potential
PCS: Primary Containment Strategy
MP: Migration Potential
SCS: Secondary Containment Strategy
PPE: Personal Protective Equipment
HVAC: Heating, Ventilation and Air Conditioning
GMP: Good Manufacturing Practices
HSE: Health, Safety and Environment
EMA: European Medicines Agency
LEV: Local Exhaust Ventilation
HEPA: High-Efficiency Particulate Air
RABS: Restricted Access Barrier Systems
Figures
Figure 1. Hazard pictograms
Figure 2. Risk matrix associated with a substance
Figure 3. Share of HPAPIs in global pharmaceutical manufacturing
Figure 4. HPAPI types and manufacturing breakdown
Figure 5. Containment risk assessment methodology
Figure 6. Risk function
Figure 7. Key concepts associated with risk
Figure 8. OEB exposure bands
Figure 9. Primary containment risk assessment methodology
Figure 10. Secondary containment risk assessment methodology
Figure 11. Primary and secondary containment concepts
Figure 12. Example of personnel airlock configuration for a containment area
Figure 13. Primary containment strategies and associated equipment
Figure 14. Secondary containment strategies and associated operational considerations
Sources
- WHO, 2010, “Technical Report Series, No. 957 – Annex 3 WHO good manufacturing practices for pharmaceutical products containing hazardous substances”.
- ISPE, 2022, “Good Practice Guide: Containment for potent compounds”.
- Bormett, D., 2008. “High-potency APIs: Containment and handling issues”. Pharmaceutical Technology Vol 2008 Supplement, Issue 4.
- WHO, 2025, “Globally Harmonized System of classification and labelling of chemicals (GHS)”, Rev. 11.
- Website European Pharmaceutical Manufacturer – Understanding the HPAPI sector
- McCleary, K., 2019 “Manufacturing of highly potent APIs with best-practice safety and containment control procedures”, American Pharmaceutical Review 2019 (September/October):144
- Website Grand View Research – High potency active pharmaceutical ingredients market (2026 – 2033)
- Website Roots analysis – Cytotoxic drugs and HPAPI manufacturing market
- ICH, 2025, “Guideline – Q9 (R1) Quality risk management”, Step 5 – Revision 2.
- ISPE, 2017, “Baseline Guide Vol 7: Risk-based Manufacture of Pharma Products (Risk-MaPP)”, 2nd Ed.
- Lentz, TJ et al., 2019, “NIOSH Technical report – Occupational exposure banding process for chemical risk management”. DHHS (NIOSH) Publication No. 2019-132
- EMA, 2022, “EudraLex vol. 4 – Annex 1 Manufacture of sterile medicinal products”.
- EMA, 2022, “EudraLex vol. 4 – Annex 2 Manufacture of biological active substances and medicinal products for human use”.
- ISPE D/A/CH Affiliate, 2016, “Containment manual”.
- European Commission – Directorate-general for employment, social affairs and inclusion, 2023 “Guidance for the safe management of hazardous medicinal products at work”.
- INSHT, 2008, “Notas Técnicas de prevención – NTP 798 Industria farmacéutica: medidas preventivas de la exposición a principios activos”.
- INSHT, 2018, “Notas Técnicas de prevención – NTP 1105 Industria farmacéutica: medidas para la prevención de la exposición a principios activos”.