Introduction to Occupational Health Categorization Systems for Active Pharmaceutical Ingredients

Since the late 1980s, pharmaceutical manufacturers and contract manufacturing organizations (CMOs) have been familiar with occupational health categorization (OHC) systems. As a review, the OHC category assignment for an active pharmaceutical ingredient is determined by its inherent toxicity and potency, and the OHC category assignment is linked to the control band assignment that determines the engineering, administrative, and personal protective equipment needed to ensure safe handling.

While there are many different occupational health categorization schemes in common use, all occupational health categorization systems share a common feature - the higher the OHC band assignment the greater the requirement for rigorous control measures. In many cases, depending upon the risk assessment, active pharmaceutical ingredients with high OHC assignments will require the use of either flexible or rigid isolators to maintain occupational exposures and cross-contamination risks to an acceptable level, and in some cases, certain CMOs may not be able to handle your compound because they don’t have in place the proper controls and facilities.

In all commonly used OHC banding systems, Category 1 represents the least hazardous compounds, while Category 4 or 5 compounds (depending on the company-specific scheme) are considered highly potent and have the lowest acceptable occupational exposure levels and demand the greatest levels of engineering, administrative, and personal protective equipment.

What is the Globally Harmonized System (GHS)

GHS stands for the “Globally Harmonized System of Classification and Labelling of Chemicals” and has been a worldwide attempt to have a globally harmonized system for defining chemical hazard classifications, labeling systems (including standardized hazard symbols) and standardized safety data sheet formats. In the European Union (EU) the deadline for chemical classification was December 1st, 2010. In the United States of America (USA), since 2015, the use of the globally harmonized system (GHS) of classification and labeling of chemicals has been a regulatory requirement.

In the EU, GHS has been an integral part of the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) registration process, and in the USA, the Occupational Safety and Health Administration (OSHA) requires that GHS requirements be used for safety data sheet (SDS) preparation. As a result, in a GHS-compliant SDS, the GHS categorization for compounds can now be found in Section 2 on SDS. GHS is a short-hand method that describes the hazards of compounds according to precise regulatory definitions. For GHS health hazards, it does this by assigning a numeric “category” level for different toxicology endpoints for which data exist. Toxicology endpoints include things like acute oral toxicity (LD₅₀), skin irritation, eye irritation, skin sensitization, genotoxicity, reproductive toxicity, carcinogenicity, etc. An example of how GHS hazard categorization would be used for acute oral toxicity (LD₅₀) is shown in the table below. A compound with an LD₅₀ of 25 mg/kg, e.g., would be a Cat 2, while a compound with an LD₅₀ of 1800 mg/kg would be a Cat 4. Categorization schemes for other endpoints may differ somewhat, but use the same basic idea. In general, the lower the GHS numerical category the greater the hazard for that endpoint, while the higher the numerical category has a lower hazard. A special designation of NC (not classified) is provided for compounds that are determined not to show that specific hazard. In the LD₅₀ case, it’s an LD₅₀ greater than 2000 mg/kg.

The interesting observation is that the numeric categories for occupational health categorization bands and GHS categories go in opposite directions! A low classification number for an OHC band indicates the compound is less hazardous, while a low number for GHS classification indicates greater hazard. Similarly, a high number for an OHC band indicates greater hazard, while a high number for a GHS categorization indicates lower hazard.

Categorization Example 1 – Vitamin D3

As an example, the occupational toxicology experts from Affygility Solutions retrieved a safety data sheet for vitamin D3 (CAS RN 67-97-0), also known as cholecalciferol, from a reputable large pharmaceutical manufacturer. The information contained in the safety data sheet is as follows:

Occupational health categorization: 5 (the highest and most hazardous) Acute toxicity (rat, oral) LD₅₀: 43 mg/kg, which corresponds to a GHS acute toxicity category 2 (moderate toxicity)

Categorization Example 2 – Acitretin

As a second example, we retrieved another safety data sheet from a different pharmaceutical manufacturer for a product containing acitretin (CAS RN 55079-83-9). The information contained in this safety data sheet was as follows:

Occupational health categorization: 4 (highest OHC category for this company and highly potent) Acute toxicity (rat, oral) LD₅₀: >4,000 mg/kg, which corresponds to a GHS categorization assignment of NC (not classified, meaning not exhibiting toxicity for that endpoint)

Categorization Example 3 – Fentanyl Citrate

As a third example, we retrieved another safety data sheet from a third pharmaceutical manufacturer for a product containing fentanyl citrate (CAS RN 990-73-8). The information contained in the safety data sheet was as follows:

Occupational health categorization: 5 (highest OHC category for this company, highly potent, and with a skin designation) Acute toxicity (rat, oral) LD₅₀: 18 mg/kg, which corresponds to the GHS acute toxicity category of Category 2.

So, as you can see from the above three examples, without a proper understanding of the differences in the two categorization systems, it would be quite easy to get the two systems confused. And, to make matters worse, there are many safety data sheets on the internet that are poorly written and contain improper classifications.

Conclusion

In conclusion, while it would have been great if the pharmaceutical industry and the regulatory agencies would have aligned their categorization systems to used the same paradigm, unfortunately, they did not. For this reason, understanding that the systems are different for OHC bands and GHS categorizations is extremely important when evaluating information from different sources (such as an OHC report or an SDS).

The expert toxicologists at Affygility Solutions have significant experience in preparing occupational health categorization reports and safety data sheets for clients throughout the world. It you have any questions please contact us.

Published December 2, 2019

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