Pharmaceutical Occupational Hygiene and The Role of Surrogate Molecules
Occupational Hygiene (OH) is the discipline of anticipating, recognising, evaluating, and controlling health hazards in the workplace to protect worker health and well-being.
Within the pharmaceutical industry, this includes the routine monitoring of active pharmaceutical ingredients (APIs), relevant excipients, and surrogate materials through air filter sampling and surface swabbing. Samples are analysed against established occupational exposure limits (OELs) using validated, highly sensitive, robust analytical methods to assess operator exposure and verify the effectiveness of exposure controls.
Cormica specialises in the development, validation, and deployment of analytical methods for monitoring occupational exposure to pharmaceutical APIs in manufacturing, clinical and laboratory environments. Our expertise supports clients in protecting employee health, demonstrating the effectiveness of engineering and procedural controls, and maintaining compliance with applicable regulatory requirements and industry guidance.
Cormica’s Approach
Pharmaceutical environments require a more rigorous approach than generic COSHH compliance alone. Occupational hygiene programmes should be underpinned by risk assessments aligned with GMP/GXP principles, occupational exposure banding frameworks, containment strategies, and robust, documented justification of exposure control measures. This integrated approach helps ensure both regulatory compliance and the safe manufacture and handling of pharmaceutical products.
Establishing an occupational hygiene monitoring program is a complex, multi-faceted undertaking. Our holistic OH package guides you through every step, including the development and validation of analytical methods for multiple active ingredient types (hormones, cytotoxics, antibiotics, controlled drug substances):
- Support in OH risk assessment, limit setting, sampling / testing protocols
- Sensitive analytical methods suitable for multiple analytes, meeting the growing demand for particularly challenging OEL / Reporting Limits
- Preparation and supply of media (swabs, filters, pre-loaded IOM cassettes); training your staff in effective sampling techniques
- Routine analysis of samples to fast turnaround times
- Analytical method development, validation and testing of proprietary APIs as well as surrogate API materials such as Lactose, Mannitol and Naproxen Sodium
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Authors:
Michael Scott is a Technical Leader in Separation Sciences at Cormica Bradford, with 30 years’ experience in chromatographic method development and validation. Since 2000, he has supported CRO/CDMO clients, specialising in HPLC development, troubleshooting and GMP-compliant validation.
Caroline is Operations Director at Cormica Bradford with over 25 years’ experience in analytical chemistry, physical characterisation, and GMP. She has led multidisciplinary teams in method development, validation, and testing, with expertise in X-ray diffraction, particle size analysis, and thermal analysis. Caroline co-founded Agenda1, establishing GMP and GLP systems, and previously managed generics development projects at Nektar Therapeutics.
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The process is typically broken down into the following steps:
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1. Understand the manufacturing environment
Develop a detailed understanding of the manufacturing environment, equipment and processes
Identify all areas of the facility / process / procedures which could result in operator exposure
Where possible, engineer out potential exposure routes
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2. Assess risks and plan sampling
Complete OH risk assessment, factoring in established engineering controls
Develop the sampling plan, ensuring all residual risk areas are included, determining the appropriate swabs and filters to be used
Train out sampling techniques to staff and assess sampling efficacy to minimise errors
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3. Develop and validate analytical methods
Develop and validate robust and sensitive analytical methods which are suitable for the API, excipients or surrogate molecules to be assessed
Include validation of analyte recovery from relevant surfaces, plus swabs and filters, in addition to standard ICH Q2(R2) compliant validation
Train out validated analytical method to staff
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4. Evaluate exposure and monitor
Undertake the OH evaluation of the facility / process, utilising the validated analytical method and agreed sampling plan / approach
If required, based on the outcome of the evaluation, regular facility monitoring may also be undertaken according to an agreed frequency (e.g. annually or per campaign)
Why and How Do We Swab?
Surface swabbing, along with air sampling, is the preferred method for monitoring the presence of potentially hazardous species within the manufacturing environment for both occupational hygiene and cleaning validation / verification. Potential contaminants are recovered by swabbing, eluted from the swab using a carefully selected diluent, and then tested down to trace levels. As a result, the selection of a high-quality swab and the development of a validated detection method (e.g., HPLC-UV, LC-MS, TOC, ICP-MS) are critical to producing sensitive, accurate, and repeatable results.
Swabs must offer:
- Minimal extractable interferences
- High analyte recovery rates
- Ultra-low particle / fibre generation
They should be compatible with the desired swabbing diluent and the chosen analytical technique, which in turn should be chosen to be suitable for the surfaces being swabbed and the analyte to be recovered. It is also very important to include ‘field blank’ swab (and air filter) sampling as controls.
It should be noted that recovery rates are a function of swabbing methodology as well as the material absorption and residue-releasing attributes of the swab. The effective use of a robust swabbing pattern is critical to ensure an accurate and reproducible collection of residues.
An example of a recommended swabbing pattern, employing two swabs, is shown below. Once the surface has been swabbed, the used swab heads should be promptly placed in the extraction solvent, according to the validated procedure.
SWAB 1
Side 1
Step 1
Flip swab over
Swab perpendicular
to the first direction
Side 2
Step 2SWAB 2
Side 1
Step 3
Flip swab over
Swab perpendicular
to the first direction
Side 2
Step 4Why Use a Surrogate?
A surrogate is a low toxicity material that can replace an active pharmaceutical ingredient (API), when the use of the API is not advisable due to safety concerns. Surrogates are used to simulate potential emissions or sampling for analytical methods, ensuring compliance with safety regulations. They are essential for assessing workplace exposure to hazardous substances and maintaining a safe working environment.
Use of a surrogate is common when performing both cleaning validation and occupational hygiene studies. In a multi-product site such as one operated by a CDMO (Contract Development and Manufacturing Organization), it may not be possible to know / predict the worst-case scenario API with which to undertake the OH evaluation. Also, the API may be in short supply, expensive or high potency. In these cases, it is possible to justify the use of a surrogate API.
Naproxen Sodium is a common surrogate used throughout the industry. It is regarded as safe, non-potent, has good detectability using UV and fluorescence detectors, demonstrates a high “dustiness” which is required for occupational hygiene studies, and it is inexpensive and readily available.
An additional advantage of using a surrogate for this purpose is that a single validated analytical procedure can be applied to multiple manufacturing and sampling scenarios, with relatively minor additional development / validation required to take account of the specific facility / process being evaluated (e.g., bespoke surfaces).
Naproxen Sodium Methodology
Cormica’s in-house Naproxen Sodium method has been developed to offer excellent sensitivity, linear range and run time / efficiency (see Table 1) for testing both swabs and air filters. The method can be adapted to your specific requirements, and Cormica can work with you to determine carry over limits if these are not already known. Swab recovery factors can be determined for your specific surfaces and used for your occupational hygiene or cleaning validation study.
The linearity and sensitivity are well established for this method, hence only minimal additional validation would be required to support the bespoke aspects of your study.
| Parameter | Values |
|---|---|
| Detection Method |
Ultraviolet (UV) Fluorescence (FLD) |
| Linear Range (UV) | 76 µg/mL to 399 µg/mL, r2 0.9994 |
| Linear Range (FLD) | 0.00004 µg/mL to 0.004024 µg/mL, r2 0.9994 |
| Sensitivity (UV) | LOD 9.8 µg/mL (19.6 µg/swab), LOQ 33 µg/mL (66 µg/swab) |
| Sensitivity (FLD) | LOD 0.00004 µg/mL (80 picograms/filter), LOQ 0.00014 µg/mL (280 picograms/filter) |
| Reporting Limit (UV) | 33 µg / 100 cm2 |
| Reporting Limit (FLD) | 280 picograms / filter |
| Run Time | 5 minutes |
Naproxen sodium is a highly suitable surrogate for manufacturing support studies where the assessment of a product specific API is not practical. In addition to in-house, validated methods for Mannitol and Lactose, Cormica has developed and validated a sensitive, efficient and cost-effective method for quantification of Naproxen Sodium in support of occupational hygiene and cleaning validations.
Where the use a surrogate such as Naproxen Sodium is not appropriate or not desired, Cormica can also support with bespoke analytical methods for your specific API (or group of APIs). With detection capabilities such as UV, FLD, MS & MS/MS and CAD we can support even where sensitivity and specificity is challenging.