Pharmaceutical Industrial Hygiene

Pharmaceuticals are intended to have biological effects at even very low dosages. These effects can pose a risk towards the people and facilities where they are handled. This is why it is important to contain or isolate pharmaceutical products. A lack of containment during production can also threaten the products themselves, which need to be protected from cross contamination. At the same time, the product can permeate the air or surrounding environment if facilities are not effectively tested and maintained.

What Level of Containment is Adequate for Pharmaceuticals?

Most pharmaceutical manufacturing activities require some level of containment, though even the most robust isolation equipment cannot assume zero exposure. This is why manufacturers need to establish risk-based thresholds that limit employee exposure and product migration. These limits are commonly known as Containment Performance Targets (CPT), which guide containment strategies and provide control limits for engineering and testing.

The most common strategies, listed from lowest to highest containment, are:

  1. Controlled general ventilation
  2. Localized capture of airborne particles
  3. Isolation barriers (optionally with a closed system transfer)
  4. Complete isolation through a remotely controlled process

What is the Best Pharmaceutical Containment Testing Method?

There are several techniques that can assess containment performance, each of which have their advantages and drawbacks. When using the actual Active Pharmaceutical Ingredient (API) is not an option, process surrogate tests are the next best indicator as they provide high sensitivity and quantitative results.

Process surrogate testing uses a substitute compound in a manufacturing process to simulate the behavior of the API. The non-toxic substitute tests the facility’s airborne containment performance before drug manufacturing begins.

A good surrogate should have similar process and dustiness characteristics to the API it is substituting, as well as low toxicity and a sensitive assay. Test conditions are designed to mimic pharmaceutical operations as closely as possible without incurring the expense or health concerns of handling the actual drug. During the surrogate testing process, air and surface samples are collected to measure airborne and surface particles against pre-determined CPTs.

Equipment Testing Using Surrogates

Surrogate testing is often conducted to assess the performance of containment and control equipment to predict the extent of worker exposure in these environments. There are three standard types of performance tests:

  1. Factory Acceptance Testing is conducted offsite on new equipment prior to shipment and installation.
  2. Site Acceptance Testing is conducted onsite for new equipment and procedures under optimal working conditions, prior to the introduction of APIs and live manufacturing.
  3. Operational Qualification Testing is conducted on equipment and procedures that are already in use.

Containment performance should be periodically evaluated on an ongoing basis, as containment equipment is known to degrade or fail over time. This testing can be performed directly using sampling and analytical methods that are specific to the API during normal manufacturing, or by surrogate evaluations. These tests help organizations that handle hazardous materials in powder forms verify that controls can achieve low Occupational Exposure Limits (OELs) for highly toxic or potent compounds. Verification is important to pharmaceutical and chemical companies as well as containment and engineering control vendors who look to support safety among employees during drug development activities.

How do You Select the Right Surrogate?

You will first need to determine your selection drivers. The selected surrogate should behave similarly to the original material and should not adversely affect the process or equipment it is testing. Although there is no perfect surrogate material, you can choose from standardized options, taking the following factors into consideration:

  • Your manufacturing process – characteristics such as flowability of your bulk powder, compactibility or adhesion of tablets and their solubility.
  • The required surrogate quantity and its cost.
  • Whether a custom surrogate needs to be manufactured.
  • The dustiness or containment challenge of the test material. These measurements often correlate with particle size distribution, where generally a decrease in particle size results in an increase in dustiness.
  • Moisture content and humidity, which decreases the dustiness of most powders.
  • The effort required to clean the surrogate under established cleaning procedures.

Common Surrogates

The table below lists the most commonly used surrogates and the properties that should be considered during the selection process.

Table 1: Commonly Used Surrogates

SURROGATE TYPE BULK COST HAZARD METHOD SELECTIVITY CLEANABLE DUSTINESS SENSITIVITY (NANOGRAMS) MULTIPLE SPECIFICATIONS
Lactose Excipient Low Low Good High Variable 2.5 Yes
Naproxen Sodium API High   Very Good High High 0.05 to 0.2 Custom
Mannitol Excipient Low Low Good High Variable 1.0 Yes
Acetaminophen API Modest   Exceptional Modest Moderate 0.5 Custom
Riboflavin API Modest   Good Low Variable 5.0 Custom

Performing Surrogate Testing

Once you are ready to conduct surrogate testing, there are several steps you will need to address:

  1. Establish containment targets or CPTs, usually based on the Allowable Daily Exposure (ADE), OEL or other health/quality limits. You may consider incorporating safety factors for any personal protective equipment that is mandatory for a specific process.
  2. Determine the means to simulate the operation by assessing the configuration of the facility, considering the number of equipment operators and running multiple tests.
  3. Select the surrogate material.
  4. Develop a sampling plan, for the area, task and operator exposure.
  5. Perform simulation and sampling.
  6. Prepare a report that provides an objective interpretation of the results, indicating whether set limits were achieved.

Surrogate testing is standardized by the International Society of Pharmaceutical Engineers (ISPE) who published a good practice guide, the latest version of which was released in 2012. Bureau Veritas actively participated in writing this document; we regularly provide advice on test methods and perform surrogate sample analysis for pharmaceutical manufacturers around the world.