Assessing Potent Compound Safety Capabilities at CMOs

Applying the systematic approach

By Allan W. Ader, Ph.D., DABT, John P. Farris, CIH and Robert G. Sussman, Ph.D., DABT

The safe manufacture of potent active pharmaceutical ingredients (APIs) and products containing these APIs requires both “hardware” — facility features, modern equipment and engineering controls — and “software” — programs, practices and procedures — to adequately protect personnel and the environment. When outsourcing pharmaceutical production to third party contract manufacturing organizations (CMOs), their technical capability to meet clinical or commercial requirements is only one aspect that needs to be evaluated. There is also a need to ensure, with the same rigor, that these CMOs are capable of safely handling potent APIs and products. Elements needed by the drug innovator and CMO involve the recognition of the degree of hazard of the API, evaluation through industrial hygiene assessment of potential exposure to workers in the pharmaceutical plant and laboratory support areas, and the application of appropriate and verified containment and control measures to maintain exposures below acceptable limits. Specific elements should include categorizing (or “banding”) the API based on inherent potency and toxicity, linking the category to safe handling practices and control strategies, developing Occupational Exposure Limits (OELs) and sensitive industrial hygiene analytical methods, implementing engineering controls to meet the OEL with emphasis on containment at the source of emissions, and verifying the degree of containment and control through industrial hygiene quantitative assessment.

Drug innovators should evaluate, assess and verify (either with internal staff or through an independent expert) whether these elements are in place as part of their overall process of qualifying CMOs. The consequences of not adequately managing potent compounds safely may include potential for delay in clinical supplies, impacts on time-to-market, lost revenue for the drug innovator (and CMO), damage to the business relationship, decreased workforce confidence, and potential liability. A comprehensive metric (potent compound safety gap assessment and Certification) is available to CMOs and drug innovators, which can qualitatively and/or quantitatively assess this capability.

“How can I determine if the CMO our company has chosen can safely manufacture our potent, toxic, cytostatic, highly hazardous, Category 3 of 4 compound?”

“Do we have the capabilities to safely manufacture a cytotoxic drug product in our facility and can we advertise this to Big Pharma, biotechnology firms and virtual companies developing new cancer therapeutics?”

As products with increasing potency and toxicity are being researched, developed and manufactured, questions like these are frequently asked by the drug innovators and CMOs, respectively, in the current pharmaceutical environment of outsourcing, off-shoring, contract manufacturing, alliance partnerships and virtual pharmaceutical companies. In assessing and verifying a pharmaceutical CMO’s
s ability to safely handle products containing potent, toxic or novel compounds, a systematic approach must be applied. The following describes the needed elements and a program to verify this through independent assessment.

Definitions

For the purposes of this paper, the following two definitions need to be applied:

1) Potent active pharmaceutical ingredient (API) – Although there is no available definition from a regulatory perspective, the following definitions have been generally applied throughout the pharmaceutical industry;

• A pharmacologically active ingredient or intermediate with biological activity at approximately 150 micrograms per kilogram of body weight or below in humans (therapeutic dose at or below 10 milligrams); or
• An active pharmaceutical ingredient or intermediate with an Occupational Exposure Limit (OEL) at or below 10 micrograms per cubic meter of air as an eight-hour time-weighted average; or
• 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
• A novel compound of unknown potency and toxicity

2) Occupational health categorization (or banding) and handling practice system – a system for grouping compounds of similar toxicity and potency and linking appropriate practices to the safe handling of these material in research, development and manufacturing work environments. For the purposes of this article, we are providing guidance for Category 3 and Category 4 of the four-category “SafeBridge” system1 or Category 4 or 5 of a five-category system, such as the one developed by Merck & Co2.

Two Misconceptions

Two misconceptions that are readily apparent within the pharmaceutical industry and especially among pharmaceutical CMOs are the following:

1. “The room is the containment; we can handle potent compounds because none of the material gets out of the room based on QA/QC samples.” These types of facilities may have a gown/degown anteroom, high dilution ventilation, and personnel in “full” personal protective equipment as exposure controls.
2. “Our barrier isolators will fully contain potent or toxic compounds; we have zero exposure.” These facilities generally have no data to support “zero exposure” or the actual performance of their control systems, although they may have more containment than in the type of facility described directly above.

In the first case, using the room as the containment is not adequate for potent or toxic compounds. The personal protective equipment (PPE) used, usually powered air purifying respirators (PAPRs) or air-line suits, are mechanical devices rated with Assigned Protection Factors (APFs) by NIOSH or other internationally recognized bodies. These APFs (the ratio between potential outside concentrations and those inside the respirator in the breathing zone of the operator) are adopted by OSHA and international regulatory agencies and cannot be exceeded. In the case of open pharmaceutical operations — such as charging a blender by open manual scooping, weighing pure API, or milling — the levels may exceed the recommended levels inside the respirator and/or APFs if no other measures are taken at the source of dust generation. Even when APFs are not exceeded, the resulting airborne API dust will contaminate surfaces of the room, the workers’ clothing, and their respirators. Surfaces, clothing, and respirators must then be cleaned and decontaminated prior to degowning to prevent re-entrainment of settled dust. The use of “full” respiratory and PPE is also not adequate for regulatory reasons (for example, it is not consistent with U.S. OSHA regulations requiring feasible engineering controls at the source).

In the latter case, the barrier/isolator or other advanced engineering controls are also mechanical devices with which the employees interact. The proper use of these devices is dependent upon operator technique. When operators are not careful, the API may be “carried out” by themselves or via equipment or final product packaging taken from the control device. Although far better than using the room as containment, the assumption that there is “zero exposure” must be verified through a program of industrial hygiene sampling using surrogate powders and/or APIs. To verify the effectiveness of controls, the drug innovator should ask the CMO for a copy of the containment verification study performed on the device. If no data are available, they should be obtained prior to manufacture of the drug, or, at the latest, during the first batch run of the drug.

So, given these misconceptions, what should the drug innovator be looking for and what should the pharmaceutical CMO have?

The Systematic Approach to Potent Compound Safety

Drug innovators should be identifying and using CMOs that can demonstrate the following elements of a systematic approach to minimizing potential worker exposure to potent APIs, as follows:

These elements should be assessed prior to the introduction of a potent API to the facility.

1. Review and Document the Potential Health and Safety Hazards Associated with API Including Occupational Health Category and Explosivity Potential

Prior to bringing a new compound in from a drug innovator, the CMO should have the capability to assess the toxicity and potency of the API and determine its occupational health category or band (1, 2). This assessment needs to be documented for each API handled and should be conducted by a professional trained and knowledgeable in occupational health, pharmacology, toxicology, occupational medicine or a related field. The representative of the drug innovator may need to supply more than just the Material Safety Data Sheet for the compound for this assessment. The drug innovator should be asked by the CMO to supply the Clinical Investigator’s Brochure, the pharmacological mechanism of action and the basis for any internal categorization already done on the API, as well as information on the safety and environmental effects of the drug. It is in both parties’ interests that this information exchange take place. The drug innovator may have to take responsibility to ensure that this information is provided. If this information is not requested by the CMO, this may indicate that the contractor does not fully understand the nature of the hazard of the drug substance or product or what needs to be evaluated to make this assessment. In addition to the health hazard assessment, the explosivity hazard of powder formulations and steps to prevent explosion should be assessed.

2. Determine Acceptable Exposure Levels and Measure Potential Occupational Exposure

It is a fundamental principle that a simple qualitative assessment of the hazard is not sufficient. To properly assess the hazard and associated risk of handling potent APIs, Occupational Exposure Limits (OELs) (“acceptable” airborne limits based on existing data for occupational exposure to a compound), and Acceptable Surface Limits (ASLs) (“acceptable” surface limits for occupational health purposes), must be developed in addition to the qualitative categorization of the compound. These values are usually not available in the early stages of product development. Different tools for effective evaluation of risk should be used as new (pharmaceutical) chemical entities (NCEs) progress along their development timelines. Since limited toxicity data are available for NCEs by definition, categorizing or “banding” should be used and a more generic approach to control taken. If very limited or no data are available, a “default” band or category requiring conservative handling practices should be adopted. This approach should be based on demonstrated control with similar substances.

When sufficient toxicological information becomes available, a scientifically defensible Occupational Exposure Limit (OEL) should be developed and documented using quantitative risk assessment methodology. This typically occurs at Phase IIb or later in drug development so the OEL will typically be applied when larger quantities are needed and where more specific process-related control can be applied. Developing an OEL means that quantitative assessment of the working environment, based on subsequent specific testing for the presence of a material, can empirically demonstrate that the working environment is safe. An OEL should not be developed without the intention to monitor against it.

Concurrent with the establishment of an OEL, it is necessary to develop an industrial hygiene (IH) sampling and analytical method to allow monitoring of the workplace to occur. The very low OELs developed for potent APIs require highly sensitive validated analytical methods. Most analytical methods use high performance liquid chromatography (HPLC) validated for air samples. However, for increasingly potent compounds, more sophisticated methods using enzyme-linked immunosorbent assays (ELISAs), radioimmunoassay (RIAs), or liquid chromatography with mass spectrometry (LC/MS) are required.

The CMO should work in partnership with the drug innovator to develop these tools for the assessment of personal exposures in manufacturing the API or drug product. This often overlooked aspect of the business relationship should be routine and should include financial responsibilities for developing such exposure assessment tools. The CMO should consider the “business advantage” of having industrial hygiene data on processes and equipment used in their facilities in order to inform prospective clients that they can achieve airborne levels established for APIs being considered.

3. Apply Containment and Controls Appropriate for the Hazard to Reduce Risk and Verify the Ability of the Containment to Achieve Safe and Acceptable Levels

Containment and controls that are designed to control exposures at the source of emissions should be employed. The sidebar below provides general controls to be applied to a pharmaceutical product manufacturing facility for potent compounds (Category 3 in a four-category system). Exposure controls should be applied at the source of dust generation Drug innovators should not hire CMOs that use PPE as the primary means of worker protection, as this may lead to unacceptable exposure.

Finished Product Manufacturing General Engineering Containment and Controls for Potent Compounds (Category 3 of a Four-Category System) • Negative differential air pressure in processing rooms relative to surrounding areas is required for secondary containment. • Room air locks/anterooms are recommended to provide an air pressurization barrier that maintains a negative room pressure differential and to serve as a gown/degown area. • Recirculation of air into non-production areas is not permitted. It is recommended that HEPA filtered room air exhaust not be recirculated. • Designated areas should be posted with appropriate notification and hazard warning. Persons entering the work area should be trained about the hazards of the compounds and in the use of controls. Controlled access to the work area is required. • Locker rooms and showers contiguous with processing/work areas are recommended. • Air showers are not recommended. Mist/water showers are preferred and recommended. • Essentially no open handling. Any open handling should be limited to only very small quantities (100 mg) and engineered local exhaust ventilation (LEV) is located at points of dust generation. • Closed material transfers and handling are recommended. • The transfer design should utilize gravity or energy features and direct connection to facilitate transfer whenever possible. • The use of intermediate bulk containers (IBCs) with split butterfly valves (SBVs) or rapid transfer ports (RTPs) is encouraged if direct connection is not possible. The use of a certified downflow booth may be acceptable if it is equipped with a primary containment or control device on or around the point of dust generation and if the booth is verified for effectiveness through industrial hygiene (IH) monitoring. • Where possible, process steps and equipment should be combined to minimize transfer points. • Where possible, process equipment/activities that generate high dust levels or are difficult to contain should be avoided. • Eliminate unnecessary/redundant handling, processing and transfers. Substitute processes/activities that generate less dust or are well contained. • Parts should be pre-cleaned in the contained area prior to removal to the cleaning area. Parts should be bagged after pre-cleaning and prior to removal for full cleaning. • SOPs including required safety provisions should be developed. Excellent work practices should be established, taught and enforced. Deviations from established work practices should not be tolerated. • Basic Engineering Control Strategy: Isolator (glove box) systems, glove bags, direct connections and closed transfer systems. Selective use of directionalized airflow booths and downflow booths (with primary control devices in place) and LEV hoods designed and engineered to ACGIH standards may be employed if effectiveness is verified through industrial hygiene monitoring.

There are a wide range of technologies and techniques available for safely controlling potent compounds in the workplace, including glove box or barrier isolator technology, powder weighing hoods (in laboratory and testing situations), vertical process trains, intermediate bulk containers, special valving (e.g., split butterfly valves), custom ventilated enclosures, local exhaust hoods, glove bags and material transfers using “bag tricks.” New technologies have been developed in the last few years, most notably flexible film applications ranging from continuous liners to disposable glove bags.

As stated earlier, simply instituting containment and control technology is insufficient for the safe handling of potent APIs and products. A program of qualitative and quantitative industrial hygiene exposure assessment including the use of surrogate powder monitoring to determine the degree of containment prior to use with the potent API and to estimate potential exposures to developmental materials for which no monitoring techniques and exposure limits needs to be in place.

4. Institute a Program of Standard Operating Procedures (SOPs)

Drug innovators should be evaluating CMOs to determine if they have general written procedures for handling and disposal of pharmaceuticals in production and laboratory environments based on their occupational health category. Furthermore, CMOs should have written procedures for specific operations such as: weighing and dispensing, solution make-up, proper use of laboratory hoods, proper use of powder weighing hoods, the appropriate PPE to wear with certain categories of compounds and conditions, proper procedures during the addition of drug substance, cleaning procedures etc. The library of SOPs should include procedures for:

• Proper use and maintenance of engineering controls or systems.
• Proper use of PPE
• Appropriate product deactivation or decontamination procedures.
• Process hazard reviews to integrate appropriate environmental, health and safety activities into manufacturing and R&D operations (for example, evaluating fire protection and risk management issues, containment and control technology options and waste disposal considerations).
• Periodic testing and maintenance for engineering controls.

5. Conduct Training Programs in Potent Compound Safety Awareness

SOPs covering potent compound operations are of no use without training employees in their use and enforcement of their use. The drug innovator should provide sufficient information on the API to help the CMO health and safety personnel to communicate associated hazard of the API and product handling practices.

6. Determine the Potential Environmental Impact of the API and Associated Manufacturing Processes

The drug innovator and CMO need to understand the environmental impact of the API. This can be achieved by conducting short-term and cost effective “screening” environmental fate (i.e., persistence) and effects tests to determine the proper disposal procedures for waste streams from pharmaceutical operations. Tests should include biodegradability and effects on aquatic organisms and sludge.

Assessment of “Hardware” and “Software”

The assessment of containment and controls and programs, procedures and practices should be conducted by experienced and knowledgeable health, safety and environmental professionals familiar with pharmaceutical operations. Our group has created and implemented a metric that determines the capability of a pharmaceutical or fine chemical company to meet current industry practices in the potent compound safety aspects of pharmaceutical manufacturing and development. The process is called the SafeBridge Potent Compound Safety Certification program3 and it assesses the strengths and weaknesses of the systems, programs, facilities and process containment in the area of worker protection. The outcome of the process alerts the manufacturer’s management of areas that may not meet current pharmaceutical industry standards or practices. The process utilizes a 60-point assessment criteria and scoring system we developed for this purpose. This process can be used as either a “gap assessment” tool for company self-evaluation or as a means to Certify, through independent objective review, that the company is competent in potent compound safety for the purpose of marketing their manufacturing capability to outside parties and potential clients.

In the same way that CMOs’ technical capability to manufacture the drug product, cGMPs, and product quality are assessed, the drug innovator should qualify the CMO in the potent compound safety management elements described above when outsourcing the development or manufacturing of a potent API or drug product. The consequences of getting this aspect wrong can include overexposures to workers, resulting in adverse health effects, worker concern over potential effects, resulting in work stoppages, interruption of clinical supplies during critical trials, environmental contamination and impact to facility and/or local wastewater treatment facilities. Including this assessment as part of the process of selecting a CMO will help speed products to market by avoiding delays in the drug development process and limit liability due to potential occupational health, safety, and environmental concerns. Management should consider systems that have metrics to qualitatively assess gaps or quantitatively measure performance to qualify CMOs prior to handling of a potent API or product.

References

1. Ader, A.W., Farris, J.P. and Ku, R.H., Occupational Health Categorization and Compound Handling Practice Systems – Roots, Application and Future, Chemical Health & Safety, American Chemical Society, July/August 2005.

2. Naumann, B. D. et al, Performance-Based Exposure Control Limits for Pharmaceutical Active Ingredients, American Industrial Hygiene Journal, 57:33-42, 1996.

3. Farris, J.P. and Ader, A.W., Assuring Highly Potent Active Ingredient Safety: The SafeBridge Certification Program. Publication in Chemistry Today, Tekno Scienze Srl, Milan, Italy, Vol. 22, No. 5, May 2004.

Allan W. Ader is vice president and principal toxicologist for SafeBridge Consultants, Inc. John P. Farris is president and chief executive officer for SafeBridge. Robert G. Sussman is managing principal of eastern operations for SafeBridge.