Handling HPAPIs: Do Your CMOs Have the Right Stuff?

Ignoring a contract partner’s ability to handle highly potent APIs (HPAPIs) safely may have serious consequences. Drug owners and contract service providers alike must understand the complexities and liabilities involved in working with HPAPIs.

Highly active or potent pharmaceutical ingredients (HPAPIs) comprise different compounds, but share one deadly characteristic: the potential to inhibit production of specific enzymes and cause cancer, mutations, development effects, or sickness, at very low doses, in those exposed to them.

Currently, there are no specific occupational health, safety, and environmental protection regulations covering HPAPIs. In the United States, the Occupational Health and Safety Administration (OSHA), the National Institute for Occupational Safety and Health (NIOSH), and the US Environmental Protection Agency (EPA) have limited specific requirements for potent compound handling in healthcare and manufacturing settings.

Industry groups in the United States and Europe have developed health risk-based approaches for setting occupational exposure limits (OELs) in such areas as cleaning validation, by setting permitted or acceptable daily exposure limits (PDEs or ADEs), to address carryover of any residual HPAPI. The result has been the International Society for Pharmaceutical Engineers’ (ISPE) Risk Mapp baseline guidance, and the European Medicines Agency’s (EMA) guidance for preventing cross-contamination.

Drug manufacturers are developing more potent drugs, and despite the lack of specific environmental and safety regulations, HPAPIs have become fertile ground for contract manufacturing and contract development and manufacturing organizations (CMOs and CDMOs), which have been actively building up capacity over the past few years. Experts warn, however, that a systematic and scientific approach is needed. Simply having containment equipment and basic procedures will not be enough to ensure safety.

Typically, large pharmaceutical companies have the industrial hygienists and occupational toxicologists on staff to evaluate the potential risks of any new HPAPI, and to conduct the necessary safety assessments. Smaller companies and CDMOs/CMOs may not have those experts on staff. Teams that visit potential contract partners may be so focused on cGMPs and product specs that they overlook questions of worker safety and environmental risk from exposure to HPAPIs.

In addition, CDMOs/CMOs may not have done a sufficiently thorough assessment to determine whether they can handle a potent new drug safely. Failure to vet potential partners thoroughly can lead to regulatory problems with OSHA and potential legal liability.

SafeBridge Consultants, based in Mountain View, CA, established a third-party certification program 15 years ago, which assesses a manufacturer’s HPAPI handling and manufacturing program readiness. The program focuses on four areas: management systems, evaluating hazards and risks, assessing engineering controls, and analyzing training and standard operating procedures (SOPs). The process also reviews such tools as OELs, industrial hygiene sampling, and analytical work. In addition, it scrutinizes containment and controls, and assesses potential environmental impact. The company has already certified a number of pharma CDMOs (see Sidebar).

SafeBridge Consultants’ roots go back to Syntex Corp., which helped establish the “control banding” approach that is used in industrial hygiene to determine the potential risk of exposure to new APIs for which no exposure data exist. Pharmaceutical Technology spoke with SafeBridge Consultants’ founder and CEO John Farris and cofounder, vice-president and principal toxicologist Allan Ader, to discuss best practices for sponsors and CMOs alike.

The certification processPharmTech: Why did you decide to go into business?

AMRI
Baxter Oncology
Corden Pharma
DSM
Excella Pharma, Germany
Novasep France
SAFC
ScinoPharm, Taiwan

Farris: With the rise of contract manufacturing in pharma, we saw the need to come up with a metric that could evaluate companies’ capabilities to conduct potent compound operations safely to minimize exposure. We had developed a tool while at Syntex to look at the industrial hygiene of our internal facilities around the world. We modified that to come up with a measurement tool for potent-drug safety that would work for any contractor and that anyone could use. It’s a weighted 60-plus criteria exercise that has been proven to be effective and objective in evaluating capabilities.

A CMO can use certification to show clients that they are competent in HPAPI manufacturing and handling. We also offer a ‘gap assessment’ or qualitative approach that can allow companies to measure their own performance using the same criteria.

PharmTech: How do companies apply for certification?

Farris: We start with a precertification review, where we send a person to take a walk through the plant, look at procedures and give the company a candid idea of whether or not they have a chance of passing. If they pass the first hurdle, we send two professionals out to do a two-day review (up to three days for companies outside of the United States).

We don’t certify new facilities because they haven’t had enough significant run time. They won’t have the data that we ask for to support the certification, and they haven’t proven that they can work consistently within industry best practices.

PharmTech: What other data do you need?

Ader: There are two key points: toxicology evaluations of hazards and materials you will handle, then the industrial hygiene studies measuring impact on workers, and the air and surface monitoring studies to show that you are containing materials and maintaining safe levels. In addition you need to show that you repeat studies to prove that you are doing this accurately and consistently with industry best practices.

PharmTech: How long does the certification last?

Farris: For the US and Europe, certification lasts for two years. During the off year, the company must do a self-assessment and share results with us. For companies in Asia, recertification is required every year.

Current practicesPharmTech: Do you think that pharmaceutical companies are lax in their handling of potent compounds?

Farris: They want to do things right but they don’t know how involved it can be. Historically, Big Pharma has struggled with potent drug safety, and, despite its efforts, over the years it has had incidents of exposure to workers. Now, these are the companies with significant resources in toxicology and industrial hygiene that are applying their skills to prevent this. If Big Pharma has trouble, imagine what a small CMO or innovator company faces.

Ader: You have to be able to recognize, evaluate, and control the hazard. These are the three basic principles of industrial hygiene and toxicology. CMOs or smaller companies may have some, but not all, bases covered. For instance, they might do a good job of hazard evaluation, but not air monitoring. Sometimes the gaps boil down to cost issues. If you’re thinking of building isolators for all your process steps, that will involve significant cost, and some might try another option that, in the end, won’t be sufficient protection for that particular compound. The evaluation by toxicologists and developing acceptable limits or appropriate occupational health categories, or bands, is key. Sometimes, that step gets missed.

Farris: Another problem is that, when smaller companies do invest in expensive and high-tech controls like isolators, some of them then figure that the job is done and they’re good to go. They fail to recognize the fact that, if you don’t measure performance, you can’t guarantee safety.

With HPAPIs, you can’t tell there’s a problem just by looking. You need to measure performance. Safe levels for some of these drugs are down in the range of nanograms per cubic meter of air, 1000 times below what you can see in air at a minimum for some of these compounds.

You can’t tell whether the isolator is leaking unless you have a catastrophic failure. It you don’t measure its performance, you won’t know if you might have a slow and potentially continuous leak and exposure. You might also pass things out of the isolator that have particulates on them and can cause exposure, and have ‘drag out’ of a room or isolator into a clean area. You won’t know if you don’t measure.

PharmTech: Because OSHA does not offer specific guidance on HPAPIs, could companies have exposure problems and could workers be affected without knowing it?

Farris: OSHA and NIOSH have published guidance on hazardous drugs, but it is intended for the healthcare industry, not for manufacturing and R&D. OSHA will get involved if an employee gets sick, and will investigate the facility. OSHA has come in and cited companies, but it’s always after the fact. There are both acute and chronic hazards. OSHA gets involved mainly in acute incidents, when workers develop a rash or symptoms from acute high exposures, or reproductive health issues.

Problem areasPharmTech: What are the top issues and questions that companies fail to consider when they are dealing with potent ingredients, both sponsors and CMOS?

Ader: Generally, there are three problem areas. They don’t have toxicology support, and if they have the toxicology support they don’t have an understanding of the pharmaceutical substance’s unique potencies and toxicities.

They haven’t run adequate industrial hygiene studies prior to startup (conducting surrogate studies on containment equipment before actual production begins), during initial production batches, and then, periodically after startup, to verify the performance of control systems.

The third, and biggest problem, is that they often don’t know what they can and can’t handle. They need to assess the capability of their equipment and facility. That is very closely related to the industrial hygiene data that they need to gather. Some companies do industrial hygiene studies with only two samples. That cannot adequately assess health risk. Studies must be scientifically supportable and use statistics in order to determine systems capability and verify performance.

Farris: You need to understand what you can and can’t handle and why, and be able to articulate that to customers. This also gives you a focus for improvement. If you want to handle the ultra-potent materials, but you know you don’t have adequate controls in place, you can then budget and plan to improve those areas so that you can grow your business.

Qualifying contract service providersPharmTech: Who should go to evaluate a CMO that’s working with HPAPIs?

Ader: Typically, pharma companies send the quality people or the formulation or process chemists who are transferring the process over to the CMO. They’re looking at timing, whether the CMO can produce to the specs that they’re trying to achieve, whether they can perform this specific reaction, or make this particular formulation as they did inhouse. They’re focused on timing and the bottom line.

Then, way down at the bottom of the list of specs, is the question of whether or not they can handle HPAPIs.

Farris: Only Big Pharma companies typically send environmental health and safety professionals out to review third parties.

Ader: Usually, the industrial hygienist is the key person, since he or she will do the exposure assessment.

PharmTech: What issues are posed by new compounds?

Farris: We’re one of the innovators, with several other companies back in the late 1980s, of the occupational-health categorization system, or control banding, where we group compounds based on toxicity and potency. We use this approach when there isn’t a lot of data and you can’t determine OELs quantitatively. Many companies use those numbers alone. But we have linked them to best handling practice, which is important. It’s really a hand and glove, with the hand being toxicity evaluation and assessment, and the glove, the handling practice and work-environment descriptors that will allow you to make the compound safely.

The cleaning validation questionPharmTech: How does this fit in with cleaning validation?

Ader: This is where the quality and occupational health aspects merge, because they both should employ some level of quantitative risk assessment. Historically, in cleaning validation, you can have carryover to the next product. Previously, you could establish a cleaning limit based on arbitrary cutoffs, such as 10 ppm, or 1/10,000 of LD-50, or half the lethal dose in rats.

These arbitrary approaches don’t use the most current risk assessment approaches to determine what is safe and what isn’t. ISPE’s Risk Mapp and EMA guidelines provide acceptable daily exposure to identify a safe amount and acceptable limit that you can administer by any route as an acceptable carryover limit. A company can use them to establish cleaning limits for equipment that comes in contact with product.

Hazard assessment established for setting an OEL are based on inhalation by workers. Risk assessments for cleaning validation limits, however, are for patients taking the next drug and might include children or sensitive subgroups. You can’t take an OEL and multiply it by 10 to come up with a permitted daily exposure (PDE) or acceptable daily exposure (ADE). There is still some resistance to applying PDE and ADE to cleaning validation, but, in December this will be required in Europe. We don’t look at this in great detail during a certification assessment, but we do look for health- and science-based limits.

Article DetailsPharmaceutical Technology Outsourcing Resources Supplement
Vol. 39, No. 17
Pages: s18-s22

Citation: When referring to this article, please cite it as A. Shanley, " Handling HPAPIs: Do Your CMOs Have the Right Stuff?," Pharmaceutical Technology Outsourcing Resources Supplement39 (17) 2015.