Thinking Inside the Box
CMOs work to contain high potency biologics and APIs
By Cindy Dubin
The need for contained handling and processing of pharmaceuticals started to rise significantly about 20 years ago with the development of more highly potent active pharmaceutical ingredients (HPAPI's). As Big Pharma was pushed to fill pipelines with blockbusters, they did so with easy molecules. Now, that those easy molecules have been taken, there are new opportunities, but with highly potent and/or toxic molecules.
Photo courtesy of SAFC (Sigma Aldrich Fine Chemicals)
Highly potent/toxic drugs are classes of compounds derived from chemical or biological processes that, when handled during manufacturing and development, pose a potential occupational risk to the handler. A toxic agent can cause a deleterious response in a biological system, such as acute, chronic or pharmacological effects. Potent compounds produce effects at low doses and cause a given, desired or deleterious response.
So steps need to be taken to train employees working with these products, keep the products contained within the process equipment and the facility--and separate from other products -- and provide workers with proper personal protection equipment (PPE). It can be 30–50% more costly to develop highly potent drugs versus traditional products. As a means of defraying the costs, both large and virtual pharmaceutical companies may be forced to outsource the development of these highly potent/toxic drugs to contract manufacturers.
Many third-party manufacturers have gladly accepted the challenge. Azopharma Product Development Group has invested millions to handle sterile and non-sterile cytotoxic products by installing five cytotoxic suites. "This is by now means an easy business to get into," says Phil Meeks, chief executive officer of Azopharma.
Within the last year, Sigma Aldrich Fine Chemicals (SAFC) announced a $29 million investment to expand manufacturing capacity for high-potency biologics at its site in Jerusalem. In August of 2007, the company's flagship high-potency active pharmaceutical ingredient-site in Wisconsin benefited from new equipment and capacity expansion built in 2008.
Combine these expansions with a number of acquisitions in the biologics contract manufacturing space in recent years, and it is clear where SAFC thinks the market is heading.
Making a Judgment Call
While the Occupational Safety and Health Administration (OSHA) ensures that employees are provided a safe and healthful working environment, there is no specific guidance about safely handling potent APIs. As a result, industry has begun policing itself. Pharmaceutical clients will periodically audit their contract manufacturers. "They want to be convinced that the contractor really knows how to handle the product," says John P. Farris, CIH, president and chief executive officer of SafeBridge Consultants, Inc., a firm that helps companies categorize the potency of their API and consults on exposure controls.
Contractors should even police themselves by asking clients as much as they can about the substance to ensure they handle it properly once it arrives at their doorstep. Surprisingly, this is a fairly new phenomenon.
Photo courtesy of SAFC (Sigma Aldrich Fine Cheimcals)
"In the late 1980s, questions were raised about these materials in development once they left the bench scale," says Mr. Farris. "Until late Phase IIB or III, toxicity and potency data is not available to determine safe limits of exposure to handlers responsible for scaling up these products. Scientists working with these materials assumed innocent until proven guilty.
But we can't think that way anymore. So, a system for classifying product into safe handling categories was developed by the Potent Compound Safety Subgroup, made up of Big Pharma companies including Merck, Abbott, Syntex, Upjohn and Lilly." Mr. Farris described the SafeBridge categories as:
Category I -- This group contains products that cause nothing worse than irritation to the eyes, nose and respiratory tract, such as aspirin.
Category II -- This is the broadest category of drugs, including anti-virals, heart medications and insulin, which can cause organ toxicity.
Category III -- This is the first tier of potent drugs that pose one or more "-genic" effects, plus potential irritation and organ toxicity. This class, which contains synthetic opioids such as fentanyl, can put a person in a serious situation and cause respiratory arrest in the workplace.
Category IV -- This category exhibits all of the characterizations of the previous three, but compounds are even more potent and effects more severe. This is the smallest category of drugs, and is the most potent at the lowest levels.
Many contract manufacturers refer to the SafeBridge categorizing system before they even make a bid for a project. Mr. Farris says: "They should know what they are getting into so they ask us to categorize potential clients' drugs for them and make a judgment as to which category a product belongs."
If there is no data available for a product, SafeBridge recommends defaulting to Category III until proven otherwise. "We have some difficulties receiving a complete set of compound data from our clients," said SAFC Pharma's Regulatory Affairs director David Bormett. "Without a clear picture of what type of product we're dealing with, we'll default to a Category III product, which assumes that the product is potent and that additional safety procedures are put in place. It would be helpful if clients had their compound and intermediates classified by SafeBridge or an equivalent."
But client information is not always reliable, according to Bob Calabro, vice president sales and marketing, Norwich Pharmaceuticals. "I had a situation once when a customer gave us a material safety data sheet (MSDS) that would have put their product into a Category III, which we are not capable of handling. According to SafeBridge, the product fell into the Category II category. We have also had the reverse occur where a client tried to convince us to manufacture under a Category II although the product was clearly at a Category III."
Some contractors use the SafeBridge system for establishing their own internal system, refining the categories even more. Azopharma, for example, has its own internal SOP to classify the products it handles, which includes Categories I through IV. According to Mr. Meeks, the company relies on unofficial industry standards to figure out the best way to categorize, and ultimately, handle products.
To date, SafeBridge has classified 2,500 drugs; 60% of which are in Categories III and IV. "As a matter of fact, 80% of new drugs today are potent, in Categories III and IV," said Mr. Farris.
Do We Have a Deal?
The more advanced method for determining the potency of a compound is the OEL. The Occupational Exposure Limit defines the allowable safe level to which a worker can be exposed to a potent drug without suffering an effect. Once set, OEL values should be achieved in the workplace and confirmed by air monitoring studies. One basis for calculating an OEL is the No Observable Effect Level (NOEL). This value is determined by testing this pharmaceutical active ingredient on individuals. The daily dosage is increased until the first tested animal or individual shows the first reaction. This NOEL is now multiplied by the average bodyweight of a human being and divided by safety factors and the volume of air breathed in a workshift, to determine an allowable limit for an operator.
Ben Venue Laboratories defines the products it handles as highly potent if the OEL is 1.0 microgram/m3 and will only handle this product in full containment, explained Valerie R. Baker, CSP, CHMM, associate director, Environmental, Health and Safety for Ben Venue.
Mr. Farris warned, however, that basis for the OEL needs to be understood: "If one is relying on the OEL number alone developed by others without understanding the underlying basis, it is possible to improperly assess the risk. For categorizing a compound in the absence of complete data, one must study the characteristics of the drug itself. Someone else's OEL can be a guidance, but there is need to go further."
As a means for going that extra step, Ben Venue also refers to Investigational Brochures, MSDS or toxicology reports for a product. The company also contracts out toxicological studies and is given a one-page monograph on health and safety in return.
"We need to work with our clients to understand the API as much as possible," he says. We won't handle anything if we can't handle it safely."
While Azopharma, too, assesses the OEL, Mr. Meeks says the chemical and physical attributes of the molecule also come under scrutiny before a project gets the go-ahead. These include the molecule's solubility, dose in final product, particle size, and the required manufacturing steps.
Build Containment and Clients Will Come
Once the decision is made to handle a highly potent drug, considerations of how to contain the product must be undertaken. Containment is the emission control and area separation of product from personnel and the surrounding environment in an effort to prevent contamination from one area to another.
As a result, contract manufacturers must have potent compound suites to contain these dangerous drugs. Typically, said Mr. Farris, pharmaceutical finish contractors have not been quick to build containment suites because of the financial investment. He says: "I urge them to spend the money. Build it and they will come."
SafeBridge has categorized handling practices to match the potency and toxicity categories:
Category I -- Safe levels are highest, so traditional control technology and some open handling can be used. Local exhaust ventilation is required.
Category II -- Local exhaust ventilation is needed, in addition glove bags and closed material transfers should begin to be implemented.
Category III -- High degree of containment and control: closed material transfers, no direct contact with the API, glove box, isolators and a closed manufacturing system.
Category IV -- The drug never sees the light of day; it is in a completely closed system.
"There is a premium for manufacturing highly potent compounds and the smart contract manufacturers will have these containment units," says Mr. Farris.
Ben Venue prides itself on being smart when it comes to handling potent drugs. Ms. Baker said the company is in the process of building an expansion for cytotoxic, genotoxic drugs, which will be fully contained and have restricted access. "There will be no crossover of employees from this area to other areas," she assures. In theory, she added, the risk is inside the box rather than in the surrounding area.
SAFC, which handles Category III and IV products, uses engineering controls to protect employees in addition to procedures, facility design and training. "The hardest part is solid or powder handling, where proper systems need to be in place to prevent any inhalation of drugs. Creating barriers for solid handling is critical, so every lab has an isolator that is a sealed and filtered environment," explained Mr. Bormett. "For handling liquid or solutions, we use closed systems that can be moved with pressure, vacuum or certain types of pumps. When the primary goal with both solids and liquids is containment, we also have secondary protection with suits and a supplied air system, customized for each project based on solvent compatibility."
Azopharma has also taken steps to contain danger with its "triple layer of protection." Mr. Meeks said a high containment suite has been set up within a mini-suite and then the employees working in that area wear the appropriate PPE. "Theoretically, the person will never have to make direct contact with the molecule," he said. And while Mr. Meeks admitted it might be extreme, the company monitors its employees' health to get a baseline before work on a molecule begins, during the work, and post-manufacturing.
"From our standpoint, we must have the engineering controls in place to control dust when handling these products," says Mr. Calabro. "It all comes down to protecting employees."
Norwich has upgraded certain areas of its facility to handle Category II products, and has provided its employees with protective equipment, like a powered air purifying respirator (PAPR) with battery-operated HEPA filtered hood. Norwich is working with SafeBridge on a project to identify the improvements needed to upgrade its Category II areas to Category III, but Mr. Calabro admitted that handling these products has made manufacturing more laborious and longer: "The reality is that this is the cost of doing business today. How much of the market do you want to participate in?"
The Wave of the Future
According to statistics from SafeBridge, approximately 80% of today's drugs are potent, an indication that this is the wave of the future. "From a pharmaceutical development standpoint, compounds that are highly potent or cytotoxic possess attributes that greatly benefit a patient," said Azopharma's Mr. Meeks. "Making product to help patients cope with their disease state is what we do in contract manufacturing and we have to do what it takes to do it the right way and bring that care to the market."
"The wave of the future is toward targeted therapies, that 'silver bullet' drug that is delivered in lower doses because it is so powerful," says Mr. Farris. "While this is great for the patient, the worker has to be protected."
But experts warn that not every contract manufacturer has the capability of handling highly potent compounds. "Many contract labs say they can handle potent compounds because that is where pharmaceuticals are going and they see the sales opportunity," said Mr. Bormett. "Few have all the facilities, equipment, systems and procedures in place to properly handle them."