Clinical trial drug makers feel regulatory heat
02/01/2008
Contract manufacturers are realizing that risk assessments demonstrating the absence of cross-contamination between products are essential for regulatory inspection.
By George Miller
Regulators are raising the bar for the majority of drugs in development, causing some problems for manufacturers but wreaking havoc with contract manufacturing organizations. CMOs???perhaps the majority supplier of the short-run drugs used in clinical trials???are attempting to respond by using science-based risk assessments, honing their contamination control processes in general, and increasingly using disposable bioprocessing equipment as well as closed processing.
Unfortunately, science can’t be hurried, and clinical trials are already regarded as among the longest and most expensive steps in the drug development process. Pharmaceutical companies trying to survive in a market increasingly driven by the encroachment of generic versions of drugs whose patents are expiring desperately need to speed up their drug development processes. So the heightened activity of regulators???all in the name of safety???is causing grief all around.
An increasing concern among regulators is cross-contamination, particularly among sensitizers, live viruses, hormones, beta lactams, and carcinogenic, cytotoxic, and cytostatic compounds (the so-called compounds of concern), says Julian Wilkins, founder and a principal at PharmaConsult US, Inc. (Bridgewater, NJ). Some drugs are intended to do harm (to cancer cells, for example) rather than the good intended by most therapeutics. “Sixty to eighty percent of all new entities are high hazard, or potent,” says Wilkins.
In their zeal to ensure safety, regulators are invoking a 1992 World Health Organization (WHO) guideline, which requires segregated and dedicated workspaces for the manufacture of certain compounds. Adopting a segregated and dedicated approach means that “it’s not too taxing on the inspector that way,” quips Wilkins.
“‘Segregate’ means to separate. ‘Dedicated’ means it can only be used for that product,” he explains. Most drugs on the market today require less than full-time manufacturing, so the equipment can be used for making other drugs during downtimes. Not so with the compounds of regulatory concern, given the segregated and dedicated mandate. “At the clinical scale, you’d have to make dedicated facilities and then throw them away if the drug fails,” he notes.
At the extreme is Brazilian regulator Anvisa, which has begun strictly enforcing the WHO guidance. Wilkins notes that for some drug makers, Anvisa has become a top priority, in sharp contrast to the case a year ago. “Drug makers are concerned with the outcome of inspections,” he says. “It affects Brazil’s ability to buy U.S. drugs.”
Anvisa is not the only regulator clamping down. In the U.S., the FDA has issued warning letters that cite a lack of defined space and inadequate risk assessment in the manufacture of potent compounds. Contract manufacturer Bell-More Laboratories, Inc. (Hampstead, MD) received one such warning (VLN # 06200780) in early January 2007. The letter cited “failure to establish defined areas or such other control systems to prevent contamination or mix-ups for handling and/or manufacturing potent compounds,” discovered during an inspection in August 2006.
The letter continued as follows:
“For example, your firm lacked an adequate assessment of the cross-contamination risks posed by the manufacture of several potent compounds (e.g. cytotoxic and hormone products, as well as other products of high pharmacologic activity) at your facility. Controls necessary to prevent cross-contamination of products were not adequately defined. Your firm lacked documentation to determine sources of potential airborne transfer, mechanical transfer, and/or mix-up in the manufacturing and handling of these potent compounds. Specifically, potent active pharmaceutical ingredients (APIs) were introduced into the manufacturing environment during sampling of APIs, formulation of batches in open equipment, aseptic filling of solutions into open vials, and lyophilization of solutions into partially stoppered vials. Furthermore, your firm’s potent compound formulation room (Class 10,000) exhausted directly into the entry room (Class 100,000) where operators move throughout the parenteral manufacturing areas, including the aseptic filling room. Your firm utilized a single air pathway for manufacturing different potent compounds. Finally, operators de-gowned after handling potent compounds in an unclassified corridor between the manufacturing area and the packaging area. Due to the above factors, possible migration of levels of potent compounds may have occurred at your manufacturing facility.”
Other items cited in the letter included a failure to adequately validate cleaning procedures and the “lack [of] adequate evaluation of possible migration of potent compounds throughout the facility.”
All of the violations cited related to Parts 210 and 211 of the 21 Code of Federal Regulations (CFR) concerning current good manufacturing practices (cGMPs). In fact, most of the dozen warning letters issued by the FDA in 2007 to contract manufacturers cite Parts 210, 211, or both.1
This global problem requires a global solution, so a professional society of drug makers has undertaken the task of developing containment procedures that are applicable worldwide. The idea is to address the fact that “international guidelines are confusing and sometimes at odds with one another,” according to Paul Wreglesworth, global technology director of AstraZeneca in the U.K., representing ISPE at the dedicated facilities session of the PDA/EMEA joint conference in October 2006 in London.
“Hazard and risk are frequently confused,” he says, according to the ISPE record of the event.2
“There is no such thing as zero risk. We can assess risk and manage accordingly to increase the degree of flexibility in manufacturing. Segregation may still be the sensible approach in some situations. But the risk management process will drive the decision process. Segregation for operational reasons should not set precedent,” concludes Wreglesworth.
At about that time, AstraZeneca “was getting wildly conflicting views from different regulators” concerning the handling of hazardous materials, according to Wilkins of PharmaConsult US.
Shortly thereafter, regulators stepped up inspections of such facilities, whether they were run by a big pharma company, a “mom and pop shop,” or a CMO. “Who is the biggest risk?” asks Wilkins, rhetorically. “The CMO. They often refuse to tell sponsors what other drugs they work on.” A CMO may have just finished producing a cytotoxic compound before starting the next job.
“The FDA recently started going after CMOs in an aggressive way,” he says. “[Inspectors] proceed under the assumption that the CMO is cross-contaminating, and it’s up to the CMO to prove that isn’t via risk assessment.”
The upshot is that CMOs respond by trying to complete assessments quickly.
Help on the way
ISPE, the not-for-profit association of pharmaceutical manufacturing professionals, has formed a containment technology forum, headed by Stephanie Wilkins, who is president at PharmaConsult US. The forum’s Risk MaPP initiative???Risk Based Manufacture of Active Pharmaceutical Products???is intended to provide guidance for the control of exposures to pharmaceutical compounds based on rigorous science, including a systematic approach to risk management.
Objectives include explaining the use of risk assessments in the implementation and verification of risk controls, and outlining a risk-based process whereby control adequacy and equipment cleaning can be verified.
More simply, the idea is to present alternative approaches to segregation and dedication of facilities to minimize the risk of cross-contamination by setting acceptable daily intake (ADI) levels, rather than such arcane and less relevant (yet still frequently cited) toxic criteria as fraction of therapeutic dose.3
A secondary objective is to ensure consistency and compliance with global regulations and guidance, particularly the International Conference on Harmonization’s guideline Q9 for quality risk management.4
A risk-assessment practitioner
Even before Risk MaPP finalization, some CMOs are using risk assessments as a part of their regular contamination control efforts. U.K.-based Pharmaceutical Profiles is one example. The contract manufacturer specializes in early clinical drug development, with expertise in drug delivery and performance in the clinic. The company’s two-story facility in Nottingham houses a Phase I clinical unit, a GMP facility for the manufacture of investigational medicinal products (IMPs), and formulation R&D facilities.
“We conduct about 30 clinical studies per year,” says Nicholas McEntee, principal manufacturing development scientist, of the combined clinic and manufacturing facility. “We have three clinical wards, so we can conceivably have three or four studies running per month.”
Manufacturing is a 24/7 operation, with the capability of producing eight to ten products per week.
“We have seven dedicated manufacturing scientists, who are 100 percent trained, plus a pool of 15 GMP-trained personnel who work alongside them,” says McEntee.
Facility for making and testing
The GMP manufacturing facility is situated on the second floor of the building, above the clinic. As a result, the company can both make and test new formulations quickly, aiding in the selection of dose levels and formulation types, even during the course of a study.
Services span purchase of start materials through to clinical manufacture, quality control testing, and turnover to qualified persons (QP release). “We can prepare a wide variety of dosage forms, including small volume parenterals, tablets, hard gelatin capsules, and oral solutions,” says McEntee. The company is licensed to manufacture and assemble IMPs within a number of different classes, including penicillins, cephalosporins, hormones, cytotoxins, and cytostatins.
Cleanrooms and prep areas
The manufacturing suite consists of three separate cleanrooms with associated preparation areas, as well as raw material and product storage areas (refrigerated and ambient conditions).
Two of the manufacturing rooms comply with Grade D requirements of the European Guide to Good Manufacturing Practice (equivalent to Class 100,000 and ISO 8) and are used to manufacture oral dosage forms. One room complies with Grade C (Class 10,000, ISO 7), which contains a negative-pressure Grade A (Class 100, ISO 5) isolator used for the preparation of small volume parenterals.
Manufacturing operations are controlled within a formal documented quality management system that complies with the requirements of the Clinical Trials Directive of the EU Guidelines to Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use.
“For manufacturing in the GMP area, we use two full-time qualified persons,” says McEntee. “Manufacturing is done the day before or the morning of clinical testing, followed by QP release, then to the clinical area, where scientists and nurses take ownership prior to dosing.”
Process validation
“For a Phase 1 trial, we might have 10 to 15 volunteers per dosing period. So we’ll manufacture 18 to 20 unit doses. We validate processes to show we get product that meets spec,” McEntee says. “Cross-contamination can be of real significance.”
Due to the small quantities required for clinical trial drugs, manufacturing runs are typically short???only two to five hours???so runs are completed within one shift. “Dedicated equipment is the way to go, though there are some exceptions [e.g., larger tablet presses],” says McEntee. “Also due to the small quantities, a lot of operations can be manually based, using a pestle and mortar. We have mechanical equipment for larger volumes.”
Disposables for bioprocessing
McEntee also adds the CMO uses disposable equipment wherever possible, to save the cost of cleaning (see “Disposables Shine in Short-run Applications”). Disposable weighing and tablet tooling also cut down on cross-contamination.
“We do an internal risk assessment at the start,” he explains. “Before we start a manufacturing run, we check to make sure that the room is being used for its intended purpose. We don’t use separate cleaning contractors. The best people [to do the cleaning] are those who use the facility every day [the manufacturing scientists]. It’s not just cleaning, it’s contamination control. And we do frequent particle counts to show we’re maintaining the air cleanliness level.”
The manufacturing scientists go through each room to make sure that all previous documentation and materials have been removed and that the room has been cleaned. Then they do their own line clearances.
Contamination routes
Once the room is set up, continues McEntee, there are four possible ways for contamination to occur:
- Raw materials
- Product
- Waste
- Personnel
“We go one step further in classification by having team members wear cleanroom suits, which minimizes shedding potential,” he confirms.
 Figure 3. Pharmaceutical Profiles currently has seven dedicated manufacturing scientists plus a pool of 15 GMP-trained personnel. Photo courtesy of Pharmaceutical Profiles. |
A restricted area is used for holding clinical materials. The materials are passed into the manufacturing area via a dedicated transfer hatch. Material packaging is swabbed with alcohol prior to transfer. Manufactured products are sent through a separate transfer hatch, so the raw materials and the finished product travel different routes. The product never leaves the room until it is finally sealed.
“We have an exceptional team of [manufacturing] people with full scientific backgrounds,” says McEntee. “That’s crucial. It gives people a fuller understanding of the quality issues. They have to be very well cross-trained.”
CMO adds clinical capability
Across the pond in the U.S., contract manufacturer DSM Pharmaceuticals, Inc., a business unit of DSM Pharmaceutical Products, announced in November that it had expanded its service offerings to include formulation development and clinical trial manufacturing for solid-dosage form products.
The company’s facility in Greenville, NC, now includes a clinical trial manufacturing area that already performs GMP production for commercial products. The clinical trial manufacturing area has both FDA and EU certifications.
“We have a Grade A environment for filling; manufacturing is done in Grade C,” says Terry Smith, vice president for business management, sterile CTM and cytotoxic. “The facility is equipped to handle both liquid and lyophilized formulations; all products are sterile injectables.”
Filling is done in a Grade A environment using HEPA-supplied laminar air flow. Standard steps between manufacturing lots include the removal of all product, followed by disinfection and sanitization. A sporicidal agent is used, says Smith.
From environmental monitoring to cleaning of the cleanrooms, the clinical trial area is consistent with contamination control procedures for the commercial arm. “But we do have separate quality systems for the [clinical trial manufacturing] area,” adds Smith. “They all meet or exceed cGMP requirements. We have very robust and solid quality systems here. We separate systems for Phase 1 and 2. We draw the line at human use.”
Robust and solid quality systems remain front and center for drug makers, as always. But when the compounds being manufactured are potent, and the manufacturer is a contractor that produces multiple compounds, regulators look especially closely for signs of cross-contamination. The traditional method of using segregated and dedicated facilities for the manufacture of such compounds is likely to become a fallback position as industry works with regulators on Risk MaPP guidance for the control of exposure to such compounds, including a systematic approach to risk management.
References
- FDA’s Electronic Freedom of Information Reading Room???Warning Letters and Responses; www.fda.gov/foi/warning.htm.
- P. Wreglesworth, “Implications for Working in a Global Environment,” pres. at PDA/EMEA Joint Conf., London, Oct. 2006.
- E.V Sargent, “Update on ISPE’s Risk-based Approach to Manufacturing Active Pharmaceutical Products Guideline (RISK MAPP), pres. at ISPE Washington Conf., June 5???8, 2006.
- ISPE Podcast, “Introduction and Update on ISPE’s New Baseline Guide: Risk-MaPP,” http://ispe.mypodcast.com/2007/11/Introduction_and_Update_on_ISPEs_New_Baseline_Guide_RiskMaPP-58418.html
Resources and contacts
DSM Pharmaceuticals Inc.
Greenville, NC
www.dsm.com
GE Healthcare
Chalfont St. Giles, Bucks, UK
www.gehealthcare.com
ISPE
Tampa, FL
www.ispe.org
Pharmaceutical Profiles
Ruddington, Nottingham, UK
www.pharmprofiles.co.uk
PharmaConsult US Inc.
Bridgewater, NJ
www.pharmaconsultus.com
Disposables shine in short-run applications
“Disposable technology has a sweet spot in the clinical trial manufacturing area due to scale,” says Nigel Darby, head of life sciences R&D at GE Healthcare, based in Bucks, UK. “It’s well suited to product development of biologics, lowering the amount of documentation for validation.”
Last October, the healthcare manufacturer introduced its ReadyToProcess disposable systems and devices for biopharmaceutical production, spanning cell culture and fermentation to final purification. The elimination of cleaning tasks???which promises safety, time, and financial benefits???could be a boon to CMOs producing toxic compounds.
“The switch from stainless steel to disposable bioprocessing technology offers several benefits to the manufacturers of toxic substances,” notes Gerard Gach, leader for product marketing for ready-to-process and filtration products at GE Healthcare. “The first is [elimination of] cross-contamination between runs in multi-use suites. That always comes up [in customer discussions]. Such contamination could cost millions.”
Disposable manufacturing components are delivered pre-sanitized or they are gamma irradiated. They are pre-assembled, causing little worry about environmental contamination. The self-contained aseptic environment is inherently sealed. “We as manufacturer [produce disposable equipment] in a controlled environment, and also establish chain of custody,” says Gach. “We double-bag products for cleanroom-to-cleanroom delivery.”
Gach adds that in pilot operations based on stainless-steel technology, there’s always the concern that residual, leachable, or bioburden contamination is introduced when plumbing the system. ReadyToProcess systems, by contrast, come with a certificate of assurance that the products meet specs for any manufacturing residuals.
In addition, hard-plumbed systems often require the breaking of seals between manufacturing runs. Seals can eventually leak, spilling drug components into the cleanroom. “With disposables, you’re not breaking lines,” says Gach.
Even though some assembly is required with the ReadyToProcess systems, it’s done with aseptic connectors that ensure a sterile connection. “After you make a connection, you don’t have to go back and steam sterilize,” Gach says. “That technology continues to develop. Those connectors are important to the vision of a complete [disposable system]. We’ve become enamored of genderless connectors, which mate right up to each other. These are truly disposable, but come with the assurance that when you so mate, it’s aseptic.”
Risk MAPP terms
Key components of the ISPE’s Risk MAPP initiative include risk assessment, risk control, and cleaning validation. Risk assessment includes hazard identification, exposure assessment, risk characterization, control of risk, verification, communication, and review. Such assessment is based on scientific knowledge that links the protection of patient, product, and employee.
Concepts of risk control include operational controls required to minimize cross-contamination and to minimize risk; exposure to all compounds including highly hazardous ones should be maintained below ADI levels. Risks can be controlled in many ways based on risk assessment, and a combination of control measures may be required. Control by segregation and dedication is always an option.
For multi-use facilities and process equipment, manufacturers must be able to consistently clean to a level where the risk of cross-contamination of one product to another can be shown to be minimal and acceptable. Cleaning validation limits are to be based on ADI levels.