The market for oncology drugs is growing as pharmaceutical companies increase efforts toward developing potent compounds. Innovative containment solutions aim to minimize workers’ exposure to cytotoxic compounds and ensure these compounds are not contaminated. 

Containment equipment vendors such as Howorth Air Technology (Louisville, KY) report growing client interest in containing development-scale equipment such as tablet presses. Manufacturers have traditionally opted to retrofit existing equipment for enclosure in an isolator, but this strategy can be problematic. Many tablet presses were not designed to be contained, and retrofitting them requires modifications that could compromise the presses’ precision and integrity, according to Darren Garvey, vice-president of sales at Howorth. Retrofitting takes time and requires equipment to be taken out of service. “There’s not an ideal [containment] solution for every tablet press that’s out there,” says Garvey.

To overcome these difficulties, equipment providers have begun to produce isolator-ready devices that can easily be retrofitted for containment. Contract developer Metrics (Greenville, NC) asked SMI (Lebanon, NJ) and Howorth to design a fully contained tablet press for its Greenville, North Carolina, cytotoxic facility in May 2008. The companies used their combined expertise to create the “Piccola-C” tablet press, which is enclosed in an isolator and provides approximately 30 ng/m

 of containment, says Garvey. The unit will be on display at this March’s INTERPHEX 2009 conference and exhibition in New York City.

The tablet press shares parts with Howorth’s isolator and fits inside it seamlessly, according to Chris Zappa, a technical service representative at SMI. Its design has fewer components to clean, as well as fewer crevices that could entrap material than traditional tablet presses. Difficult-to-clean mechanical areas and controls are located outside the isolator to simplify cleaning, says Garvey. 

Portability was one of Metrics’s main requirements for the combined unit, according to Joe Cascone, the company’s director of potent pharmaceutical development. SMI and Howorth chose a similar wheel configuration for the tablet press and isolator so that users can roll the integrated device into a facility, plug it in, and begin operation. 

The combined tablet press and isolator take far less time to install than a retrofitted device would, says Zappa.

Another of Metrics’s requirements for the tablet-press isolator was the room to house analytical instruments such as balances and friabilators inside the enclosure, says Cascone. The company wanted to eliminate the need to export tablets to determine their physical characteristics. To ensure their client’s needs were being addressed, SMI and Howorth created a full-scale model of their design so that Metrics could evaluate the enclosure’s ergonomics before receiving the final product. The integrated unit includes a work-surface area of 16 ft

, and the tablet press occupies about 2 ft

, thus leaving ample space for testing equipment. 

To improve user control, Metrics’s integrated tablet press–isolator is operated by an on-board programmable logic control that displays all machine functions in one touch-screen interface. This configuration simplifies the operation of both devices and eliminates the need for communication between two separate control systems. The control interface is located outside the enclosure, which simplifies cleaning and reduces the opportunity for contaminating potent ingredients. In addition, Metrics could easily incorporate the isolated tablet press into a supervisory control and data acquisition system because the combined unit offers one point of integration, Zappa says.

A newly built, integrated unit also has benefits beyond immediate functional advantages. A retrofitted tablet press must be revalidated, for example, but “one integrated unit means one validation protocol, one maintenance schedule, and one standard operating procedure instead of two for a nonintegrated containment solution,” says Cascone. The end user can ensure that the integrated device meets its requirements by participating in the unit’s design from the outset, he adds.

Metrics uses its contained Piccola-C tablet press to produce preclinical, developmental, and Phase I–III supplies of potent and cytotoxic solid oral dosage forms. Although vendors have only designed development-scale tablet presses for containment so far, increased interest in cytotoxic manufacturing will likely spur vendors to pursue production-scale presses that are isolator-ready, Garvey says. Creating equipment with containment in mind also could make the production of cytotoxic drugs more efficient by bringing sophisticated design, improved ergonomics, streamlined control, and easy maintenance to commercial-scale machines.

Articles

Production Lines

Innovative containment solutions aim to minimize workers' exposure to cytotoxic compounds and ensure these compounds are not contaminated.

Containment by Design for Cytotoxic Manufacturing

Quality by design (QbD) helps pharmaceutical companies achieve the US Food and Drug Administration’s desired state of manufacturing. The agency intends QbD as a framework to foster process understanding based on science. The goals of QbD are reducing risks and saving time and money by designing processes with reduced variability and low technology-transfer risk early in the manufacturing cycle. Process development (PD) and manufacturing teams can collaborate by developing a design  space and using process analytical  technology tools and   QbD  principles  with their combined experience to achieve manufacturing-process excellence.

  To  implement QbD and reduce business risks, teams should begin QbD collaboration early during PD.  I mproving the design of a process before manufacturing begins has numerous benefits.

  QbD entails scientifically designing product- and process-performance characteristics into the process to meet specific outcomes rather than  deriving these characteristics empirically from the performance of test batches. Operating parameters are derived from a combination of previous knowledge and experimental assessment, along with a cause-and-effect model that links critical process parameters to the critical quality attributes.

  Today's manual data access and disconnected analytics (sometimes called “spreadsheet madness”) are inconsistent with the goals of QbD. A process is well understood when the following three criteria are met:

All critical sources of variability are identified and explained

Quality is designed into the process so that the process itself manages variability

Product-quality attributes can be accurately and reliably predicted.

It follows that accurate and reliable predictions reflect process understanding and, therefore, risk is inversely proportional to process understanding.

  On-demand access to specific data that are available in real time in a collaborative investigational-analytics environment is a fundamental requirement for successful collaboration between the PD and manufacturing teams. Providing interactive, on-demand access for end users to   data from disparate systems (e.g., laboratory information management systems, historians, and manufacturing execution systems) in one combined form allows investigations for cause-and-effect relationships that link critical process parameters to critical quality attributes to be completed in minutes instead of months. Analytics should include descriptive (i.e., what happened) as well as investigational (i.e., why it happened) capabilities.   A ll types of data-including discrete (off-line), continuous (on-line), and paper-based data-should be included to make meaningful analyses possible.

  Collaboration must enable productivity and compliance improvements that transcend logistical and organizational issues. It also must  allow nonprogrammers and nonstatisticians to complete tasks quickly and effectively as a  team.

  Significant business, quality-compliance, and regulatory benefits  can be achieved  when teams collaborate  by using  available technology for on-demand data access and analysis.  P ayoffs include:

Reduced batch failures, final-product testing, and batch-release costs

Lower operating costs resulting from fewer failures and deviation investigations

Increased predictability of manufacturing output and quality

Reduced inventory costs from raw material, work in process, and finished product

Faster technology transfer between development and manufacturing

Faster regulatory approval of new-product applications and process changes

Fewer, shorter, and less-costly regulatory inspections

In summary, appropriate technologies such as  manufacturing process intelligence software  enable PD and manufacturing teams to  achieve shared QbD goals. Successful collaboration requires the flow of process data and information from PD into manufacturing. The lessons that manufacturing learns must be transmitted to PD, and the right data access, aggregation, analysis, and collaboration software tools must be in place to allow information to be exchanged in both directions. Only then can PD and manufacturing function as a single team with the best outcomes. 

Justin O. Neway, PhD, is executive vice-president and chief science officer at Aegis Analytical Corporation, 

In the Mixer

To implement QbD and reduce business risks, teams should begin QbD collaboration early during process development.

Bridging the Development–Manufacturing Gap to Achieve QbD and PAT

Oystar USA 
 Press produces multilayer tablets


 Oystar USA (Fairfield, NJ) offers its “FlexiTab” fully automated, single-station tablet press for small-batch production. The machine features a multilayer-tablet function to produce three-layer tablets.

The FlexiTab device is not fixed to a compression cycle, unlike other tablet presses. Parameters such as tablet weight, force, dwell, and thickness are adjustable through the unit’s touch-screen panel control system. The press’s hydraulic and pneumatic cylinders achieve compression forces as great as 100 kN and enable rapid punch displacement. Operators can thus simulate various rotary tablet presses at various speeds.

In addition to enabling the compression cycle to be modified, the FlexiTab unit’s computer and software can store compression-profile and tooling-list data. The machine uses standard Euro B and D tooling and can be operated in setup, series, step-by-step, and manual modes.

Schreiner MediPharm 
 Label system helps prevent injuries


 The “Needle-Trap” system from Schreiner MediPharm (Blauvelt, NY) is a label for disposable syringes designed to protect healthcare providers from accidental needlestick injuries. The system comprises a self-adhesive syringe label with an integrated safety mechanism that secures the needle. Healthcare providers can easily uncover the needle to deliver an injection and secure it  afterward, without altering their injection technique.

The Needle-Trap labels can be incorporated into common pharmaceutical labeling systems easily. The product is also available with optional detachable documentation labels intended to reduce the risk of medication errors. The labels can be adapted to the most common syringe types.

The system’s easy integration, flexibility, and process reliability make it a suitable solution for pharmaceutical manufacturers, according to the company. In addition, the Needle-Trap system  meets healthcare professionals’ requirements for field-use safety.

PharmTech's monthly newsletter, Equipment & Processing Report, reviews the Editor's Picks for the February 2009 edition from Oystar USA and Schreiner MediPharm.

Equipment and Processing Report-02-18-2009

Containment by Design for Cytotoxic Manufacturing

Bridging the Development–Manufacturing Gap to Achieve QbD and PAT

February 2009 Editor's Picks: Products from Oystar USA and Schreiner MediPharm