Quality must be built into the design of a facility to ensure that drugs are manufactured under conditions and practices required by the good manufacturing practices (GMPs) regulations. This principle is further enhanced by the practice of being current. FDA explains the idea of “current” as follows:

…the "c" in cGMP stands for "current," requiring companies to use technologies and systems that are up-to-date in order to comply with the regulations. Systems and equipment that may have been "top-of-the-line" to prevent contamination, mix-ups, and errors 10 or 20 years ago may be less than adequate by today's standards. (1)

In a new facility, the expectation is that the design successfully embodies cGMPs. In existing legacy facilities and as buildings age, however, ensuring compliance with cGMPs is more complicated. A review of a facility’s gowning operations can bring significant insight into the current state of cGMP compliance. 

Gowning embodies many of the major elements of cGMPs and as such is a window into a facility’s cGMPs. A highly compliant facility will have gowning operations that are clearly defined and readily understood. Such operations are easy to diagram, easy to describe, and easy to apply consistently. Conversely, confusing, complicated, or highly individualized gowning operations are indicative of a facility with compliance issues. When gowning procedures are not simple or when there is a lack of consistency and gowning exceptions are allowed, a red flag should be raised and a detailed review of the facility undertaken. The following are three major gowning characteristics to look for.

 Centralized gowning, occurring as part of the entry to a specific production area, although not a guarantee, is indicative of organized and orderly production zones. For centralization, functions of the same cleanliness grade must be grouped together and not dispersed into individualized or isolated islands of production. Centralized gowning is also indicative of organized material and personnel flows. If activities of one hygiene type are aggregated together, materials and personnel only need enter the zone once to have access to all the functions within. This can be contrasted with decentralized zones that require material and personnel to enter and exit production areas multiple times in the course of processing a single batch. Operational time is wasted on excessive material handling and multiple gowning/de-gowning sequences.

Is the protective clothing appropriate for the cleanliness level of the area?

 In classified production areas, the clothing requirements must provide the amount of protection commensurate to the type of product processed, the operation being undertaken, and the cleanliness class or grade of the space. 

We’ve seen facilities, for example, where primary and secondary packaging are combined and have only a single gowning access. As a consequence, secondary packaging must be maintained at the same high level of cleanliness that is required for primary packaging. In these facilities, the flow of materials for both primary and secondary share the same routing and result in intermixing of raw and in-process materials as well as primary and secondary packaging components. In this example, the easily identified misapplication of gowning reveals a larger GMP issue of confused and disorganized material handling. In addition, always gowning to the higher level increases operating costs in terms of gowning materials used and operational time.

Do you see gowned personnel walking outside their production areas?

 There are older facilities where the delineation between production and controlled non-classified areas is not strictly drawn. If gowned and un-gowned personnel are walking past each other in the same hallway, this is a significant problem, with potential for contamination.


  To evaluate a facility, consider asking the following questions about the facility’s gowning operations: 

Is the gowning operation easy to diagram? 

Is the hierarchy of gowning simple and clear? 

Is the hierarchy of gowning sequential relative to air classifications or grades? 

Is there clear and complete segregation of types of gowning? 

Are there exceptions to gowning protocols? 

What do gowned personnel do when they go to the restrooms? 

What do gowned personnel do when they go to the cafeteria? 

Do you need to gown and de-gown just to get to a desired destination?

Regulatory guidelines for GMPs include straightforward statements, but the application of cGMPs to a facility is not so simple nor is it obvious. Because gowning is deeply integrated into a facility's operation, many cGMP fundamentals are reflected in gowning implementation. These questions can be used to help conduct a simple, initial evaluation and to gain a better understanding of compliance issues in a facility. The result will reveal where a facility is compliant and where there is room for improvement.  Either finding will enable proceeding from a basis of knowledge and moving forward with confidence and a clear goal for maintaining compliance.


1. FDA, “Facts About Current Good Manufacturing Practices (cGMPs),” 

www.fda.gov/drugs/developmentapprovalprocess/manufacturing/ucm169105.htm

Articles

Troubleshooting

Gowning practices embody cGMPs and can be a tool to evaluate cGMP compliance.

Evaluating Facility cGMP Compliance By Reviewing Gowning Practices

Progress in continuous manufacturing for solid-dosage drugs was evident at INTERPHEX 2014, held March 18–20 in New York City. Equipment manufacturers now offer continuous lines, such as the Lodige Granucon continuous granulation and drying system and the GEA ConsiGma system that includes a high-shear granulator, dryer, in-line blender, and tablet press. Most recently, at interpack 2014, Glatt introduced the MODCOS continuous rotary chamber process insert, which can be used to convert Glatt ’s batch GPCG to a continuous fluidized-bed system. Associated equipment for continuous process lines, such as feeders, control systems, and process analytical technology (PAT), are also now available from several companies. 

“We have seen a huge increase in the amount of interest since last year’s INTERPHEX,” said Doug Hausner, associate director for industrial relations and business development with the Engineering Research Center for Structured Organic Particulate Systems (C-SOPS) based at Rutgers University in New Jersey, in 

. FDA has actively promoted use of continuous processes, and a number of applications using continuous processes are currently in review by the agency. Approval and commercial production of these products is expected to give a boost to the adoption of continuous processing technology by the rest of the industry, noted Hausner. 

Hot-melt extrusion (HME) is one type of continuous processing technology that has been embraced over the past decade, noted Charlie Martin, president of Leistritz, in 

. HME is a “battle-hardened,” proven technology that has been used for 50 years in other industries. The challenge for the pharmaceutical industry is to learn this existing technology and apply its well-known processing principles to pharmaceutical processes, said Martin. One opportunity for industry members to learn more about HME is an annual Pharmaceutical Extrusion Seminar sponsored by Leistritz, to be held on June 18-19, 2014. 

One of the initial drivers for interest in continuous pharmaceutical processing was FDA’s PAT initiative. Integration of PAT into continuous lines is an ongoing focus of research and development. “Upcoming technologies will have a real effect on what can be done in terms of real-time measurement,” predicts Hausner.

Another area of development is integrating advanced control of processes, which is of interest to regulatory agencies because it can lead to greater control and thus improved quality. Advanced control moves beyond local control of individual unit operations and incorporates an overall supervisory control system. In an advanced process control solution, data from PAT is captured in a PAT or quality-management system, explained Pamela Bruen Docherty, Life Sciences industry manager USA at Siemens, in a presentation at INTERPHEX 2014.  “In a continuous process, the data comes quickly and you want to react to it quickly,” said Docherty.  “A solution must capture and interpret the data in real-time to adjust the process parameters and keep the product within control.” The goal is to manage the data and allow real-time release of the product. 

Some question how a batch can be defined when using a continuous process. “According to FDA regulations, a batch is an amount, not the manufacturing method,” explained Docherty in the presentation. A batch is defined as a specific amount produced in a unit of time (e.g., a day) or quantity (e.g., kilograms or a tablet count) that has uniform characteristics within specified limits. The batch definition should allow traceability in case of a recall. 

One of the current needs is to develop better business models and design effective tools to measure return on investment for continuous processing, because it is quite different from existing batch processes, noted Hausner in a presentation at INTERPHEX 2014. With many aspects of continuous manufacturing in active development, further progress can be expected in the upcoming year. 

Production Trends

Progress in equipment availability, process analytical technology, and advanced process control aids ongoing development of continuous solid-dosage manufacturing processes.

Continuous Solid-Dosage Manufacturing Moves Forward

INTERPHEX, the annual pharmaceutical trade show, always presents a wide array of packaging innovations. The 2014 show (March 17-19 in New York City) included equipment designed to meet serialization requirements.  


  Videojet 8610 thermal inkjet from Videojet prints nonporous substrates like coated paperboard, blisters, film, and foil with fast-drying, solvent-based inks. The key is a patented ink cartridge designed to jet methyl ethyl ketone (MEK)-based inks “Formerly, you had to have a knock-out area for water-based thermal inkjets,” said Jim Kerper, North American sales manager for the Systems Solution Group at Videojet Technology, in an interview with 

. A shutter-based mechanism controls the printhead, which prints at a resolution of 240 x 240 dots per inch at speeds of up to 102 m/min (333 ft/min). Character height with a single printhead is 12.7 mm (0.5 in), but up to two printheads can be ganged. Higher print quality on the nonporous surfaces aids the inspection process. In addition, the unit’s preset font packages help the vision system recognize the code (e.g., to distinguish “O” from zero or “B” from 8). The serialization-ready thermal inkjet prints alphanumeric characters, as well as linear and two-dimensional barcodes including QR codes and the GS1-compliant DataMatrix code specified in serialization requirements. The printer can be supplied with an installation- and operation-qualification validation package. 


  Another serialization-ready system consists of a print/apply labeler from Domino Amjet integrated with the Intelli-Pac Manual Case Aggregation System from Omega Design. The stainless steel machine handles loose or bundled bottles and cartons. The process begins with placement of a case on a table or in a case former. A plunger-equipped printer/applicator applies a serialized label. One camera reads the case label and another captures the codes of each item in the case to establish a parent/child hierarchy. Configurable for manual or semiautomatic operation, the ergonomic system seamlessly integrates to layer-aggregation technology, case-label printer, operator touchscreen, data-management system, case-loading table, and handheld scanner. Other capabilities include unit-to-bundle data syncing, case-to-pallet data syncing, and case-forming and taping. Domino also offers equipment for applying serialized codes to primary containers. 


An advanced quality-control (QC) tool bundle from Global Vision inspects text, artwork, spelling, Braille, and barcodes and provides annotation functionality. Web-based software deploys on an on-premise or private cloud server and provides enterprise-wide access to packaging QC tools. “Proofware gives any enterprise instant access to everyone involved in the security of their brand copy and artwork throughout the enterprise,” explained Reuben Malz, president of Global Vision in a press release. “With Proofware a new level of collaboration is achieved between different teams within the organization, their customers, and suppliers” (1). Other features include report management tools to organize inspection reports and easy integration with artwork, document, and product-lifecycle management solutions. Software permits multiple inspections to be run with the same set of files. Proofware also supports e-signature, call-outs, stamps, measurement, and color inspection.


1. Global Vision, “Global Vision Releases Proofware, the First All-in-One, Cloud-Based, Packaging Inspection Suite,” Press Release, Feb. 11, 2014.

For further discussion, read the PackForum article in the June 2014 issue of 

Hallie Forcinio is Pharmaceutical Technology's packaging editor, 

Packaging & labelling

Printing, labeling, aggregation, and inspection equipment meets serialization requirements.

Packaging Innovations Displayed at INTERPHEX 2014

Garvey Corp. has developed patented solutions to vial-handling problems.  The Vial Drying System uses a conveyor to pull moisture from vials arriving from cold storage.  Vials can be dried and brought to room temperature in minutes, rather than the hours of time typical for conventional drying on trays. The drying system is mated with the Infinity Accumulator, which uses pressure-less filing to send the vials in single-file or multiple lanes at rates up to 800 vials per minute for feeding into a filler or labeling system. 

Garvey's vial-drying system and pressure-less accumulator reduces drying time and decreases the risk of vial damage.

System Improves Vial Drying and Handling

Catalent Pharma Solutions launched its Advasept technology for the advanced aseptic filling of injectable drugs. The new platform provides a glass-free, aseptically filled, primary container that reduces or eliminates many concerns associated with traditional glass vials, including the potential for glass particulate contamination and the risk of accidental breakage in transit or use. Catalent uses blow-fill-seal manufacturing technology to aseptically manufacture, fill, and seal a polymeric primary container. Advasept stoppered vials are currently produced in 10-mL, 50-mL and 100-mL sizes and are available with pop-off or twist-off tops. Containers can be tailored to meet the unique needs of customers across many markets, such as biologics, pharmaceuticals, generics, and animal health.

Catalent's Advasept platform uses blow-fill-seal technology to aseptically manufacture, fill, and seal a polymeric primary container for injectable drugs.

Equipment and Processing Report-05-21-2014

Evaluating Facility cGMP Compliance By Reviewing Gowning Practices

Continuous Solid-Dosage Manufacturing Moves Forward

Packaging Innovations Displayed at INTERPHEX 2014

System Improves Vial Drying and Handling

Advanced Aseptic Technology Provides Glass-Free Delivery of Injectable Drugs