As manufacturers focus more efforts on acquiring or manufacturing biologics, the popularity of prefilled syringes continues to rise. This product format is replacing vials, which are less convenient for caregivers and patients to use. FDA considers prefilled syringes to be combination products because they contain two regulated constituent parts (i.e., a biologic and a medical device). Even though manufacturers are responsible for ensuring the quality of combination products, some companies may not be certain about what quality system to apply to their production. 

In the absence of a final rule that governs combination products, manufacturers should contact the agency if they have questions. “The individual constituent parts [of a combination product] must be manufactured in accordance with the cGMPs applicable to that type of article,” says John Barlow Weiner, associate director for policy in FDA’s Office of Combination Products. “For example, if a facility makes an autoinjector, it must comply with the quality-system regulation at 21 

 820, and a facility that makes the drug for inclusion in the injector must comply with drug cGMP requirements at 21 

On Sept. 23, 2009, FDA published a proposed rule for combination products that draws on existing quality systems for drugs and devices. The most important message of the proposed rule “is that while the constituent parts are separate, the individual regulations that pertain to those constituent parts apply to those constituent parts,” says Mike Gross, senior consultant for combination products at Biologics Consulting Group. “At the point where the constituent parts are combined, both regulations apply.” 

From that point onward, manufacturers have the option of applying a streamlined quality system that combines the regulations for drugs and those for devices, according to the proposed rule. FDA considers drug and device regulations to be similar, but recognizes that they do not overlap in certain areas, says Gross. To create a streamlined quality system, a firm can use one regulation as its basis, then add the elements unique to the other regulation as necessary to ensure the quality of the combination product.

For example, if a combination product’s primary mode of action is its drug, then a firm can base its quality system on 21 

 210 and 211. But to be fully compliant, the firm’s quality system would have to address provisions in 21 

 820 regarding management responsibility, design controls, purchasing controls, installation, and servicing, according to the proposed rule. Likewise, a firm could opt to base its quality system on 21 

 820 if the combination product’s primary mode of action were its device (e.g., a drug-eluting stent). But to be fully compliant, the firm would have to address provisions in 21 

 210 and 211 regarding stability testing, expiration dating, and reserve samples, among other topics.

Although the proposed rule provides details about how to comply with applicable regulations, some companies find parts of it ambiguous. One source of uncertainty includes the quality-system requirements for the manufacture of components (e.g., syringe barrels) and constituents of prefilled drug-delivery systems, which some manufacturers view as drugs in functional container-closure systems, says Gross. Some manufacturers believe that drug-delivery system components should be regulated as components of a drug-product container-closure system, rather than as components of the device constituent of a drug–device combination product. But this interpretation is controversial, and companies are seeking official clarification and hope to see this point addressed in the final rule or in a subsequent guidance, says Gross.

“The proposed rule is not in force and, therefore, is not itself a regulation with which manufacturers must comply,” says Weiner. FDA inspections will continue to evaluate whether makers of combination products are operating in accordance with cGMP, based on existing regulations, “as well as with associated Agency Staff Manual Guides relating to manufacturing facility inspections,” says Weiner.

And despite its potential ambiguities, the proposed rule has found acceptance within industry. “Based on the comments received, it appears that stakeholders generally support the approach of the proposed rule with most comments seeking clarification rather than major substantive revision,” says Weiner. By the time the rule becomes final, drug manufacturers should have the information they need to produce increasingly popular products, such as prefilled syringes, in full compliance with FDA regulations.

Articles

Production Lines

Even though manufacturers are responsible for ensuring the quality of combination products, some companies may not be certain about what quality system to apply to their production.

A Hybrid Approach to Combination Products

Many companies are converting their existing cleaning processes to clean-in-place (CIP) systems, which can be more efficient and reliable than other methods. Part I of this article explained the benefits of CIP systems and described the challenges that they must overcome. The article also provided recommendations for developing and validating CIP systems. This article will focus on the components that make up a CIP system and describe how the system should be built to ensure efficiency.

A CIP system includes equipment and various components. These systems can be fully or semiautomated for minimal operator intervention. They can be fixed installations or portable systems that clean several pieces of equipment in the same manufacturing train. Figure 1 shows a fixed CIP skid unit connected to manufacturing equipment. CIP systems can also be designed and integrated into the equipment itself. Figure 2 illustrates a large vessel with the necessary components to perform cleaning without a separate CIP unit. All cleaning steps, particularly cleaning solution preparation and heating, are performed in the same process vessel.


Materials used for GMP equipment must be easy to clean, corrosion-resistant, and nonreactive under manufacturing and cleaning-process conditions. Surfaces should have a smooth appearance and be fabricated appropriately with materials that are adequate for the process. Processing equipment is primarily made of 304- or 316-grade stainless steel and with glass or hastelloy. Seals, gaskets, and closures are made with plastic and elastomers that are suitable for the intended application.

For optimal cleaning, surfaces must be free of scratches, crevices, etching, and irregularities. Polished surfaces with roughness of Ra ≤ 1.6 µm have been recommended particularly for the biotechnology industry to facilitate cleaning (1, 2). Nonetheless, recent studies suggest that surface cleanability is most affected by surface defects, rather than surface roughness (3).


 Welding is the preferred method for connecting piping that handles product and transfers cleaning solutions. A properly welded connection should not have excessive cracks, crevices, misalignments, or other surface deformities that contribute to corrosion. In the case of temporary joints used for maintenance or multiprocess reconfigurations, sanitary clamp-type connections are universally accepted for joining two similar end pieces with a centered elastomeric gasket. Variations of the clamp-type connection have also been developed for high-pressure applications. Flanged and cam-type connections must be avoided because their sealing material may not align adequately and may eventually collect residues in the gasket area.

Diaphragm and pinch valves are most often recommended and are generally considered sanitary valves. Other types of valves (e.g., ball, gate, and butterfly valves) entail contamination risk by accumulating soil and debris at gasket spindles and crevices, so they are difficult to clean in place. Ball valves used to manufacture active ingredients are commonly located at the bottom of large vessels because they can withstand high pressures. If a ball valve is installed, specific instructions should be included in the process cleaning procedure for dismantling and visually inspecting the ball valve once CIP cleaning is completed. Additional manual cleaning steps and sampling for cleanliness may also be necessary.


 Dead legs are areas in a piping system where liquid or gas can become stagnant and where water is not exchanged during flushing. For obvious reasons, dead legs should be minimized or, if possible, avoided in CIP piping. Bacteria and soil in dead-end pipe lengths and crevices are protected from flushing and sanitization procedures and eventually can contaminate the piping system. Dead-ends in piping are unacceptable unless they can be physically inspected and sampled for cleanliness. Branches or tees used for instrumentation should be positioned horizontally, and their length should be limited to 1.5 times the pipe diameter. Figure 3 depicts a dead leg and its recommended orientation.

Personnel can clean piping effectively by circulating the cleaning solution at flow rates that produce turbulent flow conditions. Usually, CIP flow rates are much higher than the flows used for manufacturing processes. The Reynolds number (Re) determines whether a flow is laminar or turbulent. This dimensionless number describes the expected velocity profile for a fluid flowing under certain parameters. For a fluid running in a circular piping, Re can be calculated with the following equation:

    
             µ                            

 is the pipe diameter, ρ is the fluid density, 

 is the fluid mean velocity, and µ is the fluid viscosity. Re numbers higher than 4000 produce turbulence that creates random eddies, vortices, and other flow instabilities that exert mechanical action on the pipe walls (4). Random eddies are better than smooth, constant fluid motion because they promote mixing and help prevent soil redeposition (see Figure 4). Most CIP designers would recommend a fluid velocity of approximately 5 ft/s (1.5 m/s) for water-based solutions to displace gases, penetrate dead legs, and fill vertical piping.

Horizontal ductwork must be sloped at 1/16 to 1/8 in. per foot of piping (0.5 to 1 cm per meter of piping). The pitch must be toward drain points. 

Pumps should be cleaned in line with the piping circuitry. When a pump is not required to operate in the CIP circuit, the flow may be directed through a bypass. In general, the hygienic attributes of a pump are the materials of construction for its main pump chamber and sealing points. With a few exceptions, pumps typically include a sealing mechanism on the rotating shaft. Most hygienic pumps have seal mechanisms outside the product-contact zone with minimal elastomeric exposure to product and cleaning solution. 

Tanks, internal components, and ancillary equipment


 Pharmaceuticals can be processed in vessels of various shapes, sizes, and configurations. If they are to be cleaned in place, processing tanks must have a conical dome and a bottom that facilitates draining. Flat bottoms, which are rare in pharmaceutical applications, need to have bottom or side drain ports. Side drain ports must be located below the end of the side wall, and the tank should be sloped toward the drain. For good results, the vessel must drain liquid at the same rate that it takes in liquid. These same principles should also be followed for CIP skid tanks.

The bottom outlet nozzle of a vessel typically requires a vortex breaker to prevent the swirling of flow. Disc and X-type breakers are most common and are easy to CIP.

Nozzle design should follow the same sanitary guidance as that discussed for piping. The length-to-diameter ratio should be close to 1.5, and the nozzle should be located on top of the vessel. For example, pressure-relief devices such as rupture discs are easier to clean when mounted directly onto the nozzle, rather than on an extension pipe. Tank insulation may affect nozzle design and may require a flared nozzle. Side ports must be sloped toward the drain point.


 Personnel can clean tanks effectively by distributing cleaning solutions with spray devices (5, 6). Various models are available, including static devices (e.g., spray balls, spray tubes, and spray bubbles) and dynamic devices that can rotate on multiple axes. Spray devices can cover large surface areas in vessels, charge chutes, vent lines, and pipes larger than 8 in. (20 cm) in diameter. In vessels, static spray devices direct the solution to the top dome, from where it cascades down in a sheeting action. In comparison, dynamic spray devices operate at relatively high pressures and rotate at various angles to produce surface impingement.

All CIP spray devices should contain drain ports that allow them to clean themselves. Periodic inspection is recommended to ensure that the spray holes are not clogged with particles and debris that can affect spray coverage and pressure.

The flow rate required to achieve the proper spray and cascading effect is 2.5 gpm per foot (31.1 L/min per meter) of vessel perimeter in a vertical tank and 0.25 gpm per square foot (10.2 L/min per square meter) of surface area in a horizontal tank. Baffles, dip tubes, nozzles, or agitators in a tank challenge the cleaning process by preventing sprayed fluid from striking the far side of the vessel walls. When these mechanical items are present, additional spray devices may be necessary to reach protrusions and shadowed areas.

Many types of agitators are available for specific manufacturing applications. Agitators with pitched blades can be cleaned with the tank-spray devices. Other types of agitators (e.g., Rushton impellers) may require spray devices below the impeller to ensure thorough cleaning. Other options for cleaning agitator blades may include immersing them in cleaning solution and adding mechanical agitation to facilitate soil removal.

The most effective way to clean vent lines, condensers, charge–discharge chutes, and ancillary equipment is by direct application of CIP solution from a spray device. Bubble sprayers connected to permanent or semipermanent CIP pipes spray upward and across to form falling films that sweep away soils.

Transfer panels play an important role in CIP systems. They are metal boards with an array of nozzles that connect multiple pipelines. Transfer panels supply and change the flow of cleaning fluids through CIP pipelines linked to multiple process machines within piping circuitry. A 

, helps to break the flow between fluids used in manufacturing without the risk of cross-contamination.

Note: Part I of this article appeared in the June issue of 

DS/EN 13311-1: Biotechnology–Performance Criteria for Vessels Part 1: General Performance Criteria 

 (McGraw-Hill, New York, 8th ed., 2008), pp. 1–56. 

Elizabeth Rivera is a technical service specialist for STERIS, 7405 Page Ave., St. Louis, MO 63133, tel. 314.290.4783, fax 314.290.4650, 

In the Mixer

The author describes the components that make up a clean-in-place system and how the system should be built to ensure efficiency.

Basic Equipment-Design Concepts to Enable Cleaning in Place: Part II

BETE Fog Nozzle
 Nozzle cleans tanks efficiently


 BETE Fog Nozzle’s HydroWhirl Poseidon rotating tank-washing nozzle combines slow rotation and a high-impact spray pattern. The nozzle does not include bearings, which enables it to rotate slowly at a nearly constant speed over the operating pressure range. The slow rotation is intended to clean tanks more efficiently than static and rotating spray balls by increasing the impact of cleaning fluid and increasing spray dwell time on the target surface.

The HydroWhirl Poseidon unit cleans and lubricates itself, and this design is intended to eliminate process contamination. The nozzle is made of PTFE, and the clip-on pin is made of 316 stainless steel to withstand corrosive environments and harsh cleaning fluids. The product is available in six standard models, each of which offers eight connection options. The nozzle is appropriate for tank diameters as large as 22 in. in pharmaceutical applications that require low water, energy, and chemical consumption.

Continental Disc
 Pretorqued holder ensures accurate loading and sealing


HPX-PT pretorqued holders from Continental Disc incorporate high-strength steel socket head cap screws to ensure accurate loading and sealing of the HPX rupture disc. The HPX-PT pretorqued holder allows the disc to be correctly fitted in the workshop using precise recommended torque levels before the complete assembly is installed between the flanges in the process-system relief stream.

The unit’s cap screws maintain a seal between the holder and rupture disc to prevent the disc from slipping or leaking in the holder after it is removed from the vessel nozzle or pipe flange for inspection. Once the disc has been inspected, the holder and disc may be reinstalled.

In addition, the HPX-PT pretorqued holder has a durable, tapered seating surface designed to prevent rupture disc slippage and to provide a bubble-tight seal over various HPX rupture disc sizes, materials, and burst ratings. The HPX-PT pretorqued holder is appropriate for active-ingredient processing plants and fill–finish plants that require sanitary connections and environments.

PharmTech's monthly newsletter, Equipment and Processing Report, reviews the Editor's Picks for the July 2011 edition from BETE Fog Nozzle and Continental Disc.

July 2011 Editor's Picks: Products from BETE Fog Nozzle and Continental Disc

 We’re attempting to validate a clean-in-place process using total organic carbon (TOC) as the analytical method. Our swab-sample recovery tests are giving us inconsistent results. Recovery values range from 95% to 205%, and there seems to be no correlation with the amount of drug product deposited on the coupon. What could be the problem?

A: TOC, unlike high-performance liquid chromatography (HPLC), is a nonspecific analytical method. The advantage in cleaning validation is that TOC can detect excipients, partial reactants, and detergents, in addition to the drug product. When coupled with visual inspection and other indirect tests, TOC can help minimize the overall contamination of the final product. However, because TOC is a nonspecific method, you need to account for and minimize potential sources of error to achieve consistent results. The erratic recovery in your studies is likely associated with one of these errors.

First, the measurement device should be capable of achieving the desired level of accuracy, sensitivity, specificity, and reproducibility per 

 <1225> and the International Conference on Harmonization’s Q2 (R1) can help validate the analytical method. Use spike samples (i.e., pure water samples spiked with a known quantity of the target organic compound) to challenge the instrument accuracy before performing the swab-recovery tests. The swabs, vials, and coupons also can influence the consistency of results. Organic contaminants on these materials can contribute to the overall TOC result. Be sure to use swabs that have been certified for low TOC background. Swabs used in conjunction with HPLC methods often have high and variable organic content because it is not a crucial parameter for HPLC. Similarly, the vials selected for the testing should be certified for low TOC content. If you are cleaning the glassware yourself, use a mild caustic cleaning agent followed by thorough rinsing with low-TOC water. Finally, the coupons should be cleaned properly. They could be baked in a furnace to burn off residual organics or cleaned using a mild caustic detergent, then rinsed thoroughly with low-TOC water. 

—Kevin Aumiller, senior applications specialist at GE Analytical Instruments 

If you have a problem with your equipment or process, an industry expert may have the solution. Please send your question to 

 and we may be able to provide an answer in a future issue. All questions will remain anonymous.

Troubleshooting

We?re attempting to validate a clean-in-place process using total organic carbon (TOC) as the analytical method. Our swab-sample recovery tests are giving us inconsistent results. Recovery values range from 95% to 205%, and there seems to be no correlation with the amount of drug product deposited on the coupon. What could be the problem?

Equipment and Processing Report-07-20-2011

A Hybrid Approach to Combination Products

Basic Equipment-Design Concepts to Enable Cleaning in Place: Part II

July 2011 Editor's Picks: Products from BETE Fog Nozzle and Continental Disc

Erratic Recovery-Test Results