A company’s contamination-control plan is an important document designed to formalize the rationale, methods, and validation of contamination-control procedures in a manufacturing facility. The plan is a valuable tool for pharmaceutical, medical device, and personal product manufacturers and should be written to address all phases of the facility’s life cycle. Specifically, the contamination-control plan should achieve the following goals:

Minimizing the bioburden throughout the manufacturing processes. This step is important for reducing the challenge posed to the sterilization process (i.e., in sterile manufacturing) or to the finished-product bioburden (i.e., in nonsterile production).

Minimizing the level of batch residual cross-over contamination. This step reduces the chance that chemical contaminants from previous batches will come into contact with a product manufactured on the same piece of equipment.

Minimizing the level of cleaning-material residual contamination. This step reduces the chance that chemical contaminants from cleaning agents will come into contact with a product manufactured on a given piece of equipment.

This article will describe the role of bioburden in the contamination-control plan. The control of bioburden in modern pharmaceutical manufacturing relies on several mutually supporting activities. Accurate information about the type and number of microorganisms in a facility is the basis for controlling bioburden, therefore personnel must use validated sampling and testing methods for bioburden. In practice, this requirement means that personnel must develop a validated sampling plan that identifies sample sites, establishes a predetermined frequency of sampling, and mandates the regular evaluation of data generated by the environmental-monitoring program. Valid methods for testing utilities (e.g., water, process gas, and air) and surfaces also are required.

In addition to measuring bioburden in the facility, personnel should take steps to minimize and monitor bioburden in the manufacturing process. A validated cleaning and sanitization program for the equipment and facility is crucial to success in this regard. The contamination-control plan should describe how the cleaning and sanitization program will be validated and monitored for continuing effectiveness. The contamination-control plan should include consideration of incoming raw materials, the validation of the cleaning and sanitation programs, the control of personnel, in-process bioburden and control, and environmental monitoring. 

Controlling the bioburden that enters the facility is another necessary step. For example, personnel should accept raw materials (e.g., excipients, water, and active pharmaceutical ingredients [APIs]) and components only after they are certain that these materials meet bioburden requirements and all other incoming-material specifications. A certificate of analysis generally is sufficient evidence of adequacy.

Because personnel are the greatest source of contamination in a facility, plant managers should exercise due care to protect the process from the operator. Appropriate gowning requirements should be in place, but they vary depending on the process, product, and manufacturing site. 

Ambient and process conditions can affect the characteristics of APIs and other materials, thus environmental control and monitoring are two crucial elements of the contamination-control plan for sterile and nonsterile production facilities. All manufacturing facilities should restrict access to crucial areas (i.e., generally areas of product exposure to the environment) and should establish and justify relevant control over these areas in terms of background bioburden contamination levels. The adequacy of this control is demonstrated through passive and active viable microbial monitoring of the air, and through monitoring the relevant surfaces with contact plates or swabs.

In addition, well-defined standard operating procedures (SOPs) are necessary for training and procedural consistency. No supervisor can be present at all locations at all times. Thus, each operator must be aware of his or her role in contamination control and know how to minimize the overall risk to batch integrity. The contamination-control plan should cite the need for clear SOPs on all aspects of manufacturing, monitoring, and control.

Bioburden control is simplified when a manufacturing process is well-defined and understood. As part of the process-validation procedures, the manufacturing process should be evaluated for its potential to limit or eliminate bioburden through bioburden-reduction steps. This evaluation can be performed using hazard analysis and critical control point analysis or the failure modes and effects analysis approach. Organic solvents, heat, and other elements can greatly reduce the bioburden of a process. Other factors, such as compression and associated shear, for example, should be evaluated for their ability to reduce the risk of excessive microbial contamination. The finished product’s water activity also should be analyzed for its ability to limit the growth of potential bioburden present in the product. 

The requirements for bioburden control and monitoring are described in the pharmaceutical good manufacturing practices in sections 21 

 211.165(b). The “Orange Guide” of the European Union provides detailed guidance on aspects of this program, and additional guidance may be found in 

 <1117> and the Parenteral Drug Association’s technical report #13, “Fundamentals of an Environmental Monitoring Program.”

Developing a contamination-control plan is a proven method to document a comprehensive system for minimizing or eliminating product contamination. This control plan should describe all aspects of the production process and environment and provide the rationale for the control measures taken. The plan also should describe minimal requirements for those measures and provide guidance on the system in place to monitor that state of control.

Scott Sutton, PhD, is the principal at The Microbiology Network, 150 Parkway, N. Chili, New York 14514, tel. 585.594.8273, 

Articles

In the Mixer

A company's contamination-control plan is an important document designed to formalize the rationale, methods, and validation of contamination-control procedures in a manufacturing facility. The author describes the role of bioburden in the contamination-control plan.

The Role of Bioburden in the Contamination-Control Plan

’s new “Troubleshooting” column. When a process does not produce the expected results, or when a piece of equipment behaves strangely, even experienced personnel sometimes may be at a loss to understand the reason why. This column will be a forum to discuss production problems. Readers will submit anonymous questions, which equipment vendors and industry professionals will attempt to answer. In this way, the column may help promote greater understanding of the industry's products and processes.

Q: Our dry-powdered product is not meeting a critical final-quality specification related to the particle-size distribution. We use a volumetric dry-material feeder and jet mill to create the finished product. When we charge the feeder hopper with a batch of material, the resulting particle-size distribution changes from the beginning of the run to the end of the run. Maybe the load in the mill (i.e., the feed rate through the system) drops off because the material is sensitive to head load and we have no feedback control on the material feed rate. Why doesn’t our particle-size distribution stay consistent throughout the run? How can we meet our final-quality specification?

A: Try performing additional testing in the laboratory using a gravimetric feeder, which has a scale that is monitored by a controller. The controller uses the data from the scale to calculate a feed rate and provide a feedback control loop to maintain a set feed rate.

It is indeed likely that your material’s flow properties are sensitive to head load, and without the feedback control loop, the feed rate drops off as the feed hopper empties. The control loop in the gravimetric feeder should be able to increase the speed of the auger. This increased auger speed could compensate for the change in material flow that results from the change in head load. Also, the increased auger speed could help maintain the feed rate for more than 95% of the hopper capacity. Using a gravimetric feeder that provides a feedback control loop could increase your product quality and yield. 

—Chad Lorensen, business-development manager at Schenck AccuRate (Whitewater, WI)

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

An industry expert answers a reader's question about using a volumetric dry-material feeder and jet mill to create a finished product.

Insufficient Product Yield

Johnson & Johnson’s interest in acquiring vaccine maker Crucell  and Novartis’s completion of a vaccine-manufacturing plant in North Carolina are two recent indications of the ongoing growth in biopharmaceuticals. Lower-cost follow-on biologics are an attractive option for many patients, especially in light of the country’s persistent economic problems. But manufacturers of follow-on biologics face challenges that their small-molecule counterparts do not face. For example, the biopharmaceutical industry saying has been that “the process is the product.” But the fact that an innovator’s process is protected by patents and kept secret would seem to pose problems for a company that intends to produce a follow-on biologic.

The past 15 years have witnessed great improvements in analytical techniques, and the makers of follow-on biologics have applied these techniques to learn all they could about therapeutic products. Existing technologies, such as chromatography and electrophoresis, have become more selective and sensitive. New technologies, including mass spectrometry and surface-plasma resonance, now provide important insights into proteins’ structures and functions. “We now can much better characterize proteins than [we could] 30 years ago,” says Terry Gerrard, president of TLG Consulting. These days, a follow-on biologics company “may know more about the reference product than the innovator did.”

Manufacturers use the detailed knowledge they gain from improved analytical techniques to develop processes that produce biopharmaceuticals with the same attributes as those of the reference products. As a company examines various batches of the reference product extensively over the course of three or four years, new and existing characterization methods can reveal differences in product attributes more clearly than before, thus indicating changes in the innovator’s manufacturing process. This extended analysis shows follow-on manufacturers the full range of the reference product’s attributes, which the manufacturer can use as “goalposts” with regulatory authorities, says Mark McCamish, global head of biopharmaceutical development at Sandoz, the generics unit of Novartis.

Analytical techniques, such as glycan analysis and various bioanalytical assays, help a follow-on manufacturer select the right cell line and develop the appropriate bioprocess and purification process for its product. During process development, in-line and real-time analysis can enhance personnel’s understanding of the process steps. Together, analytical data and information regarding process parameters help manufacturers identify the process steps and parameters that must be controlled to achieve the desired quality attributes. The recent availability of test methods with enhanced sensitivity help to improve companies’ understanding of innovator products and facilitate process development. And the recent establishment of an approval pathway for follow-on biologics allows manufacturers to begin process development sooner than before.

Studying the reference product with enhanced analytical techniques thus can help follow-on manufacturers establish a process that matches the innovator’s process results or product attributes as closely as possible. But the processes do not have to match exactly. “We’re not bound to accept the process that the originator developed 10 or 15 years ago. We tend to use state-of-the-art process technologies that may have come on board since the originator created their own product. That means we can create a new process from scratch. It’s often streamlined and more efficient than the originator’s process,” says McCamish. The maker of a follow-on biologic has to engineer its process in any way possible to achieve the necessary product attributes. “That’s a difference between us and an innovator,” says McCamish. 

Advances in analytical techniques, processing technologies, and purification methods may mean that the traditional industry saying is no longer true. “The biosimilar manufacturer’s burden isn’t to understand the original manufacturing process. It is the responsibility of the biosimilar manufacturer to understand 

process,” says Gerrard. If a follow-on manufacturer uses a certain column or method of fermentation, it must understand what variables can affect that manufacturing process and whether these variables will affect the product. 

“We’re always going to come up with better manufacturing processes,” says Gerrard. As a follow-on manufacturer, “I don’t need to know a thing about the innovator’s process,” she adds. Follow-on manufacturers have a certain amount of flexibility in process development because different processes can yield the same product, as demonstrated by innovators that have won regulatory acceptance for their process changes. But this flexibility does not mean that the process itself isn’t important. “We need a rigorous manufacturing process that can yield a consistent product, one that you understand and control,” says Gerrard.

Analytical methods have made great strides in the past decade, and the industry now understands more about proteins’ structure and function than ever before. Scientific and technical advances will likely continue, potentially making follow-on manufacturers’ work easier and enabling innovators to develop new therapies that improve patients’ lives.

Production Lines

Improvements in analytical techniques may call for a re-evaluation of the biopharmaceutical industry saying that "the process is the product."

What's More Important, the Process or the Product?

AdvantaPure
 Overmolded fittings reduce entrapment


 AdvantaPure’s Overmolded Tri-Clamp Ends are suitable for applications such as transferring media, dispensing, and final filling. Because polypropylene fittings are thermally mated to the end of the tubing, the overmolded products provide a completely smooth inner diameter that reduces the opportunity for bacterial entrapment, compared with barb-type fittings. The overmolded fittings also eliminate leakage and minimize the risk of contamination because they do not rely on mechanical connections.

The Overmolded Tri-Clamp fittings are available for various sizes of polyvinyl chloride, thermoplastic elastomer, and thermoplastic rubber tubing. The fittings do not restrict flow or the inner diameter of the tubing. Clients can choose fitting models that are injection molded from 

 Class VI thermoplastic polyester elastomers or polypropylene. The Tri-Clamp Ends are certified free of animal-derived ingredients and are designed to be cleaned and sterilized easily. In addition, AdvantaPure can provide molded silicone assemblies and various single-use process components.

NETZSCH Premier Technologies 
 Nanoparticle mills provide efficiency and control


 The DeltaVita line of ultrafine nanoparticle mills from NETZSCH Premier Technologies includes devices appropriate for the wet grinding of batch sizes from 0.05 to 2000 L. The mills’ high-energy input and high flow rates in a recirculation process enable them to complete 10 cycles in the time it takes other mills to complete one. Continuous high-flow throughput ensures that the entire batch passes the mill several times before the process is completed while the batch tank is continuously agitated. The milling process is continuously monitored, which helps control the end point of the process and yield the desired product quality.

The DeltaVita mills incorporate NETZSCH’s Zeta grinding system, which uses small grinding media to produce fine end products in the nanometer range. The machines are designed for easy cleaning, repeatability, and easy validation. The units are isolated for operator safety, and their wetted parts are manufactured according to good manufacturing practice standards.

PharmTech's monthly newsletter, Equipment and Processing Report, reviews the Editor's Picks for the January 2011 edition from AdvantaPure and NETZSCH Premier Technologies.

Equipment and Processing Report-01-19-2011

The Role of Bioburden in the Contamination-Control Plan

Insufficient Product Yield

What's More Important, the Process or the Product?

January 2011 Editor's Picks: Products from AdvantaPure and NETZSCH Premier Technologies