Q. My network failed and I had to scrap my batch because my historian did not collect the required data. How do I upgrade the reliability of my network to maintain data continuity if my network fails again?

A. Data collection for regulatory compliance is a crucial function for pharmaceutical manufacturers that makes network reliability and data continuity of upmost importance. When reviewing the reliability of a network, first consider incorporating redundancy into your connections and switches. Added redundancy increases network resilience in the event that a switch or connection fails. Second, work closely with your company’s IT group to proactively monitor network health within the process control system. Managed switches have the intelligence to detect issues, such as when cables are broken, switches are powered down, or network loops are accidently broken. Another way to identify potential problems is to use situational alarming. Process engineers are able to acknowledge alarm events that might jeopardize the network and use the information they receive to identify and address issues almost immediately. Third, review network configuration against your IT and control system vendor recommendations. Proper network configuration is crucial to preserving your network’s security and resiliency in the event that a failure occurs.

Building a redundant, fault-tolerant network as described above is a dependable but expensive solution. An economical and reliable alternative is to collect the data at the equipment level, in the process control-system rack, and push it up the network to a site-level historian when the network is available. 

Equipment-level historians are designed to stand alone, with limited software footprint and no server connections, which makes the unit inexpensive to deploy and helps reduce the risk of data loss due to network or other system interruption. The unit’s onboard memory maintains a continuous data buffer that allows it to offload and forward that data up the network when the connection is available. This is especially important with original equipment manufacturer skids that may have a latent connection to the network. Another benefit of equipment-level data collection is the ability to collect data at higher speeds, allowing for a more granular view into your process. For example, traditional historian events are recorded every 2–3 s, but collecting data in the rack allows you to record process parameters as frequently as every 10 ms. This high-speed sampling rate can enhance investigations and batch analysis, which can ultimately improve product quality and speed time to market, thus increasing production volumes.

—Jason Wright, PlantPAx product manager, Rockwell Automation.

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My network failed and I had to scrap my batch because my historian did not collect the required data. How do I upgrade the reliability of my network to maintain data continuity if my network fails again?

Maintaining Data Continuity When Networks Fail

Companies manufacturing sterile drug products using conventional filling and packaging methods continue to face challenges. Prominent among these challenges are component related defects, microbiological contamination control, and aseptic process validation. Blow–fill–seal (B/F/S) is a method for aseptically filling sterile healthcare products, which, if used properly, can help address these challenges.

B/F/S technology is an automated method for forming and filling plastic containers with liquid product in an uninterrupted, continuous process. In the container blowing step, plastic beads are melted at high temperature and formed into a hollow tube or parison, which is cut to the desired length. Two halves of the container mold close around the parison, and air is blown into the parison to expand it into the shape of the container. The partially-cooled container is immediately filled and sealed.


B/F/S technology offers several advantages for sterile packaging. Product contact surfaces are cleaned and sterilized in place and sterile contact surfaces are protected from environmental contamination with HEPA-filtered or equivalent air. In addition, machine designs create a physical barrier, restricting personnel intervention during the container formation and filling process.

 Operations personnel are the main source of microbiological contamination in the cleanroom and, therefore, represent a potential product contaminant. Automated, well-designed B/F/S operations minimize the need and opportunity for human intervention, thus reducing the risk of microbial contamination. In addition, B/F/S typically involves small container openings and short product exposure times, further lessening the likelihood of microbial ingress.

 Product seal failures can result from defects in glass and other types of packaging components (e.g., closures). Damage or defects can occur to packaging components during transport and handling, before product filling, or due to variations in the component manufacturing process. Because B/F/S technology does not use supplier-made containers or (in most cases) closures, using B/F/S eliminates shipping and handling damage. In addition, container formation is controlled by the B/F/S product manufacturer as the container is formed immediately before the sterile product is filled and is not affected by flaws in vendor process control.

 B/F/S is a fully automated process that requires little operator involvement, if any. Therefore, its operations are more predictable than manual operations, less variable, and less prone to error. More of the process is controlled by the product manufacturer rather than by component suppliers. This can further reduce process variability, thus resulting in a process which is easier to validate.


Despite these sound advantages, wider use of B/F/S has been limited by concerns such as:

nonviable particulate levels in the environment surrounding the B/F/S machine

exposure of product to the elevated temperature of the formed container

gas and moisture barrier properties of container plastics.

 Relatively high levels of nonviable particulates are generated by the plastic extrusion and cutting process. B/F/S machine manufacturers have taken steps to address the plastic particulate issues by designing better machine enclosures to isolate and protect the product contact surfaces from environmental conditions. Some B/F/S line designs place particle-generating equipment away from the filling zones and isolate with walls and barriers. For some products, closed-parison systems, in which the inside of the parison is continually bathed with sterile air and is not cut, can be used to further protect product contact surfaces.

 B/F/S containers remain at an elevated temperature of up to 60 ºC for several seconds after filling (1). It is speculated that other types of plastic with a lower processing temperature can be used to reduce this temperature. To reduce the effect of exposure to elevated temperature container surfaces, filled product can be cooled soon after filling and sealing.

 Plastics typically used for B/F/S containers provide a relatively low barrier to oxygen or moisture, especially as compared to traditional glass containers (i.e., vials and syringes). For oxygen sensitive products, filled units can be placed in foil pouches or other secondary packaging. Inert gases can be used in these secondary packages to lessen risk for oxygen permeation. Process development and product stability studies using products filled using the B/F/S process, container, and packaging can provide evidence of product compatibility. Companies considering the use of B/F/S should take steps to assure that the heat and permeation issues do not have an adverse effect on product quality.


The Blow-Fill-Seal International Operators Association (BFSIOA) and the Parenteral Drug Association (PDA) have been working together to create a comprehensive technical report containing practical and scientific information regarding the use of B/F/S for aseptic manufacturing of sterile products. The report will be based on BFSIOA’s “Points to Consider” document, dialogue with industry, and input from the newly-created PDA B/F/S Industry Group. This guidance on best practices, as well as scientific rationale and data to support those practices, will help the B/F/S industry continue to improve its technology for advanced aseptic processing.


 1. W. Lin, P. Lam, S. Faulhaber, and S. Sane, 

 (7), 22-29 (2011). 
2. Blow Fill Seal International Operators Association, 

Ken Muhvich is principal consultant of Micro-Reliance LLC, Rock Hill, South Carolina, tel: 803.324.7734, mobile tel: 803.322.2262, 

Harold Baseman is COO at Valsource LLC,918 Horseshoe Pike, Downingtown, Pennsylvania, tel: 610.269.2808, 

In the Mixer

Using blow–fill–seal technology to form and fill a plastic container in a continuous process addresses sterile packaging issues such as package defects, contamination, and process validation.

Blow–Fill–Seal Technology Meets Challenges of Sterile Packaging

Contained manufacturing is becoming increasingly important as a greater number of APIs in development have higher potency. Manufacturing systems must be designed to protect product quality and patient safety by preventing cross-contamination and to protect workers through environmental, health, and safety (EHS) controls. Containment addresses both patient and worker safety, but the challenge is finding the appropriate level of containment that manages risk at a reasonable cost.

The International Society of Pharmaceutical Engineering (ISPE) launched the 

Risk-Based Manufacture of Pharmaceutical Products (Risk-MaPP) Baseline Guide

, which provides a scientific risk-based approach, based on ICH Q9, to manage the risk of cross contamination to achieve and maintain an appropriate balance between product quality and operator safety (1). The guide was published in September 2010, and industry members are evaluating the concepts. A key concept in Risk-MaPP is controlling crosscontamination to the Acceptable Daily Exposure (ADE), which represents  an acceptable amount of drug that may be contained in another product without causing harm to the patient.  For worker safety, a similar value,  the occupational exposure limit (OEL), is an acceptable airborne concentration that workers may inhale during an eight-hour work-shift. Companies can put a quality program in place using ADEs as the basis for acceptance-for materials with any level of potency-to show that they are managing risk to acceptable levels, explains Stephanie Wilkins, president of the consulting firm PharmaConsult US, which provides facilitation to firms implementing Risk-MaPP principles, and cochair of the ISPE Risk-MaPP Baseline Guide Task Team. In many cases, the approach is being used by large-scale generic-drug firms and by CMOs in response to actual or potential regulatory action.

Companies are increasingly asking for assistance in calculating ADEs, says Robert Sussmann, managing principal for Eastern operations at Safebridge Consultants, which provides EH&S consulting for the pharmaceutical industry. A robust and transparent ADE monograph is essential in properly documenting the risk assessment, Sussmann adds.

“Companies are anxious to see how the regulators treat the Risk-MaPP approach,” says Wilkins. She comments that a January 2011 FDA Warning Letter to Teva Pharmaceutical Industries regarding cross-contamination used similar wording to RiskMaPP, which some in the industry construed as FDA’s unofficial buy-in to the RiskMaPP approach (2). EMA’s concept paper, published in Oct. 2011, also suggests using “a more scientific approach…to establish threshold values” (3). A first draft of the guidance was to be discussed in February 2012, with draft guidance published in June 2012 and final guidance in March 2013. However, the methodologies developed by the EMA guidance for calculating ADE may be different than those outlined by Risk-MaPP, predicts Sussmann. Having an official direction from EMA would be a big step forward that the European industry would readily follow, says Richard Denk, director of the pharmaceutical department at Hecht Technologie.

Changes in industrial hygiene practices are moving slowly because of the costs involved, says Julian Wilkins, founder and vice-president of PharmaConsult US. In the last few years in the US, however, the Occupational Safety and Health Administration (OSHA) has become more involved in identifying problems for workers in the pharmaceutical industry and requiring corrective action. OSHA’s involvement will drive increased use of containment, predicts Wilkins, who notes that containment equipment must be practical, not costly or unwieldy.

One of the biggest trends in containment is toward flexible and disposable systems rather than hardwall isolators, says Sussmann. For highly hazardous substances produced in multipurpose facilities, traditional technologies are not easy to clean and the risk of material remaining on the surfaces is too high, says Denk. Disposables solve these problems, but have limitations with some solvents, he notes. New technologies with improved, cleanable surface qualities need to be developed, proposes Denk. The International Society of Pharmaceutical Engineering (ISPE) Germany/Austria/Switzerland section’s Containment Group is currently writing a containment manual, with a draft expected mid-2013. The manual will provide industry guidance on the basics of containment and will answer questions such as how to compare transfer systems, where the critical areas are located in a containment facility, how to validate a containment facility, and what is important to know when cleaning equipment or a facility, says Denk.

Baseline Guide: Risk-Based Manufacture of Pharmaceutical Products (Risk-MaPP),

 (Tampa, FL, Sept. 2010)
 2. FDA, “Letter to Teva Pharmaceutical Industries” (Rockville, MD), Jan. 31 2011.
 3. EMA, 

Concept Paper on the Development of Toxicological Guidance for Use in Risk Identification in the Manufacture of Different Medicinal Products in Shared Facilities

Production Lines

The growing use of high-potency APIs is leading to changes in how the pharmaceutical industry looks at containment.

Achieving Containment in High-Potency Manufacturing

AdvantaPure
 New AdvantaTube sealer and sterile welder are preprogrammed for AdvantaFlex TPE tubing


 AdvantaPure supplies thermoplastic elastomer (TPE) tubing for pharma and biopharm, single-use, fluid transfer applications such as disposable molded manifolds, tubing assemblies, peristaltic pumps, and sample retention. In response to customer requests, the company introduced the AdvantaTube sealer and the AdvantaTube sterile welder, which are preprogrammed to seal and weld the company’s AdvantaFlex TPE tubing. Settings for other types of TPE tubing are also available.

Fitzpatrick Company
 Contained system for roll compaction of powders

Fitzpatrick introduced the Contained Chilsonator System (CCS1025) for roll compaction of powders that is designed to fully contain all product in its processing and receiving sections and allow use in cleanrooms. An optional product containment system can be added at the discharge. The feed system design uses a horizontal feed screw to meter material and a vertical, precompression screw to deaerate and transport material to the compaction rolls. In some applications, an optional vacuum deaeration system can be used to assist in drawing entrained air from the product, thus improving compaction efficiency.

PharmTech's monthly newsletter, Equipment and Processing Report, reviews the Editor's Picks for the April 2012 edition from AdvantaPure and Fitzpatrick Company.

Equipment and Processing Report-04-18-2012

Maintaining Data Continuity When Networks Fail

Blow–Fill–Seal Technology Meets Challenges of Sterile Packaging

Achieving Containment in High-Potency Manufacturing

April 2012 Editor's Picks: Products from AdvantaPure and Fitzpatrick Company