A cleaning validation lifecycle starts with the cleaning assessment, in which the cleaning activities that need to be conducted are chosen. Assessment is followed by development and validation. Once validation is completed, the equipment can be used. The next stage of monitoring continues until something changes, and then the cycle begins again with assessment.


  To be sure that your existing cleaning validation methods and documentation meet current requirements, you should perform a cleaning gap assessment. Assess what gaps there are between your documentation and current expectations from investigators. Determine whether your gaps are defendable as is, can be bridged with additional work, or are sufficient to warrant revalidation. In some cases, companies have not revalidated for anywhere from 3 to 10 years, and will likely need to revalidate. If you have a cleaning validation program that is current, however, then you might just need to do a change assessment. If you have made a change to your system then you must assess that gap between the cleaning state and current requirements to determine whether the change does not impact your cleaning validation, can be bridged with additional work, or needs a complete revalidation based on that change.


  Cleaning development can involve a design of experiments or directed development. The objective is to gain process understanding to ensure that your new or revised cleaning procedure is in a state ready for validation. Ideally, validation will demonstrate that your cleaning procedures are effectively and consistently reducing product and cleaning agent residues from the product contact surfaces down to acceptable limits. Cleaning validation should also demonstrate that storage conditions do not allow for proliferation of microorganisms (i.e., clean and dirty hold times). Campaign length should also be considered; a cleaning validation should show that equipment will be clean after the maximum campaign length.  You should not conduct cleaning validation after a single batch, for example, and then run 100 batches without supporting evidence. 


  Monitoring will ensure that the validated cleaning process for the product-contact equipment remains in a state of control and is maintained in a validated state. As part of the validation step, you should do a risk assessment to determine how often you need to test in the monitoring phase. Initially, for example, you should monitor at least once a quarter to build a database; monitoring may be needed less frequently once a database is established. 


  Inevitably, changes will occur, and can involve the equipment, cleaning process, or product matrix, for example. When a change is encountered that potentially impacts cleaning, then the validation lifecycle starts over again. In the past, people might finish the validation step but not have an effective monitoring program.  Monitoring is a good way to identify changes and to keep a cleaning validation program at the forefront.

Richard J. Forsyth is principal consultant with Forsyth Pharmaceutical Consulting, tel. 484.535.1688, 

Articles

Troubleshooting

The cleaning validation lifecycle includes assessment, development, validation, and monitoring.

Understanding the Cleaning Validation Lifecycle

Continuous manufacturing, regardless of the application, can result in more consistent processes and products. Advantages include reduced energy, water, raw material consumption, waste generation, product losses, and downtime, in addition to lower capital and operating expenses. For the pharmaceutical industry, additional benefits include reduced human intervention. The biopharmaceutical industry is taking steps towards the realization of integrated, continuous manufacturing of biologic drugs with two changes. First, perfusion has moved from concentrations of 10–15 million cells/ml a decade ago to a now well-established upstream process at concentrations of 50-80 million cells/ml. Second, simulated moving-bed chromatography is in the adoption phase for downstream separation and purification. Some of the challenges include the large existing batch-based infrastructure, the traditional separation of upstream and downstream operations, and the need to develop new technologies for downstream processing steps.


  “At Genzyme, we envision an integrated system in which media enters the system at the front end and purified drug substance comes out the other,” states Timothy Johnson, associate director of commercial cell culture development at Genzyme. “It will take numerous steps to get there,” he adds, “but we are moving one unit operation at a time towards continuous biopharmaceutical production, and there are no issues that are so technologically complex that we won’t be able to develop appropriate solutions.”

 The biggest notable achievements, according to John Bonham-Carter, vice-president of business development with Refine Technology, come from CMO companies such as Gallus and Rentschler and from end users such as Genzyme, who have shown that continuous processing is possible today using existing equipment in a reliable setting. “It is the integration of different technologies that is novel, rather than any new technology itself,” he notes. 

a senior scientist with Novo Nordisk’s Biopharm Research Unit, adds that the work done at companies like GE Healthcare, Genzyme, and Novo Nordisk has helped demonstrate that continuous processing is not overly complex. “We have shown that going from batch to continuous is achievable and manufacturable. The technologies are available today; what is required is a fresh approach (and some guts) to switch to continuous processing.” 


  In small-molecule manufacturing, the switch to continuous processing is hindered in part by the vast batch-based infrastructure (and associated skill/knowledge base) in the biopharmaceutical industry that is cost efficient and familiar. “Many companies have invested significant time and money in batch processes, and are thus understandably unwilling to make major investments in new techniques,” notes Tiainen. In addition to the need to convince the decision-makers at biopharmaceutical manufacturers of the advantages and cost savings, it is also necessary to overcome user “fears” about unknown processes, particularly linking upstream and downstream operations, according to Stéphanie Dubois, cell culture lab manager and application specialist with Pall Life Sciences. 

 With respect to technology on the upstream side, Genzyme has come to appreciate the crucial importance of media formulations and has invested in finding optimal solutions, according to Johnson. The perception of increased process complexity is another issue, but as the number of companies exploring continuous processing increases and wider application of this knowledge occurs, this issue is gradually diminishing, according to Bonham-Carter. Tiainen adds, however, that there is not enough down-scaled and laboratory-sized equipment to enable wider exploration of continuous processing, particularly with respect to downstream processes.

Once the needed technology is developed on the downstream side, the issue of integration of upstream and downstream operations for fully continuous production lines will need to be addressed, which will involve managing the impacts that changes in one process step have on other steps down the line, according to Bonham-Carter. Tianen agrees that the interdependency of unit operations is currently a potential issue for product quality.

This particular hurdle leads to another key challenge–overcoming the divide between upstream and downstream groups within biopharmaceutical companies. “Implementation of integrated continuous manufacturing projects requires collaboration between groups. There is definitely much more communication internally at Genzyme than previously existed, and the traditional boundaries of the organization are beginning to subside,” Johnson comments. He also notes that two-way collaboration with supplier of materials, equipment, sensors, and automation and control systems is necessary for achieving effective solutions for continuous processing. 

— Cynthia A. Challener, PhD, is a contributing editor for 

.  Further discussion on this topic will appear in 

 May 2014 Bioprocessing & Sterile Manufacturing e-book. 

Production Trends

Both upstream and downstream processes can benefit from continuous manufacturing advantages.

Advances in Continuous Biopharmaceutical Manufacturing

guidelines on Good Distribution Practice (GDP) 

for medicinal products for human use, which were published and came into effect in November 2013, include changes in the rules ensuring that appropriate temperature conditions are maintained during transport.  Coolchain expert Tony Wright, CEO of Exelsius Cold Chain Management, discusses the new requirements for temperature-controlled pharmaceutical distribution. 

Q: In your work with the International Air Transport Association (IATA), you have been at the heart of the new standards and regulatory reforms that are sweeping through the air cargo sector. How ready is the industry for the implications of EU GDP Chapter 9?

Wright: To many of those companies already operating in the pharmaceutical logistics and distribution sector, the revised EU guidance was not so much of a surprise since they were already operating to a high level of GDP compliance. Many smaller companies, however, have found themselves to be now much more part of an auditable supply-chain process, in which service level agreements, quality management systems, and other requirements have been a considerable challenge. Some have needed to quickly undertake an analysis of the compliance capabilities, including the essential element of training. I think it will continue to be a challenge to some, but the overall long-term effect must be to have a better regulated and compliant supply chain.

Q: What impact do you see the new GDP having on pharmaceutical logistics generally and on controlled-room-temperature (CRT) distribution?

Wright: The new EU GDP brings approximately 80% of all finished pharmaceutical products under the requirements for temperature control during transit, which is creating a huge demand for effective, affordable CRT solutions. The economic imperative of providing workable CRT solutions at an affordable cost will result in big changes in coolchain practices and procedures, and the best practitioners will benefit commercially while those that drag their heels are going to suffer.

Q: Air freight by definition is a global business. To what extent will the recent changes in the EU GDP regulations influence what is done in other parts of the world?

Wright: Industry participants often ask why there is not a single global standard for the transportation of temperature-sensitive pharmaceuticals. Though some differences remain between guidance published by the EU, FDA, United States Pharmacopeia (USP), the World Health Organization, and other country-specific regulations, I do believe that there is evidence of a closing of that gap of difference. More recent, new or amended regulations (e.g., 

<1083>) have all placed similar emphasis upon quality agreements, written contracts, and supply-chain integrity as well as other practical aspects of temperature management. I think this is a good step forward and I am also pleased to see the continuing cooperation between the EU and FDA in the drive towards common improved standards.

Q: Where, in your view, are the biggest vulnerabilities in the air cargo coolchain at the present time?

Wright: There are a number of weaknesses in contemporary coolchain practice, such as a lack of adequate training. Although many of these weaknesses are being addressed by the new standards, I believe that the most intractable of these failings relates to the lack of essential advance planning or 'gap analysis' that should go into pharmaceutical distribution. Even the best manufactured solutions, whether active or passive, have limitations and are clearly impacted by any unnecessary exposure to inappropriate temperatures whether on an airport tarmac area or in the ‘last-mile ‘ of distribution. And it's a problem that has being significantly magnified by the inclusion of CRT products in the new EU GDP. 

There are several possible blackspots and bottlenecks during the distribution phase when shipments can be subject to unforeseen temperature spikes. However, robust systems and procedures that can close the 'tarmac gap' during pre- and post-flight handling will simultaneously address some of the other vulnerable points in the air-cargo process and greatly secure overall GDP compliance.

Q: Who needs to be taking ownership of these problems?

Wright: The management of temperatures throughout the logistics cycle is ultimately the responsibility of the pharmaceutical manufacturer or shipper who must take the lead through the supply chain. It is their legal duty to do this. However, the implementation of the standards in the field is down to the hundreds of organizations (e.g., airfreight carriers, forwarders, haulage concerns, airport operators, customs departments,  inspection agencies) that together form what amounts to a long distribution trail for pharmaceutical products. Meeting the new and future temperature standards needs to be a coordinated, team effort throughout the supply chain, which will require the necessary investment in new protection systems, monitoring regimes, training, and education.

Tony Wright is CEO of Exelsius Cold Chain Management, 

Packaging

Tony Wright, CEO of Exelsius Cold Chain Management, answers questions about the new requirements for temperature-controlled pharmaceutical distribution.

European Union Regulation Reforms Affect Cold-Chain Management

AdvantaPure’s AdvantaPass patent-pending wall pass-through technology is designed for transferring fluids between manufacturing suites during bio/pharmaceutical production. The system combines single-use tubing and isolation-chamber assemblies with in-wall,  permanent stainless-steel components to eliminate cleaning validation issues between product-transfer processes. AdvantaPass offers complete isolation between manufacturing environments when transferring multiple lines of fluid through a single wall portal. Moving fluids without the need to physically move bins and totes removes the risk of breakage, spillage, and lost pharmaceutical product associated with bin transfer. The technology offers a practical, safe, secure, and easy way to move large volumes of liquids from one room to another while maintaining separate atmospheres and minimizing cross-contamination risks.

The AdvantaPass wall pass-through system from AdvantaPure permits aseptic transfer of fluids between suites.

Wall Pass-Through System Enhances Aseptic Transfer

Powder Systems Ltd’s (PSL’s) universal Milling Isolator is applicable for situations that require multiple mills, micronizers, or air jet mills for a single process. The isolator can be used for laboratory or full-scale processes. An explosion protection system is fully integrated into the design. The glovebox offers a nitrogen-purged environment, nanogram containment, a small area to clean, and better control over cross-contamination. Multiple drum sizes can be integrated using the drum-hoist system and pneumatically sealed docking. The glovebox features a unique L-shaped window with enhanced access for changing, stripping, and cleaning mills within the glovebox. PSL’s Milling Isolator uses a lift-up window for enhanced viewing and ergonomics. 

A universal Milling Isolator from Powder Systems Limited (PSL) handles multiple mills.

Equipment and Processing Report-04-16-2014

Understanding the Cleaning Validation Lifecycle

Advances in Continuous Biopharmaceutical Manufacturing

European Union Regulation Reforms Affect Cold-Chain Management

Wall Pass-Through System Enhances Aseptic Transfer

Milling Isolator Handles Multiple Mills