Capturing and managing key process data can reap significant benefits - as AstraZeneca has recognized. Part of the company's process research and development (PR&D) operation is located at its Loughborough (UK) facility, where new manufacturing processes are developed. The site also houses a pilot plant for primary (bulk active drug) manufacture. 	

In November 1999, AstraZeneca commissioned AspenTech (Cambridge, UK) to install its information management system (IMS) InfoPlus.21 at the pilot plant. The platform, which has been in use since August 2000, captures and analyses live and historic process data from the plant, and also gathers data from a number of other sources. The data are then available for secure, long-term storage whilst being easily accessible for analysis, allowing creation of a complete batch end report. Sources of data include	

manually entered data, such as batch data (yield, purity, finished product weights, comments) and campaign data

Fourier transform infrared (FTIR) data (currently under implementation)

vent header exhaust analysis system data (also currently under implementation).

Figure 1 illustrates a schematic of the system. Since implementation, the system has been used in many ways across a number of manufacturing and business processes. The current and potential benefits have been examined and analysed. Current benefits include predictive maintenance and reduced downtime; improved process analysis and time saving; and enhanced process development and technology transfer.	

Predictive maintenance and reduced downtime

Process engineers use the IMS to highlight any deviations from default or validated operating norms, prompting corrective action to ensure the output product complies with registered quality specifications. Examples include the following:				

Critical systems. Actively monitoring critical systems, such as the thermo fluid unit, gives engineers the information they need to maintain operations with significantly reduced downtime. 	

The IMS can be used, for example, to monitor reactor vessel integrity 24 hours a day during test runs. Engineers can then predict any necessary maintenance and so avoid unexpected downtime, which traditionally can be up to several days per year.				

These two benefits together increase plant availability by approximately 10–15 days annually (that is, by 4–6%). Other benefits include Control loops. The software monitors how well control loops are working and prompts corrective maintenance. If, for example, process parameters have deviated from compliance or validated limits, the system's analytical tools evaluate the divergence, allowing an early return to normal operation. Deviations must be proved not to have detrimentally affected product quality.	

Overnight data. Gathering and monitoring of overnight test data is automatic, so analysis and trends can be available on a computer by the next morning. 	

Maintenance. Trend data can be accessed following any contracted out maintenance, for easy 'before' versus 'after' comparisons of equipment performance. This helps validate that process key performance indicators (KPIs) are unaffected. It also enables faster post-modification qualification testing and gives increased confidence in process consistency. It can avoid expensive batch failure and product write-off, as well as the detrimental impact on new product development.	

Commissioning. Engineers can validate that a process or piece of equipment conforms to a design specification for commissioning a new plant in alignment with performance qualification activities.	

The software can show that a plant is in control and fit for purpose. Effective preventive maintenance needs data capture and operational performance trending as a prerequisite, and the IMS automatically provides this. Additionally, process validation is quicker and process knowledge is enhanced.	

Improved process analysis and time saving

The fundamental benefit to process chemists is that data are gathered automatically. The data generated are useful in assessing a batch's suitability - it can make the difference between scrapping a batch and proving that it is passable. Having access to real-time and historic process information leads to significant process improvement and savings in resource time, batch cycle time and the time to achieve key milestones in development projects. 				

Data gathering. By using the tool for historic and real-time process monitoring of all process parameters, data gathering time is reduced to virtually zero, allowing more time for process enhancement. Trend analyses that in the past were difficult can now be performed. More robust processes can result, and potentially large write-off costs avoided.	

Deviation. In the event of deviation from process parameters, the process chemist must prove the batch integrity to QA standards. Process data captured by the system provides the evidence easily, so decisions can be made quickly. 	

Batch cycle time. The process of passing a batch is speeded up significantly, as all the data are readily available in real-time, and batch records can be kept up to date during manufacture. For example, process material may go into a 'hold' status (such as distillation), requiring continuous monitoring. The software allows the process to be monitored from the desktop, while generating parts of the batch record. Ultimately, there are time savings here both in terms of human resources and the overall batch cycle time. This may lead to faster release for clinical trial. 	

Enhanced process development and technology transfer

The IMS can be used as a development tool, as the earlier examples show. More robust and cost-effective manufacturing processes have been developed as a result of using the data capture and process trending tool. When a process is passed from the laboratory to the pilot plant, the plant chemist can see all the data and can make recommendations to improve cycle time and process robustness. For example,				

A process procedure stated 16 hours of flow hydrogenation. However, trend analyses proved that hydrogen uptake stopped after 4 hours, reducing the process time by 75% for that step. 

Another production process stated 10 hours drying in an oven. Monitoring the procedure showed this could be reduced to 4 hours without compromising product quality.

Bringing an IT system into an operations setting hopefully yields the expected benefits. Typically, though, other unforeseen opportunities emerge as users become more familiar with the system's capabilities. Some of these are readily achievable with little change; others may require tweaks to the system before they can be realized. The remainder of this article discusses the possible future benefits that encompass these two categories.	

Measurement is the prerequisite to increasing plant availability and utilization. The necessary KPI measurement and calculation is currently a manual and labour-intensive process, using overall equipment efficiency (OEE) techniques. Also, data granularity is poor. The IMS continuously monitors the plant, and with only minor modification, the OEE can be automatically calculated and monitored with high accuracy. 	

Improved batch analysis: The batch functionality of the platform is already undergoing validation. When this is done, PR&D engineers are keen to make historical analyses of clean-in-place, start up and manufacture. Batch functionality allows users to compare different procedures so they can improve plant operations. Also, linking the software to quality assurance (QA) systems allows cross referencing and data analysis of many more batch pertinent parameters (such as QA test results trended against process performance or input raw materials). Additionally, batch-to-batch analyses allow the output quality to be compared with a 'gold batch' standard, and the impact and importance of different process parameters to be understood. This ultimately leads to more robust batch manufacture, more predictability in the shop floor schedule and, at the bottom line, a lower cost of goods in pilot plant and eventually in commercial manufacture.	

Automated process monitoring and improved consistency: This is essentially already happening, but could be taken a step further by the relatively easy modification of linking automatic monitoring and alarms, signalling the need for maintenance (rather than waiting for an out-of-compliance alarm to occur). The most significant benefit would be fewer batch failures and, therefore, a lower annual cost of batch write-off.	

Process change justification: As the wealth of data in the system increases, so does its ability to provide evidence for justifying process improvements that would otherwise be locked into difficult to access paper batch record systems.	

Enhanced development and technology transfer: Changes in business process, such as technology transfer, can be made to stick and be more effective when applied simultaneously with system improvements or implementations. Numerous technology transfer dossiers, data and reports flow from development to commercial operations. These can be simplified, streamlined and made more accessible by using the software to automate parts of this process. The IMS can also be used for queries and will provide valid information in seconds rather than hours or days. The ability to refer back to historic batch data from a remote desktop at, say, a commercial operations facility will give a true insight into the manufacturing process that will make technology transfer both more effective and faster. Additionally, if the system was also used at the commercial manufacturing site, further rapid development based on real data trends is enabled at that site. Development staff can return to the pilot plant and remotely monitor the commercial batch manufacturing activity. The implications for smooth technology transfer, collaborative development, speed to market, cost of goods of the commercial product and cost of the development project, are considerable. In effect, using the software in this way provides a common process information management system from development to commercial manufacture.	

Two particular possible benefits needing further application development are considered. 				

Advanced process monitoring: This would entail automated monitoring of key events, while also applying technologies such as multivariable statistical process control (SPC), inferential monitoring and neural networks. The benefits of this could be: early warning of potential process deviations; online inferred measurements of values that cannot be measured directly (such as colour); and derivation of relationships from the raw data to predict immeasurable inferred parameters, thereby explaining process cause and effect.	

Batch record automation: Currently generated manually, this process is time consuming and can introduce errors. The automatic generation of the process data components of the batch record (21 CFR Part 11 compliance) would ease this burden for process chemists, and enable them to add more value in developing processes. This could be achieved using the IMS integrated with a full manufacturing execution system (MES), inclusive of electronic batch records to automatically produce the full and compliant batch record. 	

This illustrates the benefit potential for process improvement in the pharmaceutical industry by using information technology systems normally associated with more manufacturing-centric process industries. Pharmaceutical companies are starting to use these systems across commercial manufacturing sites producing both the bulk active drug and drug product, as well as in their pilot plants. The benefits will ultimately translate into bottom line cost reduction, and in the current aggressive business environment, that has to be a very welcome prospect. 	

Articles

Features

This case study examines the benefits of introducing process information management software to a pharmaceutical pilot plant. The advantages illustrate the potential for process development and commercial manufacturing improvements that are available to the pharmaceutical industry.

The Benefits of Process Information Management in R&D - A Case Study

Advances in information technology (IT) and communications technology are beginning to increase productivity and efficiency across a myriad of research and production practices. Technology generally promises much, but is unlikely to remove the common reliance upon peers and colleagues when sharing work. Indeed, the capability to enhance the processes of teamwork and production in the pharmaceutical industry is what technology is increasingly beginning to address. This is nowhere more applicable than in the construction and management of valuable data - in the form of documents and records.	

The commercial pressures that affect pharmaceutical companies are very strong, although the rewards can be lucrative. The simplest economic perspective applies, whereby hours and days are directly quantified in dollars or euros - the crucial determinate of success and survival is the speed at which product reaches the market. Quality can often be pushed and pulled by the constant pressure on costs that hang heaviest on the doorways of research and development (R&D) facilities and marketing departments that are responsible for producing documents of exceptional length, frequency and complexity. These include technical materials, brochures, licensing applications, preclinical report writing and records of research, reviews, investigations, validations and approvals. All of these will be generated as a result of team collaboration, as demonstrated in Figure 1.	

Figure 1:  The efficiency of working together.				

Broad knowledge management (BKM) systems have been the technology drivers behind more efficient data sharing. Often with an intranet (or extranet) at its core, the very existence of these systems has encouraged users to provide rich content for the greater good of others. The globalization of pharmaceutical companies has thrown working parties together from all over the world and extended communications from a position of 'down the corridor' to 'across the ocean.' This has heightened the existing need to share an awareness of data and to agree on a final position. The data trawl at the heart of the search for the human genome, for example, would not have been successfully undertaken without effective systems that safeguarded against exhausting resource through replication. However, even with an abundance of data to draw upon, the practice of constructing documents (research results, recommendations  and analysis reporting, for example) remains the same.	

The value of effective document change management

Despite the many benefits that a pharmaceutical organization can reap from the technological advancements made in terms of gathering and processing data, such advancements have also increased the pressure placed upon an organization to increase its productivity, time to market, cost savings, document quality whilst simultaneously reducing its margin of error. Document change management plays a pivotal role in dictating whether a company rises to these challenges or allows itself to be plagued by unnecessary document management problems. In our experience, organizations that have chosen to invest in document change management have approximately a 60% increase in productivity in the document production life cycle. Organizations that choose to ignore this issue will be left to face the following costly problems associated with poorly managed document production:				

inadequate identification of changes and entries to electronic document records

the inability to compare document versions

unmanageable levels of document proliferation

the inability to review documents in parallel

reduction in document quality and integrity from ad hoc methods of sharing and contributing to documents.

Document management systems (DMSs) have been in widespread use for some time as a response to the need for greater document control. Documentum (Pleasanton, California, USA) is arguably the DMS of choice for the pharmaceutical industry - and is generally accepted as the de facto standard. Systems such as this provide the data repositories for our documents. Other interconnecting parts that make up the process of document work provide the transport (such as e-mail and notification) and the principal elements of work flow (critical path and job triggering, for example). Together, these constitute a pharmaceutical company's method for developing documents in a safe, structured and efficient way.	

In the midst of ever-developing IT solutions for document control, communication and work flow, little attention has been paid by software developers to the matter of identifying physical document change. 	

The responsibility for collating, organizing and recognizing minute changes to documents of all sizes has not been adequately supported by pharmaceutical technology. Developing change recognition is the start of providing a comprehensive, accommodating document solution (Figure 2).	

Figure 2:  The last piece of the document jigsaw.	

DMSs have evolved to the point where they almost seek to provide one-stop solutions for the document construction and review process. For the most part, this evolution has been driven by business demand for content management, the electronic manifestation of knowledge management (KM). This demand has led to a focus on the higher level aspects of the document construction process, particularly organizational and communications channels. This has been at the expense of lower level aspects, such as actually working with reviewers' changes and comments. The result of this is that the development of programs that can work with such granular elements as individual reviewers' changes has been comparatively slow. Nevertheless, the efficiency gains among the higher level processes is leading increasingly to a demand to clear out bottlenecks among the lower level processes.	

The most prevalent document comparison/collaboration tool that addresses change identification can be found in the toolbars of Microsoft (MS) Word. The 'Track Changes' option enables a user to simply indicate areas of text that should be deleted from a document, and which should be added. A novel function. Yet, within the type of professional environment outlined above, this proves to be woefully inadequate on a number of counts. The tool can only be employed on a one-to-one basis, therefore, it does not allow for parallel review because of its linear person to person nature. With extra participants, the shortcomings of A's document being amended by B, and going back via C and D are clear; complexities add up, and the process of re-review is very problematic and time-consuming. Continued amendment of the same document often results in corruption, with different metadata and text/font styles adding confusion. The need to maintain the integrity of an original document through ownership by a managing author, and the need to open up collaboration among multiple contributors both go unanswered. There is also no integration with an existing DMS or enterprise content management (ECM) system. 				

The publishing tool, Adobe, has a 'collaboration feature' that is more advanced but shares the same shortcomings concerning document integrity and effective multiple collaboration. Time inefficiencies are not overcome by either of these tools, despite the basic ability to recognize change in some way.	

Document change management (DCM) is the process of enabling various contributors to quickly and accurately communicate and report change on a document - no matter how complex. In most document writing, when a number of parties are involved, there is a very strict hierarchy among the authors. Theoretically, one author will create a document and be ultimately responsible for its final form. All others who contribute to it only have the right to make suggestions. In the pre-Internet age, this system would probably be implemented simply through the use of paper faxes. The originating author would keep the original document and send out faxed copies to contributors. Contributors could then only mark suggestions on their fax copy, in ink - thus forever protecting the original. In the likely event of dealing with a highly complex 300 page document, however, the major drawbacks to this are obvious. E-mail communication has revolutionized these outmoded practices, and offers far more flexibility and ease of access for users.				

The restrictions of e-mail document collaboration, however, also become immediately apparent. Despite the capability to e-mail a document to literally any recipient in the world, the practice of collaboration can only effectively be managed on a one-to-one basis. Not only that, the original document is also open to corruption from imported styles and metadata. Persistent changing of a large document with imported material or among more than two correspondents often generates one of three outcomes: a mess, a corrupt file or a massively inefficient use of time.	

Today, DCM software provides the solution to these difficulties. By working alongside a DMS or ECM, the security of a document is ensured. The process of keeping track of proposed changes from multiple parties is automated into a single interface. Working on documents with people is no longer an arduous process. Document content collaboration becomes a manageable task that actually inspires people to work together.	

The originating author of a given document uses the DCM software to send a replica of their original document to all contributors - but not the document itself. By doing this, the author maintains complete control, as the document never leaves the security of the document management system. Additionally, there is no danger of hidden metadata or the inclusion of unwanted macros or foreign styles into the original document, as the DCM software strips all of this away. 	

21 CFR Part 11, e-CTD and other standards

The benefits of DCM are particularly applicable to the pharmaceutical industry, when considered in the light of electronic data and submission regulations. The introduction of the 1997 US Food and Drug Administration (FDA) regulation, 21 CFR Part 11, for how pharmaceutical companies needed to set up their computer systems and processes had a major impact on the demand for technological solutions and a technical awareness across the three principal markets of Europe, Japan and the US. The move from drawer to desktop has not only been introduced - it is practically enforced. Equally, the rapidly approaching common technical document (CTD) and e-CTD regulations are certain to have a profound effect on these issues. 				

CTD is a global standard for the format and structure of regulatory submission. This defines a directory structure for what are often extremely large documents. e-CTD is the electronic equivalent and is expected to accelerate the process of submission across the different parts of the world. Where previously, physical pallets of paper were sent to regulators as part of the submission process, now document collaboration solutions can deliver these electronically, offering time efficiencies and content integrity.	

A solution specific to the European pharmaceutical landscape, jointly endorsed by the European Federation of Pharmaceutical Industries and Associations (EFPIA) and the European Medicines Evaluation Agency (EMEA) is in the process of being developed for product information management (PIM). The PIM solution will be the first simple production system supporting the electronic submission and management of product information (summary of product characteristics [SPC], label and package leaflet) in the European regulatory procedures. The implementation of this technology will support the establishment of improved business processes, which will improve information quality and reduce duplication and rework in industry and agencies, creating more efficient and faster work processes. It is hoped that this will prove extremely useful in the event of resubmissions.	

At the user end, systems have to be extremely easy to use - largely because scientists have developed a reputation for being generally uncomfortable with IT. The most successful DCM systems will empower, motivate and inspire users to maximize their technology's potential and work with each other. The establishment of user groups by software companies has been ensuring the successful development of user interfaces (UI) for many years. This is crucial with a DCM solution, as its whole raison d'etre is to simplify the complex and present it comprehensively, enhancing existing infrastructure while adhering to strict regulatory requirements. An effective pharmaceutical-specific DCM solution will enable the user to				

increase efficiency/productivity - providing instant return on investment

facilitate electronic documentation formatting

ensure document security - encryption/stripping of metadata.

The latest advances in DCM allow contributors to view one another's suggestions. This extends the capability of the managing author to control the life cycle of the document and encourages up-to-the-minute debate and deliberation regarding salient points. In a strong peer environment (such as pharmaceutical, legal, financial or other consultancy) where discussion often reaches academic levels, this is crucial. 				

"The strength of a team is more than the sum of its parts," it has been said. In that case, not only is the quality of documents produced by a company of professionals a lasting testament to its proficiency - so is its speed at being completed and used.	

Article reprints may be purchased from Steve McQuair.	

With the advent of regulations such as 21 CFR Part 11 and the introduction of the electronic common technical document, it is becoming increasingly important to be able to enhance and fully utilize data management systems. Document change management is a vital tool in the construction and organization of valuable information, and can play a key role in the all-important process of getting a product to market.

The Need for Effective Document Change Management in the Pharmaceutical Industry

Most active pharmaceutical ingredients (APIs) are manufactured by chemical synthesis in which fine chemicals and intermediates undergo significant chemical change through a series of multistep processes. These synthesis processes typically include the use of organic solvents and, therefore, traditionally require organic solvents for process cleaning. A growing trend exists in the industry to move away from solvent-based cleaning to aqueous cleaning whenever possible, driven by safety, regulatory and economic factors.	

The recent release of the International Conference on Harmonization (ICH) Q7A GMP Guidance for APIs has generated significant worldwide interest and discussion concerning the validation of API manufacturing processes. However, limited published information is available regarding the design of an efficient and validatable cleaning process for API manufacturing.1 	

Synthetic API manufacturing involves many pieces of equipment for reaction and separation processes. Typically, these include reactors, condensers, crystallizers, centrifuges, distillation or extraction columns, filters, dryers and associated pipes. The nature, level and tenacity of the residues encountered in the process equipment may vary widely even within the same production train. Cleaning reactors, where aggressive and prolonged processing conditions are encountered, may pose a different challenge from the cleaning of separation equipment such as centrifuges or dryers, in which slurries or solids may be caked onto the surface. A variety of materials such as glass, polytetrafluoroethylene (PTFE), hastelloy, stainless steel and polymers are used in the construction of process equipment. A good cleaning process will take all these variables into account to ensure that all surfaces that come into contact with the product are safely and effectively cleaned.		

The traditional approach to cleaning has been to use an organic solvent, usually the same process solvent used in the synthesis of the API. This approach focusses mainly on the solubility of the active ingredient and frequently ignores the varying effects of the solvent on different surface types, the chemistries involved and the processing conditions previously mentioned. The most widely used cleaning solvent in the industry is methanol; other commonly used solvents include acetone, dimethyl formamide and ethyl acetate. 	

The cleaning process often starts upstream with the introduction of the cleaning solvent into the reactor. Reactor capacity can range from 50–500 gal for a pilot plant to more than 3000 gal for large-scale manufacturing processes. Solvent-based cleaning typically involves agitating a solvent in the reactor vessel, circulating it through pipes, and refluxing the heated solvent through an overhead riser and condenser system. Refluxing condenses the solvent vapours on overhead vapour lines and condensers, thus allowing for wetting of the surfaces and possible residue removal by dissolution in the solvent. Although this type of cleaning is similar to the processing step in a reactor and, therefore, has advantages, it is often very slow and gradual because of the limited level of "action" or mechanical force on the various overhead equipment 	

surfaces. For this reason, it is not uncommon for as many as 5–10 solvent boil-outs to be required to clean some tenacious residues.	

The API is usually soluble in the organic solvent. Solubility data are often easily accessible.

The solvent may be readily available and routinely used in the manufacturing process.

Solvent residue analysis is simple, and may be unnecessary if the cleaning solvent is the same as the process solvent in the next batch.

Coverage of overhead surfaces is possible by solvent vapour refluxing. This allows difficult-to-reach areas to be cleaned without using spray devices or modifying equipment.

Disadvantages of organic solvent cleaning

Residues other than the active ingredient (such as degradants) may be present on the surface and are not soluble in the cleaning solvent.

The solubility of a solvent does not necessarily indicate the rate of solubility. Vapour refluxing is a time-consuming process. The action or force acting on the surface during this process is very limited. The residue also has the potential to redeposit in overhead pipes and on surfaces as the solvent evaporates.

Solvents are flammable and may require special consideration for equipment design, storage, handling and transportation.

Environmental issues associated with solvent-based cleaning processes can be significant. Solvents such as methanol are hazardous air pollutants that require compliance with specific regulations.2 Applicable regulations in the US include 40 CFR Parts 9 and 63 National Emission Standard for Hazardous Air Pollutants (NESHAP), and the pharmaceutical Maximum Achievable Control Technology (MACT) standards. Water effluent limit guidelines are covered under 40 CFR Parts 136 and 439.

Discharging large amounts of cleaning solvents may be an issue with corporate and community images. In addition, spent organic solvents are usually either recovered or incinerated, thus adding to the overall cost of manufacturing. For this reason, several pharmaceutical corporations have set goals for solvent reduction.

Not all surfaces in an API process train can be easily cleaned without manual intervention. Organic solvents can be toxic by inhalation, so special safety procedures and protection may be required.

Aqueous-based cleaning processes are the norm in finished pharmaceutical and biotech industries. Two broad categories of aqueous cleaning agents are used in these industries: single-component commodity cleaning agents such as sodium hydroxide or phosphoric acid; and formulated cleaning agents, which are multicomponent cleaners that take advantage of several cleaning mechanisms.3		

Although commodity cleaning agents are widely used in the biopharmaceutical industry because of their simplicity and ready availability, they have limited soil-suspending and cleaning ability for the tenacious residues typically encountered in the API industry. Formulated detergents take advantage of the synergy of various components in the formulation. Like commodity alkalis, but unlike organic solvents, a formulated cleaner can include alkalis to enhance solubility and help in the hydrolysis of the residue. Formulated detergents can also contain surfactants that provide better wetting, surface action and emulsification, chelating agents that break down complex metals such as calcium and iron, and dispersants that prevent particles from reaggregation.	

Table I:  Evaluation of detergent chemistry.	

However, vapour refluxing is not usually an option with aqueous cleaning agents as it is with organic solvents because of the non-volatile nature of the active ingredients in most aqueous cleaning agents. If aqueous cleaning agents were refluxed, then only the water would vaporize, and the cleaning effectiveness in the reactor dome, vapour lines and condensers would be minimal. Aqueous cleaning, therefore, requires direct liquid spray or recirculating flow coverage across all surfaces.	

Advantages of aqueous-formulated detergent cleaning

Aqueous formulations are not flammable, which reduces storage, transportation and handling costs.

Aqueous systems can be more effective at cleaning because they can incorporate multiple cleaning mechanisms.

Aqueous systems do not pose air-emission or environmental risks.

Formulations can be sprayed safely at higher temperatures, thereby allowing for higher levels of two key cleaning parameters: mechanical action and temperature.

Aqueous systems are often more cost-effective for the overall process.

Disadvantages of aqueous-formulated detergent cleaning

It may be necessary to install spray devices in vessels and modify associated equipment to achieve the liquid coverage across surfaces that is essential for cleaning.

Cleaning agents are often proprietary formulations and only available from a limited number of suppliers.

Residue limits for the detergent must be set and validated analytical methods are required for detergent residue analysis.

Selecting appropriate cleaning agents may need laboratory cleaning studies or vendor recommendation.

Numerous API manufacturers have weighed these advantages and disadvantages, and have adopted aqueous detergent cleaning processes where possible for API manufacturing. However, successfully converting from solvent cleaning to aqueous cleaning is not simple. It requires an understanding of the chemistry, equipment, engineering, validation and cost issues associated with solvent substitution, and a process to systematically address these issues.	

Selecting the right chemistry. The solubility of an API in an organic solvent is a function of the polarity of the solvent. In the case of aqueous cleaning, solubility is a strong function of the pH of the cleaning solution. Certain functional groups are more soluble in an alkaline cleaning solution and others are more soluble in an acidic cleaning solution. For example, amino acids, diols, triols, organic acids, polysaccharides, saturated oils and waxes are generally cleaned better with an alkaline cleaner. Aldehydes, alkaloids, amines, bicarbonates, carbonates, ethers, insoluble hydroxides, ketones, metal oxides, pyridines and pyrrolidines are more likely to be cleaned with an acidic cleaner. However, selecting cleaning agents on the basis of solubility alone may be inappropriate because other mechanisms may be involved in the cleaning process. Table I lists the solubility data of APIs in detergent systems. These detergent chemistries were evaluated in the laboratory and the cleaning processes were successfully implemented in the field process equipment. For confidentiality reasons, the exact drug active and cleaning chemistries are not disclosed. Three detergents were used: a potassium hydroxide-based detergent (D1); a glycolic acid-based detergent (D2); and a phosphoric acid-based detergent (D3).		

Studies. Cleaning studies using stainless steel coupons were performed. Approximately 10 g of each drug active was coated onto an area of approximately 100 cm2, allowed to dry overnight and subjected to agitated immersion cleaning. These studies showed that drug actives A1 and A3 could be cleaned from surfaces using a 2% solution of detergents D1 and D2, respectively, at 60 Â°C for 45 min under agitated immersion conditions.	

In the case of drug active A2, cleaning studies showed that it could not be cleaned off coupons by any detergent (D1, D2 or D3) alone. However, detergent D3 in combination with another detergent additive was able to clean active A2 at 60 Â°C with 90 min of agitated immersion. This demonstrates that the solubility of an API in a cleaning agent may be misleading and may not be a good measure of the agent's ability to effectively clean that residue from surfaces. Although the solubility of these APIs in the detergents was very low, they were subsequently cleaned successfully from process vessels using aqueous detergents. These provided cleaning mechanisms other than solubility, including solubilization, emulsification, wetting and dispersion.	

Selecting the right chemistry and cleaning parameters is very important for the success of a solvent substitution process. Cleaning studies can be conducted in the laboratory by coating the API residue on surfaces, drying or baking them to simulate actual process conditions, and then screening various detergents to determine the right combination of chemistry and cleaning parameters. These parameters include the cleaning time, agitation levels, the cleaning agent concentration and the application temperature. The studies should account for worst-case conditions that may be encountered in the process equipment. Among the issues to consider are the soil residue condition (dried, baked and caked), the nature of the surface, surface finish, ratio of the soil to surface area, soil redeposition and foaming.3		

Figure 1:  Concentration of active and cleaning agent.	

Equipment design issues. The API industry uses a variety of substrates for manufacturing vessels. The most common of these are 304 or 316 stainless steel, glass-lined, PTFE-lined and hastelloy substrates. Evaluating the compatibility of cleaning agents with these substrates is important to ensure product integrity and equipment protection.	

In the case of glass-lined reactors, for example, the concentration and temperature of alkaline cleaning solutions should be limited because of the possibility of etching glass surfaces by overuse of alkaline solutions. Data and technical support from cleaning agent and equipment vendors can be used to determine the isocorrosion curves for cleaning agents on glass-lined equipment. Also, after using the alkaline cleaning agent, the glass surfaces must be thoroughly rinsed with water, ensuring complete coverage across all surfaces, to avoid localized etching of the glass when the reactors are heated. If data are not available, laboratory substrate compatibility studies should be conducted under typical exposure parameters and conditions.	

Cleaning process pipes can be a major challenge in API manufacturing processes. One of the commonly encountered causes of cleaning problems in process pipes is the inadequate flow rate of the cleaning solution. It is recommended that the average flow rate of cleaning solutions through pipes is >5 ft/s. This is a commonly accepted design practice for clean-in-place (CIP) systems in the pharmaceutical and biotech industries. In an API manufacturing plant, it is not uncommon to find larger-diameter pipes in which this high velocity is not feasible. In those situations, a close examination of the pipe layout is necessary to assess the flow coverage, the potential for gas and particle entrapment and the level of flow turbulence.4 In large diameter pipes, such as overhead risers that lead to condensers, it may be necessary to install spray devices to ensure adequate coverage.	

The proper design of process piping is essential for good cleaning performance; if they are not appropriately designed for cleaning, it is important to identify the problematic areas and then either modify the piping or develop an appropriate cleaning procedure. Dead legs should be minimized to have a length-to-diameter (L/D) ratio <1.5. In existing systems where this ratio is exceeded, the flow and coverage in those areas must be examined and the cleaning ability validated. This may involve one or more corrective measures, such as increasing the flow rate; reversing the flow direction if appropriate; changing the orientation of the dead leg; reducing the dead leg by pipe modification; diverting the cleaning solution through the dead leg as another loop; or dismantling and manually cleaning those areas.			

Table II:  API and cleaning agent concentrations and Table III:  Ract and Rca values for each rinse.	

Ball valves, which are used extensively in API manufacturing, can be difficult to clean. These may have to be manually cleaned if adequate CIP methods cannot be demonstrated and validated.	

Cleaning strategies. In some processes, eliminating cleaning solvent may involve significant equipment modifications and the installation of several spray devices to provide complete coverage. If this is not feasible, an alternate approach could be to reduce, rather than eliminate, the use of organic solvents. This strategy would involve aqueous cleaning by agitated immersion to remove most of the residues from process equipment, followed by a solvent-vapour reflux step to reach some of the overhead areas that the aqueous cleaner cannot cover.	

A follow-up solvent flush can be used for API residue-sampling purposes after aqueous cleaning, even in situations with established good aqueous cleaning coverage. Another reason for using a solvent after aqueous cleaning is to remove the residual rinse water from the system. The solvent used in this final step is usually polar, has good water miscibility, and is often the process solvent used in the subsequent batch. 	

Organic solvents are frequently used in the manufacture of active pharmaceutical ingredients. They have, therefore, normally also been used for process cleaning. However, a number of factors have encouraged the industry to change from solvent-based to aqueous cleaning. This article considers current cleaning practices, related issues and the author's experience of switching from one cleaning method to another.

Aqueous Cleaning and Solvent Substitution in Chemical Synthesis API Manufacturing

The US Food and Drug Administration's (FDA's) 21 CFR Part 11 (often abbreviated to 'the Rule') specifies audit trail requirements in general terms. The Rule remains in force, despite the fact that it is currently under review and the draft guidance that FDA had issued to assist organizations with interpretation has been withdrawn. In the absence of specific guidance, audit trail is, nevertheless, essential both for regulatory compliance and to prevent the loss of valuable business information. 	

The Part 11 section that covers audit trails (11.10e) reads: "Use of secure, computer-generated, time-stamped audit trails to independently record the date and time of operator entries and actions that create, modify or delete electronic records. Record changes shall not obscure previously recorded information. Such audit trail documentation shall be retained for a period at least as long as that required for the subject electronic records and shall be available for agency review and copying."	

The best strategy for audit trail configuration is not always clear. In addition, the functionality for audit trails available in commercial software, commercial packages or legacy applications may be less than ideal. There are a number of questions regarding audit trails that require consideration when formulating a compliance strategy:	

Is it necessary to audit all information and if not, precisely what information must be audited? 

Maintenance of an audit trail for record creation can generate large amounts of information. What is the best way to approach this? 

What is the difference between version control audits and simple audits? When should each type be used? 

Generally, applications that use commercial database management systems (DBMS) can be configured to support compliance without too much difficulty. Functionality within applications that manipulates electronic records without using DBMS are much more variable; some are full-featured, others much less so.	

Good clinical, laboratory, manufacturing and pharmaceutical practice (GxP) regulations may specify records that must be audited, but this is not always the case. It is possible to audit all records, although this incurs high storage and processing overheads, and useful information may be difficult to retrieve from redundant data. Therefore, it is important to review records, particularly when they are high-volume, and ask: "Is there a regulatory or business need to audit trail these records?" 	

Figure 1: An audit configuration in LIMS.				

A cautious approach is recommended, wherein the default is to audit all records - unless it is clear that there is no business or regulatory requirement.	

There are two fundamentally differing strategies to achieving a compliant audit trail, version control and audit trail control. The distinction is not made clear, or indeed mentioned, in either Part 11 or its preamble; however, it is a distinction that is made by predicate rules and is familiar to those working with paper documents in a GxP environment.				

Version control. The distinction between the two strategies can be made clear by examples from paper-based systems. A paper-based example of version control is updating a standard operating procedure (SOP). Here, the 21 CFR Part 58 predicate rule states: "A historical file of standard operating procedures, and all revisions thereof, including the dates of such revisions, shall be maintained." (Part 58.81) Therefore, when an SOP is updated, an entire copy of the superseded version must be retained.	

Audit trail control. For audit trail control of an analytical record, the same document states: "Any change in entries shall be made so as not to obscure the original entry, shall indicate the reason for such change, and shall be dated and signed or identified at the time of the change." (Part 58.130) Therefore, in contrast to modifying an SOP, it is not necessary to retain an entire copy of the unmodified record and reissue a completely new amended copy when modifying a paper analytical record; it is acceptable to amend and annotate the existing paper copy.	

Advantages and disadvantages. Both of these approaches can be mimicked by electronic systems. A change to a record can force an entirely new version to be issued (version control) or the change can be applied to the existing version and the 'value before change' recorded in an audit record (audit trail control). Either approach allows historical records to be retrieved. With audit trail control, historical records may be reconstructed by 'rolling back' the audit changes and restoring the 'before change' values up to the point of interest. Version control's principal advantage is that all historical records exist in their entirety and no reconstruction is necessary. Both approaches also allow details of record changes to be retrieved. With version control, detailed 'before' and 'after' change information can be reconstructed by comparing the record versions before and after the change. With audit trail control, the detailed changes are explicitly recorded and no reconstruction is necessary. The major disadvantage of using version control is that vastly more information must be retained, and retained for the lifetime of the records. 	

In the absence of detailed FDA guidance, it is highly likely that, theoretically, either version control or audit trail control alone will be sufficient to comply with Part 11. However, to comply with a predicate rule, version control may be mandatory.	

It should be noted that the two approaches are not mutually exclusive: both can be used. This is analogous to a situation where a new version of a document is reissued, and although a copy of the previous version is retained, a change history section is included in the new version to summarize what changes were applied.	

Full-featured applications will also provide a prompted or silent audit. A prompted audit requires the operator to enter a reason for the action, whereas a silent audit does not. Silent audits are, therefore, a good electronic analogue of the typical good manufacturing practice (GMP) paper record modification when an alteration is justified by a handwritten annotation. However, prompted audits can be laborious and tedious to use, particularly when a single logical amendment results in the alteration of many physical records and the operator is forced to repeatedly enter the same reason.	

Audit trail discussions mainly focus on record modification, but Part 11 mandates audit of record creation and deletion. Most DBMS can be configured to audit trail all record creation events. Doing this, however, can almost double both transaction processing time and storage requirements. To view this as mandatory under Part 11 is to misinterpret the regulation. It is only necessary to separately audit record creation when the record does not itself contain creation audit trail information.				

When the electronic record format includes the identity of the creator and a compliant creation time-stamp, all the record creation audit infor- mation is captured within the record itself. Comment 73 in the Part 11 preamble makes clear that this strategy is acceptable: "The agency advises that audit trail information may be contained as part of the electronic record itself or as a separate record. FDA does not intend to require one method over the other." 	

Some applications prevent physical record deletion and use an alternative strategy of marking records as deleted without physically deleting them. In such cases, it may not be necessary to configure deletion audit events. However, in contrast to record creation, record deletion is rare and the cost of taking the cautious approach (auditing all deletions) is likely to be low.	

Taking laboratory information management system (LIMS) audit trail functionality as an example, most commercial LIMS automate the creation of audits when operators modify information against a sample, test, result or other entity. Advanced LIMS allow any field from any table to be audited and conditions can be set to dictate what, and what not, to audit (Figure 1). Some modern LIMS allow more complex conditions that govern the creation of audits; for example, audits may activate on only finished product samples rather than in-process quality control (QC) samples, or audits may only occur on changes made by certain operators.	

Further to defining detailed configuration for all record formats, it is useful to write an overall audit strategy document for each GxP application that defines and justifies what different approaches are used. Examples of guiding principles that can be included in such a strategy document are as follows:				

Static information (reference information that is routinely used during a long period) should be version controlled. 

Dynamic information should be audit trail controlled. 

Dynamic information comprises one-off transaction records that document actions and events - for example, methods and specifications are static, whereas test results are dynamic.

Predicate rules may mandate version control.

All electronic signature records must be audited.

Regulatory information must either be version controlled or audit trailed. For non-regulatory information, an audit trail may be used if it is judged to provide useful information.

When version control is used, an audit trail may still be useful as it provides an easy way to compare version differences. Silent audit should be used.

Creation of records is seldom necessary because the purpose of the audit trail is to record modifications. This is compliant under Part 11 provided that the identity of the user creating the record and the time-stamp are recorded within the record. By definition, there is no 'previous' information to be held in the audit record data structure.

In many cases, a single prompted audit applied to a summary record can be used to comment several changes to subsidiary or dependent records. Silent audit may be used to record subsidiary record changes.

The availability of all necessary audit trail features must be of primary importance when selecting and upgrading software applications under Part 11. Even if an application allows all the possible configurations described in this article, achieving a compliant audit trail strategy remains a complex task. Determining and implementing the best approach requires detailed consideration and documentation, combined with a good understanding of the application, the business and the regulations. 	

Until specific audit trail requirements are available from the US Food and Drug Administration, manufacturers must define their own parameters for software system compliance and decide for themselves how to meet those requirements.

Configuring Software for Compliance with 21 CFR Part 11 Audit Trail Requirements

Part I of this study showed that the optimum release kinetics of lipid formulations are obtained using hydrogenated castor oil (HCO) with theophylline and polyvinylpyrrolidone (PVP) when ethanol is used as the pulverization liquid.3 In this second part, formulations containing a higher active drug range were tested and summarized (Table I). 	

When ethanol was used as the solvent (batches ML13 and PE3), it took a long time to obtain both very small spheres and a significant amount of fine fraction powder. In terms of process feasibility, the best results were obtained when water was used as the pulverization liquid with formulations containing a high theophylline content. 

For batches using water as the solvent, and for the majority of smaller fractions (sphere size ,0.315 mm) for formulations using ethanol, the study showed a regular distribution of the different fractions between 0.315–0.8 mm (Figures 1-4). The morphological study highlighted a regular and spherical aspect for all batches with sphericity coefficients close to 1 (1.094 for batch T14 and 1.029 for batch T15) (Figures 5 and 6). 	

Table I:  Formulations and main results of spheres with a high percentage of active drug associated to lipidic excipient.	

In vitro dissolutions were conducted using the paddle method on spheres of 300 mg with sizes ranging from 0.315–0.80 mm. Similar profiles were observed regardless of batch size or the percentage of active drug (Figures 7 and 8). Batches T14 and T15, which had the same formulations, showed particularly good reproducibility.	

As in Part I of the study, lipid spheres formulated with HCO retain their matrix properties (in terms of delay of drug dissolution), even with a higher percentage of active drug. All dissolution profiles studied demonstrated good kinetic release reproducibility of the active drug from spheres, regardless of the batch size manufactured. This may confirm the benefit of using HCO as a lipid component for manufacturing spheres using the rotary fluidized bed process.4 This lipid component helped to produce spheres with good reproducibility. The spheres obtained presented good quality morphological aspects and prolonged drug release profiles corresponding to "micromatrix" components. 		

1.	P. Gauthier and J.M. Aiache, "Applications of Rotary Fluidized Bed Processing, Part I: Manufacturing Spheres," Pharm. Technol. Eur. 13(9) 22-34 (2001).				

2.	P. Gauthier and J.M. Aiache, "Applications of Rotary Fluidized Bed Processing, Part II: Fizzy Spheres," Pharm. Technol. Eur. 13(10) 32-37 (2001).	

3.	P. Gauthier and J.M. Aiache, "Manufacture and Dissolution Studies of Lipid Spheres: Part I," Pharm. Technol. Eur. 15(10) 55-66 (2003).	

4.	J. Swarbrick and J.C. Boylan, The Encyclopedia of Pharmaceutical Technology, Volume 7 (Marcel Dekker, Inc., New York, New York, USA, 1992) p 484. 	

Previous articles have presented a general review of the different types of spheres that can be obtained using a rotary fluidized bed process.1,2 Part I of this study focussed on lipid spheres prepared using hydrogenated castor oil for formulations with low active drug content. The feasibility of the process and the main characteristics of spheres obtained were also studied. In Part II, formulations with higher concentrations of active drug are examined.

Pharmaceutical Technology Europe-11-01-2003

The Benefits of Process Information Management in R&D - A Case Study

The Need for Effective Document Change Management in the Pharmaceutical Industry

Aqueous Cleaning and Solvent Substitution in Chemical Synthesis API Manufacturing

Configuring Software for Compliance with 21 CFR Part 11 Audit Trail Requirements

Manufacture and Dissolution Studies of Lipid Spheres: Part II