85Innovations in Pharmaceutical Technology

Manufacturing

The average cost of moving a new drug through thedevelopment process in the US ranges from $300 millionto $1.2 billion. Drug development takes an average of 12to 15 years, leaving only five to eight years of patentprotection. Only one in 10,000 candidate compoundssurvives the development process, receiving new drugapproval and ultimately reaching the marketplace. Nowonder, then, that drug companies focus on processinnovations to drive down the costs of discovery,development and commercialisation, and acceleratetime-to-market. But a surprising proportion of thediscovery and development lifecycle is still based onmanual and disconnected process steps – leading todelays, inefficiencies and potential risk throughbreakdowns in technology transfer.

Now, pharmaceutical companies are looking to recipenormalisation as a means of accelerating time-to-market,reducing waste and improving regulatory compliance. Thisarticle discusses recipe normalisation, process definitionmanagement, the associated industry standards and thetechnologies designed to both streamline regulatorysubmissions and embed quality standards into the processfrom the earliest developmental stages.

QUALITY BY DESIGNQuality by Design (QbD) seeks to make quality afundamental part of the development process from theearliest possible phases of the lifecycle, using automationand standardisation to enforce consistency and control. Thegoal is to build quality into the design, rather than attachingit as a downstream step or test in the lifecycle. QbDprinciples have been used for decades in chemical and high-tech manufacturing with great success. Life sciencecompanies have been slower to adopt, but this is changingas a result of aggressive evangelism from the US FDA.

Essentially, QbD requires researchers to define anddocument the Critical to Quality (CTQ) attributes of themanufacturing process. CTQ attributes may includecontrol settings, material purity and any other variable thatis critical to the ultimate quality of the active pharmaceuticalingredients. In QbD, CTQs are identified through rigorousDesign of Experiments in late phase discovery and early

development. Once identified, the CTQs are refined,documented, reported and monitored throughout theproduct lifecycle.

A key foundation for QbD is process definitionmanagement, which defines detailed process logic as well asparameters for manufacturing phases that include inputs,process parameters and outputs. Process definitionmanagement can therefore provide a framework fordefining, managing and submitting CTQs for any regulatedbatch manufacturing process.

ROOM FOR IMPROVEMENTEngineers typically use flowcharts to create processdefinitions and recipes to map out the steps of themanufacturing process. The quality specifications andparameters behind each step are meticulouslydocumented in a separate document, often a spreadsheet.Each time a parameter changes, the spreadsheet must beupdated accordingly. In turn, flowcharts andspreadsheets reveal five distinct opportunities forimprovement in recipe management:

Version ControlFlowcharts and spreadsheets are often managed as separateand independent artifacts, and so they can easily becomeout of sync. Version control and synchronisation of theseartifacts is critical to improving recipe management.

Content Re-UseFlowcharts and spreadsheets provide no mechanism for re-using the elements, which codify documented bestpractices. Process definitions for similar compounds,authored at different times by different process engineers,should be able to share process innovations and bestpractices – essentially ‘chunks’ of recipes. Physical orprocess mechanisms do not exist to feed back innovationsfrom commercial or early clinical manufacturing to earlierprocess design activities in late phase discovery.

Knowledge ManagementProcess definitions collectively represent the intellectualproperty of a life sciences firm, yet there is no simple way of

Process Definition ManagementBy integrating disconnected business processes, batch process definitioncan be transformed into an automated, seamless, end-to-end operation.

By Paul Wlodarczyk at JustSystems

Paul Wlodarczyk is Vice President of Solutions Consulting for JustSystems. With more than 20 years of specialisedexperience in enterprise content management and knowledge management, he leads and supports engagements that require analysis and improvement of content lifecycles. Prior to JustSystems, he spent more than 18 years at Xerox (Rochester, NY) as a Service Line Manager for a content lifecycle consultancy with Xerox Global Services.

IPT 26 2008 28/8/08 11:13 Page 85

searching the content and structure of recipes to enableresearchers in one product line to discover relevant processinnovations in another. Moreover, documentation formatsand standards are rarely consistent, further complicatingknowledge-sharing, content re-use and technology transfer.

Technology TransferTechnology transfer is a significant weakness in thedevelopment process. When a process definition (usually ina spreadsheet or document) passes from R&D to pilotmanufacturing to become a recipe, the information fromthe flowcharts and spreadsheets needs to be transferred tothe Manufacturing Execution Systems (MES). Today, thisprocess is manual. Re-keying process logic and parameters istime-consuming and subject to error; this puts quality atrisk, reduces yield by increasing waste from bad batches andadds to cycle time. A typical manual technology transfertakes four to eight weeks. With the right tools and approachfor technology transfer, the process may be completed indays rather than months. For certain biologic-basedblockbuster drugs, the revenue benefit associated withtechnology transfer may be US $1 million per day.

Regulatory SubmissionsThe fifth and probably most significant area of opportunityis regulatory submissions. As QbD becomes a regulatoryframework, it will require reporting on all CTQs and thecontrols in place to manage them. CTQs will need to bereported from the earliest pre-clinical submissions throughto large-scale manufacturing. Rather than being part of aseparate process, the process definitions can provide aframework for organising, managing and reporting onCTQs throughout the product lifecycle.

BARRIERS TO EFFECTIVE RECIPE MANAGEMENTOne barrier to process definition management has been theabsence of a standard tool for process specification duringformulation. Another barrier is converting a processdefinition into an executable recipe. Many MES solutionshave recipe editors and use standards-based formats, such asISA-S88, to represent process flows. In the MES, the recipeis authored so that it promotes execution rather than processdefinition. However, because recipes are not created in thesesystems until manufacturing, their use does not providebenefits upstream in the product and process lifecycle.

Another barrier is the wide array of standards forrepresenting the process definition itself duringformulation. While this is addressed by S88, even industriesthat have widely adopted S88 typically use it to executemaster and control recipes, but not to represent standardprocess definitions.

A third barrier is interoperability. At execution, masterrecipes must be able to be imported by a variety of enterprise

systems in the manufacturing process. They often need toshare master data from manufacturing, such as references toequipment and materials. Normalisation of recipes as S88procedure models within a single operational language is abest practice for enabling QbD.

THE RISE OF XML FOR REGULATORY SUBMISSIONSSince the FDA mandated the transition from PDFsubmissions to XML-based submissions, XML tools havechanged the way that pharmaceutical companies dobusiness. Corporate adoption of XML continues toaccelerate, and not only to meet these regulatory mandates;companies are also starting to realise the efficiency thatXML-based systems bring to many elements of the lifecycle.But using XML for regulatory submissions is only part ofthe equation. XML-based systems have far greaterapplications and can help to track, define and streamlineinformation throughout the product lifecycle, from latephase discovery to commercial manufacturing.

XML AS A PROCESS DEFINITION ENABLERThe current management of formulations in pharma andbiotech relies heavily on the use of unstructured documents– flowcharts and spreadsheets – to capture manufacturingprocess logic and parameters. Spreadsheets can typicallygrow to be thousands of rows in length; there is no simpleway of abstracting only the CTQs from a formulation forreporting purposes. Finally, there is no method forimporting these documents into execution systems, and sotechnology transfer – the process of converting formulationsand process definitions into executable master recipes forprocess connected devices – is time-consuming, iterativeand error-prone. XML-based tools and standards canalleviate many of the challenges that life science companieshave faced with traditional documentation.

BatchML can address a host of technology transfer andinter-operability requirements of recipe management.BatchML – an industry standard for batch processing thatconsists of a set of XML schemas – has high potential as amethod for representing data for S88-based formulations,and enabling information to flow between systems forsubmissions, recipe and formula management, execution,asset management and quality control.

BatchML implements the models and terminology inthe S88 standard and is an excellent tool to use whenexchanging S88-based data, providing a set of XML-typeand element definitions that may be used in part or in wholefor batch, master recipe and equipment data.

AN AUTOMATED, START-TO-FINISH ALTERNATIVEWith all of the places for the process to break down in theflowchart-and-spreadsheet scenario, documentation of

86 Innovations in Pharmaceutical Technology

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process (flowcharts) and quality (spreadsheets) cannotcontinue as separate systems. A single, automated solution isneeded to take authored process definitions to executablerecipes based on re-usable steps and actions. One promisingmethod normalises the creation, management and transferof S88 process definitions using BatchML. By supportingboth the S88 graphical standard for procedural models andBatchML, this approach is compatible with other BatchMLapplications – such as MES, product lifecycle managementand compliance solutions.

Master recipes are created as S88 procedure models,stored as BatchML, and centrally managed within a systemof record. Using the S88 model as a graphical userinterface, the process flows are drawn, and then parameterscan be attached to each node of the S88 hierarchy throughproperty sheets. The parameters and the drawing arebound and synchronised. All of the underlying CTQparameters are up to date, because they’re centrallymanaged in the process definition. In turn, processmanufacturers can for example: improve informationtransfer between engineering and manufacturing; increaseefficiencies through process re-use across products usingrecipe building blocks and through recipe normalisation;and reduce waste from failed batches through improvedtechnology transfer and management of CTQs.

With this new method, process definition becomes aseamless, end-to-end process, utilising the same toolsthroughout. These integrated elements facilitatetechnology transfer and submission, saving time andmoney. Forrester Research reports that a single day ofdelay on a US $1 billion drug can cost a manufacturerUS $2.74 million in lost sales. An acceleration of just twoper cent could mean 58 to 73 extra days on the market,a revenue difference of US $158-200 million.

Pharmaceutical companies spend vast sums ofmoney to bring drugs to market, so incrementalimprovements can make a huge difference to the bottomline. Yet cost-cutting measures can’t come at the expenseof quality. Fortunately, companies can embed qualityinto their processes, improve productivity, reduce costs,mitigate risks and ease regulatory review with a QbDinitiative that automates batch process definition. Byintegrating disconnected business processes formerlylocked in static flowcharts and spreadsheets, companiescan improve not only internal operations, but externaloperations with contract manufacturers, partners andregulatory officials.

The author can be contacted atpaul.wlodarczyk@justsystems.com

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