Drug Design & Manufactuing Using Product Lifecycle
Drug Design & Manufacturing usingProduct Lifecycle ManagementMarch 2011
Drug Design & Manufacturing using Product Lifecycle Management March 2011TABLE OF CONTENTSAbstract . 3Abbreviations . 4Market trend/ Challenges . 5Functional Building Blocks of a Pharmaceutical Product LifecycleManagement system . 6Structured Electronic Drug Development Record (eDDR) . 6Drug Portfolio & Project Management . 8Integrated Clinical Supply Chain Management . 9Technology Transfer . 9Personalized Drug Development . 10Integrated Quality & Risk Management . 11Packaging & Collateral Management . 12Global Product Registration . 13Conclusion. 15Reference . 16Author Info . 17 2011, HCL Technologies. Reproduction Prohibited. This document is protected under Copyright by the Author, all rights reserved.
Drug Design & Manufacturing using Product Lifecycle Management March 2011AbstractProduct Life Cycle Management has evolved in Automotive,Aerospace & Defence and Hi-Tech verticals providing acollaborative platform to automate their Product development R&Dprocesses and data management. Similarly PLM can provide anintegrated platform to automate the pharmaceutical processes fromDrug discovery to secondary manufacturing or simply lab tolaunch. Most organizations use a number of tools & solutions tomanage the recipe, material & equipments, batch processes, Labdata management, document management during pre-clinical andclinical trials in the drug discovery and generic drug developmentareas. These solutions to a large extent are fragmented & do notstreamline the R&D process as a structured program.Drug Discovery & Design is a lengthy process which needs todriven under the ever increasing competitive pressure and fear ofloss of profit margins due to Patent Expiration.This whitepaper focuses on explaining how drug discovery &development process driven in PLM environment can help toensure shorter time to market, system driven and consistentpharmaceutical processes, a common collaborative platform tomanage eCTD and technology transfer for bulk manufacturing. 2011, HCL Technologies. Reproduction Prohibited. This document is protected under Copyright by the Author, all rights reserved.3
Drug Design & Manufacturing using Product Lifecycle Management March 2011AbbreviationsSl. No.AcronymsFull form1PLMProduct Lifecycle Management2FDAFood and Drug Administration3eCTDElectronic Common Technical Document4GxPGood Practices5ICHInternational Conference onHarmonization6eDDRElectronict Drug Development Record 2011, HCL Technologies. Reproduction Prohibited. This document is protected under Copyright by the Author, all rights reserved.4
Drug Design & Manufacturing using Product Lifecycle Management March 2011Market trend/ Challenges Phlegmatically evolved PDM in pharmaceutical IndustryPLM is evolved from automotive, aerospace & defense industriesand then embraced by other verticles like Hi-Tech &Pharmaceutical. It has undergone the journey of evolution fromPDM to PLM in these industries. Pharmaceutical domain does nothave standardized product data modeling software andcollaborative electronic data managed like CAD software. Some ofthe companies in Pharmaceutical domain are using PLM for productportfolio management & art work and packaging. PLM products arestill need to evolve for managing pharmaceutical product designdata and act as collaborative platform within internal departmentsacross the enterprise and with external groups. Smaller companies cannot afford cost of implementationPharmaceutical domain specific solutions are available at very highcost. This investment is huge for a small biotech companies. One ofthe solutions for this could be using the open source PLM platform.Other way would be using on-demand PLM model on cloud.There are open source PLM solutions coming up in the marketthese days. The vendors of these solutions and also current PLMproduct market leaders has to come up with lighter version of thesolutions with pharma specific processes, that will help SMBsegment of pharma companies to meet their demand and budgets. Pharmaceutical Industry is mischarged for unrelatedEngineering ComplexityPharmaceutical Industry involves totally different type of complexityworld which could be related to physical and chemical complexity,storage, shelf life related complex problems. Current PLM productsare much evolved to handle engineering complexities and hence thecost is also in proportion to the engineering complexities solved withPLM. The PLM vendors should have domain specific costing whereone need not end charging more to pharmaceutical customer forengineering/ CAD complexities handled by the software. Less Matured pharmaceutical domain specific processes inPLM spaceAs earlier stated PLM has started its journey fromautomotive/aerospace products and thenembraced bypharmaceuticals, it is just a matter of time for PLM to evolve andbecome mature enough to cater the needs to industry. As currentprocesses are more inclined towards automotive, aerospace, it willsurely need some maturity to be widely accepted by pharmaceuticaldomain. 2011, HCL Technologies. Reproduction Prohibited. This document is protected under Copyright by the Author, all rights reserved.5
Drug Design & Manufacturing using Product Lifecycle Management March 2011Functional Building Blocks of a PharmaceuticalProduct Lifecycle Management systemCurrent PLM is mostly used to manage projects, documents,Artwork & Packaging and related CAD data management. Thereare many other areas in Pharmaceutical where the PLM processescan help to automate and streamline many areas.Broadly PLM can useful for Enabling Drug Discovery & Design on principles of GxP,QbD, API formulation,Pre-clinical trials,Clinical Supply Chain Management, Recipe Management.The following diagram summarizes the functional building blocks ofa Pharmaceutical Product Lifecycle -Structured Electronic Drug Development Record (eDDR) Standard Drug Discovery & Development Life CycleDrug design is an iterative process which begins when a chemistidentifies a compound that displays an interesting biological profileand ends when both the activity profile and the chemical synthesis 2011, HCL Technologies. Reproduction Prohibited. This document is protected under Copyright by the Author, all rights reserved.6
Drug Design & Manufacturing using Product Lifecycle Management March 2011of the new chemical entity are optimized. Traditional approaches todrug discovery rely on a step-wise synthesis and screening programfor large numbers of compounds to optimize activity profiles. Overthe past ten to twenty years, scientists have used computer modelsof new chemical entities to help define activity profiles, geometriesand reactivities. Major Phases and sub-phases in a typical drugdiscovery process have been depicted in diagram below.PLM can help to store the electronic drug record in phases. Theelectronic drug record includes drug formulations at everyintermediate state, the linked test results, drug regulatory relatedinformation, product quality assurance & control documents, drugpackaging/artwork, geography specific packaging, regulatoryinformation.Currently all the drug development records are either available innon electronic format or available at different places in variousformats, There is a single collaborative platform available in PLM fordocument management which can be extended for electronic drugdevelopment record (eDDR) management.Drug Design & Discovery Data Version ManagementIn data rich industry like pharmaceuticals, knowledge tends to beweakened unless there is proper knowledge management, transfermechanism.Current drug development process does not facilitate the idea ofCentral repository where all the research data can be stored,version controlled and collaboratively used by all the stakeholderswhile work is in progress. Multiple stakeholders can work withmultiple protocols, processes together to achieve the common goalby offering visibility, flexibility across various isolated islands of aPharmaceutical organization. 2011, HCL Technologies. Reproduction Prohibited. This document is protected under Copyright by the Author, all rights reserved.7
Drug Design & Manufacturing using Product Lifecycle Management March 2011With PLM systems, as the data is available centrally the backupsrelated to data can be ensured. Only designated people can begiven access to the product data. There will be standardization interms of the research processes if the product data is available incollaborative portal.The following diagram depicts how PLM application helps.PLM provides a common collaborative platform for maintainingeDDR. Various important stakeholders for drug development likepharmaceutical scientist, engineer, and change analyst andmanufacturer engineer can have life cycle specific view of theelectronic drug record at various stages of drug development. PLMprovides basic lifecycle management and traceability with allcorresponding artifacts effective at specific period of time.Drug Portfolio & Project ManagementAn efficient drug portfolio management is the key factory for toimprove the drug development productivity. Like any other productthe drug product life cycle consists of many offshoot projects whichneed to be managed throughout.PLM‟s Portfolio and project management features provide aneffective way to monitor and control the timeline and cost in drugdevelopment process which is a pressing need to keep profitmargins under control in the competitive environment. It also helpsto track and control the risks associated with various phases ofproject/ sub-project phases. This is a proper tool to track theaccountability and better resource management.As mergers and acquisition (M&A) activities continue companies arein need of a common platform to harmonize their product portfolios 2011, HCL Technologies. Reproduction Prohibited. This document is protected under Copyright by the Author, all rights reserved.8
Drug Design & Manufacturing using Product Lifecycle Management March 2011and enhance the visibility across entire product line & customerpipeline. This also helps to achieve better utilization of sharedresources, optimize the supply chain and logistics for the newlymerged entity.Integrated Clinical Supply Chain ManagementFollowing are the factors which are driving a stronger need of aClinical Supply Chain Management in a pharmaceutical industryContinuous Mergers & Acquisitions causing lots of similarities ingeneric portfolio, The opportunity of cross selling ensuring betteroptimization , resource utilization of the newly merged entity leadingto proper portfolio harmonization.The Adaptive Clinical Trials (ACT) methodology is accepted by thePharmaceutical industry as a way to accelerate drug development,reduce costs and improve time to market. It allows statisticians andscientists to configure and evaluate different alternate designs,different adaptive elements of design. This involves a great deal ofcollaboration with external agencies. PLM provides a highlycollaborative common platform for successful integration of supplychain management.An effective Drug development technique, like quality by design(QbD) allows shortening drug approval time span and efforts forCommercial Manufacturing.Logistics optimization improves better utilization of infrastructure,consumable resources.Technology TransferDevelopment and transfer of knowledge artifacts is a critical processfor drug development.Internal/ External Secured CollaborationTechnology Transfer is consisting of sending unit(s) and receivingunit(s) to transfer electronic design record of Product, Process orMethodology. Technology Transfer is considered successful if areceiving unit is able to reproduce the transferred product, processor methodology as per specification agreed with sending unit.It is a bridge to join gaps between customer, regulatory authorityand pharmaceutical organization.Technology Transfer is used to transfer following types ofdocuments in pharmaceutical industries: 2011, HCL Technologies. Reproduction Prohibited. This document is protected under Copyright by the Author, all rights reserved.9
Drug Design & Manufacturing using Product Lifecycle Management March 2011 Drug FormulationDevelopment ProcessQuality ControlMass ProductionClinical TrialsKnowledge ManagementDue to increasing attrition there is lot of leakage in knowledge baseof an organization. Due to widespread geographical locations, thereare many cases of reinvention of wheel. There are certainchallenges in Technology Transfer executed traditionally which canbe addressed by PLM like: Dilution in Knowledge base leading to reinvention of thewheelConfused ownership of responsibilitiesDelayed approvalsPersonalized Drug DevelopmentPersonalized Drug Development model provides tailored healthcareto suit individual patient in whatever possible manner. Advancementin the field of molecule profiling may allow a greater deal of help inpersonalized drug development. As the time progresses there willbe a need to combine the genetic information of patient, Pharmacogenomics optimizes the drug therapy as per the patient‟sgenotype to ensure maximum efficiency and minimum side effects.PLM has capability to facilitate the personalized drug development.The following diagram illustrates how PLM can help for personalizeddrug development. 2011, HCL Technologies. Reproduction Prohibited. This document is protected under Copyright by the Author, all rights reserved.10
Drug Design & Manufacturing using Product Lifecycle Management March 2011The principle of personalized drug design can be very easilyadapted for product development of artificial biomedical implantslike dental implants, pacemakers, orthopedic implants & ProstheticLimbs. In place of the genomic database there need to be physicaldimensions specific to the patient needs to taken into consideration.Integrated Quality & Risk ManagementDrug Regulatory HarmonizationHarmonization is a process of integrating national standards of drugdevelopment with international standard for efficient drugdevelopment.Generic drug development has a typical harmonization process forgetting the product approved by regulatory authority like FDA;similarly the branded drug also needs to confirm certain norms andcompliances. PLM can provide a strong platform to achieveharmonization needs of any pharmaceutical industry.Globalization has brought into greater importance of an approach touniformity in the formulae of the more powerful remedies, in order toavoid chance to patients when a prescription is dispensed in adifferent country from that in which it was written. Attempts havebeen made by international pharmaceutical and medicalconferences to settle a basis on which an internationalpharmacopoeia could be prepared.The purpose of ICH is to reduce or obviate the need to duplicate thetesting carried out during the research and development of newmedicines by recommending ways to achieve greater harmonizationin the interpretation and application of technical guidelines andrequirements for product registration. Harmonization would lead to amore economical use of human, animal and material resources, andthe elimination of unnecessary delay in the global development andavailability of new medicines while maintaining safeguards onquality, safety, and efficacy, and regulatory obligations to protectpublic health.Risk ManagementThe process of identifying risk, creating mitigation plan, contingencyplan to ensure the drug discovery, development & manufacturingexecutions.In early 2002, the FDA announced its “Pharmaceutical CurrentGood Manufacturing Practices (cGMPs) for the 21st Century: ARisk-Based Approach.” The FDA defines a Risk ManagementProgram (RMP) as, “a strategic safety program designed todecrease product risk by using one or more interventions or tools.”The Risk Management Plan consists of various elements like 2011, HCL Technologies. Reproduction Prohibited. This document is protected under Copyright by the Author, all rights reserved.11
Drug Design & Manufacturing using Product Lifecycle Management March 2011 Risk Management PlanRisk Identification TechniquesRisk Evaluation TechniquesRisk Response PlanningRisk & Issue Management PlanPLM provides tools for effective risk management.Packaging & Collateral ManagementPackaging and collateral are basically 2D/3D graphic designs, videomaterial which are useful for packaging and selling the drug. Thesegraphic components are subject to various changes, co-authoringby group of people and require certain sort of approvals to beeffective. PLM already has a strong platform to integrate withvarious graphic designs CAD tools which can be extended for2D/3D packaging data management. Rest graphic content can beversion controlled using document management functionality ofPLM.Packaging Data ManagementPackaging is defined as collection of neutral foreign componentwhich surrounds pharmaceutical product from the time of productiontill consumption.Manufacturer are under constant pressure to meet ever increasingneed of packaging and artwork management to fulfill consumerdemand, increasing awareness of environment friendly packaging,meeting different external environment specific requirements like:ooooProtection against external influences that can alter theproperties of product.Protection against biological contaminationProtection against physical damageTamper proofing, Child proofing, Anti counterfeitingAs most of the products in pharmaceutical domain come with anexpiry date, there has to be a mechanism to correlate thepharmaceutical product with packaging and same has be executedby the product assembly lines, by the Manufacturing ExecutionSystem after taking input from Product Lifecycle Managementsystem.Packaging CAD data management, collaboration and visualizationis a necessary feature as the design and development of packaginghas to incorporate various legal, scientific, branding collateralparameters taken into consideration.The QC testing needs to done on packaging and results need to beavailable for following type of testing 2011, HCL Technologies. Reproduction Prohibited. This document is protected under Copyright by the Author, all rights reserved.12
Drug Design & Manufacturing using Product Lifecycle Management March 2011oooooooVisual inspectionDimensional TestPhysical TestChemical TestMicrobiological TestPressure TestTemperature TestCollateral/Artwork ManagementThe labeling in current pharmaceutical industry has been complexdue to evolution in technology. The label has to contain humanreadable information likeooooooThe artworkStatutory legal informationIngredients and allergy information,Storage instructionsDosage informationPlaceholder for printing the manufacturing date/ expiry date.It should also contain placeholder for printing machine readableinformation likeoooBar CodeRFIDHologram stickers for identifying genuine product.As mentioned in above sections the 2D/3D graphic design content,document facilitating the electronic records of packaging CAD andcollateral can be collaboratively maintained using PLM.Global Product RegistrationProduct RegistrationThe product registration artifacts are mandatory requirement andneed to recreate every time an organization is going for the productregistration under different geography as part of statutory and legalrequirement. PLM provides facility to create reusable productregistration artifacts, which is definitely a saving in terms of effortand money.Electronic Common Technical Document (eCTD)It was developed by the International Conference on Harmonization(ICH) Multidisciplinary Group 2 Expert Working Group (ICH M2EWG). As of January 1, 2008, the U.S. Food and DrugAdministration announced that the eCTD is the preferred format forelectronic submissions. To date; over 98,000 eCTD sequenceshave been submitted to the FDA. 2011, HCL Technologies. Reproduction Prohibited. This document is protected under Copyright by the Author, all rights reserved.13
Drug Design & Manufacturing using Product Lifecycle Management March 2011It is an interface for the pharmaceutical industry to agency transferof regulatory information. The content is based on the CommonTechnical Document (CTD) format. The eCTD is a messagespecification for the transfer of files and metadata from a submitterto a receiver. A cumulative eCTD message can be viewed using aneCTD viewer. FDA revealed during the 2009 DIA Annual Meetingthat it is looking at draft legislation to require eCTD.Providing facility to manage eCTD will be a mandatory requirementfor generating the compliance, harmonization results. 2011, HCL Technologies. Reproduction Prohibited. This document is protected under Copyright by the Author, all rights reserved.14
Drug Design & Manufacturing using Product Lifecycle Management March 2011ConclusionPharmaceutical Industry can ripe the benefits of PLM not only inmedicine packaging but also can be very well used for controllingand managing the R & D processes. The typical functional areaswhich can benefit with PLM Implementations are: Drug Portfolio & Project ManagementDrug Design & Discovery Data ManagementDrug Discovery Data Version ControllingPersonalized Drug DevelopmentDrug Regulatory Harmonization 2011, HCL Technologies. Reproduction Prohibited. This document is protected under Copyright by the Author, all rights reserved.15
Drug Design & Manufacturing using Product Lifecycle Management March generic-drug-development-rd/Personalized Drug ed medicineRegulatory ional Conference on Harmonisation of Technical Requirements for Registration ofPharmaceuticals for Human UsePharmaceutical Risk article/pharma-riskmgmt.pdfClinical Supply Chain hain-clinical-supplymanagement.jhtml 2011, HCL Technologies. Reproduction Prohibited. This document is protected under Copyright by the Author, all rights reserved.16
Drug Design & Manufacturing using Product Lifecycle Management March 2011Author InfoKapil Jadhav is Technical Manager in PLM practice forHCL. With post graduation in Software Engineering,Graduation in Computer Engineering from NationalInstitute of Technology, Surat (India), he has around 9years of experience in delivering IT solutions & consultingto clients in discrete Manufacturing Industrial Equipments,Automotive, Aviation, and Pharmaceuticals. He has widerange of experience in PLM implementation using EnoviaMatrixone, Oracle Agile PLM and Aras Innovator withreputed customers like GE Energy, GE Aviation, CumminsEngine Business Unit. Currently he is focusing on GreenDesign Workbench & other PLM initiatives. 2011, HCL Technologies. Reproduction Prohibited. This document is protected under Copyright by the Author, all rights reserved.17
Hello, I’m from HCL’s Engineering and R&D Services. We enabletechnology led organizations to go to market with innovative products &solutions. We partner with our customers in building world classproducts & creating the associated solution delivery ecosystem to helpbuild market leadership. Right now, 14500 of us are developingengineering products, solutions and platforms across Aerospace andDefense, Automotive, Consumer Electronics, Industrial Manufacturing,Medical Devices, Networking & Telecom, Office Automation,Semiconductor, Servers & Storage for our customers.For more details contact eootb@hcl.comFollow us on twitter ndourblogVisit our website http://www.hcltech.com/engineering-services/About HCLAbout HCL TechnologiesHCL Technologies is a leading global IT services company, workingwith clients in the areas that impact and redefine the core of theirbusinesses. Since its inception into the global landscape after its IPO in1999, HCL focuses on „transformational outsourcing‟, underlined byinnovation and value creation, and offers integrated portfolio of servicesincluding software-led IT solutions, remote infrastructure management,engineering and R&D services and BPO. HCL leverages its extensiveglobal offshore infrastructure and network of offices in 26 countries toprovide holistic, multi-service delivery in key industry verticals includingFinancial Services, Manufacturing, Consumer Services, Public Servicesand Healthcare. HCL takes pride in its philosophy of „Employee First‟which empowers our 72,267 transformers to create a real value for thecustomers. HCL Technologies, along with its subsidiaries, hadstconsolidated revenues of US 3.1 billion (Rs. 14,101 crores), as on 31December 2010 (on LTM basis). For more information, please visitwww.hcltech.comAbout HCL EnterpriseHCL is a 5.7 billion leading global technology and IT enterprisecomprising two companies listed in India - HCL Technologies and HCLInfosystems. Founded in 1976, HCL is one of India's original IT garagestart-ups. A pioneer of modern computing, HCL is a globaltransformational enterprise today. Its range of offerings includesproduct engineering, custom & package applications, BPO, ITinfrastructure services, IT hardware, systems integration, anddistribution of information and communications technology (ICT)products across a wide range of focused industry verticals. The HCLteam consists of over 79,000 professionals of diverse nationalities, whooperate from 31 countries including over 500 points of presence inIndia. HCL has partnerships with several leading Global 1000 firms,including leading IT and technology firms. For more information, pleasevisit www.hcl.com
the solutions for this could be using the open source PLM platform. Other way would be using on-demand PLM model on cloud. There are open source PLM solutions coming up in the market these days. The vendors of these solutions and also current PLM product
member requests a refill of the drug, at which time the member will receive a 60-day supply of the drug. If the Food and Drug Administration deems a drug on our formulary to be unsafe or the drug’s manufacturer removes the drug from the market, we will immediately remove the drug from our formulary and provide notice to members who take the drug.
Free drug (a) Tumor Drug-loaded NPs (b) F : Schematic contrast of drug biodistribution a er injection of free drug (a) and drug-loaded NPs (b). self-assembly), targeted drug delivery processes, and the current state of NP computational modeling. Directions for future research are also discussed. 2. Self-Assembled Nanoparticles as Delivery Vehicles
If the Food and Drug Administration deems a drug on our formulary to be unsafe or the drug’s manufacturer removes the drug from the market, we will immediately remove the drug from our formulary and provide notice to members who take the drug. Other changes. We may make other changes that affect members currently taking a drug. For
(drug-drug interaction), food, beverages, dietary supplements the person is consuming (drug-nutrient/food interaction) or another disease the person has (drug-disease interaction). A drug interaction is a situation in which a substance affects the activity of a drug, i.e.
the construction of drugs, drug users, drug producers and drug traffickers as ‘the antagonistic drug Other’ (Herschinger, 2011) or existential threat. Initially the ‘Other’ was seen to be drug users, however gradually drug trafficking organisations (DTOs) and then ‘narco-terrorists’ became seen as the most dangerous drug ‘Other .
Drug- Drug Interactions Need to understand: The disposition or handling of each drug The therapeutic window of each drug . ARV Co-Med TOXICITY . TFV HIV FDA Center for Drug Evaluation and Research. Clinical Pharmacology & Biopharm Rev 2014 Gupta SK, et al. IAS 2015. Vancouver, CA; #TUAB0103.
potential for a drug to be a substrate, inhibitor, or inducer of that process, we can predict the potential for drug interactions. In Vitro models/Tools Reza Fassihi Ph.D. 20 The integration of in vitro and in vivo (both animal and human) data can identify the role of transporters in drug‐drug interactions.
WiFi, with all of the basic details of the authentication (user, venue and device details). This can be useful if you want to trigger real-time events or load data to your CRM without making repeated requests to BT Wi-Fi’s RESTful company API. To use Webhooks, you will need to create your own listener that receives and parses JSON in the format specified in the instructions below. The .
