BIOVIA ONE QUALITYSOLUTION BRIEF

A Total Quality strategy will not only ensure compliance but lead to improved product quality with increased consistency and reliability, reduced costs, improved productivity, and improved cross-functional collaboration. In order to successfully implement a Total Quality strategy organizations need to include their Quality relevant processes, materials, documents, and metrics for all phases of the product lifecycle from ideation to post-market. And Quality Excellence can only be achieved when Quality is not just treated as a series of projects but becomes a behavioural change enabled by tools and systems. Then Total Quality will help to reduce time-to-market, achieve competitive advantage and protect the brand.

Today’s science-based companies are very aware of the relevance of Quality in conducting a successful business and sustaining competitive advantage. Therefore, many enterprises do have a Total Quality Strategy in place that includes all areas of the organization; they even publish their commitment to Quality. The statements span from founding a company based on Quality to including a commitment to Quality in their statement of purpose or product descriptions.

Unfortunately Quality is often still considered to be costly and non-value adding. But is it really Quality that is costing the company money? Or is it compliance, the mere adherence to regulations such as those published by the US Food and Drug Administration (USFDA), the European Medicines Agency (EMA) or the International Organization for Standardisation (ISO) without going any further? If being compliant means only satisfying the regulations and guidelines, it is non-value adding for the actual process and is wasteful according to the lean principles (“muda” is the Japanese term that has been widely adopted in lean manufacturing and agile software development). Simple process compliance only adds additional steps and therefore adds cost and time. Compliance with global standards typically translates into 35% higher manufacturing and maintenance costs1. As this doesn’t add any value; it is “valueless effort.”

Compliance alone is not enough. Compliant processes can still produce products of low Quality. But processes also need to be repeatable with low variability. High variability and a low Sigma value (like the typical 3 Sigma processes found in the Pharmaceutical industry) require additional means to ensure quality. In many process production operations, this is achieved through Quality Testing as a function of Quality Control. When Quality is “tested into the product,” waste is inevitable.

With a closer look, we see that it is not Quality itself that is costly but more the lack of Quality. The “Cost of Poor Quality” (CoPQ) is the losses caused by poor-quality products and processes. Studies estimate the CoPQ accounts for 10-40% of a company´s turnover2.

Considering this, it should be a major strategy for any organization to make Quality an integral part of every process throughout the entire product lifecycle. Designing and reworking processes with Quality in mind will not only improve Quality. It will also result in more efficient processes. This approach – Quality by Design (QbD) – ensures consistent product quality through statistical, analytical and risk-management methodology in drug design, development and manufacturing3. The approach is highly endorsed by the FDA; the International Conference on Harmonisation (ICH) has developed compliance guidelines. The QbD approach results in leaner processes, less variability and higher quality. As a consequence, Quality improves efficiency and reduces costs.

FDA AND QUALITYThe FDA has recognized that blindly following regulations without considering the actual Quality of the process and the product is not a recommended course of action. Regulatory Compliance and Quality are not the same. In fact, the hyper-focus of many industries on compliance is often an obstacle to Quality. Firms managing manufacturing Quality risks by driving Quality across the organization tend to be more productive, with fewer complaints and investigations per batch, and smaller Quality units with lower Quality-related costs than competitors. With the FDA’s “Case for Quality Initiative,” the agency is now working to implement policies that go beyond mere regulatory compliance to provide a greater focus on manufacturing quality. Regulatory compliance can be a by-product of well-designed and -executed processes producing the highest quality product.4

“…we want to encourage firms to prioritize quality and encourage their boardrooms and their pocketbooks because quality costs money,”

Howard Sklamberg, J.D., FDA’s Deputy Commissioner for Global Regulatory Operations and Policy.

QUALITY IS A CULTUREWhat does it mean for an organization that wants to take a strategic approach to Quality?

In general terms, Quality is the conformance to some predefined requirements and fitness for a specific purpose. Quality must be considered as the prevention of deviations that don’t comply with the requirements. This is similar to a “Right-First-Time” approach, a Quality Management concept that defect prevention is more advantageous and cost-effective than defect detection and associated rework.5 Quality should not be seen as just a cure whenever an issue arises, which is highly inefficient, comes with significant associated costs, and can even lead to loss of reputation.

To achieve Quality, companies must be capable of understanding, optimizing and predicting products and processes throughout the organization and the lifecycle of a product from ideation to commercialization.6 Appropriate tools and techniques include process mapping, histograms, cause-and-effect diagrams, check sheets, Pareto diagrams, graphs, control charts, scatter diagrams, etc. They should not be used standalone but be part of a strategic approach to delivering Quality through a dynamic process of continuous improvement and innovation.

Another relevant aspect of Quality is standardization - consistently maintaining the same industry standards throughout a manufacturing process, and metrics will help to realize and validate this. Metrics are the basis for defining, measuring and monitoring Quality. Metrics for Quality include, for example, lot acceptance, complaints, Out-of-Specification (OOS), Annual Product Review (APR) or Product Quality Review (PQR), Corrective Action Preventive Action (CAPA) effectiveness, process capabilities or performance.7 They are included in the submitted “Request for Quality Metrics Guidance for Industry” from the FDA.8

Most importantly, Quality is not just one or a series of projects. To have the expected deep impact on an organization, Quality requires a behavioural change – Quality must become a culture.

QUALITY AREASA strategic quality approach affects four major areas.

1. Processes are critical for developing and manufacturing products, ensuring their Quality Control (QC) and proper administration. Quality needs to be built in through the entire product lifecycle and all related processes. Development has to ensure therapeutics are developed with the specified Quality, Safety and Efficacy characteristics. Manufacturing processes for therapeutic products require organizations to follow guidelines outlining the minimum requirements for assuring that products are of high Quality and do not pose any risk to

The FDA is working on proposals “like differentiating manufacturers based on their overall quality capability and interacting with them on the basis of that differentiated assessment.”

Steven Silverman, Director, CDRH Office of Compliance, FDA

Quality is not a series of projects - Quality is a culture

consumers or the public. Good manufacturing practices (GMP) are the practices required to conform to the guidelines recommended by the agencies. QC is the part of GMP that is concerned with raw materials, intermediates, packaging materials and finished product sampling, specifications, and testing including stability and environmental testing. QC also covers the organization, documentation and release procedures necessary for ensuring that all required and relevant tests are carried out, and that materials are not released for use, nor products released for sale or supply, until their Quality has been judged to be satisfactory. Quality Assurance (QA) covers all matters that influence the quality of a product.

Administration processes cover activities such as order processing and finance; from a production process perspective, they also include ‘tracking and tracing’ of raw materials, semi-manufactured goods and end products (genealogy).

2. Materials include items such as components (e.g., raw materials, ingredients, process water and gas), containers, and finished products. The final product – the therapeutic in its finished dosage form that has undergone all stages of production, including packaging in its final container and labelling – needs to be of proven Efficacy and Safety and be fit-for-purpose with established specifications for identity, strength, purity and other characteristics. The Quality of the raw materials selected to manufacture a therapeutic can significantly affect the Quality, Safety and Efficacy of the end product; hence, it is important to ensure the right materials are selected, to know the supply chain and be able to answer questions like these. Is the raw material a “generally recognized as safe” [GRAS] material without any known toxicological concerns? Are there any interactions with the drug substance? Is the material compatible with the finished product? Is the availability of the material limited? Is a replacement material available, if necessary?

3. Documentation is a basic requirement for Quality. Under a quality system, written procedures are followed and procedural deviations are justified and documented to ensure that the manufacturer can trace the history of the product, and that processes for product release are complete and recorded.

The first tier of documentation is the policy manual. This is the document that defines what will be done and why. The second tier of documentation is quality procedures that describe the methods that will be used to implement and perform the stated policies. The procedures define who should perform the specific tasks, when the task should be done and where the documentation will confirm that the task was performed. Work instructions are usually department-, task-, or product-oriented and define how a job will be done. Data and records are a way of documenting that the

policies, procedures and work instructions have been followed. They are used to provide traceability of actions taken on a specific product or batch of products. Data and records are the documented evidence of what has been done – from ideation to commercialization; they are the actual proof.7

A Total Quality strategy needs to ensure Regulatory Compliance and Operational Excellence through high quality processes, documents, materials and products underpinned by meaningful metrics.

4. Metrics and Analytics are an objective measure of the quality of a product, process or site as well as of the effectiveness of systems associated with the manufacture of therapeutics products. Good indicators are measuring product and process variability and deviations. Quality metrics are used to monitor quality control systems and processes and drive continuous improvement efforts and innovation in drug manufacturing. They may include elements such as customer satisfaction, supplier quality and performance, manufacturing defects, complaints and cycle times. In manufacturing such metrics include the lot acceptance rate, product quality complaint rate, confirmed Out-Of-Specification (OOS) rate, Right-First-Time rate or recall rate. Quality metrics are the basis for initiatives like Manufacturing Process Improvement (MPI), Quality by Design (QbD), Continued Process/Quality Verification (CPV) or Continuous Process Improvement (CPI).

GENERAL REQUIREMENTSBecause Quality touches every part of an organization and involves overlapping responsibilities, a company wishing to establish a successful Quality strategy needs to begin by fostering communication and collaboration between the teams and parties involved. For executing the Quality strategy, the necessary tools and techniques need to be put into place. But this is not enough. An all-encompassing Quality culture and commitment are necessary for a successful long-term Quality strategy. Quality needs to be the mindset of the company. The organization needs to move from compliance (where process tasks are only added to comply with regulations) to Quality (where the processes are designed to be reliable, repeatable, minimally variable and maximally efficient). Actions need to move from (repeated) corrective actions to preventive actions as the organization identifies the root causes of the issues and avoids them. Overall, the organization needs to step away from mere functional excellence with low impact on quality and efficiency and towards proactive end-to-end Quality and Business Excellence that will have a significant impact on their bottom line, ultimately making the organization more competitive and successful.

CHALLENGESAlthough a Total Quality strategy is required and executable, there are challenges that can make the actual implementation difficult. Quality procedures and the processes need to be developed and it must be ensured that they are followed consistently. Examples are procedures for submissions or for quality testing. While ensuring consistency in developing methods and procedures might already be laborious, enforcing the execution of these procedures can be even more demanding, especially as it can lead to time-consuming, non-value-adding checkmark activities. This is mainly the case when processes are paper-based, disjointed and cumbersome while at the same time highly visible and heavily scrutinized both internally and externally by the FDA. Therefore, the entire process should be revisited with a view to ensuring and optimizing both compliance as well as efficiency. With this approach, Quality Control and Quality Assurance are less likely to be perceived as bottlenecks, which happens in many organizations.10

The Quality process needs to ensure that the right input materials of the right quality are used for the right purpose; different purposes may require different specifications of the material used. All inputs to the manufacturing process must be reliable and Quality controls will regulate the receipt, production, storage and use of all inputs. Organizations will manage and document any changes to materials and make necessary adjustments to the process to avoid unintended consequences.12 With traditional paper-based systems, technicians can spend a lot of time

A Total Quality Strategy comprises all areas of the organization and all stages of the product lifecycle

“The pharmaceutical quality control laboratory serves one of the most important functions in pharmaceutical production and control.”11

FDA, GUIDE TO INSPECTIONS OF PHARMACEUTICAL QUALITY CONTROL LABORATORIES

searching for raw materials. They often reorder existing stock that cannot be found and are unsure where regulated materials are stored, resulting in inefficiency, heightened compliance risk and increased operating costs.

With thousands of documents created within all Quality related processes, it is a challenge to ensure that all documents are managed and maintained throughout their lifecycle in accordance with regulations mandating version control, review, approval, distribution and lifecycle management. Typical submissions, from research through trial, include New Drug or Biologic License Applications (NDA, BLA); Manufacturing and Quality Assurance documents like SOPs, methods, work instructions and specifications; as well as deviations, CAPAs, audits, change controls and complaints; and Corporate Compliance documents in functional areas like marketing, human resources, IT, legal and sales.

It is crucial to quickly aggregate all required data from the different documents and sources in order to measure and analyze Quality-relevant metrics for use in monitoring dashboards, reports, documents, submissions, and process improvement. The challenge is the abundance of data generated by process development, manufacturing and quality functions and the fact that it is data of different types that reside in different sources and documents and are organized differently and stored in different formats in different electronic sources, and sometimes even on paper. This makes data access and aggregation burdensome. For optimal analysis and interpretation, data needs to be contextualized with information about the date of creation, the author, the batch, the process, the site and the genealogy for upstream and downstream correlations. Traditional manual methods such as spreadsheets are tedious, error-prone and waste valuable time. The data analysis tools must also be validated before they are used for making GMP- or ISO-relevant decisions. This is an additional burden for Quality.

The overall challenge for Quality is to ensure both Regulatory Compliance and Operational Excellence through high quality processes, documents, materials and products underpinned by meaningful metrics. At the same time processes need to be streamlined and cost efficient to reduce compliance costs and cost of poor quality. Quality Excellence will increase productivity and enhance Quality while ensuring compliance.

SUPPORTING SOLUTION FROM BIOVIAThe BIOVIA One Quality solution includes capabilities for Quality Process Management, Quality Control and Testing, Materials Quality Management, Quality Document Management and Quality and Process Data Analytics.

Quality Process Management helps organizations to standardize and automate business processes that manage the collection, tracking and analysis of information and the resolution of related issues. Capabilities include SOP and content management with all quality management processes for CAPAs, deviations, audits, validation, customer complaints and other events management processes and multi-site change control.

The BIOVIA One Quality solution includes capabilities for Quality Process Management, Quality Control and Testing, Materials Quality Management, Quality Document Management and Quality and Process Data Analytics.

Core components are a rules-based workflow engine, data dictionary, business rules engine, audit trail, forms manager and advanced reporting.

Product Lifecycle Specific Processes are supported by dedicated solutions for Method and Procedure Development, for Batch Execution/Electronic Batch Record (EBR) for Manufacturing and Lab Management/Lab Execution for Quality Testing. Each of three solutions supports the specific workflows and helps manage the plethora of different Quality-relevant data that are generated.

Method and Procedure Development provides the flexibility as well as the compliance capabilities needed for route design, method development and formulation design. It accelerates the design, documentation, storage and secure sharing of formulations with templates for standardized protocols, powerful searching and experiment cloning capabilities. The solution supports IP, 21 CFR Part 11, GLP and GMP with document versioning, forms-level audit trails and signatures.

Quality Testing builds compliance and Operational Excellence into quality lab operations. It includes capabilities for lab management and execution supporting the full workflow of quality testing from test requests to the creation of certificates of analysis including direct data transfer from an Enterprise Resource Planning (ERP) System and/or Laboratory Information Management System (LIMS), from a consumables and instrument inventory and the lab equipment itself up to the transmission of results for final release.

EBR provides an electronic environment for procedure execution and electronic batch recording to efficiently and compliantly document the execution of any procedure or recipe. The solution provides improved batch record keeping and compliance for a low cost of ownership without the large overheads of a complex Manufacturing Execution System (MES).

BIOVIA supports Quality and Product Lifecycle specific processes.

Materials and Sample Management helps organizations manage their evolving materials and sample processes and workflows. Capabilities include the accurate managing, tracking and reporting of materials and sample quantity, location and safety data while meeting safety and regulatory requirements, including barcode labelling, remote inventory control and Material Safety Data Sheet (MSDS) management. The solution helps to maintain a listing of all the materials in a facility while also keeping track of where they are in real-time quantity and monitoring usage.

Sample Management supports the workflow of samples from collection and submission to disposal. Capabilities include inspection lot management, specification management, sample chain of custody management, execution of quality testing and verification of fitness for purpose as well as genealogy, result review and reporting.

Quality Document Management helps organizations to create, manage and securely store documents, using built-in password policies to protect against unauthorized access and support Electronic Signatures per FDA 21 CFR Part 11 requirements. It ensures that the correct content is created, reviewed, approved, consumed, distributed and retired.

BIOVIA helps organizations manage their evolving materials and sample processes and workflows.

BIOVIA allows customers to effectively and reliably control Quality Documents and Content.”

The solution includes Content Management and advanced search and retrieval, flexible process control and configurable reports, built-in system administration, secure audit trail, automated version control, and automated PDF rendering. Supported documents are policies, procedures, Standard Operating Procedures (SOPs), work instructions, R&D documentation (clinical, regulatory and manufacturing), legal documentation, sales and marketing collateral, HR policies and reports including Corporate Integrity Agreements (CIAs).

Data Monitoring, Analysis and Reporting helps organizations to utilize the abundance of process and quality data in a more user-friendly, organized (contextualized) form for improved process knowledge supporting initiatives like QbD (Quality by Design), PAT (Process Analytical Technology), PR (Process Robustness) and CPV (Continued Process Verification). It provides process development, quality and manufacturing users with a validated environment for self-service, on-demand access to process and quality data from disparate databases and paper records. It automatically aggregates and contextualizes the data and enables ad hoc statistical investigations and analysis with automated validation-ready workflows.

BENEFITS OF THE BIOVIA ONE QUALITY SOLUTIONThe BIOVIA One Quality solution allows customers to:

• Have a comprehensive approach for Total Quality that ensures Compliance and Quality Excellence in all Quality relevant areas throughout the entire product lifecycle

• Reduce compliance costs and costs of poor quality with a solution that allows for pre-emptive action• Standardize and automate quality processes, increase efficiency and accuracy of business

processes and activities and proactively improve business performance• Remove bottlenecks and compliance risks from laboratory-related processes in Development,

Manufacturing and Quality through integration, automation and harmonization• Accurately manage materials and samples from receipt to disposal, address EH&S lab safety

requirements and reduce regulatory and quality risks, hazards and costs• Ensure enterprise-wide consistency of all quality documentation as well as compliant lifecycle

management • Reduce errors, minimize non-value-add manual tasks and improve efficiency by replacing

disconnected and/or paper- and spreadsheet-based systems with a solution that integrates key components of the corporate Quality strategy

• Improve product and process quality throughout the entire product lifecycle with improved consistency and reliability through enhanced process understanding and knowledge sharing

BIOVIA One Quality increases efficiency, reduces costs and improves quality and compliance by addressing all relevant aspects of an organization’s corporate Quality strategy. When properly implemented, the solution can reduce time-to-market, increase sustainability, protect brand reputation, and enhance competitive advantage.

BIOVIA enables organizations to easily obtain Quality Metrics in a validated environment.

BIOVIA One Quality increases efficiency, reduces costs and improves quality and compliance by addressing all relevant aspects of an organization’s corporate Quality strategy.

ABOUT BIOVIABIOVIA provides a scientific collaborative environment for advanced biological, chemical and materials experiences. The sophisticated enterprise system of modeling, simulation, laboratory, and quality management enables innovation for science-based industries.

BIOVIA supports industries and organizations that rely on scientific innovation and quality to differentiate themselves in the marketplace.

BIOVIA is dedicated to science and innovation enhancing the end-to-end process of discover, design, deploy and deliver to obtain high value, realize sustainable business and improve lives.

BIOVIA solutions are used by more than 2,000 companies in the pharmaceutical, biotechnology, energy, chemicals, aerospace, consumer packaged goods and industrial products industries.

1iSix Sigma, Apply Cost of Poor Process and Product Quality to Life Sciences Industry: http://www.isixsigma.com/industries/pharmaceuticals/apply-cost-of-poor-process-and-product-quality-to-life-sciences-industry/)

2Marcus Thomasson & Johanna Wallin, Cost of Poor Quality; definition and development of a process-based Framework: http://publications.lib.chalmers.se/records/fulltext/177665/177665.pdf

3http://www.fda.gov/newsevents/testimony/ucm378343.htm

4http://axendia.com/blog/2014/03/19/show-fda-your-commitment-to-quality-2/

5http://www.businessdictionary.com/definition/right-the-first-time.html#ixzz3kmPHJG3l

6Quality (Pharmaceutical Engineering Series), Kate McCormick, ISBN 0-7506-5113-X

7http://axendia.com/blog/2015/08/19/ispe-fda-and-the-metrics-future/#more-2866

8http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-gen/documents/document/ucm455957.pdf

9https://totalqualitymanagement.wordpress.com

10www.pharmamanufacturing.com/whitepapers/2004/118.html

11http://www.fda.gov/ICECI/Inspections/InspectionGuides/ucm074918.htm

12FDA Guidance for Industry Quality Systems Approach to Pharmaceutical CGMP Regulations, September 2006

WP-9758-0916

Our 3DEXPERIENCE® platform powers our brand applications, serving 12 industries, and provides a rich portfolio of industry solution experiences. Dassault Systèmes, the 3DEXPERIENCE® Company, provides business and people with virtual universes to imagine sustainable innovations. Its world-leading solutions transform the way products are designed, produced, and supported. Dassault Systèmes’ collaborative solutions foster social innovation, expanding possibilities for the virtual world to improve the real world. The group brings value to over 190,000 customers of all sizes in all industries in more than 140 countries. For more information, visit www.3ds.com.

©20

15 D

assa

ult S

ystè

mes

. All

righ

ts re

serv

ed. 3

DEX

PER

IEN

CE®

, the

Com

pass

icon

and

the

3DS

logo

, CA

TIA

, SO

LID

WO

RKS

, EN

OVI

A, D

ELM

IA, S

IMU

LIA

, GEO

VIA

, EXA

LEA

D, 3

D V

IA, 3

DSW

YM, B

IOVI

A, N

ETVI

BES

, and

3D

EXCI

TE a

re c

omm

erci

al tr

adem

arks

or

regi

ster

ed tr

adem

arks

of D

assa

ult S

ystè

mes

or i

ts s

ubsi

diar

ies

in th

e U

.S. a

nd/o

r oth

er c

ount

ries

. All

othe

r tra

dem

arks

are

ow

ned

by th

eir r

espe

ctiv

e ow

ners

. Use

of a

ny D

assa

ult S

ystè

mes

or i

ts s

ubsi

diar

ies

trad

emar

ks is

sub

ject

to th

eir e

xpre

ss w

ritt

en a

ppro

val.

Dassault Systèmes CorporateDassault Systèmes175 Wyman StreetWaltham, Massachusetts02451-1223USA

BIOVIA Corporate EuropeBIOVIA 334 Cambridge Science Park,Cambridge CB4 0WNEngland

BIOVIA Corporate AmericasBIOVIA 5005 Wateridge Vista Drive,San Diego, CA 92121USA