Biophorum Annual Report 2017

THE BPOG REPORT 2017

Connect.

Collaborate.

Accelerate.

Collaboration Group Participation Drug Substance (BPOG DS) Development Group (BPDG) Fill Finish (BPOG FF) Information Technology (BPIT) Technology Roadmapping (BPOG TRM) Supply Partner Phorum (BPOG SPP)

AbbVie

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Ajinomoto North America Inc. Alexion Amgen

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Asahi Kasei

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Astra Zeneca

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BASF Bayer Healthcare Biogen

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Bosch Bristol-Myers Squibb & Company Chugai Cook Pharmica

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EMD Serono

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Emerson

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GE Healthcare Life Sciences

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Ipsen

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PM Group Regeneron Pharmaceuticals

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Sanisure

CONNECT. COLLABORATE. ACCELERATE.™

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Takeda Pharmaceutical

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Thermo Fisher Scientific UCB S.A.

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Sartorius Stedim

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Sanofi

VWR

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Samsung Biologics

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Novasep

Roche

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Hovione ImmunoGen

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NNE

Shire

High Purity New England

Janssen Pharmaceuticals

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GSK Biologicals S.A.

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SABIC

G-CON Manufacturing Inc

GSK Pharmaceuticals

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Pall Life Sciences

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Ferring FUJIFILM Diosynth BioTechnologies

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M+W Group

Novo Nordisk

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MilliporeSigma

Pfizer

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Meissner Filtration Products

Nordson Medical

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Eli Lilly

Lonza

NewAge AdventuaPure

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Eisai (Morphotek)

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Kyowa Hakko Kirin

Merck MSD

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Kaiser Optical Systems

Novavax

CRB

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Contents Now with QR codes to link you to the white papers and guidance documents.

Simply download a QR reader on your phone and scan these codes to take you straight to the document you want.

Overview Your industry. Your collaboration

04

Six phorums

06

Benefits of membership

08

Regulatory interaction

10

Drug Substance Becoming a vehicle for strategic industry change

12

Post-approvals strategy piloted with ANVISA

14

Landmark leachables guide

16

Reducing raw material variability.

An industry-wide initiative

18

Technology Roadmapping If you see this symbol the download is only available to representatives of BPOG members via the internal website.

Viewing online? Click here.

First edition published

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Suppliers and the Technology Roadmap journey

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Fill Finish Fill Finish

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Rapid micro in Grade A

25

Commercial-scale lyophilization

26

Visual inspection: Delivering a standardized approach for classifying particles

28

BioPhorum Development Group BioPhorum Development Group

30

Host Cell Proteins

31

Formulation team offers a perspective on drug product robustness studies

32

Bioassay 34

Supply Partner Phorum Supply Partner Phorum

37

BioPhorum IT Collaboration BPIT: The BioPhorum IT collaboration

40

Deliverables 2016-2017 Published papers

43

3

Overview

Your industry.

Your collaboration.

Is the pharmaceutical industry good at innovation?

The prevailing view would, perhaps, be that ‘no, it isn’t because it is a conservative and risk-averse industry’. However, a more informed view might point to evidence in the manufacturing supply chain area (at least) that invention and finding more effective ways of doing things are happening more frequently and faster than ever before.

Take manufacturing capacity, for example. In the past, if there was a need for additional capacity then the options would be either to build a new plant or go to contract manufacturing organizations (CMOs). The current problem is that new facilities take too long to build and CMOs are highly utilized from a capacity perspective.

to find novel approaches to rapidly create new installed capacity, then it is also necessary to design and develop better process technologies to drive down manufacturing cost. Payers want greater value from their spend and there is huge unmet market need, particularly in developing economies. Access to drugs is a prime driver for change.

Innovative and collaborative business solutions are solving the problem.

We are seeing dormant facilities on drug company sites being brought back to life in partnership with CMO expertise (Merck/MSD and Fujifilm).

There are joint ventures between biopharmaceutical companies and CMOs to exploit new flexible technologies, such as single-use systems (Sanofi and Lonza), and infrastructure-ready sites are being planned where new facilities can be plugged in quickly in line with demand (GE Healthcare, Cork BioPark).

Innovation is an expensive business, so priorities need to be established and resources need to be channeled into the right areas. This will be aided by the BioPhorum Operations Group (BPOG) Technology Roadmap. More than two years hard work by experts from across the industry is about to bear fruit.

Necessity is said to be the mother of invention. Well, if it has been necessary 4

CONNECT. COLLABORATE. ACCELERATE.™

The Technology Roadmap details gaps and potential solutions across a range of capability areas: process technologies, in-line monitoring and real-time release, modular and mobile facilities, automation, knowledge management and supply partnership management.

By bringing this insight into the public domain, clarity on the most important

gaps will enable focused application of investment, often involving crosscompany collaborative groups.

Some of these new technologies have been in the works for some time, but haven’t reached widespread adoption in the commercial manufacturing environment.

Pfizer is to be congratulated on its announcement to build ‘an advanced modular facility based on single-use biomanufacturing technology’ in Hangzhou, China, to supply commercial biologics locally and regionally – the first Western company to do so.

Others are sure to follow, rapidly.

If the publication of a technology roadmap helps pull the industry forward in a concerted, focused way, then there are factors still holding it back. The complexity of the global regulatory environment is, by all accounts, getting worse. Industry consortia can only continue to work for harmonization and regulatory innovation. BPOG’s Regulatory

Overview

Interaction team continues to facilitate engagement with key health authorities and other stakeholder organizations in this space. One BPOG workstream recently demonstrated how progress could be made by meeting with ANVISA (Brazil’s health agency) to explore the vision of ‘one global submission process’. A number of practical improvements to benefit the regulators and the industry were identified.

Digital technology is an enabler for innovation in our sector as much as in any other. There are signs the slow uptake is becoming a thing of the past.

A number of companies are developing digital strategies and realigning their organization structures to support change. Convergence of operational technology and information technology is a core element. GlaxoSmithKline’s Immersive Intelligent Manufacturing laboratory is a great example of seeking to accelerate innovation by demonstrating the ‘art of the possible’. The BioPhorum IT (BPIT)

team has successfully developed and disseminated a Digital Plant Maturity Model, which is helping members to assess where they are on the journey to fully automated, integrated and adaptive operations. If you want to track a new trend that currently is more conceptual than reality, then ‘use of robotics in manufacturing’ would be a good one.

Innovation must be applied to hardedged technology and softer business processes to meet the needs of business and the market. It is also relevant and necessary in the context of attitudes and behavior. This is clear in the Supply Partner Phorum (SPP), where suppliers and drug companies are advancing relationships through innovation to drive out non-value-adding waste from the inbound supply chain.

The key is less about novelty and more about successful implementation of standardized approaches across the industry. Without implementation the best innovation in the world cannot generate value.

Disruptive and implementable innovation appears to be taking hold more effectively across our industry.

It is important this continues. Product variety and technology platform diversity are set to explode over the next few years. Cell and gene therapy is one example where commercialscale manufacturing capability is being set up. The resulting additional skills requirements, supply chain complexity and regulatory challenges will be significant. Accelerated innovation will help meet the challenge. Collaborative processes working across the industry ecosystem will also make a contribution.

BPOG is fully committed to playing its part in facilitating multi-company team working and in supporting innovation.

Simon Chalk July 2017

5

Overview

BPOG’s six Phorums provide benefits across all biopharma operations The BioPhorum collaboration consists of six separate Phorums, all of which focus on common biopharmaceutical challenges. This structure allows companies to align their interests to Phorums and collaborate with similarly committed organizations.

In each Phorum, leadership teams develop and agree workstreams’ missions to make industry change happen. All workstreams are supported by BPOG’s dedicated facilitators and guided by the industry’s leading Regulatory Affairs professionals in the Regulatory Interaction group.

Inevitably, interests can overlap between teams and with bodies outside of BPOG. So one of the primary roles of our facilitators is to ensure that connections are made and scopes agreed that deliver synergies, avoid duplication and deliver the best results from our collective efforts.

BPOG influence RE

Companies

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2204

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Drug Substance

Development Group

Fill Finish

Information Technology

Change programs

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Supply Partner

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Technology Roadmapping

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Industry SMEs

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Overview

Drug Substance is the original BPOG collaboration and given its size and maturity is probably our most productive. As the name implies, Drug Substance is focused on delivering the best solutions to the challenges of biological drug substance manufacturing. But it also picks up several key generic topics such as Human Performance, Single Use Technologies and Post Approval Submissions. In the last couple of years, this community has developed strong governance and project management tools to help it to deliver its program of industrial change in the best way possible.

The Development Group supports the industry in its quest for better and faster process development. Formed in 2011, the Development Group brings the benefits of our collaboration to the drug development community which has enormous challenges given the proximity to IP. Despite this, we have identified how to successfully connect process development organizations and provide a space where subject matter experts (SMEs) can collaborate on shared issues such as QbD and process characterization, cell line technologies, molecule selection and accelerate improvements across the process development arena.

Fill Finish is where you find a strong representation of the world’s top sterile filling operations. Its mission is to collectively develop and implement the safe, predictable, lean and agile drug product manufacturing processes needed by our high value and low volume biopharma pipelines. Recent initiatives include the development of harmonized risk assessments for Environmental Monitoring and particle risk, as well as the advancement of key technologies such as airborne particle counting and computer modelling of Lyophilization.

Information Technology (or BPIT for short), is the latest of our end user collaborations and implementation groups. Its mission is to accelerate the delivery of ITimpacted business goals and help to unlock the value of the pharmaceutical industry’s current and future information technology opportunities. Established in 2016, with senior IT representation from leading biopharma companies, it has quickly adopted strategic positions on digital transformation in biopharma manufacturing and introduced new guidance and tools to drive efficiencies in compliance and quality management.

Supply Partner Phorum is the first of our new collaborations where customers and suppliers meet as partners with the aim of transforming our inbound supply chains.

The group’s vision is one of short integrated supply chains, providing end-to-end visibility and helping to build quality in at source. To realize this vision the group are working to align customer – supplier processes, increase standardization at key points and create a culture of openness and trust. The starting point has been the development of best practice guidelines for mapping the supply chain to improve adverse event management and business continuity planning, and the development of approaches for improving forecasting and demand planning to reduce inventory and supply shortages.

Technology Roadmapping is the sixth and final Phorum in BPOG and its role is to establish a dynamic and collaborative technology management process that accelerates innovation by engaging with industry stakeholders to define future needs, difficult challenges and potential solutions. In this Phorum, bio manufacturers, supply partners, leading academics, regional innovation hubs and agencies all play an active role, building and communicating the roadmap and finally closing the loop by monitoring industry progress. The collaboration is already building closer technical relationships between industry stakeholders and informing company technology strategies and ultimately all involved expect to see the faster development and adoption of new technologies across the industry.

Regulatory Interaction is not a Phorum but an overarching service engaging and aligning with regulatory stakeholders, with a mission to accelerate the work of all BPOG Phorums and Workstreams. As our industry develops advanced, best practice manufacturing systems we often experience varying degrees of understanding and confidence between manufacturers and regulators.

This can lead to uncertainty, solution dilution, or over-engineered and ultimately, slow innovation and improvement. To counter this, the BPOG Regulatory Interaction Team provides informal dialogue with agencies, offers industry views and listens to wider agency perspectives, helping teams to position and focus their efforts in the most productive way to move the industry forward.

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Overview

Benefits of BPOG membership come at many levels For individuals and companies alike, within the BPOG community the rich exchange of data, the sharing of experience and the pooling of change efforts makes us all more productive and effective.

Synchronised implementation of change

BPOG members know that great results come from collaborations with strong foundations, where teams understand the common ground and develop a bedrock of trust. We build from foundations up, layer by layer, and benefits come with first contact and keep on accruing as teams work towards their goals

Industry engagement with regulators

VALUE DELIVERED

Co-developed best practices and adoption approaches Shared experience and knowledge Comparison of competence Contacts and networks

INDIVIDUAL BENEFIT

BUSINESS BENEFIT

INDUSTRY BENEFIT

Contacts and networks

Shared experience and knowledge

Industry engagement with regulators

Your subject matter experts (SMEs) need to know all the answers, but who do they turn to? Our collaborations bring the industry’s SMEs together, not in 3s or 4s, but in invaluable support teams of 20, or 30 or more.

Plugging your people directly into the global network of experts.

It’s not unusual for teams to pool data from 15 to 20 companies describing the details of working approaches, massively expanding everyone’s knowledge of rare failure modes or new approaches.

In this way helping you to work out how to solve those imponderable challenges facing your business.

You don’t just need good solutions; you need ones acceptable to agencies. With the combined intellect and connections of many leading company RA specialists we now get great guidance on direction, positioning and increasingly we debate with agencies. Giving companies the confidence to adopt innovative solutions to industry issues.

Comparison of competence

Co-developed best practices and adoption approaches

The first law of collaboration is simple, when SMEs come together they benchmark. They probe for deltas and understand what they and your operations have got right, but also the gaps, highlighting areas for improvement. Giving confidence in your systems and providing clear priorities for action.

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CONNECT. COLLABORATE. ACCELERATE.™

In our complex world, sometimes no company has ‘the whole’ answer, so we combine our views and build harmonized solutions to take practice forward. With BPOG’s industry reach and company approvals process, biopharma solutions are created that all buy into and can be trusted to work.

Synchronized implementation of change Sometimes it takes a co-ordinated mass approach to turn a good idea into industry wide reality. BPOG recognizes this and increasingly our leaders and communities are developing and acting as one with synchronized implementation plans.

Overview

9

Regulatory Interaction

Regulatory Interaction The Regulatory Interaction team develops links with global market regulators and introduces the innovative technology in the Technology Roadmapping project at California Separation Science Society (CASSS).

Patrick Swann Vice President of CMC Regulatory Affairs, Biogen

Creating a meaningful dialogue with regulators to smooth the way for innovation is understandably a key goal for biomanufacturers and as Patrick Swann, Vice President of CMC Regulatory Affairs at Biogen explains “One of the biggest challenges we face as an industry is diverse global regulatory requirements.” New innovations are associated with numerous unknowns and global markets may be hesitant to commit limited resources to develop new technologies in an unknown regulatory environment. Additionally, even in the mature markets, it is common that one regulatory authority may agree, while another regulatory authority may disagree. Swann stressed that “we need harmonization, but it takes time.”

A key to regulatory achievement is engagement. Jonathan Dakin, Facilitator and Regulatory Interaction Lead at BPOG, explained that the Regulatory Interaction Team engages with each BPOG workstream in order to determine the specific regulatory issues within the industry. Additional engagement with company regulatory contacts and industry organizations allows issues to be validated and solutions refined.

The Regulatory Interaction Team continues to develop and strengthen contacts and engage regulatory authorities in the more established markets, such as at the The Food and Drug Administration (FDA), the Medicines and Healthcare products Regulatory Agency (MHRA) and the European Medicines Agency (EMA) and is also seeking to develop contacts within global markets, such as Latin America and Asia.

The Regulatory Interaction Team is also engaging and developing relationships by collaborating with organizations such as CASSS. As part of this, members from the Technology Roadmap teams attended the CASSS/Well Characterized Biotechnology Products (WCBP) meeting in January 2017 in Washington, D.C. The Technology Roadmap Phorum has been instrumental in developing a plan for future technological innovations for the industry. During this process, it was recognized that many of the difficulties identified in regard to technological innovations include regulatory dimensions. At the CASSS/ WCBP meeting, the team presented their roadmap and regulatory challenges to raise awareness and to seek feedback on the work done to date.

The presentation included the technical and regulatory challenges facing the implementation of In-Line-Monitoring (ILM) and Real-Time-Release (RTR).

The goal of ILM-RTR is to speed up the manufacturing process, improve process control and to allow biopharmaceutical products to be released in a more timely manner. ILM-RTR has the added benefits of reducing costs and improving quality. Swann was instrumental in the preparation of the CASSS/ WCBP presentation and described the key regulatory concerns of ILM-RTR.

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Regulatory Interaction

Global acceptance of RTR and development of rapid microbiological methods and testing The global acceptance of RTR and the development of rapid microbiological methods and testing require regulatory support and risk assessments. This can be accomplished by directly interacting with regulatory authorities through opportunities such as training sessions and conference presentations.

Diverse global regulatory requirements The existence of diverse global regulatory requirements limits innovation development and acceptance. Countries may be hesitant to take on new innovations due to resource constraints, which can lead to regulatory diversity.

It is important to identify countryspecific constraints and engage emerging markets through organizations such as International Council for Harmonization (ICH), World Health Organization (WHO), or the Pharmaceutical Inspection Convention/Cooperation Scheme (PIC/s). Engaging authorities at international conferences such as CASSS CMC Strategy Phorum for LATAM will also allow progress to be made.

Process robustness Authorities may be hesitant to support ILM-RTR because of a lack of knowledge about the process. It is important to properly communicate the advantages of ILM over traditional monitoring, including less deviation and risk and increased patient safety. The team proposes that this will be accomplished by leveraging metrics data and sharing this data with health authorities.

Security of supply chain Regulatory authorities are concerned that new manufacturing processes may lead to drug shortages or problems with supply.

It is necessary to ensure the security of the supply chain by demonstrating to regulatory authorities that controls included in ILM-RTR are robust and better than traditional end-product drug testing.

Demonstration of value of continuous manufacturing In addition to the value of ‘routine’ manufacturing, it is important to demonstrate the potential of continuous manufacturing to support, for example, pandemics.

The CASSS/WCBP presentation was well received and the conference attendees had a strong desire to know more about what was being proposed and how to move forward.

“The interactions really show that we represent a major industry voice for when we talk to regulators,” said Dakin. The Technology Roadmap includes consideration of the regulatory challenges and potential solutions towards successful implementation.

Swann explained that publishing shared documents describing a best practice guide for the industry are extremely valuable. “It means that you have an industry approach that is not just reflecting an individual company’s bias and desire, but rather an overall vetted consensus approach for the industry as a whole.”

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Drug Substance

Drug Substance Becoming the best vehicle for Industry change As DS has become all about implementation, the members’ leaders have redefined their role and how decisions are made, making the Phorum the best possible vehicle to drive change and deliver returns.

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Drug Substance

BPOG Drug Substance (DS) has been for many years the most active collaboration, simultaneously driving industry change across a broad range of topics including such diverse subjects as human performance, microbial control, continued process verification (CPV) and disposables to name just a few. The DS program and ambition levels had grown to such an extent by early 2016, the group’s leaders decided it was necessary to refresh the Phorum’s program management and governance and bring it inline with the new reality. Above all they wanted to maximise it as a vehicle for change and in the process make sure that their subject matter experts (SME) were collaborating on the topics that offer the highest return on investment.

In addition learning about collaboration has occurred over the years and there was a realization that BPOG is great at delivering certain types of result.

The leaders were keen to build on this and focus the DS programs on:

• closing some of the prioritized Technology Roadmap gaps • most importantly, not forgetting our primary focus of delivering those ‘diamonds’ that support members in maintaining today’s licence to operate Making this transition has taken 18 months starting in June 2016 at BPOG 26, where a model for effective governance was introduced. A face-toface meeting in Atlanta (BPOG 27) took this further with the introduction of a gated, decision-making process that provides greater transparency around overall program decisions. For every new topic introduced or where there is a significant change of scope, there is a voting mechanism at each phase in workstream’s lifecycle (see diagram).

As part of the governance program, a series of touch points have been instituted, including four quarterly calls a year and portions of the agenda at the L2 face-to-face meetings. This ensures the process is being continually managed both in terms of program design and effective delivery to plan.

DS L2 decision making process Do we have x companies? What do we want to see before the next L2 decision? Does the team need changing?

Prepare one-page proposal for new/revised workstream or deliverable including (co-)implementation options.

Form team to expand upon Rol, deliverable(s), benefits and acceptance criteria e.g. use AskBPOG company surveys.

Justify

• supplier co-design and the implementation of robust and compliant supply of key commodities.

• leveraging the common biomanufacturers’ voice to the agencies—a good example is the post-approval submission process (see ANVISA page 14).

into self-organizing communities of practice—for example Continuous Process Verification (CPV), MultiProduct Facilities and Reliability.

One example is how the disposables workstream has been restructured.

Disposables technologies are key now and over the 10-year vision of Technology Roadmap. As the uptake of these technologies increases, then so does the outsourcing of biomanufacturing compliance to our supply base. This challenge was put to a cross-section of SMEs from the DS Phorum, Technology Roadmapping team and key suppliers at BPOG 28, held in March 2017 in Philadelphia.

Define deliverable(s) including detailed plan for their implementation e.g. timelines, resource, communications.

Execute and implement deliverable(s) at member companies either individually or together.

Plan

Implement

Initiate

Min. 5 companies agree to develop full charter together

Min. 10 companies agree to develop detailed plan.

Min. 10/15 companies agree to implement/ co-implement deliverables.

Robust SUS performance

SU auditing guide

Change notification

Testing/validation standards

Q release practice

SUUR

Review benefits and acceptance criteria and share conclusions.

Consider need for CoP.

Close

Min. 10 companies agree to establish CoP.

E&L

Standardization Supply base robustness

The outcome was an agreed five-year program that aims to deliver the product specifications that meet the needs of the Technology Roadmap, and that are produced in robust and compliant supply chains. The governance process has overseen the specification of several workstreams to deliver this plan. Each with a strong business case and a clear resourcing plan, which will in increase the productivity of the teams.

The transition in governance approach will be completed by the end of 2017.

Meaning that teams will be working on topics that are strategically important to every member company; and they will engage with their fellow stakeholders, including suppliers and agencies, to ensure the industry is aligned to the solutions and thereby accelerating strategic biomanufacturing change.

As new priority topics begin to queue up in the program hopper, slots of capacity need to be created. We are doing this by converting workstreams that have delivered and are less critical 13

Drug Substance

Post-approvals strategy piloted with ANVISA The PAS team gets to work in partnership with the South American regulator to speed up submission and review processes.

Joe Kutza

Lou Antinori

Director and Group Manager at AstraZeneca

Senior Director in Global Chemistry Manufacturing & Control, Pfizer

Pharmaceutical companies regularly change their methods and add new sites for manufacturing drug substance or product, and gaining approval for these changes can be a difficult and costly business. Understanding the requirements of the regulatory authorities is key to speeding up the process. In 2015, the BioPhorum Operations Group (BPOG) Post-Approvals Strategy (PAS) workstream was established and it quickly became apparent that US and Europe is not where the majority of challenges lie. The time taken in Europe and the US for a post-approval change to be approved is, on average, less than six months and companies have a common understanding of the regulators’ requirements, who in turn provide good levels of service— responding within the timelines they stipulate. This is not the case with the rest of the world however, where response times can expand to two or even three years for the same change. This is further complicated by many countries now devising their own guidance, but not having sufficient resources to deal with the volume of products and changes coming through from the industry in reasonable timescales.

Having identified those countries that were hot spots for long approval times, the group sought out one that was willing and able to change, and Brazil gave all the right signals that it was looking to improve the process. According to Joe Kutza, Director and Group Manager at AstraZeneca: “We picked Brazil for a couple of reasons: it showed red on the heat map and we, at AstraZeneca, had contact with ANVISA (the Brazilian health authority) already”. The group approached the Head of the Biologics Review division for Brazil, Dr Daniela Marreco Cerqueira, and a teleconference was held to discuss the key issues.

Kutza said: “At the meeting we focused first of all on the issue of global post-approval management and then discussed all the things that were challenges; for instance, ancillary documentation and data requirements being inconsistent with other major markets. We gave specific examples that we had obtained from each of our companies, including situations where we’d made a submission that took either two years or more to get submitted had unusual questions, or it wasn’t clear on the classification of the submission.” The case studies compared the timelines and process taken by Europe and other reference countries with those taken by Brazil.

Out of this meeting came the idea to develop an educational workshop for ANVISA and the team from BPOG conducted a workshop for 15 representatives from ANVISA’s biologics organization. The objectives of the meeting were to increase the speed to market for quality products and those in demand by patients; to share perspectives on change submissions; and to reach a common understanding and to explore opportunities to be more efficient in submissions.

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Drug Substance

Held on 30 March 2017, the meeting involved a number of sessions introduced by subject matter experts from the BPOG team, using a number of case studies, and followed by open discussions. The session topics and subject matter experts were: • ICH Q12 development and alignment (Joe Kutza, AstraZeneca) • Stability data and riskbased decisions (Joe Kutza, AstraZeneca) • Shipping validation and regulatory perspectives (Tim Wagner, BMS) • In-situ audit feedback and improvement opportunities (Lou Antorini, Pfizer) • Comparability studies and risk-based evaluations (Kavita Ramalingam Iyer, Merck) • Continued process verification (CPV) and its role in maintaining product quality (Aaron Goerke, Roche/Genentech)

Levels of change and best guidance models As part of the BPOG team, Lou Antinori, Senior Director in Global Chemistry Manufacturing & Control, Pfizer, presented on levels of change in the industry: “I looked across a number of health authority guidance documents and regulations on post-approval change variation and I compared them to the current published ANVISA guidance. I compared what the category of filing was and what types of documentation were required for submission to gain approval of those variations.

In most cases ANVISA had the right category of change and the right documentation conditions, but they required half the shelf life of the stability of the product at the time of submitting the application. This meant that companies needed to generate more stability information just for them, causing a big delay.”

It was proposed that ANVISA might change its guidance to bring it in line with the rest of the world, who normally only require three months of stability data at the time of submission.

Implementing ICH guidance was another recommendation to come out of the workshop especially as ANVISA has just joined as a full member of ICH and has just passed a new regulation proposing that it would review postapproval changes within 180 days of submission. Further recommendations included work on expediting ANVISA’s progress towards the implementation of electronic common technical document (e-CTD) submission systems.

The work with ANVISA is a significant step for the PAS team towards the potential reduction in time for approval in Brazil. If ANVISA can continue to make changes along the lines discussed in Brazil, there could be as much as a year’s saving in parallel manufacture, reducing both effort and cost.

• Levels of change, change types, requirements and conditions across regulatory authorities (Lou Antorini, Pfizer) • e-submissions and opportunities to become more efficient in submission and review (Kavita Ramalingam Iyer, Merck) 15

Drug Substance

Landmark leachables guide Best practices guide for evaluating risk from polymeric single-use systems provides a practical approach to leachables risk assessment and management.

The guide is set to change the way leachables risk is evaluated for single-use manufacturing equipment review processes.

The rapid uptake of single-use systems (SUS) and SUS components in pharmaceutical manufacturing has created both significant opportunities and complex challenges for the biopharmaceutical industry. Compared with their conventional (reusable) counterparts, polymeric SUS components provide manufacturers with a tangible means to enhance flexibility, speed and efficiency – all key components for driving the industry forward and getting much needed medicines to patients faster. A drawback, however, has been the enduring concern that polymeric compounds have the potential to leach compounds into the process stream, to the detriment of product quality and conferring potential risk to patients.

Aidan Sexton Senior Process Validation Engineer Janssen Biologics Ireland UC

Regulatory guidelines to ensure the safe and effective use of SUS are in place; however, interpretation of the regulations and development of a knowledge base has been left to individual companies. This has led to a diversity of approach within the industry in determining if SUS components pose leachables risks and, if so, how to perform leachables testing. In many cases this has led to excessive testing, with multiple companies performing similar testing – all of which adds costs and time to the manufacturing process without imparting benefit.

Enter the BioPhorum Operations Group (BPOG) Extractables and Leachables (E&L) team. Following the successful development of the Extractables Protocol, the team has now published a robust best practice guide for evaluating leachables risk. The guide covers risk assessment and appropriate leachables study design, as well as analytical methods to identify, assess, communicate and mitigate the potential risks that leachables pose to product quality and patient safety.

Ken Wong Deputy Director Process Technology, Sanofi Pasteur

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BPOG’s best practices guide for evaluating leachables risk from polymeric single-use systems used in biopharmaceutical manufacturing which is published on the BPOG website and freely available to all, outlines best practice parameters to consider when designing leachable studies, to ensure that the studies are sufficiently powered to provide a complete understanding of leachables data and that the maximum value can be derived from the data generated. It also offers proven analytical techniques and important considerations for effectively detecting and identifying leachable compounds that have resulted from contact with SUS during manufacturing processes.

Drug Substance

“The guidance document addresses an existing gap... While the regulations ... have been in place for a significant amount of time... there has not been a consistency of approach across the biopharmaceutical industry to meet regulators’ expectations.”

Viewing online? Click here.

BIOPHORUM OPERATIO NS GROUP (BPOG) BEST PR AC GUIDE FOR EVALUATING TICES LEACHABLES RISK FROM POLYMERIC SINGLE-US E USED IN BIOPHARMACE SYSTEMS UTICAL MANUFACTURING

Aidan Sexton

Aidan Sexton, Senior Process Validation Engineer for Janssen Biologics and a lead author of the guide, noted: “The guidance document addresses an existing gap relating to the assessment of leachables for manufacturing systems. While the regulations relating to leachables have been in place for a significant amount of time in the case of single-use manufacturing systems, there has not been a consistency of approach across the biopharmaceutical industry to meet regulators’ expectations.”

Another principal author of the guide, Ken Wong, Deputy Director of Process Technology for Sanofi Pasteur, said: “There are several factors we wanted to consider in developing the guidance.

One is to complete the story from extractable to leachable – to have a comprehensive end-to-end solution for all the member companies and also to push for a common E&L qualification approach to single-use technology that can facilitate understanding of this complex area with regulatory agencies. The second concerns the risk-assessment model; every company has its own and how do I know my riskassessment model makes sense?

By benchmarking each other we

developed a set of core principles which should also support regulators in understanding nuances in approaches employed between companies or products.”

He continued: “We have produced a landmark publication which will impact the industry going forward.”

Importantly, the inclusive, unified approach gained from the crosscompany collaboration has the potential to streamline and strengthen the regulatory process. “To demystify the regulatory agencies’ expectations, we need to have a single voice to share our E&L best practices to the agencies.” said Wong. Sexton added: “One of the challenges we have as an industry is that, historically, everyone has taken a different approach to E&L, So, by adapting the guidelines to our own individual company needs, at least the overall approach will be the same.”

company, by taking an approach that’s aligned to the guidance,” said Sexton.

According to Wong “The supply base is starting to understand the need for it from our perspective now,” he said. “We’re trying to work with suppliers, add value to their process and make sure this is a true partnership with them. We provide a point of contact to each supplier who wishes to implement the BPOG standard extractable protocol. Currently, we are working with 23 suppliers.”

The team intends to work on implementation of the guidelines in 2017 and to continue its efforts to expand its reach in the industry.

A collaborative partnership with suppliers and regulatory agencies as well as end-users is the ultimate goal. “To advance the knowledge and push through the challenges in the industry for everybody,” said Wong.

The E&L team believes implementation of the best practices outlined in the leachables guidance document will yield numerous benefits. “I think one of the key benefits here is that the industry can demonstrate patient safety in a more consistent manner, from company to

17

Drug Substance

Reducing raw material variability.

An industry-wide initiative.

A guide detailing what the biopharmaceutical industry needs from its suppliers should help to reduce raw material variability according to BPOG’s team.

Luc Kupers

Julian Goy

Program Manager, Global MSAT at Sanofi Specialty Care Operations

Facilitator, RMV Workstream, BioPhorum Operations Group

As the third most regulated industry after nuclear and airlines, pharma is accustomed to working within a rigid set of guidelines – the problem for the industry, however, is that many of its suppliers are not. Consistency in the quality of raw materials used in medicines is of course crucial in terms of patient safety, drug efficacy, and in reducing wastage during manufacturing.

But how can companies effectively control this area of the supply chain?

The BPOG Raw Material Variability workstream has come up with the answer, a detailed document outlining what industry needs from its suppliers, why it needs it, and why good manufacturing practice is so important.

Viewing online? Click here.

Not surprisingly, those suppliers not familiar with the workings of pharma are often unaware of the reasons why eliminating variability in raw materials can assure patient safety and help companies meet regulatory demands.

“Indeed, certain raw materials were never intended for pharmaceutical use so suppliers can find it difficult to appreciate why a biopharma customer, that provides only 3% or 4% of their business, puts 80% of the demand on their technical and quality people,” says BPOG’s Julian Goy.

PATIENT-CENTRIC REQUIREMENTS FOR THE SUPPLY OF RAW MATERIALS INTO BIOPHARMACEUTICAL MANUFACTURING

18 CONNECT. COLLABORATE. ACCELERATE.™

The beauty of this document, he maintains, is that “companies don’t have to come up with their own explanations for their suppliers, they can cut and paste what they need from it”.

Drug Substance

The document, ‘Patient-centric requirements for the supply of raw materials into biopharmaceutical manufacturing’, published last June, covers 10 key areas of best practice. In summary these are:

Patient-centred organizational culture – this section explains the importance that raw material suppliers play in bringing a product to the patient, and why they need to adopt a patientcentric organizational culture.

Risk management – suppliers may consider information about their own suppliers to be intellectual property so this section explains why a cause analysis may be required by a regulatory agency.

Control and elimination of sources of variation – discusses how sources of variation in raw supplies can lead to product quality issues, which affect patient safety and drug efficacy, and result in costly manufacturing inefficiencies.

Traceability, transparency and trust – looks at the critical issue of suppliers understanding their own processes and starting materials and the importance of supply chain mapping exercises.

Good manufacturing practice (GMP) – pharma is producing to GMP, and to ensure the quality of the product so must its suppliers.

Technical due diligence and audits – it’s not sufficient for suppliers to say they are good, manufacturers must obtain proof this is the case.

Fit-for-purpose specifications – looks at how suppliers can work closely with biopharmaceutical manufacturers to align a raw material’s specifications with its intended use

Root cause investigations – outlines the need for root cause analysis in the event of an issue with the raw material, and its consequences.

Change notification and early warning – this section deals with change notification, sets out guidelines, and discusses the importance of the two parties working together to understand what changes may impact biopharmaceutical manufacturing.

Data management – considers why data sharing is an increasingly critical aspect of relationships between suppliers and biopharmaceutical manufacturers.

“These are industry best practices, benchmarked by comparing what biopharmaceutical companies are doing in this field, so when you use this document you are able to speak with one voice – the voice of the industry – which of course is much stronger than if you deliver this message to a supplier as an individual company. This can only help our negotiations with suppliers,” says Luc Kupers, Program Manager, Global MSAT at Sanofi Specialty Care Operations.

The document has already been downloaded by 150 people. Moving forward, the intention of the workstream is to ensure its implementation in a more coordinated way. A taskforce has been set up to look at how this can be achieved within the wider industry, and within the numerous departments in each company.

As a first move, Luc has written a guidance paper on how to use the document, and has presented at several conferences. A small webcom or video presentation is also planned this year that will enable suppliers to do some of the training themselves.

It is important we get this message out, says Luc. “I gave a presentation to the personnel of a raw materials company and I said to them: ‘that powder you’re producing is helping us bring this product to the patient’. They weren’t aware of how their raw ingredient was being used, but once they realized it was helping patients they were more respectful of what they were producing, and of the quality required.”

19

Technology Roadmap

BIOMANUFACTURING TECHNOLOGY ROADMAP The first edition sets a broad vision for the future of biomanufacturing that will catalyze industry action Current trends in the biopharmaceutical industry – including continued market growth, the arrival of new product groups, cost pressures and the trend towards localized manufacturing – are exerting unprecedented pressure on biomanufacturers to innovate biomanufacturing platforms.

To accelerate the industry’s journey, a technology roadmapping process has been established to determine common biomanufacturer needs and to share them openly with supply partners, academics, regulators and government agencies so that directions can be aligned and collaboration enabled.

By participating in a dynamic, technology management process, member organisations are building close technical partnerships, improving the risk-reward profile for new technology development and enabling faster adoption of new technologies.

Thirty-one member companies contributed to the first edition, with additional input from academics, supply partners and agencies. Over 160 people are now actively involved in the roadmapping process. We see the first edition as an initial step, setting a broad vision for the future of biomanufacturing that will catalyze industry action.

Through a process of visualizing the future manufacturing scenarios, six expert teams were tasked with roadmapping the key enabling technologies and capabilities, including: in-line monitoring and realtime release; knowledge management; supply partnership management; process technology; automated facility; modular and mobile.

Participation levels in this first edition of the roadmap demonstrate that the industry will openly share technology strategy and that organizations are broadly moving in the same direction with shared challenges. The development of the roadmap has highlighted the importance of collaboration to overcome challenges and to develop solutions that will benefit all stakeholders and, ultimately, our patients.

Production of the first edition has imbued such a sense of momentum that participants have now taken their ambitions a step further: mobilizing collaborative technology development projects in the areas of greatest impact and most urgent need. By pooling industry effort, user requirements will be standardized to provide focus, development efforts expedited and validation accelerated.

This effort is an evolving, dynamic and open process. We welcome comments from all industry stakeholders and look forward to continued growth in membership, further accelerating and broadening our industry impact.

20 CONNECT. COLLABORATE. ACCELERATE.™

“Once you have a common goal, in order to reach that goal you can’t just wish your way to reaching it.

Not all available avenues will lead to success.

In order to get there, you need certain enabling technology,” Rajesh Beri Technical Director Research and Technology at Lonza.

Technology Roadmap

Figure 2: Enabling technologies and capabilities vision and ben Enabling technologies and capabilities

Vision

Benefits

Process Technology

Process intensification – intensifying production through highly concentrated reactants and products, and combining unit operations into single units

• Minimalized capital investment • Streamlined validation processes • Decreased total cost of goods

Continuous processing – new separation and media technologies, coupled with advanced automation and process control

• Flexibility for smaller patient populations • Speed • Reduced cost and reduced facility size

‘Plug and play’ for fast response to capacity demands, with minimal staff, time to changeover and regulatory observations that delivers products of lowest cost and highest quality, from receipt of raw materials to final drug product

• Quicker and cheaper facility builds and lower lifecycle costs • Readily available and usable data • Reduced manufacturing deviations and non-conformances • Streamlined real-time release • OPEX reduction

Fully Automated Facility

Modular and Mobile

In-line Monitoring and Real-time Release

scale and relocate, using ‘plug and play’ standard designs and standard validation approaches

Enhanced in-line monitoring unlocks potential for robust material characterization, process control and assurance of product quality

• Speed to clinic and market • Rapid tailoring of capacity to meet demand • Manufacturing process available in weeks • Mobility and repurposability of facilities throughout lifecycle • Reduction in CAPEX • Enabler of real-time release, product released in 1–2 days • Improved product quality, operational efficiency and Reliable Supply

©BioPhorum Operations Group Ltd

EXECUTIVE SUMMARY

Hardware for advanced in-line monitoring devices, including indirect and multi-attribute sensors Software to enable multivariate analysis, predictive models and closed feedback control loops Knowledge Management

Integrated knowledge of product and process technology across the development, manufacturing and commercial value streams

• Accessible and applicable biomanufacturing information and knowledge, driving down development costs

Supply Partnership Management

Supply Partnership Management undertaken in a spirit of openness and trust to drive successful collaboration, making best use of technology and integration of systems and processes

• Lower cost/quality ratio for raw materials, services and CAPEX investment • Faster to develop, produce and make changes • Safe, innovative supply chains

Download here now Executive Summary

Modular and Mobile

BIOMANUFACTURING TECHNOLOGY ROADMAP EXECUTIVE SUMMARY

BPOG Technology Roadmap 1

Overview

In-line Monitoring and Real-time Release

Process Technologies

Knowledge Management

Automated Facility

Supply Partnership Management

Viewing online?

Click on the QR code to download.

21

Technology Roadmap

Suppliers and the Technology Roadmap journey Bringing suppliers into the technology roadmapping process was transformative, mirroring the change we need to see over the coming years in the interconnectedness of our supply chains.

The discussion between suppliers and biomanufacturers are extremely powerful.

The interaction with each other is where we actually make the big changes, we create the innovative quantum leap and that’s where we start enhancing our industry, moving the industry forward to where we should be.

The work on developing the first edition of The Technology Roadmap highlighted many inherent problems within the biopharmaceutical manufacturing industry. The first of these problems was the need for a big step change in the way that supply partners and biopharmaceutical companies interact with each other. The team felt that there needs to be significant development of openness and trust to allow the harmonization of methods and levels of interaction and data exchange. This would bring it in line with other high technology fast moving industry sectors such as semiconductors, automotive, robotics and software development where the evolution of supply partnerships has become much more symbiotic than purely transactional.

Involving suppliers in the creation of the first edition of the BPOG Technology Roadmap has been crucial to its success. Supply partnership management can impact positively on the value chain for biopharmaceuticals; namely influencing speed to produce clinical materials and to get first product to market as well as on scale up to full production which all rely heavily on the interaction between supply partners and the biomanufacturers concerned.

According to Charles Heffernan, Business Transformation and Technology Innovation Lead at GSK “ Collaborating with the suppliers worked very well. It helped to inject some fresh blood into the effort, adding a different perspective. The new team members were willing to pick up the torch and carry things forward.”

The supply partnership management team focused on their own future goals but also on becoming an important element and contributor to all of the other enabling technologies and capabilities identified by the Technology Roadmapping teams Technology Roadmap’s supply partnership management team envisions a future industry characterized by the following elements: •

creating a series of standards for materials, components, specifications, documentation and more

•

focusing on delivery and performance in addition to the traditional focus on innovative technology; this allows customers to reward great manufacturers that sustain business and not just the great innovators that get selected early in a development cycle

•

creating more flexibility, agility, and interchangeability that will lead to greater opportunity for suppliers for new and additional applications as well as improve supply chain continuity

•

creating lean and efficient supply chains driven by ‘super’ integration of business systems between customers and suppliers

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Technology Roadmap

Five key enablers are required to deliver the industry vision and these are openness and trust, standardization, built-in quality, electronic data exchange and forecasting and demand planning.

The main drivers for moving toward this vision are cost, speed and flexibility and according to Maik Jornitz, CEO at G-CON Manufacturing Inc. “There are multiple concerns within our industry; the first is that we want to improve our processes and technologies to be able to reduce costs respectively to fulfill the desire to deliver affordable therapies.

The other aspect is the maintenance or progression of our existing processes to avoid ageing, therefore the potential risk of break-down, a major reason for our current drug shortage problem.

Speed in capacity deployment and flexibility in the manufacturing location or product portfolio are becoming the next pressing issues.”

The pressure on total cost to supply should be driven down by volume usage; improvements in supply chains, and upfront capital investments being reduced by implementing more flexible, process intensified designs. A key challenge is maintaining quality with raw material variability being kept low while product availability remains high. Using automation quality will be built-in to minimize the opportunities that exist for errors to occur in the design process.

Integration between suppliers and manufacturers will enable much improved forecasting and inventory planning with both sharing information on material usage and replenishment timing. Built-in quality, supply chain management and the use of new technology such as blockchain database should make it possible to achieve real-time, just-in-time resupply.

Removing duplication of effort through standardized testing would eliminate the need for end users to test raw materials again, and only a frank discussion between manufacturers and suppliers can resolve why such practices exist.

The ideal situation for electronic data exchange and supplier integration is plug and play without bespoke couplings but this again relies on manufacturers and suppliers understanding and agreeing on the appropriate platforms

and languages to standardize equipment.

This does present legal challenges such as intellectual property expectations around ownership and right-to-use as well as the length of commitment on both sides.

For a supplier, what has it meant to be a member of The Technology Roadmapping team? For Jornitz, “There were two aspects that I found extremely motivating and encouraging – the first was to learn from biomanufacturers what their needs are and also what their concerns are.

We learn from each other and, hopefully in a team with the regulators, work on required solutions for improvements or to eliminate pain points. The second is when

discussing new technologies, realizing that one can be the technology scout for the industry and support with valuable information.”

Supply partnership management is key to the successful implementation of the developments that the Technology Roadmapping teams have highlighted.

It can only come about through increased openness and trust which would allow the integration of data, the setting of standards for equipment, supply chain planning, upfront change notifications and much more that would transform the industry and supplier relationship to a combined team effort.

Openness and trust • Collaboration: suppliers as an extension of the biomanufacturer • Development: transparency of technologies, harmonized industry standards • Regulatory: process characterisation and supplier controls. Provision for plug and play.

Quality built in • Removal of duplicated effort • Quality requirements: industry accepted templates and protocols • Optimized testing: Reduced duplicate testing.

Control variation at source.

Forecasting and demand planning • Transparency of capital planning • Transparency of short and long term demand • Industry supply chain risk analysis and shared business continuity for key supply chain constraints

Standardization • Industry standard audits and auditors • Harmonization of RM testing requirements • Standard supplier validation

Electronic data exchange and supplier integration • Common EDE standards, common format demand information

23

Fill Finish

The Fill Finish Phorum The drug product operations of BPOG members routinely deliver essential particle free, sterile product in high integrity closures. So why bother to collaborate in the BPOG Fill Finish Phorum?

The reality is that one of the greatest challenges is not so much running high performing operations, it’s more about proving control through measures that show ‘negatives or the absence of failures’. What is the significance of releasing another ‘essentially particle free’ batch, finding no contaminants in a room, or once more finding no filter integrity problems? Does that mean you are in control or that your measure is soft and you missed a problem? It’s an important question and one that is often pondered.

The companies in BPOG Fill Finish all have very good reasons to believe they are in complete control, but aren’t

24 CONNECT. COLLABORATE. ACCELERATE.™

sitting on their laurels. They are all working hard to push the mastery of their processes to new levels of excellence. This theme runs through many of the workstreams, as they know that control and its proof are key to moving their operations forward. Whether in optimising lyophilization cycles with validated computer models, or in adopting new technology such as active air monitoring, to give us better and more immediate control. For the members demonstrating control is key and doing it in line with others in the industry can only make advancement easier.

Fill Finish

Making RM happen in grade A Biofluorescent active air monitoring technology is being used by the team to make the elusive holy grail for the pharmaceutical industry – continuous manufacturing.

The BPOG Fill Finish’s rapid micro workstream is working on an argument that biofluorescent active air particle counting technology can test for airborne contaminants within isolators more effectively than conventional settle plates counting and active air monitoring. Important for the supply chain, these instruments report the number of microbes in an isolator in real-time, eliminating interruptions to the supply chain for plate checking in the micro lab. So why isn’t it being more widely adopted?

There has been a shortage of hard evidence to demonstrate the technology is better than conventional practices and a lack of guidance on how to implement. Moreover, companies have lacked the expertise and resources to push this forward. Hoping to advance the case for introducing RM technology, the team expects to publish its first white paper on the importance of the technology for isolator and restricted access barrier systems (RABS) soon, together with some guidance on how to use the instruments. Two more papers will follow on RM’s application in A-E grade rooms and in the use of biofluorescent counters for investigations and room recovery.

The BPOG effort consists of 13 companies. The advantages of adopting a multi-company approach to finding a standard method for the industry are clear. Company representatives reference the strength the collaboration provides and the clear consensus that has emerged on the best strategy for implementation. In addition representatives are sharing the effort required to collect and validate the data

and assess the costs involved, making progress faster, and getting an approach adopted quicker, working as a team.

Conventional tests for microbial contamination are cumbersome and not an exact science and, because of time delays in receiving the results, can lead to uncertainties in how to proceed when a contaminant is found.

“Given rapid micro is a relatively new technology it makes more sense for the industry to start off with a consistent position on its use, which in turn makes it easier for the regulatory agencies to regulate, and so we move together and adapt and refine these standards over the years,” said Dawood Dassu, Facilitator of the RM workstream at BioPhorum.

To this end, members of the workstream are currently carrying out a series of pilot studies.

results and have employed a postdoc fellow to work on this for us.”

Lonza is also running a pilot study on air monitoring for the workstream, and preliminary results convinced the company of the robustness of the technology. It is now running its second pilot for RM testing of water systems. In the longer term, hopefully the entire industry should benefit from the work of this collaboration.

Collaboration can accelerate the adoption of new technology and as one representative says “what makes the BPOG workstream stand out from other groups is that people are much more open and the thinking more innovative. We want to keep patient safety at a high level but we’re not restricted to written words, which allows us to discuss subjects more freely and makes us open to possibilities.”

As Marja Claassen, Senior Microbiology Specialist at MSD Netherlands, explained: “We have been testing rapid micro methods for more than 10 years at MSD. While we are convinced of the technology, we have a science-based validation system, so we want to prevent the risk of accepting an inferior method – and these risks are present when you follow current rapid micro guidelines, such as false positive signals masking lack of sensitivity. We are looking at statistical methods to evaluate the 25

Fill Finish

Commercial-scale lyophilization Use of a mathematical model that allows shorter cycles without expensive engineering runs is being enabled by the BPOG Fill Finish Lyophilization collaboration

Dr Serguei Tchessalov Associate Research Fellow, Biotherapeutics R&D at Pfizer

Dr David Latshaw II Scientist at the Janssen Pharmaceutical

Since 2016, the BioPhorum Operations Group (BPOG) Fill Finish Lyophilization collaboration has been looking at increasing the use of mathematical modeling at the commercial scale. The team has agreed core principles for the model and educated each other on how to use the modeling tools.

manufacturing and provide a potent troubleshooting tool. To achieve this, the collaboration is adopting a twopronged approach: promoting the model within member companies, and engaging with the regulatory agencies with a view to developing guidelines and setting standards.

The benefits of modeling are clear.

A lyophilization (lyo) cycle can take anywhere up to four days for some products, so a model that can help minimize the cycle length and help determine temperature and pressure settings for a product could significantly cut manufacturing resources, and make technical development and transfer a lot faster.

As a first step, the collaboration organized a face-to-face workshop in Colorado last July. Participants received training on the model from Tchessalov.

At the heart of the BPOG initiative is Dr Serguei Tchessalov, Associate Research Fellow, Biotherapeutics R&D at Pfizer.

Tchessalov has taken the model developed by Dr Michael J Pikal back in the 1980s and made it more suitable for commercial lyophilization. “Now, anyone who has Excel on their computer can use this model,” said Tchessalov.

Within Pfizer, the model has already demonstrated cost savings both in clinical and commercial manufacturing.

“In clinical manufacturing, for example, we don’t do engineering runs,” said Tchessalov.

Cherie Pankhurst-Lang Senior Associate Scientist at Biogen

26 CONNECT. COLLABORATE. ACCELERATE.™

“We use the model every time we transfer the process. Engineering runs can cost between $50,000 and $100,000, so if we save on three or four engineering runs you can see how much money the company saves overall using this model.”

The BPOG collaboration is championing the use of the primary drying model to encourage and enable more companies to use it; with the ultimate goal that it will replace engineering runs in all commercial-scale

“Being able to talk to more experienced people within the collaboration has saved us a huge amount of time because we don’t have to keep reinventing the wheel,” said Cherie Parkhurst-Lang, Senior Associate Scientist at Biogen.

“The training was also very important because you can’t understand the model just by looking at it.”

Not only did the workshop bring members up to speed on the model, but 2016 also saw them agree to use the same or a very similar model in principle, allowing the industry “to speak to the regulatory agencies with a unified voice,” said Parkhurst-Lang. The US FDA also showed itself to be much more positive and open to this innovation than the collaboration had expected.

In just one year the collaboration has ensured lyo experts within BPOG are in a position to act as individual champions of the model within their companies. One of the scientists leading the way is Dr David Latshaw II, Scientist at the Janssen Pharmaceutical Companies of Johnson & Johnson.

“Within J&J we’ve been building business cases to show the viability of the model, such as taking a legacy product, building the model for it and showing if there is room

Fill Finish

“Engineering runs can cost between $50,000 and $100,000, so if we save on three or four engineering runs you can see how much money the company saves overall using this model.”

Dr Serguei Tchessalov

for improvement in the cycle,” he said. “With development products, for example, we’ve looked at the original recommendation of the cycle, applied the model and shown how savings can be realized in terms of undertaking fewer engineering runs, or cutting down on cycle times so we can schedule more runs.”

[there are] willing to share their experiences the better for our industry.”

In 2016, Tchessalov and the BPOG Lyophilization collaboration made this possible and brought a more cost- and time-efficient lyophilization process for the industry that bit nearer.

But while significant progress is being made within companies in learning how the model works and how it can be used to improve performance, there are a myriad of details that anyone using the model needs to understand – and the guidance currently available is insufficient.

To bridge this knowledge gap and to increase awareness of the model outside the collaboration, the group intends to publish two papers this year, on lyo modeling and best practice, in a joint venture with LyoHub, a consortium based at Purdue University in the US. This should also help move conversations forward with the regulatory agencies.

“We are still learning how to use the model for different applications,” said Tchessalov. “But the more companies 27

Fill Finish

Visual inspection: Delivering a standardized approach for classifying particles What began as a member survey has precipitated the development of a cross-industry approach to create a standardized particulate control classification tool, aiding biopharma to align practices where previously no guidance existed.

Marcel Uijlen Associate Director Global Sterile Site Support at MSD

Particulate contamination in parenteral products is an industry-wide problem and is consistently the leading cause of product recalls. Several years ago, the Particulate Control workstream members identified a series of gaps in the guidance relating to classifying particulate defects.

While a common language exists, “There are currently no guidelines and every company has their own interpretation of what the standard is – what one company classifies as a critical particle, another may classify as a major particle,” explained Marcel Uijlen, Associate Director Global Sterile Site Support at MSD and a member of BPOG’s Particulate Control workstream.

Additionally, some member companies described regulatory pressure to reclassify visible particulates without a clear scientific rationale.

This reclassification could lead to unwarranted production delays or product holds. A paper in the July 2015 issue of the PDA Journal, entitled ‘Industrial perspective on the medical risk of visible particles in injectable drug products’, explained that reclassification of visible particles – for example, from major to critical may not be medically necessary and that the presence of certain visible

28 CONNECT. COLLABORATE. ACCELERATE.™

particulates may not pose as great a medical risk as intuition might suggest.

As a result of the lack of guidance in this area and to address the inconsistent regulatory message, the Particulate Control workstream members concluded that an investment in creating a standardized approach for the classification of particulates was vital to the entire industry.

The first task of the Particulate Control workstream was to create an aligned methodology – using a common, scientifically based approach – that could be adopted by the industry to classify particles. The methodology informs the use of an associated riskclassification tool, which generates an objective numerical value based on several vital factors, relating to the patient, the product and the process. Since each company has its own specific needs and practices, they can then take the objective data obtained from the risk-classification tool and apply the criteria – and the particle classification – that best meets their needs and tolerance for risk.

“We think that this tool will help to assess the issue of particulate material and offer a scientific manner for companies to explain how a particulate

Fill Finish

is classified as critical or major. It will help the industry assess particulates in the same way and with the same methodology, and creates an industrywide approach,” explained Uijlen.

Uijlen hopes that the coming year will bring the industry closer to a standardized approach. He explained that the workstream has plans to finalize the riskclassification tool, test the approach against a number of case studies and implement it across the industry. To promote the tool, members of the workstream plan to publish an explanatory paper, followed by presentations at conferences in the USA and Europe to highlight their work and describe the standardized approach.

By presenting the tool at conferences, Uijlen anticipates that more companies, which are not BPOG members, will become aware of the advantages of using a standardized approach, be willing to assist in further refining the tool and ultimately implement the approach within their own production facilities.

The risk-assessment tool will also be a valuable asset for regulatory discussions. Once regulatory authorities, and the industry as a whole, accept the tool, the ambiguity that currently exists within particulate classification will be greatly diminished.

The Particulate Control workstream has high hopes for continued development of the standardized approach within the industry and anticipates that its longer-term goals will bring these hopes to fruition. Long-term goals that arose from the initial member survey include developing the setting and application of acceptable quality limits (AQL) and developing approaches to harmonize disposition procedures, with a particular focus on defect investigations.

The risk-assessment tool is a prime example of what can be accomplished through the co-operative actions of BPOG members. Recognizing that a problem exists is worthwhile, but being able to come together to develop and implement a solution demonstrates the value of the collaboration. “It is good that pharmaceutical companies work together so that they can look at problems and interpret existing guidance the same way. It can do a lot for the whole industry, as well as MSD. This will help us become stronger as a pharmaceutical group and allow us to have a bigger footprint in the regulatory world,” said Uijlen.

“There are currently no guidelines and every company has their own interpretation of what the standard is – what one company classifies as a critical particle, another may classify as a major particle.”

Marcel Uijlen

29

Development Group

Development Group

The collaborative nature of BPDG’s white papers has helped bolster new claims and initiated scientific debate within the industry and with regulators.

The BioPhorum Operations Group’s Development Group (BPDG) has continued its strong collaboration across 12 point share topics, involving 19 member companies. Last year saw the Viral Clearance team publish its first position paper in the PDA Journal and present at several conferences in Europe, North America and China.

This year the group has a number of publications in various stages of production from the following teams: Formulation, Host Cell Protein (HCP), Monoclonality, Viral Clearance and Forced Degradation. BPDG’s defining strategy is ensuring that all the white papers include an abundance of data that would have been difficult to generate individually, but collectively will help support new claims and stimulate scientific discussions both within the industry and with regulators.

These discussions may go some way toward influencing the industry and regulators in these concepts.

BPDG has initiated three new point shares in 2016–17: BioAssay, CMC (Chemistry, Manufacturing and Controls) Considerations for Expedited Development and Development Outsourcing; while the point share

30 CONNECT. COLLABORATE. ACCELERATE.™

on Evaluation and Implementation of New Technologies reached its conclusion in August 2016. The BPDG collaboration continues to develop benchmarking data, best practices and industry positions. These deliverables are not the endgame by any means, they are the stepping stones of a multiyear journey by member companies toward the goals of each point share.

We’ve seen an increasing interest in conducting benchmarking surveys across the BPDG community on various topics, some of which are not being covered in our point shares or workstreams. Within the last six months, we’ve shared the results of surveys on: • development stability • bulk drug substance container • ready-to-fill bulk drug substance • cell line technologies • molecule selection • investigational new drug (IND)enabling toxicology material.

The team is delivering the 2017 program and in Q3 will start developing the 2018 program of new point shares and sponsor-level face-to-face meetings.

Development Group

Host cell proteins This team is just months away from publishing a risk assessment tool to help reduce HCP-related risks and assist in producing biologics that are safer for the patient.

A new risk-assessment tool for measuring host cell proteins (HCP) should be available this year. Focusing on the manufacturing process through process development, this tool will help companies to tackle the risks associated with HCP within the development lifecycle.

HCP constitute a major group of process-related impurities in a drug. Any company that can accurately identify and monitor HCP in its biotherapeutics is more likely to overcome regulatory hurdles, accelerate drug development and reduce a drug’s potential to elicit an unpredictable immune response in patients. The risk-assessment tool should provide the industry with a start for assessing HCP risk and can be adapted by companies to fit their own specific situation and expertise. It is the product of the BioPhorum Development Group (BPDG) collaboration, comprising biopharmaceutical industry leaders and small biopharmaceutical technology companies, led by Fengqiang Wang, Associate Principal Scientist at Merck.

In 2015, the United States Pharmacopeia (USP) and European Pharmacopoeia (Ph. Eur) published new guidance

on HCP measurement and control*, but the monograph did not provide effective tools for assessing risk. Few publications have covered this topic, notably those of Christina de Zafra et al from Genentech, which focused on clinical risk assessment, and Dr DG Bracewell of University College, London, which looked at process and analytical capability to reduce risk. To help further the industry’s understanding of HCP, the BPDG collaboration has concentrated on the process-specific aspects through identification of HCP-related risk factors found during bioprocess development – performing phase-appropriate risk assessment, establishing a risk-reduction strategy and defining mitigation activities.

Surveys conducted on key topics enabled the collaboration to make considerable progress on the risk assessment initiative, including the development of a riskassessment methodology and risk-scoring tool. The tool will enable qualitative and semi-quantitative assessment of risk regarding HCP. The BPDG collaboration has also shared case studies, including one on antibody reagents’ qualification through 2D coverage assessment with SpotMap software analysis, shared by Julie Nishihara (Genentech/Roche), and the use of depth filtration for HCP removal during downstream development, shared by Tom Klimek (Eisai/Morphotek),

allowing members to gain a better understanding of the importance of assay qualification and its application in downstream process development for better HCP control. According to Wang, this has left members “energized and positive” about establishing a risk-assessment tool in 2017.

But what has led to the success of this point share? “Instrumental in the success of the collaboration has been a clear purpose, with topics for discussion priority-ranked by members,” said Wang. “As well as good engagement and leadership, members can freely share their knowledge and experience and have the flexibility to set up on-demand calls to address the most critical topics. Having members with diverse backgrounds and skill sets who bring new ideas can lead to innovation and innovative approaches to problem solving.”

Individual member companies can also benchmark their own practices against their industry peers. Wang explained: “The collaboration has helped Merck shape its overall HCP strategy and identify gaps in our current practice with HCP risk control and reduction, as well as enabling us to take proactive action to prevent similar problems happening within our own companies.”

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*USP Chapter 1132 and EUP 2.6.34

Development Group

Formulation team offers a perspective on drug product robustness studies A position paper recommending best practices should steer the industry in the right direction.

The Formulation Point Share’s first faceto-face meeting, held in late 2015, led to a pivotal year for the team, culminating in the development of a position paper on biopharmaceutical drug product (DP) formulation robustness. The team spent much of 2016 writing, reviewing, and refining the paper. It is expected to be published in 2017.

Sorina Morar-Mitrica, PhD Senior Investigator GlaxoSmithKline

Formulation and manufacture robustness studies are essential to developing robust pharmaceuticals that ensure the quality of the product administered to the patient. However currently there is little guidance, literature or even agreement on the scope, design and execution of these studies.

“It was a challenge we all embraced,” said Sorina Morar-Mitrica, PhD, Senior Investigator with GlaxoSmithKline, who has been a member of the Point Share since its inception in 2013. The position paper was the outgrowth of a benchmarking survey executed by the Formulation Point Share that laid bare a dearth of literature, guidance, and alignment related to the design, scope, and execution of biopharmaceutical drug product robustness studies. The benchmarking survey also revealed a lack of harmonization performing these studies and even a lack of agreement on the scope, design and the way in which they are executed. The importance of these studies cannot be overrated, they are critical for ensuring the quality of the products that patients receive.

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“During discussions, we tried to bring in some literature references just for comparison with our own internal company practices,” said MorarMitrica. “We realized that, while there is a lot of literature around robustness of a small molecule, there isn’t much out there around biopharma DP robustness. That was pretty much the start of the manuscript idea.”

The paper titled “An inter-company perspective on biopharmaceutical DP robustness” focuses on drug product robustness, their scope design and execution and includes three case studies to illustrate that the ideal robustness study design for a biopharmaceutical DP is a balance of experimental complexity, statistical power, scientific understanding and risk assessment. Maintaining that DP robustness consists of both formulation and manufacture aspects, studies integrate the principles of quality by design (QbD), and feed into critical quality attribute (CQA) finalization, the development of control strategies and the setting of commercial specification. To develop the DP design space, most companies use robustness studies as well as risk assessments and experimental design.

The paper will contain recommended best practices for biopharmaceutical drug product robustness studies The Formulation Team hopes the paper will generate industry-wide conversations about the topic and

Development Group

perhaps act as a mechanism for mobilizing other companies that have a significant presence in the industry but are not currently part of the BPDG. “Having the rest of the industry engagement and the regulatory engagement is where we should be aiming for the future,” said MorarMitrica. Sharing regulatory feedback, to the degree possible, is another important benefit of the collaboration that brings value to the point share members and, ultimately, to the patients the industry serves. “Regulatory feedback as a result of our regulatory submission is really what drives the biopharma industry, and there are no opportunities for us to share that kind of regulatory feedback in a systematic way,” said Morar-Mitrica. The point share “fills this gap around communication and knowledge exchange,” said MorarMitrica. “We are focused on delivering internal projects, and therefore, we take less time than someone in academia would to share our results.”.

“It’s validating, it’s motivating and it gives me more confidence to really look at our strategy.”

Marla Abodeely, PhD Associate Director and Head of Bioassay Analytical Method Development at Shire Pharmaceuticals, representative of the Bioassay team

With its first position paper nearing publication, the Formulation Team is already gearing up to tackle new challenges. “To me, the future is about sharing the outcome of our discussions and our surveys,” said Morar-Mitrica. Future endeavors may include a second paper, possibly around high concentration formula or another topic yet to be determined.

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Development Group

Bioassay Overcoming complexity through driving discussion and shaping best practice

Gael Debauve, PhD Associate Director of Bioassay Development for New Biological Entities at UCB

Marla Abodeely, PhD Associate Director and Head of Bioassay Analytical Method Development at Shire Pharmaceuticals

John R. White, PhD Director of Biopharm Assay Development at GlaxoSmithKline

34 CONNECT. COLLABORATE. ACCELERATE.™

Developing a bioassay is a complex, rigorous undertaking, encompassing several issues, including understanding all of the mechanisms of action associated with the therapeutic. Other issues cover developing the technology, and qualifying and validating the assay. There is also intrinsic variability in almost all assays, and differences between biosimilars and the original biologic only compound the complexity and interpretation of the results.

Keeping pace with the complexities of the field while meeting regulatory requirements in an industry that is rapidly evolving is no small challenge.

The BioPhorum Development Group (BPDG) Bioassay Point Share was formed to encourage the adoption of best practices. “I had a lot of questions about bioassay and I felt a bit alone,” said Gael Debauve, PhD, Associate Director of Bioassay Development for New Biological Entities at UCB. “My manager advised me to propose a bioassayspecific topic and to prepare some questions I’d be keen to share with other companies. And that’s how it began.”

Launched in February 2016, the point share was greeted enthusiastically. “This is really interesting because you get to focus in on bioassays specifically and all the issues that come up,” said Marla Abodeely, PhD, Associate Director and Head of Bioassay Analytical Method Development at Shire Pharmaceuticals.

“It’s really uncovered assumptions I’ve had and clarified issues, which makes it easier to find solutions.”

Debauve reflected on the merits of the collaboration: “The forum is a unique place where ideas can be discussed and challenged with others who have experience in the field. This helps one to be more comfortable with the strategies we put in place within our corresponding companies, because if

we see that the same trend is observed with the other companies it means that we are moving in the right direction.”

Abodeely agreed: “It’s validating, it’s motivating and it gives me more confidence to really look at our strategy.

I know what the industry is doing and, if it feels like another path might be better, it gives me more confidence to explore that other path, that other strategy, and to do things that are right for the therapy and the patient.”

The Point Share conducted a survey on bioassay format. “Medically, we need to think about something that is representative of the mechanism of action,” said Debauve. “We have to deal with biological material that is quite complex and variable, and at the end we need to have an assay that is quality control friendly – this is the challenge.”

John R. White, PhD, Director of Biopharm Assay Development at GlaxoSmithKline added: “It has to satisfy the regulators and we need to understand how they will accept the results, because they can have a different take on the results. The regulatory environment is such that the competent authorities see all these assays coming from different companies and so the agencies have a broad perspective on how companies are dealing with various issues. Before BPOG, companies didn’t really have that equivalent process and so each of us could be dealing with the same issue in different ways. We weren’t really talking to each other in broad terms.”

Although still in the early stages, the team aims to develop a white paper to propose best practices. “If we can have an organized approach across the industry, this adds more weight to what we can propose to regulatory agencies and we can try to identify

Development Group

“Before BPOG, companies didn’t really have that equivalent process and so each of us could be dealing with the same issue in different ways. We weren’t really talking to each other in broad terms.”

John R. White, PhD Director of Biopharm Assay Development at GlaxoSmithKline

what we can propose to best address their expectations,” said Debauve.

Members believe they are already deriving value. “It makes our group sharper and motivated,” said Abodeely.

“It motivates you to strive to do even better. To really fine-tune what we are doing and really understand all the fundamentals behind it, and know we’re not alone with the same struggles. It makes the quality of our work better.”

White added: “I think there are multiple ways that you could approach some of the problems we face. Certainly, hearing what other people have done can allow you to narrow that approach down, so that clearly adds value. Obviously, we can’t discuss products we are working on by name, but we can discuss the difficulties we sometimes face with satisfying the regulatory environment and making sure we meet those challenges.”

Widening the dialog to include multiple perspectives also brings value, said Debauve. “For example,

I really appreciated when we invited in a supplier of curve-fitting software,” he said. “For me, it was a unique opportunity to have in-depth discussions with a software provider and to reflect with other experts on how the problem was seen by this software provider, and we were also able to challenge them.”

The team continues to benchmark bioassay optimization, analysis and validation. It has volunteered to share case studies and will continue learning from each other as it moves towards the development of best practices.

“Certainly we haven’t got to the end of where we need to go in this area,” said Debauve. “I think the other area that may be interesting would be to get some representation from the GMS, the global manufacturing supply organizations, because we are also developing assays that can be passed along to either a clinical research organization or to a global manufacturing organization, which then has to run the assay on a day-in, day-out basis in order to release the drug supply.”

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Supply Partner Phorum

36 CONNECT. COLLABORATE. ACCELERATE.â„¢

Supply Partner Phorum

Supply Partner Phorum The Supply Partner Phorum (SPP) is unique in our industry in taking a fundamental look at our supply chains, how we work together and questioning how suppliers and customers can recast them into far more efficient and effective assets for everyone.

Marin Santore Manager of Global Procurement at Bristol-Myers Squibb

Alison Reppy Supply Chain Manager of Operations in Nutrition & Health at BASF

Tonya Jackson Platform Manager for Biologic Solutions at BASF

It has become increasingly evident within the industry that progress and improvements in issues such as supply chain communications, raw material quality, and forecasting require the cooperation of both the supply side as well as the manufacturing side of the industry. Despite this realization, up until now, there has not been a place where suppliers and customers can come together to take the generic steps necessary to deliver improvement across our supply chains.

BPOG formed the SPP in 2016 with the hope that it would provide the means to allow open, noncommercial communication between manufacturers and suppliers. According to Marin Santore, Manager of Global Procurement at Bristol-Myers Squibb, “These conversations probably weren’t happening as openly a couple of years ago. There are probably many reasons why we were reluctant to have these conversations in the past, such as intellectual property protection. But the SPP is a safe environment where we’re not talking about a specific process. We’re talking about how to improve things like forecasting and supply chain that could benefit both organizations greatly.”

Some of the goals of SPP are to improve the relationships between manufacturers and suppliers, and decrease raw material variability. The SPP accomplishes these goals through two workstreams: Supply Chain Mapping and the Forecasting and Demand Planning workstreams.

According to Alison Reppy, Supply Chain Manager of Operations in Nutrition & Health at BASF, “The industry requires full transparency of the supply chain for raw materials. Supply chain mapping helps to identify recommendations for business continuity plans to mitigating risk of supply interruptions in the industry. This directly impacts drug supply and patient safety.”

Many of the aspects of this workstream are driven by regulatory authorities and include issues such as ethics, agriculture, transportation, and storage.

The goals of the Forecasting and Demand Planning workstream are to improve the forecasting for raw materials to ensure the supply chain will be able to meet the ever changing needs of the industry.

“Raw materials manufacturing can have long lead times or planning horizons, and therefore requires accurate forecasting to ensure resources such as people, storage, raw materials and packaging are available for production. It is becoming clear that a key component for successful demand forecasting is transparency and understanding between suppliers and manufacturers, which we hope will be improved through the efforts of BPOG SPP,” explained Reppy.

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Supply Partner Phorum

Despite the fact that the SPP has only been in existence for one year, the group has been extremely active. The two workstreams meet every two weeks, and the SPP leadership team meets monthly.

Both workstreams are currently in the process of writing best practices guides.

The papers will include topics such as forecasting and demand planning and what they mean to the industry, a description of the level of integration and sharing between manufacturers and suppliers, and what can be done in the future to improve manufacturing and supplier relationships. Santore explained that the workstreams anticipate holding face-to-face meetings among their members in mid-to-late Spring to review the first drafts of the position papers and to submit them shortly after these meetings.

The position papers will be the group’s first step in making improvements within the industry for suppliers and manufacturers. The long-term goals of the SPP include developing and implementing solutions for the whole industry and continuing to develop relationships between manufacturers and suppliers. The phorum is also in the process of beginning a third workstream called the SPP Leadership Group Governance Task Team. The goal of this group is to increase the knowledge of self-governance and how to apply it within the workstreams.

38 CONNECT. COLLABORATE. ACCELERATE.™

SPP anticipates that the inclusion of a governance program will increase productivity and accountability within the workstreams, and promote progress that the industry expects.

The SPP team hopes that companies continue to see the advantages of participating in a collaborative group such as BPOG. Currently, approximately half of the SPP members are from the manufacturing side and half are from the supply side of the industry. Santore believes the success of SPP depends on continued diverse recruitment to the group. “Recruitment is an ongoing process. My hope is that the more companies we have join, the more diverse experiences we will have and the better off we will be,” said Santore.

However, recruitment is not limited to a single type of manufacturing company. According to Santore, “diverse company participation is important. It is important to recruit all types of companies: small, large, biotech, pharma, biopharma, and suppliers.

Adding to that diverse perspective will be the key to our success.”

Tonya Jackson, Platform Manager for Biologic Solutions at BASF, explained from a supplier perspective that being active in the BPOG SPP group has been extremely valuable to BASF. “BPOG SPP membership means BASF can participate in the guiding of industry standards, best practices, and technological

improvements. This has also been an opportunity for BASF to demonstrate that our commitment to the industry goes beyond supplying a single key raw material. BASF expertise in chemistry is now more accessible to support the industry. This has been a valuable opportunity to hear the feedback around past variability in raw materials, and the opportunity to use what we have learned to make improvements.”

Santore believes SPP has the potential to be an institute of change for the industry. “This Phorum is unlike any other forum I have participated in; it really fosters innovative conversation between both parties, and through our partnership we are really going to be able to achieve great things.” Jackson added, “the top benefit for BASF has been increasing our understanding of the industry requirements, standards, and expectations. It has been beneficial for us to gain an understanding of what is taking place holistically across the industry and where the gaps and concerns are.”

Santore emphasizes that the success SPP has attained to this point would not have been possible without the support of the L1 members and their sponsorship of these activities. “They play an important role in this organization. Without their support it would be really difficult to move initiatives forward,” said Santore.

Supply Partner Phorum

“This Phorum is unlike any other ... I have participated in; it really fosters innovative conversation between both parties, and through our partnership we are really going to be able to achieve great things.�

Tonya Jackson Platform Manager for Biologic Solutions at BASF

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BioPhorum Operations Group IT

BioPhorum Operations Group IT (BPIT) The collaboration provides a cohesive starting point for biopharmaceutical IT leaders to build on the insights garnered and to share their digital transformation plans and experiences. Importantly, it represents a uniting of minds and industry experts who are catalyzing the call to action within the broader ecosystem to align and focus the development of capabilities, technologies, standards and know-how.

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BioPhorum Operations Group IT

BPIT defines the biopharmaceutical digital plant of the future The IT Phorum’s recently published white paper provides companies with a template for transforming their operation from a paper-based factory into a fully automated one.

The first full year of the BioPhorum Operations Group IT (BPIT) collaboration was a fruitful one, culminating in the publication in December 2016 of a seminal white paper, the development of a digital plant maturity model to aid transformation in biopharmaceutical manufacturing. The paper, which amassed the insights and expertise of 20 industry experts from 11 member companies, guides readers through the various stages of digital maturity, from simple paper-based plants to the fully automated, integrated adaptive plant of the future.

It is intended to be used as a tool for those companies in the industry wishing to benchmark and plot their digital journeys, and it highlights the challenges and opportunities that are commonly encountered by companies in their quest to advance their maturity levels.

The digital plant maturity model described in the paper provides BPIT member companies with a detailed reference model and a simple tool for assessing technological maturity in their plants.

Viewing online? Click here.

THE DEVELOPMENT OF A DIGITAL PLANT MATURITY MODEL TO AID TRANSFORMATION IN BIOPHARMACEUTICAL MANUFACTURING

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BioPhorum Operations Group IT

The model functions as a framework for the development of IT roadmaps that are designed to enhance manufacturing operations and allow for the realization of future manufacturing processes and capabilities that capitalize on the potential value of data integration and advanced analytics.

Another important benefit the model provides is the ability to more easily communicate with software suppliers about the capabilities that the biopharmaceutical industry needs in order to achieve its vision of a future state-of-the-art digital plant. This easier communication can, in turn, help to influence the future development of software products and technologies that will enable the industry’s vision to come to fruition.

The digital plant maturity model provides an authoritative framework of reference to discussions with both external vendors and internal business partners because it is based on a wealth 42 CONNECT. COLLABORATE. ACCELERATE.™

BioPhorum Operations Group IT

of experience and solid benchmarking across biopharmaceutical IT. For the members of the collaboration, the process of putting the digital plant maturity model into practice has already begun, with a number in the process of using the model to help define their strategic plans from a technology perspective for the next five to seven years, thus determining the investment required and the value of getting there.

The development of the digital plant maturity model is emblematic of the value the BPIT collaboration espouses, challenging the individual visions of member organizations and getting them to look beyond what they normally do.

So far, ten BPIT member companies are actively using the model and assessment tool to review their roadmaps and/or to conduct plant-maturity assessments across their manufacturing networks.

The BPIT team is continuing its forward motion in 2017 with the evolution of several new workstreams, each of them an outgrowth of the team’s

work on the digital plant maturity model. One is concerned with common challenges encountered in the endto-end supply chain, particularly with respect to ensuring visibility across the manufacturing network and extended supply chain, which is becoming an increasingly complex undertaking.

Another workstream is exploring what the operator or technician of the future will look like—how the increase in technological knowledge changes the job of the employee on the floor.

A third workstream is exploring smart maintenance—utilizing analytics and data to improve the reliability and support of the equipment that is used to run work sites. Finally, a compliance workstream was kicked off to explore issues related to data integrity, cloud computing and agile delivery in a good manufacturing practice environment.

The creativity and the output from these new workstreams will emanate from the close collaboration of the BPOG member companies, offering the ability to reach out to peers in a safe environment.

Deliverables 2016-2017 The BPOG teams collaborate to develop best practices, industry positions and benchmarking data that move performance forward for the industry.

These deliverables are intended to support the implementation of best practices in operations and facilities across the industry and to enable alignment with suppliers and agencies alike. The deliverables are not an end in themselves, but rather stepping stones to enable improvement and better results in our operations.

If you see this symbol, the download is only available to representatives of BPOG members via the internal website.

Drug Substance

Viewing online? Click on the URL to view.

Continued process verification (CPV)

Closed systems: temporary openings of

A roadmap for the implementation of CPV, published in the PDA Journal, provides a step-by-step guide in a more accessible form. It enables creation of CPV plans for a wider community, meaning compliance with US Food and Drug Administration (FDA) guidance is expedited and greater control can be exerted on processes in the long term.

BPOG partnered with an academic institution—Biomanufacturing Education & Training Center at Worcester Polytechnic Institute, Massachusetts—to conduct a program of experiments to demonstrate the ability to sanitize temporary openings in functionally closed systems.

A roadmap for the implementation of continued process verification

Study showing new cleaning methods obtain functional closure in CNC areas shared with industry

https://tinyurl.com/y74nyyk7

https://tinyurl.com/yaxsysbh

Extractables resource pages The Standardized Extractables Protocol implemented by BPOG member companies is a user-driven standard that enables faster qualification of single-use systems, by significantly reducing expensive end-user testing at the point of qualification. Accessed via the dedicated extractables webpages on the BPOG website, it includes FAQs and a quarterly newsletter that reaches more than 200 supplier representatives. The webpages also provide direct access to the extractables team for all interested parties.

The extractables and leachables portal https://tinyurl.com/y9f7plvj

BPOG response to Annex 2 This paper, published in the PDA Journal, is an interpretive response to Annex 2 of Eudralex—Volume 4; the European Union (EU) guidelines for good manufacturing practice (GMP) of medicinal products for human and veterinary use. Using a quality risk management (QRM) approach, facilities can be designed and processes operated at reduced cost and complexity.

BPOG response to Annex 2 https://tinyurl.com/yccey6g2

Change notification of single-use systems Working in collaboration with BioProcess Systems Alliance (BPSA) to bring industry together, the group has produced a white paper, entitled: An industry proposal for change notification procedures for single-use biomanufacturing equipment. The paper, which is co-published by BPOG and BPSA, aims at improving process of communicating change, encouraging and educating suppliers.

An industry proposal for change notification practices for single-use systems http://tinyurl.com/ycdtu8r8

Leachables guide The best practices guide for evaluating leachables risk from polymeric singleuse systems used in biopharmaceutical manufacturing represents the consensus position of many of the industries end-user SMEs. The guide is in four sections, focusing on risk assessment, leachables study design, analytical methods and lessons learned from experience. This guide has made a significant difference in influencing the draft of USP<665> to ensure acceptance by end-users and resulting in the reduction of resources on testing.

Best practice guide for evaluating leachables risk from polymeric single-use systems used in biopharmaceutical manufacturing https://tinyurl.com/ycqrc7ay

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Viewing online? Click on the URL to view.

Drug Substance Human performance case study

Reducing total cost of ownership (TCO)

This is a valuable resource for those aiming to implement human performance. In just two years Lonza reduced human error-related quality deviations and non-conformities by more than 40% across 13 sites globally.

A further members’ best practice guide recommends how total cost of ownership (TCO) and reliability can be incorporated into user equipment and facility requirements specifications (URS). Evidence shows that when TCO and reliability factors are built into a URS in this way lifecycle costs are reduced at the project design phase of a program.

This report details how Lonza delivered these results and the methodology used.

Lonza Error Prevention System – changing human performance in pharmaceutical operations https://tinyurl.com/yaxpqe8c

Reliability guidance for design phase project management: total cost ofownership (TCO) and user requirement specifications (URS

Operator competence This BPOG white paper outlines a new approach to operations training that enhances proficiency and performance while maintaining a positive compliance position. Topics covered include: What is a competency-oriented approach? What is the link between document and training structures? and How might you implement such an approach successfully?

Training for biotech manufacturing operator competence https://tinyurl.com/y954c56m

https://tinyurl.com/yasfpnk6

Elastomer change-outs

Microbial control

An additional member guide details how to identify and reduce elastomer changeouts (ECO) where they are not needed to control cross-contamination in multi-product facilities. The report details how ECO should be considered as a segment of an overall changeover assessment and discusses the role of preventive maintenance, cleanability coupon testing, good engineering practices etc. It then focuses on the data that should be generated to demonstrate that soft parts do not harbor residues from the previous product campaign(s), allowing you to lessen your dependency on ECO as a control.

This members-only paper focuses on mold monitoring in biologics drug substance facilities and processes, covering recommendations on subjects commonly encountered in the establishment of a monitoring program, such as mold trending, responding to mold isolation events and best practices on mold prevention. These recommendations assist in refining current mold control strategies, as well as developing control strategies for new processes, facilities and products.

Elastomer change-out – justification for minimizing the removal of elastomers in order to prevent cross-contamination in a multi-product facility

Maintenance effectiveness review This members’ guidance document helps organizations understand how to assess and track maintenance effectiveness in an efficient and consistent way. As well as being key to driving reliability up and costs down, application of the recommendations will help organizations compare and benchmark performance and demonstrate compliance, in a consistent and defendable way to regulators.

Mold control and detection in biological drug substance manufacturing facilities: an industry perspective

Maintenance effectiveness review – metrics to demonstrate the health of your maintenance organization and processes

https://tinyurl.com/ybkzh8wl

https://tinyurl.com/y72cnedo

https://tinyurl.com/ya9btdcb

Investigation and root-cause analysis This report details how to improve investigation and investigator effectiveness and further the maturity of human performance practices in our industry. It draws on current best practice in world-class industries and contains 14 recommendations for implementation by member companies. Adoption will increase effectiveness, improve robustness of investigations, preclude event recurrence and raise organizational learning.

Multi-product facility This guide for members details how, with the use of risk-based tools and supporting data, the changeover activities of multi-product facilities can be significantly reduced and, under well-controlled and characterized operations, concurrent manufacturing may be achieved. The guide, developed by a large team of end-user experts, details how the changeout of small parts and elastomers as well as the collection of changeover cleaning samples can be significantly reduced or eliminated.

Investigation and root-cause analysis best practices

Guidelines for risk-based changeover of biopharma multi-product facilities

https://tinyurl.com/y8a6o2dx

https://tinyurl.com/ybyer3sb

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Deviation management system (DMS) This guide for members, supported by examples, details a methodology for implementing riskbased, innovative quality solutions that free up operational performance while delivering the appropriate level of quality oversight.

This approach can deliver savings of 12,000 person hours (c. $450,000 per site) per annum for an average site with a 500 head count.

Practical how to guide to implementing risk-based approaches in quality systems https://tinyurl.com/yaow8kt4

Fill Finish Raw material variability (RMV) Pharmaceutical manufacturers require suppliers to provide technical information to help assure the quality of the medicines produced and fulfill regulatory requirements. This link takes you to the standard technical questionnaire (STQ) developed by the RMV team that is aimed at significantly reducing redundancy and duplicated effort, for member companies and suppliers alike. In 2017, the RMV team will work collaboratively to incorporate the STQ into a similar document produced by Rx-360.

Raw material technical questionnaire

Pre-use post-sterilization integrity testing (PUPSIT) The adoption of PUPSIT controls has been a goal of the European Medicines Agency (EMA) for some time and is mandated in Annex 1. However, many in the industry view the controls as a net risk. This survey, available to members, details PUPSIT adoption rates, the rationales used for non-adoption and the challenges of PUPSIT use.

PUPSIT survey and summary https://tinyurl.com/ycdlh6m4

https://tinyurl.com/yc2373qa

Raw material supply requirements The control and elimination of sources of variation in raw materials is essential to ensure patient safety, medicine efficacy, product quality and process performance. This industry supported guidance package describes 10 key areas of best practice, ranging from organizational culture to technical due diligence and audits. It recommends a collaborative and aligned approach between suppliers and manufacturers for understanding and mitigating risks, with a goal of increasing transparency, visibility and trust. Members’ companies are encouraged to train relevant functions in its use, e.g. procurement, quality and communications.

Patient-centric requirements for the supply of raw materials into biopharmaceutical manufacturing

Small flexible filler URS For many drug product (DP) operations, typical filling machines are oversizing and inflexible, not just for clinical but for many with commercial demand too. This user requirement is a statement of the size, speed, flexibility and features that many DP operations want to see equipment manufacturers start to target and provide standard modularized solutions around.

Small flexible filler URS – end-user needs https://tinyurl.com/y9ledp2b

Container closure and integrity testing (CCIT)

Stopper quality particle count method comparison

While the US Pharmacopeia’s “informational” chapters are not compulsory, the publication of certain parts of USP<1207> caused the subject-matter experts in the CCIT concerns that some points might reset regulatory expectations, so the group developed a response that they sent to the USP team and published.

This survey of the methods used to count visible and sub-visible particles in elastomer stoppers

by BPOG members and stopper manufacturers demonstrates that there are significant differences in the way that particles are counted and reported. Few companies follow the ISO standard, which is 13 years old and no longer sufficiently sensitive to detect particles at the levels currently being achieved, or the lower levels required by the industry.

Response to the publication of USP<1207> https://tinyurl.com/j3dttsu

BPOG Stopper Quality team particle count method comparisons https://tinyurl.com/y9yc5a5l

https://tinyurl.com/y9ekgzzx

Lyophilization modelling education pack During 2016, the Lyophilization team agreed an educational package that details how an operation can develop and utilize a computer model for a commercial-scale process. This pack is available to all members of the workstream and was presented to the FDA during Sept 2016.

Commercial-scale lyophilization modelling education pack https://tinyurl.com/yclbcwgn

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Development Group Viral clearance study comparison

CMC regulatory clinical qualification specs

Considerable resources are spent within the biopharmaceutical industry to perform viral clearance studies, which are conducted for widely used unit operations that are known to have robust and effective retrovirus clearance capability. The collaborative analysis from the members of the BioPhorum Development Group Viral Clearance working team considers two common virus reduction steps in biopharmaceutical processes: low-pH viral inactivation and viral filtration. This appeared in the PDA Journal in June 2016.

During 2016, the team benchmarked and shared a case study on clinically qualified specifications and completed a survey on internal reports and agencies, to review the implications of attaching documents or summaries to regulatory submissions.

Bioassay formats survey A benchmarking survey on bioassay formats has compared and contrasted different approaches and regulatory responses to the data generated.

Bioassay formats survey https://tinyurl.com/y7zu84m6

CMC Regulatory point share – clinically qualified specs Q1, 2016 https://tinyurl.com/y8xv3klc

Retrospective evaluation of low-pH viral inactivation and viral filtration data from multiple company collaboration https://tinyurl.com/y7avc3gg

Analytics surveys During 2016, the Analytics point share team shared knowledge and experience on automation of lab processes, including liquid handling, bioanalytical methods and whole process automation. The team refreshed the glycan analysis survey that incorporated inputs from nine additional companies and pioneered sharing the output, using “Ask BPOG” to allow more material to be shared.

The topic on automated data acquisition, analysis and transfer with contract research organizations (CROs) demonstrated the range of approaches used by some companies, but also highlighted the limitations in this area for companies.

Qualification of scale-down models

Bioassay development and analysis survey

Companies are clearly investing a lot of time and effort into small-scale models. The team is keen to understand what is important from both a regulatory and technical viewpoint when applying small-scale models to the manufacturing and/or commercial scale. In 2017, the team split into two groups focusing on upstream and downstream. The teams defined key areas they would like to learn about and have since been sharing aspects of scaledown model qualification through case study presentations followed by detailed technical discussions.

The team has considered bioassay development by evaluating an arranged presentation on fitting model definition and assessment from SoftMax. The team benchmarked bioassay development that covered a choice of assay suitability criterion and the software used for analysis.

Analytics surveys

Upstream and downstream qualification of scale-down models case studies

https://tinyurl.com/ydxwfsu9

https://tinyurl.com/y8s37n7j Qualification of scale-down models surveys https://tinyurl.com/yaydgz9s

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Bioassay development and analysis survey https://tinyurl.com/y9nl97ce

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