More Past Events

ISPE Washington, DC Conference – Education, Networking and Lots of Fun!

by Rick Pierro

It’s entirely appropriate that the ISPE Annual Regulatory Compliance Engineering Conference be held right outside the nation’s Washington DC capital. After all, that’s where the FDA big wigs hang out and they don’t have to go very far to give fabulous talks on regulatory trends and issues for the 500 or so ISPE delegates that gathered from across North and South America this past June 2-6.

Educational talks were well attended, with delegates coming from Canada to Brazil to hear the latest updates on topics like the following:

• Science and Risk-based Approach (for C&Q): Application of the New Guide, Installation and Verification (In Support of ASTM E2500);
• Regulatory Perspectives on Hot Topics, Regulatory Trends, and Observations;
• Application of the New Risk-MaPP ISPE Baseline® Guide GAMP® 5: Enabling Innovation and Technological Advance.

But interesting educational talks were not the only things brewing at the Conference. Approximately 80 of the nation’s top vendors participated in the table top show; 17 national committee meetings (COP, Education, Member Services, Student Development, Regulatory Affairs, etc) were held; and representatives from 15 ISPE Chapters met together for a full 8-hour day (16 hours if you include our networking event) to exchange ideas, best practices and discuss plans for the future.

The Boston Area Chapter was well represented at these meetings with Doyle Johnson (Vice President), Mike Denault (Past President) and Rick Pierro (President) attending the North American/South American Affiliate Council (NASAAC) meeting, In addition, Dave Novak headed up the Membership Services Committee and presented the results to the entire NASAAC.

But the best part, as always, were the networking events. This is often where the deals are made, ideas are hatched, and friendships are formed and the Washington Conference was no exception. For example, the Boston Area Chapter representatives took the Puerto Rico Chapter leaders out for dinner one night and learned all about ISPE in the Caribbean, discussed regulatory requirements with the Argentina Affiliate and chatted about European business growth with the United Kingdom Affiliate. By the time the week was over, many of the delegates, myself included, were already looking forward to the next Conference to be held in Boca Raton, Florida in October!

Preparing for an FDA Audit: Everything You Need to Know but Were Afraid to Ask

by Joyce Chiu with photos by Mike Denault and Rick Pierro

The March 18th educational program sponsored by the ISPE Boston Area Chapter was held at Biogen Idec in Cambridge. Chapter President Rick Pierro opened with a thank you to our generous hosts, commenting that the event was sold out, with about 95 members and nonmembers in attendance. He then turned the floor over to Program Manager Dave Truex who introduced the evening’s speakers: Ron Branning, President of Ron Branning & Associates and former Vice President of Quality Operations at Genentech; and Mike Cross, Senior Manager of Quality Engineering at Biogen Idec.

FDA Inspections: A Management Perspective by Ron Branning

With 38 years as a Quality professional in biologics, biotech, devices, pharmaceuticals and plasma, Ron was a highly energetic and entertaining speaker.  Drawing upon his worldwide experience working with small to large companies on everything from consent decrees to new product approvals, Ron’s presentation was accentuated with war stories and interesting anecdotes.

What are senior management concerns when it comes to FDA inspections?  Senior management wants to avoid business interruptions and personal liability.  Therefore, preparedness is the key, including a professional compliance team, internal and external assessments, and mock inspections. The main areas for focus include the quality system, facilities/utilities/processes, adverse events, laboratory out-of-specifications, CAPA and validation, as well as product release and rejections.

From a management perspective, Ron advised a focus on the top 10 issues - those that FDA inspectors will inevitably look for, based on a company’s own documented evidence.  During the inspection, backroom documentation staging and expert presenters, trained and rehearsed, need to be in place.  In addition, the status of any remediation efforts needs to be updated and preemptive discussion with FDA considered.

During Prior Approval inspections, a company needs prepared responses to FDA’s questions, with appropriate backup documentation and internal experts available. Tours of the production area and QC lab, batch records and stability data all need to be ready as well.

Senior management’s role is to open the meeting, set the tone, obtain daily updates, preside over the closeout and lead continuous improvement efforts afterwards; but should stay out of the way and let subject matter experts do their job. In closing, Ron emphasized the importance of management’s commitment to compliance, creating credibility and transparency, and sticking to “the truth, the whole truth, and nothing but the truth” as the golden rule when it comes to FDA inspections.

Regulatory Inspections: A Deckplate Perspective by Mike Cross

Biogen Idec is a licensed commercial drug supply facility, with its products distributed worldwide, from five trains of 2,000L scale in two distinct areas.  There are more than five products and about 30 lots annually, with a staff of 300 in manufacturing, engineering and support and 35 in QA. With 10 years at the company, Mike has had experience with CMO inspections as well as several major agency inspections. Based on Mike’s presentation, Biogen Idec has a well planned and executed inspection process in place, with attention paid to every detail.

In the past six years, Biogen Idec has had inspections by nine agencies; these include FDA, EMEA and Mexican, Japanese and Brazilian agencies.  In order to remain ready, weekly inspection preparation meetings are held with senior staff. For actual inspections, there is a well laid out flow with a “war room,” document room, inspection room and other closely related areas. Each room has a designated lead, scribes (for note taking), topic leads and inspection consultants; internet access, projection and video conferencing capabilities, etc. are provided where needed.

Mike described the sequence of events comprising the inspection process beginning with the opening day, including organizing presentations and daily wrap-ups.  Inspections usually focus on the timeframe between the last inspection and the present, including any citations, utilities, product controls and changeover, supply chain, quality system, stability program and exceptions handling. If caught with a “gotcha,” it is OK to ask for a timeout to strategize and respond, according to Mike. The final wrap-up is done with senior management involvement, to solidify response timing and expectations. In summary, a successful FDA inspection takes a year-round commitment, with an eye towards planning, preparation, a strong quality system, and clearly defined roles.

Despite a rather dry topic, Ron and Mike delivered well-thought out presentations, with interesting details and stories that everyone could relate to.  They both did a wonderful job!

ISPE Boston Area Chapter Student Poster Contest Gets Tougher!

by Rick Pierro with photos by Yatao Liu, Mike Principato and Eric Marchese

Seventeen ISPE graduate students and two ISPE undergraduate students carefully and anxiously placed their research posters on the wall and nervously waited for the five judges to approach. The annual ISPE Boston Area Chapter Student Poster Competition had begun.

On April 2, student members of ISPE Chapters from Northeastern University, Worcester Polytechnic Institute (under formation), Boston University and the UMass Amherst assembled at Northeastern’s Dodge Hall to compete for first prize and an all-expense paid trip to Boca Raton, Florida in October to compete in the ISPE International Student Poster Competition and attend the ISPE Annual Meeting. The competition this year was unusually tough. The students were given only five minutes to explain their research and posters and five additional minutes to answer questions fired at them by the five judges.

The judging this year was done by Henry Brush of Alkermes, David Novak of AMEC, Marcia Steger of Massachusetts Biologics, Michael Denault of Denault Associates and Rick Pierro of Superior Controls. Special thanks were given to Professor Rebecca Carrier and the four ISPE Student Chapter Officers of Northeastern University, Lisa Grady, Michael Principato, Kate Forrister and Eric Marchese, who prepared for and hosted the contest. The Student Chapter also provided the pizza and soda which energized the judges throughout the evening.

The presentations went on for several hours and the judges meticulously totaled the points for each one. And finally the winners were announced. Padmaja Magadala, a graduate student attending Northeastern University, won with her poster titled “Epidermal Growth Factor Receptor-Targeted Engineered Gelatin Nanovectors for Gene Delivery and Transfection in Pancreatic Cancer Cells.” Sindhura Ganga, also of Northeastern University, was the runner up with her poster titled “Multifunctional Nanoemulsion System for Combination Paclitaxel and Curcumin Delivery to Human Glioblastoma Cells.”

Incredibly, the top two undergraduate students tied for first place in the undergraduate category. The judges decided that in this unusual situation it was only proper to send both the winners to Boca Raton. They are Jason Lajoie of UMass Amherst with his poster “Directed Evolution of RhII Protein” and Akshay Navaladi of Boston University with his poster titled “Role of Micro-Environment Stiffness in Directing Mouse Embryonic Stem Cell Differentiation.”

Special thanks go to the five judges for their tireless diligence in reviewing each poster and to all the students who participated. I believe I can speak for all the judges in saying we were truly amazed at the advanced and fascinating research being done in our universities and the dedication and expertise brought to each project by the students. Now on to Boca Raton in October for the ISPE Annual Meeting and International Student Poster Competition...stay tuned for the results.

Talking Shop at Science Center

by Arkady Mayblyum with photos by Mike Denault and Doyle Johnson

On Tuesday, April 22nd Genzyme Corporation hosted the ISPE Boston Area Chapter Talking Shop: “The Love Hate Relationship Between Engineering and Quality” at its new Science Center in Framingham, MA. The program format encouraged open dialogue between talk shop panelists and the members of the audience on the issues which have been near and dear to everybody involved with the industry.

All three panelists, Gael DeAmicis (Principal Validation Engineer at Bristol-Myers Squibb), Linda Graf (QAV Manager at Wyeth Biotech) and Greg Ruklic (Principal Engineer at Wyeth Biotech), have worked in both quality and engineering roles throughout their impressive biotech/pharmaceutical careers and had no trouble engaging the audience in a free-wheeling discussion of the topic.

After a short introductory presentation by Greg Ruklic, Linda Graf and Gael DeAmicis each talked about their approach to executing projects with heavy engineering and quality involvement. A few members of the audience, which was slightly tipped towards engineering, went on to share their own “war” stories. Very early in the program it became evident that the quality, validation and engineering groups are acting more and more as partners rather then nemeses as in the past.

Faced with the tremendous pressure, pharmaceutical and biotech companies are looking at the cost of compliance as one of the most significant areas of improvement. The introduction of the ASTM E2500-07 Standard Guide for Specification, Design, and Verification of Pharmaceutical and Biopharmaceutical Manufacturing Systems and Equipment started a new trend shifting a lot of quality responsibilities to engineering. This is forcing engineers to be more involved in quality issues and quality professionals to become Subject Matter Experts (SME) in certain engineering disciplines.

The new ASTM Standard was brought up on numerous occasions throughout the evening, triggering discussions on execution of commissioning and validation activities for projects of different scale; and also led to discussion of the potential effect of other standards like the ANSI/ISA S88 Batch Standard and ANSI/ISA S95 International Standard for the Integration of Enterprise and Control Systems on the industry’s future.

Overall, it was very encouraging to see that there is a lot more Love than Hate in the relationship between engineering and quality.

Special thanks to Genzyme Corporation for hosting the program, to Stan Rotkievicz from Genzyme and Monique Sprueill of Bristol-Myers Squibb for coordinating the event for ISPE; and to the panelists, Gael DeAmicis, Linda Graf and Greg Ruklic and the Boston Area Chapter Educational Program Committee for an extremely interesting and thought-provoking evening.

February’s Joint Program with MIT’s Professional Institute: Continuous Improvement in Biologicals Manufacturing and Process Analytical Technology (PAT)

text and photos by Wes Hyman

In February, the ISPE Boston Area Chapter was very fortunate to have MIT Professor Charles Cooney address our Members as part of a joint educational program with MIT’s Professional Institute. Professor Cooney is a professor of Chemical and Biochemical Engineering in the Department of Chemical Engineering at MIT. In addition to his academic credentials, his extensive background in biotech includes consulting for a number of biotech and pharmaceutical companies, serving on Genzyme’s Board of Directors and chairing the FDA Advisory Committee for Pharmaceutical Science from 2004-06.

Though it is impossible for me to capture the level of sophistication and technical detail Professor Cooney brought to his topic, I will attempt an overview of the broad themes he conveyed during his presentation. His introduction to the topic provides a good place to start:

A major challenge in biological manufacturing is continuing to improve the process while operating to maintain regulatory compliance. There is a normal variation in biological performance; however, in the drive to assure regulatory compliance and replicate the standard batch, we create a tension between learning from the variance and seeking to eliminate it. Analytical technologies provide us with multiple lenses on the process to probe the relationship between operating variables and process performance. The FDA’s PAT initiative creates an atmosphere in which multiple analytical tools can be leveraged for continuous improvement.

He then went on to highlight current trends in biologics manufacturing. From the clinical perspective, these include ever-increasing molecular complexity, larger pipelines, increasing late-stage rejections of candidate drugs and evidence of a more personalized medicine defining the smaller markets. On the regulatory side, there is an increased focus on risk, heightened interest in understanding process science and a heavier regulatory burden from new products and amended applications. Lastly, on the marketing side of the spectrum, he described an increasing number of dosage forms, greater diversity of package inserts in global markets and pressure to reduce prices while increasing access to the latest products.

While discussing the major challenges of process design and operation, Professor Cooney pointed out that metrics and goals are very important. “We need to know where we want to go and have the analytics to measure where we are (relative to our product specifications) and understand how the process affects the important properties of the product.” There is also uncertainty. He said we need to assess and reduce this uncertainty to an acceptable level to manage risk across the value chain.

Professor Cooney described PAT as a system for designing, analyzing, and controlling manufacturing through timely measurements (i.e. during processing) of critical quality and performance attributes of raw and in-process materials and processes with the goal of ensuring final product quality.

Attendee and Chapter Vice President Doyle Johnson was struck by the evolution of PAT “from simple measurements of pH and cell density to more complex analyses of genetic information” as described during the presentation. With this more advanced type of PAT, it should be possible to better ensure bioequivalency and lead to a greater pace of innovation in biopharmaceuticals, according to Johnson.

When I spoke with Professor Cooney prior to his presentation, I asked him about the industry’s acceptance for the use of PAT. He indicated that while there has been slow acceptance of PAT, it is something the people can embrace and should feel comfortable with while translating it into actual practice. He said PAT is being more rapidly accepted by the larger companies, but could help the small firms even more. Biologic process development demands good understanding and requires that you are able to measure what is going on in order to use PAT successfully, he continued, and said he sees it as being an integral part of the future of biologics manufacturing.

In summary, the program was extremely timely and informative, and benefited greatly from Professor Cooney’s academic credentials and real world experience. Audience members paid rapt attention during the formal presentation and followed up with a series of detailed questions that demonstrated the depth of their expertise and intense interest in the topic.

Equally important, the event allowed attendees to trade information about PAT, its use within their own companies and its evolution as a universally accepted continuous improvement methodology. And, as always, the networking reception was well received (especially the lobster thermidor, chicken pot pie, and mac and cheese appetizers) and provided a great way for people to interact with their peers and gain valuable industry insight.

Let’s Get Together and Spread Out: Millipore R&D Center

by Joseph A. Naughton, AIA, LEED® AP with photos by Warren Patterson

The new Millipore BioProcess R&D Center in Bedford shows us how smart space design and equipment management results in better work space and more of it. According to the company’s Web  site, the 110,000 square foot building contains 47,000 square feet of lab space, consolidates multiple functions and fosters “an even more collaborative approach for the up to 500 professionals who will work there.” About 50 ISPE Members from the Boston Area Chapter gathered at the newly expanded campus on March 11, 2008 to learn more about the design process that created the new facility and to view the results for ourselves during a comprehensive plant tour.

Our hosts included some very proud and gracious scientists from Millipore and an equally proud contingent from ARC/Architectural Resources Cambridge, the designers for the new facility. We began the evening with some light hors d’oeuvres and good conversation in the new dining/presentation room, which, even at dusk, was filled with an abundance of natural light and views out to a carefully manicured natural landscape.

Following a brief introduction by Educational Program Committee member Dave Truex, ARC’s Thomas Loring opened the evening with an overview of the primary drivers behind the project, the internal team Millipore mobilized to guide the decision-making process, and the external team Millipore engaged to implement the plan. He then described the process Millipore and ARC utilized to bring vision to reality in the relatively short time frame of 22 months. The basic components of the planning process included: Master Planning in which goals and opportunities were identified, Program Development in which needs and consolidation possibilities were investigated, and Schematic Design in which a number of options were reviewed and converted into the optimal solution for Millipore.

The physical design concept at Millipore is essentially open labs versus closed, open offices versus closed. According to Robin de la Parra, Millipore Director of Core Research Support and our host for the evening, the culture prior to the expansion project was based on a closed lab and closed office solution so some skepticism surrounding the effectiveness of the open concept was apparent. At the time the concept was first unveiled, she estimated that only about 20 percent of the population was convinced of its benefits; today that figure is in the 80 percent range and climbing.

Even our Millipore tour guide admitted that she could count herself as part of the original 20 percent club and was initially tentative about the functionality of the open configuration. While there are certain advantages associated with the closed office configuration, after approximately 8 months of working in the new facility, she believes that the benefits of communication and collaboration that are now evident every day have moved her firmly into the 80 percent club.

The “parti,” or the basic relationship of the various spaces to one another, arranges the office spaces in banks with a proportionate number of one-on-one meeting rooms opposite the lab zone with breakout areas in centralized areas accessible to each individual lab. These shared break-out areas are marked by a double height interconnecting lounge type area with open stair connecting the floors and surrounded by small, medium, and large conference and presentation rooms. The color palette throughout the building was rich with light warm tones and subtle accents and an interesting assemblage of bamboo, tile and carpet for aesthetic interest and sound control.

The labs were grouped into bench lab pods adjacent to process lab pods, each linked by shared instrumentation and equipment zones in central locations. In addition to the shared instrumentation and equipment rooms, the building includes a secured central store with inventory that is bar code stocked and tracked. Scientists access the store with a security card and obtain materials needed from the store by simply keying in the bar code on the items needed; the system maintains a fully automated and up-to-date inventory with automated purchasing support and a charge account to each lab for materials consumed.

The beauty of both the shared instrumentation/equipment zones and the automated central store is, that by centralizing these functions and automating the scheduling and inventory of each respectively, Millipore scientists have been able to move equipment and materials that used to take up space inside the labs, out of the labs to free up valuable bench and floor space that can be better utilized by people and their work. The Millipore team proved that smart design, lean equipment management and automated inventory and charge accounting has resulted in a better working environment, allowing the many talented individuals who work there to be even more efficient and productive than before.

In terms of real dollar impacts, because Millipore is working at higher equipment utilization than before, their equipment purchasing needs have declined from previous levels, improving their equipment budgets. And the higher usable space that resulted in the labs meant that the 10-foot lab module is effectively more generous than in the previous model. Translation: this building is bigger on the inside and smaller on the outside which means the building cost less money for what is effectively more usable space.

We left the Millipore facility with many good impressions and we would like to thank our friends at Millipore for their hospitality. The people who run the facility have shown how a careful planning and design process will yield impressive results and an optimal facility solution. They were really able to get together and spread out.

Mt. Sunapee Welcomes Boston Area Chapter Annual Ski Trip

by Doyle Johnson with photos by Rick Pierro and the author

This year the (sold-out) ISPE Boston Area Chapter Ski Trip went to a new venue, Mt. Sunapee in New Hampshire. Another difference was a new bus driver, Jack. Jack went to Cornell University (alma mater of your humble author for this article) and had no sense of direction, a characteristic we found curious for a bus driver. Still, he was a pleasant enough chap and as long as we told him (repeatedly) how to get there, it was no problem.

Well, almost. As we entered the Sunapee State Park, Jack told us that the bus transmission had a problem and was refusing to shift. He planned to stop the bus, shut it off, count to 10, and then pray that the transmission reset itself. As luck would have it, Jack’s prayers were answered and we did not end up having to walk up the hill with all of our ski gear.

We arrived at the mountain in time to make the first tracks of the day and the conditions were super thanks to the excellent job of grooming the runs the folks at Sunapee had done, plus the fact that it being Friday there were no lift lines at all. The sun warmed the back side of the mountain first and softened things up just enough to create excellent skiing conditions. We all stopped for lunch on the deck outside to enjoy the sun and the spicy chili.

In the afternoon the front of the mountain was softer and we all made multiple runs up and down the Express Quad and it's assortment of blue and black diamond runs. It was during this time that your author made a valiant attempt to keep up with Mssrs. Crowley and Grunwald but to no avail! By 4pm we were all skied out and enjoying some refreshments in the Horsefeathers bar, and by 6pm we piled back into the bus for our ride home (still telling Jack which way to go: "No, Jack, 93 South!").

When you consider we had a great day of skiing, the company of some 56 fine people, lunch and after-ski drinks plus a bus ride made only slightly longer by a few wrong turns, the $50 cost seemed an incredible bargain. We hope that next year even more people take advantage of this ISPE Boston Area Chapter March tradition!

Project Management: “The Tail Wags the Dog?”

by David MacDonald with photos by Peter Teague

Project Management came to the Boston Area Chapter of ISPE on Tuesday, November 13, 2007. The room was full at the Royal Sonesta in Cambridge, as two excellent speakers explored several facets of the complex area of project management. One speaker focused on small projects and the creation, care and feeding of project teams and the second speaker focused on how to control massive capital projects and how to develop a global project management standard for a multinational.

Niall Johnson, Associate Director of Capital Projects/Facilities, Engineering & Planning for Millennium Pharmaceuticals, spoke first. He described several drivers for utilizing project management and project management tools. First, the FDA has estimated that there is $60 billion of opportunity cost in the pharmaceutical industry. In the FDA’s quest to lower drug prices, the industry will be forced to start minimizing that opportunity cost. Project management is just a set of tools to allow us to do business better. In addition, there is a need to leverage individual project success to business success, which is, after all, our overall goal. Project management includes tools to make sure that individual project goals are aligned with the overall company business goals.

Johnson defined a project as a set of activities having both a start and a finish, leaving a wide range of topics as possible projects. Only about 50 percent of a typical project is in the execution of the project. The rest is in the initiation, planning, verification and closure. The project can succeed or fail just as easily in these phases as in the more visible execution phase. The challenges faced in a project are different for each level of stakeholders - the industry, the individual business, the specific project team and the individual project team member.

One of the keys to project success involves addressing Project Risk. Putting your head in the sand about the risks in a project is not a good option. Likewise, saying that we want “no risk” is unacceptable. Instead, we need to not rely on intuition, but identify what the real risks are and manage, monitor, and mitigate those items. But the list of risks that you are managing needs to be short (less than 10) and well-prioritized (those risks that are real and important).

Johnson discussed two key project documents, the Project Initiation Document and the Project Planning Document. The Project Initiation Document is the project charter. It should be short, 3-4 pages, and should clearly state the business case, project boundaries, risks, constraints, expectations and success criteria. The Project Planning Document has more detail, delving into user requirements, process block flows, project work breakdown structure and preliminary schedules (less than 15 tasks). This document should also clearly define the success and acceptance criteria.

Wrapping up his section, Johnson reminded the attendees that all projects are change and so are challenging. The real definition of project success is “Would you be willing to do the project again with the same people?” The soft side of project management and project leadership are as important to the success of the project as the technical skills.

Jeremy Gross, a Principal from PMA Consultants, then continued the evening with a session on Project Controls, Schedule Integration and Project Reporting. Gross reminded the audience that in the structural construction side of the business, GMP means guaranteed maximum price, having nothing to do with the FDA (so we have to keep a close eye on our three letter acronyms).

He went on to discuss Project Controls. This is not project accounting, but a tool kit for project management, used to ensure that past mistakes are not repeated. It includes a disciplined approach to estimating, scheduling, cost controls, monitoring, trending, forecasting and reporting the project. And it includes a feedback loop to capture data and lessons learned. Gross reported that the benefits of using this tool kit include early warning signs and reliable forecasting as well as lower cost growth, lower total cost and less slippage in the project schedule.

PMA was involved with developing a global standard for project schedule integration for large scale projects for Johnson & Johnson. One single large project could consist of 30,000 items, so no single person looks at all the items. Each smaller portion of the project has to be managed with a schedule and plan which an individual could understand. These individual plans then have to be wrapped up into the overall master schedule. Only with a very disciplined approach could all of the sub-project schedules be managed, integrated, updated and reported successfully. The updating of the project progress and its schedule becomes an intricate task in itself, with progress data reporting cut-off dates and schedule-update dates.

Even the reporting of the status of a project becomes a disciplined art. Gross pointed out that there needs to be multiple levels of reports generated, depending on the needs of the report users. At the highest level, there are Executive Level Reports which quickly capture the essential high-level information on project costs and schedule. They must be quickly and easily read and understood, and should be in a standardized format. Dashboards have proved useful at this level to quickly convey the necessary information. Just taking a report from Primavera will not work at the executive level. Meanwhile the Project Manager needs to be looking at detailed tabular reports and resource availability and demand curves. These need to be both customized for the needs of the project manager and as standardized as possible for consistency and ease of understanding.

PMA was so successful in helping J&J on one of their massive capital projects that J&J senior management asked for their help in standardizing the company’s global approach to capital project management. This demonstrated the versatility of the project management tools that both speakers had described, covering the range between a conference room renovation to a global multi-billion dollar a year capital program.

For more detail, readers are invited to view the presentation overheads on the Boston Area Chapter Website at http://www.ispe.org/boston/events.

Its All in the DOCS: Planning CTD/eCTD CMC Submissions

text and photos by Deepen “DJ” Joshi

At the January 15th Educational Program (EP), the ISPE Boston Area Chapter continued its mission of combining timely information on a topic of current interest to the industry with an opportunity for informal discussion and networking among peers. The topic of discussion that evening - Common Technical Document (CTD), the current worldwide standard for content and format of submissions of Investigational New Drug Applications (INDs) and New Drug Applications (NDAs) - was a welcome one and the first time the Chapter has devoted an EP to the topic of regulatory documentation.

Rick Pierro, President of the Boston Area Chapter, jump-started the program by sharing some of the Chapter's upcoming events and giving a warm welcome to the panel of speakers, all of them distinguished experts from the regulatory domain. Speakers included Michelle Herrera Foster, PhD (CTD Quality Consulting), Fiona Sibley (CTD Quality Consulting) and Yolanda Hall (Datafarm), all of whom gave formal presentations; and panelists James Blackwell (BioProcess Technology Consultants) and Tish Webber (Wyeth BioPharm).

She then went on to describe the data which, under the current EU regulations, has to be contained in Module 3 so that it can be determined whether the drug/biologic in question is of appropriate pharmaceutical quality. She also discussed the importance the electronic version of the Common Technical Document (eCTD) may have now and in the future. The eCTD is expected to fully replace the “paper” CTD, thereby reducing the quantity of paper received by regulatory authorities on a daily basis to a reasonable level. In addition she stated that the CTD is required in EU, Japan and Canada for marketing applications, “highly recommended” by FDA for NDA/BLA and required by Center for Drug Evaluation and Research (CDER) for eCTD submissions.

During the course of her presentation, Dr. Herrara Foster suggested treating CTD as a live document throughout the submission process and explained the advantages and challenges of that approach. She also skimmed through the following sub-topics: key CTD needs and tools that would bring more efficiency to the process, difference between various sections of Drug Substance (DS) and Drug Product (DP) for Module 3, and correlating the CTD Module 3 to the NDA, BLA and MAA. She identified the new sections required by the CTD and listed high level points that would enable the development of CTD from IND (Phase 1). She enlightened the crowd with examples of Module 3 reports and types of reports, namely full report, summary report, high level summaries (for Module 2) and reports on file for inspection. The panelists contributed additional information as needed to fill in gaps and/or provide a different viewpoint or example to clarify the issue at hand. This exchange allowed the audience to appreciate the regulatory documentation challenges and what is considered an appropriate and balanced approach.

The second part of the EP was dedicated to the presentation of CMC CTD case studies by Fiona Sibley. The case studies on purification, process development, viral clearance and sterilization validation helped the audience to understand the applicability of CTD to their respective domains. Although they may not have received a comprehensive understanding of the mundane challenges in the preparation of CTD, the case studies served as a “lens” through which the attendees could view and better appreciate the intricacies involved in CTD/eCTD development. In her conclusion, Ms. Sibley recommended that submission-ready validation reports and other reports be written in advance so that summaries and data tables can be copied for the CTD at filing time, thereby saving effort and reducing stress. The participants acknowledged that following these recommendations would prove valuable in increasing the efficiency of the process.

Following the CTD overview and case studies presentations, Yolanda Hall covered Electronic Common Technical Document (eCTD) Considerations. She said that the eCTD is a part of the ICH initiative to provide a common format for the industry-to-agency transfer of regulatory information that is acceptable across the ICH regions of the United States , Japan , and the European Union. She also explained how the eCTD introduces the use of an “XML backbone” as a new way of approaching electronic submissions. This benefits both sponsors' organizations and agencies by providing a mechanism to record all interactions and highlighting changes between submissions.

Ms. Hall provided highlights on eCTD specifications Module 3, reiterating that granularity is the key to successful eCTD. She explained the relationship between XML and Templates as it applies in Modules 2 and 3, and the importance of defining the directory structure, file organization, file names and their boundary values. Participants requested further clarification on the technological investment (small scale investment vs. large scale investment), Life Cycle Management (LCM) of submissions as well as of documents, including correlation between the two. She remarked that benefits include the efficiencies gained by content reuse between submissions, the ability to submit simultaneously to the three largest pharmaceutical markets around the globe, and the simplification of the maintenance process throughout the submission lifecycle enabled by the XML backbone structure.

During the final wrap-up discussion, the panelists sought to summarize some of the key themes of the three presentations. They handled the follow-up questions round-robin style, providing a variety of perspectives, solutions and applicability, where possible, to add further clarification. Audience members working in the same domain also joined in, sharing strategies that are being used in their own companies.

In sum, attendees gained a better understanding of CTD and eCTD and their applicability to manufacturing, process automation and related domains, and were able to make new friends and meet with existing ones while spending an evening on the cutting edge of all that is new and exciting in the industry. This certainly is priceless!

A Sure Bet: Chapter Officers Enjoy ISPE Annual Meeting in Las Vegas

by Doyle Johnson

The 2007 ISPE Annual Meeting was held this year at Caesar's Palace in Las Vegas . Caesar's Palace is the 12 th largest hotel in the world with 3,348 rooms. Over 2,500 ISPE members from around the world journeyed to Las Vegas . Your Chapter was represented by Rick Pierro, President; Mike Denault, Past President; Doyle Johnson, Vice President; and Amy Poole, Chapter Manager.

The first event was a Student Luncheon on Sunday, with 56 Students from all over the country. Rick spoke of the path he took to found his own very successful integration business and also be on the board of directors of several other companies. Doyle spoke of his career path and how even as a young graduate just starting out in the workplace he had an influence on others. Sean Sommer of Parsons spoke about his career through engineering, project management, and into business development. It was fun to talk to the students, answer their numerous questions and be so well-received by them.

Sunday through Wednesday were educational sessions mixed in with committee meetings on ISPE business and future planning. We discovered some best practices of other Chapters that might be useful for us and types of events that could also go over well in the Boston Area Chapter.

Monday night was a social gathering at Margaritaville. There was live music and livelier discussions. For instance, I found out from Nuala Calnan of Project Management Group in Dublin , Ireland that the E2500 standard is already having an impact over there.

Tuesday's luncheon was the main event, with Bob Best (ISPE President) and Bruce Davis (Director of AstraZeneca and incoming ISPE Chairman) telling about the past year and future plans. The Keynote session on Monday morning was also a highlight. Gary Convis, Chairman of Toyota Motor Manufacturing Kentucky, spoke of how he built a company focused on quality and employee empowerment. If you think you spend a lot of time interviewing candidates for jobs at your company, consider this fact: Toyota interviews on average 25 people for each person they hire.

At the same session, Charles Portwood, President of Technical Operations and Product Supply at Wyeth told us about how Wyeth has seen benefits from totally integrating all of their information systems, and Uri Boneh, Director of Global Engineering for Teva explained how to make a cost-effective (he did not like the word “cheap”) generic pill (OSD) plant outside Jerusalem.

Tuesday evening was the Roman Festival at the hotel's Temple Pool , which was a beautiful setting for more camaraderie. Wednesday was the last of the educational and committee meetings before we all returned home. It was great to meet so many people from other parts of the world and realize how similar are the problems we all deal with (both professionally and within the ISPE Chapters). If you have not attended Annual Meeting before, you should plan on joining us next year - 26-29 October, 2008 - in Boca Raton , Florida . See you there! ?¡

Genzyme Center Tour Wows Chapter Members

by Wes Hyman with photo by Peter Teague

About 20 ISPE members from the Boston Area Chapter gathered for an exclusive tour of Genzyme corporate headquarters in Cambridge on 21 August 2007. Genzyme Center has received the highest rating issued by the US Green Building Council, the nation’s foremost authority on environmentally responsible building practices. The building received a Platinum certification under the Council’s LEED® (Leadership in Energy and Environmental Design) Green Building Rating System™, which was created to define “green” building by providing a common standard of measurement.

Genzyme is one of the world’s leaders in the biotech industry and what began as a small startup in 1981 has now grown to a global company with more than 10,000 employees and annual revenues of $2 billion. Genzyme Center formally opened in 2004 and currently houses 900 employees. Our guide said that the corporate core values include innovation, transparency, collaboration, and the entrepreneurial spirit, all of which are reflected in this marvelous building.

What really strikes you first when you enter the building is the lighting. There is a lot of light reflected throughout the interior of the building. Our tour guide pointed out the glass exterior and the central atrium that reaches up 12 floors to the top of the building. She indicated that the building used 80 percent natural light and only 20 percent artificial light. Sunlight is distributed throughout the building using a natural light enhancement system. On the top of the building is a group of complex mirrors called Heliostats, which are used to track the path of the sun and help guide light inside the building. A chandelier of prism tiles reflects sunlight into the atrium and throughout workspaces in the office areas. There is a computer that controls the blinds and automatically tracks the sun’s position and then opens the blinds in order to let in light and at the same time deflect glare and heat. There is a “light wall” comprised of highly polished aluminum strips that make up reflective panels as well as a reflecting pool that further distributes light throughout the interior of the building.

There are 18 exotic gardens located throughout the building plus a vegetative roof garden which is used to help lower the storm water runoff and heat concentration of the building area. Genzyme boasts that the building played a significant role in the transformation of a contaminated “brownfield” site into a mixed-use urban community locale. In addition, the building uses 34 percent less water than a conventional office building. Dual flush toilets and waterless urinals cut down on water usage, as does the use of moisture sensors in the landscaping to reduce watering to a minimum.

We were able to visit the 11th floor to see the loggia. The observation area provided a splendid view of the city and we were able to observe the automated shade controls there which help conserve energy and maintain moderate temperatures throughout the building. We also saw the double glass curtain wall that covers 32 percent of the building and provides for fresh airflow and improved insulation throughout the building.

Genzyme was careful in their materials use for the new building. Seventy-five percent of all materials used in the building contains recycled contents. Ninety percent of all waste from the construction site was recycled or reused. We saw a wood floor that was made from a reclaimed white oak. The cooling system uses waste steam from a nearby power plant to cool the building, and the roof-mounted solar panels were paid for in part by a grant from the Massachusetts Renewable Energy Trust Fund. Other benefits from this innovative and unique building include the following:

• 58% of employees who work in Genzyme Center said they were more productive in the new building than they had been in the company’s former headquarters.
• Genzyme Center employees recorded sick time at a rate that was 5% lower than the combined rate for employees working at all other Genzyme facilities in Massachusetts.
• The building’s energy costs were estimated to be 42% less than those of a comparable conventional building.

Editor’s Note: Excerpts from Genzyme press releases and web-based information were used as additional sources for this article.