Recent Events

The Sun Shines on the 6th Annual Golf Outing

by Sylvia Beaulieu

On August 18th, the Boston Area Chapter once again hosted our annual golf tournament. During a summer plagued by nonstop rainy days, we lucked out with beautiful, sunny weather. And we tried a new course - Ferncroft in Middleton - that proved to be a great venue. I heard many good things about the course and the service and all the golfers seemed to have a wonderful time - even if the pin placements were hard or, as someone stated, “I think they’re illegal.”

The day started early at 6:30am for registration/breakfast and a 7:30am shotgun start. As folks came around to the 10th hole, they were greeted at the putting green by Sherri Pelletier of Structure Tone who sponsored the $10,000 Putting Contest. They also got to sample Dewar’s Scotch at the Dewar’s table. (No one was quite sure whether that helped or hindered their putting skills.) In any case, no one won the big bucks but Eric Hoaglund came the closest by sinking a 30-foot putt. Congratulations, Eric!

As the golfers started to come in from the course, they gathered on the deck for appetizers and cocktails and told stories about their golfing adventure. We then moved into the tent for dinner and raffle prizes. Doyle Johnson, the Chapter’s new President was master of ceremonies and once again brought his quirky sense of humor to the task. I will miss that. I have had the pleasure of running the tournament for 4 years but as the Chapter’s new Vice President, I think it is time for someone else to plan, worry, stress out, shop for raffle prices and get up at 5am to get everything ready for registration. Bob Lewis of Erland Construction has graciously agreed to take over from me next year - Bob, get ready to receive my box full of golf stuff...

Congratulations to all of the day’s winners. The winning teams:

 And the individual winners:

Many thanks to all of our Golf Outing corporate sponsors who help to make this event a big success for the Chapter year after year. This year the thanks go to Steris, DECCO, Structure Tone, GxP Automation, Superior Controls, Invensys, Integra, CRB Consulting Engineers, A/Z, Bovis Lend Lease, Columbia Construction, Commodore Builders, Erland Construction, GMP Lab Products & Services, North Shore Mechanical, Parsons, RDK Engineers, The Richmond Group and The Chisholm Corp. I also want the thank A/Z, Plastic Concepts and Integrated Process Technologies for their donations to the raffle.

Water, Water Everywhere at May Educational Program

by David MacDonald

The topic of water - a topic that always draws a crowd - returned to the educational program of the ISPE Boston Area Chapter on May 20, 2008. The room at the Royal Sonesta in Cambridge was filled with members who had turned out to hear two of the area’s long time experts (each with 20+ years experience) discuss this ubiquitous but complex topic. The first speaker gave a wide-ranging overview of purified water: types, specifications, contaminants and contaminant removal techniques, while the second explored the use of ozone as a technique to produce purified water and maintain good biological control.

Brian Hagopian, Vice President of Research and Development for MarCor Purification, spoke first. His was a daunting challenge, covering “Water Purification 101: From Tap to Pure, Understanding the What, Why and How” in less than an hour. Hagopian quickly demonstrated his enthusiasm for his topic and his high skill as an educator, keeping the entire room with him during the whirlwind tour of the subject. The talk covered three areas. First, “What contaminants are found in water?” - second, “Which of these contaminants must be removed and why?”- and finally, “What are the basic technologies for removing these contaminants?” Interlaced with the technical discussion were many humorous asides, keeping the room light and the audience alert.

The basic groups of contaminants discussed were suspended solids, dissolved salts, low molecular weight organic materials, high molecular weight organic materials (also known as colloidal materials), bacteria (and other biological contaminants) and dissolved gases. Each class of contaminants has its own properties and requires differing approaches for removal.

Hagopian then raised the issue of why we should care about water contaminants and which contaminants need to be removed. The simple answer is that water is the most abundant single ingredient coming into contact with our products. It is the carrier fluid in the vast majority of the pharma / biotech processes. Reducing the variability of pure water quality increases the repeatability and robustness of these processes. The second simple answer is that there is a long list of organizations (led by FDA and USP) that say that we will control the quality of water used in pharmaceutical operations.

Then there was a quick review of specifications for various grades of water. The FDA is mainly concerned with two types of Pharmaceutical Grade Water: USP Purified and USP WFI. Hagopian compared these two grades versus semiconductor grade water. The comparison was eye opening, with semiconductor grade having many more specifications and much tighter limits. And semiconductor grade water is routinely produced in high volumes.

The next topic was a survey of the technologies used for contaminant removal. For particles, the technologies include (in order of increasing fineness) particle filters, membrane filters, ultra filtration and reverse osmosis. Salts are removed by ion exchange, small organics by carbon filters and bacteria by UV sanitizers or TOC-reducing sanitizers. Distillation is the gold standard as it removes the water from its contaminants and the heat effectively kills all the bacteria.

Hagopian concluded by reviewing the largest local problem contaminants. These are the seasonal turnover in the local surface water supplies and the low molecular weight organic contaminants present in many public water sources. In closing, we were reminded that this was just the very basics of purified water, barely scratching the surface of a vast and complex subject.

Bob Livingston, President of Arion Water, was the next speaker, on “Best Practice for the Use of Ozone in Life Science Applications.” This talk started with an introduction to using ozone as a key part of the water purification system and then presented some real life case studies. Livingston’s thesis is that ozonation is an attractive choice to replace heat shock and chemical sanitization in high purity water production. Ozone is especially useful in improving the microbiological aspects of purified water production.

Livingston noted that purified water is too often conducive to microbiological growth. The relatively high limits on TOC and conductivity specified by USP Purified Water can support the growth of biofilms in the water production and distribution systems. Biofilm is a thin layer of bacteria and organic matter that occurs under the viscous boundary layer, at the interface between the bulk water phase and the solid system components, such as piping, filters and resins. Typically biofilms are kept under control in pharmaceutical water systems by the use of periodic heat or chemical sanitization cycles. Heat sanitization will control the growth of biofilms but will not completely remove existing biofilms. In comparison, semiconductor purified water systems operate at ambient conditions without heat sanitization cycles. Instead, they use nutrient deprivation as their control strategy. In extremely nutrient deficient environments, bacteria will not attach to surfaces. If the bacteria don’t attach, they won’t form biofilms in the distribution loop or elsewhere.

Ozone can be added to the water production system and /or the water storage and distribution system. Ozone serves two purposes. First, it is very effective at killing a wide range of microbial actors including spore forming species. It is orders of magnitude more effective as a sanitant than chlorine. Second, it can be used to remove the TOC contaminants of purified water through oxidation. Livingston stated that you can’t get control of the microbiological aspect of purified water until you get high purity (and low TOC) in the distribution system.

In one case study, a 500-gallon DI water system had been idle for 6 years. When the system was restarted, the bacteria count was too high to measure. Ozone was injected into the water and in less than a day the TOC was reduced to < 5 ppb and the bacteria count was <1 CFU/100 ml. In a second case study, an operating system of good design produced water with acceptable TOC and bacteria counts for 14 months. The system still exhibited build up of biofilms and started showing periodic bacteria excursions. The system was modified to use ozone to reduce and control the TOC level. By reducing the TOC level to < 2 ppb, the bacteria count was reduced to < 10 CFU/100ml with no excursions, without the use of chemical sanitization. When Livingston stated that ozonated water cleans out existing biofilms, light bulbs went on over the heads of many in the audience.

Livingston then briefly reviewed the choices for ozone manufacturing methods, means for dissolving ozone in the water and destroying the residual ozone. When introducing ozone into a water system, use of the appropriate materials of construction is one key. Another key consideration is the need for online measurement of effective ozone level control. There has been recent progress in this measurement.

Ozone has been used for intermittent sanitization of distributions loops, passive microbial control via TOC reduction and routine process sanitization. One key point is that there is a need to rinse the use points with ozonated water to keep them sanitized. One real advantage of ozone sanitization is that is creates no additional wastewater and doesn’t leave a residue which must be cleaned from the system before use.

The speaker’s conclusion is that TOC control - at levels well below that required for USP Purified Water - is essential to the good operation of a DI water system. And ozonation is an effective treatment for reducing TOC and bacteria counts and removing biofilms.

Both speakers’ presentations are available for members at the ISPE Boston Area Chapter web site at www.ispe.org/boston/events.

You Want it When?!?

If you’ve ever wondered how in the world you’re going to get your MVR done in time to get the FDA to approve your HPH2Os, CDAs, and CEs as scheduled, you might want to hear what these experts had to say about phasing your C&Q and building your BOD to finish PDQ and report more ROI to your CEO!

by Joseph A. Naughton

Over 100 of ISPE’s finest gathered at the Royal Sonesta Hotel in Cambridge on June 17, 2008 to catch up with fellow industry professionals and to engage in some light conversation focusing on challenges and solutions in merging quality and facility requirements with accelerated schedules, the never ending desire to change the plan once it’s set, and the pressure to get on line faster. Leading the discussion were two of the region’s seasoned facilities implementation and validation gurus: Michael Marino and Charles E. Pappalardo. They spoke at both the micro and macro scales about common challenges and solutions to relieve the pressure and reduce the temperature the process often involves.

Mike began the discussion with a presentation titled “Controlled Environment Commissioning and Qualification: Using a Phased Approach to Meet Schedule Demands.” The setup is as follows: For virtually every project there is a firm construction schedule and a firm manufacturing startup schedule, and stuck in the middle is the Commissioning and Quality (C&Q) system process, which would be fine except for what Mike refers to as the C&Q “squeeze” factor. The C&Q squeeze typically results from construction delays pushing the construction finish out and/or operational pressures that pull the manufacturing start date in. The net effect is that C&Q typically gets squeezed into an increasingly narrow crevice of time between the finish of construction and the start of manufacturing activities. To deal with this recurring challenge, Mike recommends a phased approach to C&Q.

The phased approach is designed to document and execute a logical and defendable Qualification Plan (QP) to commission, certify and qualify Controlled Environments (CEs) and systems that saves time by synchronizing simultaneous construction and C&Q activities. This synchronized and simultaneous approach allows C&Q activities to start as individual systems are finished and turned over, as opposed to waiting until the entire construction process is complete before starting the C&Q plan. The way this works is as follows: The team must allow the qualification process to be split up into phases for each of the areas being constructed and generate, execute, and approve each document set as the individual systems comprising the project are turned over by the construction process. Of course all this synchronization and simultaneity sounds great but it can only happen by building the right plan which Mike recommends you lay out with a QP flow chart showing the major steps in the process including:

1. Defining the roles and responsibilities for each team member;
2. Identifying the specific team players including a third party commissioning team;
3. Developing the project quality scope including a task list with durations and assignments;
4. Formalizing multiple Master Validation Plans (MVPs) that document in detail the scope of each qualification with acceptance criteria; and
5. Establishing systems boundaries for the MVPs and C&Q plans.

Once the structure is set, you can advance your C&Q plan with the commissioning component. The commissioning process starts with the development and approval of a Design Intent Document (DID) that goes to a third party commissioning company as early on in the design and construction process as possible. The DID should be structured to accommodate a parceled approach to approving building systems such as the HVAC system, building automation system, and pure water system, to name a few. The plan should be integrated into the design phase with agreed-upon formats for reporting well in advance of construction (synchronized) in order to reap the time-saving benefits of simultaneity mentioned above.

The Qualification process starts with the development of an “all-encompassing” quality plan that documents the phased approach and establishes multiple MVPs for each of the individual systems approvals. The MVP is usually the first document read by the Qualification auditor, which is why it needs to describe in detail what you’re going to do and include the “why rationale.” The MVP should also describe at what point in the qualifications process manufacturing can begin.

Qualification requirements are organized into Installation Qualification (IQ), Operational Qualification (OQ), and Performance Qualification (PQ) categories. The IQs should cover the as-built conditions for your Controlled Environments (CEs) and related systems including High Purity Water (HPH2O) and Clean Dry Air (CDA) to name a few. The IQ is a formal verification that the rooms were installed as designed and working properly with respect to temperature, humidity, particulates, etc.

Upon approval of the IQ, the room or system is ready for the OQ review. The OQ is a verification that the CEs and related systems and critical utilities are operating over time as required by the MVP. The OQ includes static tests reflecting “at rest” conditions as well as dynamic tests on a 24-hour/5-day operation capturing the “in operation” conditions and any variation. Upon successful retest and approval of any corrective measures or deviation remediation, the OQ is approved and the CE and related systems can be released for process validation runs (though not in-human use manufacturing) and the PQ stage.

The final qualification, the PQ, is intended to test the “routine” operation of the CE and related systems and usually involves a minimum of 2-3 manufacturing weeks and/or 2-3 lots worth of product. Once again, following any corrective action needed, retest and approval, the PQ is approved for the given system. The qualification results for the IQ, OQ, and PQ are summarized in a Master Validation Report (MVR) that identifies any failures and resolutions, system acceptance documentation, and which is approved by the auditor, and the CEs and systems are released for in-human manufacturing. Another benefit of the phased approach is that it can be planned at the front end to accommodate “staggered” manufacturing process validations at the back end.

It should be noted that while the phased approach is a good shock absorber to C&Q squeeze, it also often results in more paperwork to “stitch” the parcels together in the documentation for the MVR. Mike indicated a threefold increase in paperwork should be contemplated when using this time-saving but more documentation-intensive approach. Clearly the C&Q process leading to a successful validation is onerous, but using the phased approach can help take some of the pressure and heat out of the “squeeze.”

Following Mike’s in-depth view of the validation process, Chuck took a step back and focused his discussion on the larger issue of moving a project quickly from concept to completion in a presentation titled “Accelerating Advanced Infrastructure Delivery.” He began by outlining some of the most commonly voiced challenges facing the prototypical development project. These include the need to:

have it yesterday,
cut the budget,
comply with the regulations but keep it “flexible,”
make major changes to the program when you’re pouring concrete,
understand that every end user is “Customer #1,”
keep multiple team members “in the loop,”
minimize maintenance,
maximize product production,
get to market now, and
keep quality job number 1.

While there is no perfect solution to such a complicated process with as many variables as you will find in your every day biopharm development project, there are some key measures that, when carefully applied, will make the process move much more smoothly and ensure a higher degree of success: Based on his own experience, Chuck outlined the following success factors:

• Stressing the importance of team coordination,
• Achieving an early integration of key stakeholders,
• Developing comprehensive programming up front,
• Setting realistic budget expectations,
• Setting credible schedule expectations, and
• Driving execution.

Team coordination starts with appropriate prequalification and selection of critical consultants to assure that the team chemistry is balanced and the necessary areas of expertise are well covered. In a market where every consultant is trying to win every commission, prequalification is critical to prevent an inadvertent “perpendicular” selection to a specific project need.

The team process also needs to be well defined and consistently visible in meeting notes, action items, gate keeper logs, accountability, critical dates, and milestones. The gate keeping process is the structure that allows the team to rigorously track changes to the project plan after a program or Basis of Design (BOD) has been approved by the project’s key stakeholders. The log provides a formal presentation and reflection record of team decisions that may have both short-term and long-term impacts. The log will show, for example, that a conscious team decision was made to change the chiller plant from two 1,500 ton chillers to three 1,000 ton chillers to achieve operational redundancy, even though it cost more money and could take more time to complete. The log keeps the entire team involved and the project memory current. This brings us to the next critical component which is the early integration of key stakeholders.

The early integration of key stakeholders and functional experts during the BOD process will increase internal project support, maximize scope capture from the outset, and provide for an “all in” BOD. Key stakeholders should include representatives from Quality, Validation, Engineering, OPS, Facilities, IT, Security, R&D, Procurement, and Real Estate departments in addition to end users. And by having an “all in” BOD, the chances for establishing a truly realistic budget and schedule are maximized.

The BOD process, also referred to as programming, generally represents about 2 percent of the total project cost for a facility. The BOD derives from the strategic plan and typically results in a physical space program describing the types and sizes of spaces contemplated for a particular capital asset, with concept design and specification defining the basic scope of the project. Key stakeholders, designers, planners and cost estimators should be integrated into this process to confirm that needs are adequately identified and project costs including design, construction, furniture, equipment, land and financing are covered by the BOD.

This information is then packaged and used to develop return measurements, such as Return on Investment (ROI), Net Present Value (NPV), Internal Rate of Return (IRR) and Payback, for presentation to management and the request for a “go- no go” decision. As stated above, the BOD typically represents about 2 percent of the project cost, so if the response is a no-go, your risk is limited. If the response is a go, the next step is to refine the BOD and request the next level of funding for the Design phase which represents another 10-12 percent of project cost. This incremental approach to project funding requests is part of Chuck’s approach to setting realistic budget expectations.

Setting realistic budget expectations can be promoted by first organizing the development process into three manageable slices of work effort and owner resource commitment:

1. The Basis of Design (BOD) or programming and concept development effort representing approximately 2 percent of project cost;
2. Design and preconstruction leading up to a Guaranteed Maximum Price (GMP) or “Bid,” representing approximately 12 percent of project cost, and
3. Construction, commissioning and validation, representing approximately 86 percent of project cost.

By requesting approval for each of these phases incrementally, you avoid the potential to over commit owner resources and keep expectations within well defined limits. Upon approval of the BOD phase described above, the design and preconstruction phase can begin. This phase involves issuance of Request for Proposals (RFPs) and selection of a design team to prepare construction documents and produce the project performance specifications. Once again it is critical to integrate your key stakeholders into this process, as was done in the BOD phase, to assure a continuity of the “all-in” support system and scope capture that will undergird your cost and schedule estimates.

Toward the end of the design and preconstruction phase, Chuck recommends utilizing the 80-100 percent complete design documents for inclusion in a Request for Proposal (RFP) to Construction Managers (CMs). The CM RFP is intended to solicit qualitative and quantitative proposals, including estimates for construction cost and schedule reflecting the BOD and current design. Upon receipt of the CM proposals, and often a third party check estimate, you will have the scope, cost, and schedule information, as well as stakeholder buy in, to make another financial presentation to management for your next “go- no go” decision. A positive response from management at this stage allows you to move into the construction commissioning validation phase that will bring the new facility on line.

Setting credible schedule expectations is akin to the discussion on programming and budget above, in that you will want to assure full integration of all support team schedules (Commissioning, Quality, Validation, Engineering, OPS, Facilities, Equipment, IT, Security, R&D, Procurement, and Real Estate, and Construction) in a master schedule prepared by the CM. This process, for example, can help to avoid the C&Q squeeze that Mike spoke of earlier, with construction commissioning, quality, and validation all integrated in the planning and implementation phases of the development. It is also important to revise the schedule regularly to accommodate any refinements or necessary adjustments that may require a recovery plan to maintain set milestones. A two-week look ahead is also recommended, and constant communication among the stakeholders is critical and can be encouraged by the use of a project FTP site to host project data.

Finally, driving execution of the plan relies on strong leadership, enforcement of accountability and measurement of key performance indicators (KPI) to gauge progress and make course corrections as necessary. Chuck recommends carefully interviewing critical team members such as the CM superintendents and project managers to ensure appropriate experience and team chemistry. Strong leadership will also benefit from periodic team building to maintain focus, direction, enthusiasm, and productivity. Enforcing accountability by each project team member is critical and can be done by penalizing low performance and rewarding achievement. Accountability also entails identifying team weaknesses and making changes and other corrective action early to maintain project momentum and efficiency. Finally, defining and measuring KPI in terms of schedule adherence, budget adherence and team coordination is critical to good project management.

Clearly the facilities development process, on both micro and macro scales, is faced with challenges that require careful advance planning to achieve positive outcomes. We can see how a phased C&Q plan is a great way to deal with the C&Q squeeze that so often occurs as construction dates are pushed out and manufacturing dates are pulled in. It is also helpful to know that these large endeavors can be effectively disaggregated into a smaller subset of tasks and incremental approvals to limit risk and better protect owner resources. When coupled with earlier involvement of key stakeholders, these tools allow us to build better solutions to strategic planning needs and report more ROI to the CEO!