Build new...or upgrade?

That’s the dilemma facing many bio-pharm companies looking to broaden their manufacturing capabilities to meet ever-changing strategic goals.

Growing market demands may favor expansion, which traditionally has meant new plant construction. But current economic uncertainty coupled with high energy costs, is raising a red flag among corporate financial managers who caution against assuming additional capital risk exposure.

As a result, many drug producers are opting to upgrade existing plant facilities to accommodate new product and manufacturing technologies, increase containment levels, and facilitate handling of flammable solvents required for certain types of chromatography operations. Along with this, operators are striving to improve product throughput and speed-to-market through process debottlenecking initiatives designed to enhance clean utility capacity such as water or clean-in-place (CIP) systems.

Another key driver of this trend is the recent increase in bioreactor production, especially as relating to monoclonal antibody products. Innovations in bioreactor operations, especially controlled nutrient and advanced cell line development are helping to provide much higher product yields.

Downstream operating capacity and support functions, such as buffer prep, must likewise be increased to improve manufacturing throughput. To achieve that, manufacturers are employing large-scale usage of in-line dilution of concentrated buffer solutions to supply increased buffer capacity while minimizing the need for large equipment.

Underscoring the challenge that confronts the biopharm industry to optimize its plant efficiency and product market life, several international drug producers are designing and building facilities to manufacture biosimilars (biogenerics).

Many facilities constructed in recent years already incorporate the basic capabilities needed to adopt future technologies, support multi-product operations and meet international regulatory compliance. Although some now employ single-use technology, with the right process engineering expertise they can be easily reconfigured for new product and manufacturing processes.

Modification of existing facilities to produce second generation products is a prudent alternative to improve product speed-to-market and maximize economic return on assets. As a recognized leader in developing projects for the biotechnology industry, IPS has extensive expertise in this type of project application and provides economic and flexible solutions that improve manufacturing utilization.

Teaming up for innovative solutions

How does a pharmaceutical leader like Bristol-Myers Squibb (BMS) deliver viable solutions to help meet the challenges of Alzheimer’s, diabetes, hepatitis, HIV/AIDS, cancer and many of society’s other clinical needs?

One way is by keeping pace with the highest standards of manufacturing technology to support its product development pipeline. Most recently, this was reinforced by a facilities redesign initiative to combine early and late phase cGMP clinical manufacturing and development scale-up at the company’s new Pharmaceutical Development Center of Excellence R&D site in New Brunswick, New Jersey.

As part of that evolution, BMS launched its Clinical Supplies Manufacturing and Drug Product Technology Expansion Project, earning it the 2008 ISPE, Interphex, Pharmaceutical Processing Facility of the Year Award (FOYA) for Equipment Innovation.

Dual–phased approach
The BMS team of corporate and third-party planning, design and construction specialists followed a phased approach to the project, with a goal of creating a flexible facility for multi-product clinical scale manufacturing and processing of solvent–based and potent compound products.

Under Phase I, a 93,000 square foot Clinical Supply Operations (CSO) facility was created to support three key manufacturing functions: a parenteral area equipped with an isolated vial filling line to satisfy sterility and containment requirements; a second zone dedicated to handling OSD products within Active Pharmaceutical Ingredients (API) bands one through four; and a third facility for OSD band five drugs.

In addition, to help ensure product integrity and operator safety, the facility supports full containment for expanded Oral Solid Dose (OSD) operations, incorporating what has been described as the most flexible continuous barrier line in the United States. The new CSO complex is capable of processing oral solid dose batches of up to 400 kilograms and parenteral liquid-fill batches of up to 250 liters.

Phase II of the BMS project called for approximately 39,000 square feet of expanded capabilities to supplement existing OSD operations, and housed a new stand-alone Product Technology Center (PTC) for product development and scale-up. Typical PTC batch sizes can range from 20 kilograms to 100 kilograms. This facility is also designed to handle API band one through four operations.

Expanded oral solid dose operations allow BMS to manufacture Long Term Stability batches to aid in product scale-up and technical transfer to commercial manufacturing sites with batch sizes at least one-tenth of commercial scale.

The Product Technology Center is the first clinical facility to utilize continuous process sterile isolators, representing a significant advancement in integrating technology into drug development.

Collaboration a key to success
The need to coordinate and manage multiple disciplines was a key element of the BMS expansion project. Flexible, adaptable design, critical construction scheduling and tight budget management were imperative to the project’s success.

To accomplish a project of this magnitude, BMS called upon unique process and facilities engineering and construction talent. For project design development, master planning, construction documentation and administrative services, the company turned to IPS Incorporated, Lafayette Hill, Pennsylvania, a leader in the design of pharmaceutical manufacturing facilities.

In addition to the Facility of the Year Award, BMS was recognized with federal and state government health and safety awards throughout the project. Included among these was the OSHA Voluntary Protection Program Star Demonstration Site award for outstanding safety and health management.

Enhanced speed–to–market is among the many benefits BMS expects to derive from its new facilities. But increased capacity and technical innovation will also help the company meet vital future pharmaceutical development and pipeline needs of medical service providers and patients worldwide.

Sustainable Design and Green Building Tips for Biotech and Pharmaceutical Projects

Sustainable design and green building are becoming major factors in project development. While sustainable design does not necessarily have to cost more, it does involve a bit of planning to ensure it adds value. Whether the request comes from a client, or is simply a practice you would like to implement in your projects, there are a range of steps that can be taken, from very small to very large, to contribute to sustainable design. Below are several tips to serve as a guide during the design/build stages of biotech and pharmaceutical projects to contribute to sustainability.

• Plan Early to Establish Green Goals for your Project.
  The earlier you decide to build green, the more opportunities there are to incorporate cost-efficient sustainable solutions into the design. Having a plan will guide the project team in making decisions and provide an easy way to achieve the company’s environmental goals and budget.



• Utilize the LEED® Score Card as a Guide.
  Whether you choose to certify your project or not, utilize the USGBC LEED score card to help establish baseline sustainability goals. The LEED guidelines are a great brainstorming tool and will stimulate the innovation process.



• Utilize Life–Cycle–Costing to Establish “Go/No Go” Hurdle Rates for Sustainable Options.
  For many projects first cost is very important, but being sustainable isn’t about the short-term. It’s about taking a long-term or a life cycle view.



• Site Building for Optimum Energy Performance.
  Utilize the site orientation to take advantage of passive solar energy savings and natural day-lighting.



• Consider an Energy Star Roof.
  Utilize a light color (white) roof to reduce heat gain to the built environment. Dark roofs can be 60% hotter than lighter color roofs and impact the selection of HVAC equipment required to cool the structure.



• Utilize Low-E Glazed Windows.
  Utilize low-E (emissivity) glass. Many manufacturers offer high-performance glazing systems. This higher efficiency glazing reflects more heat and at the same time allows more light to enter the structure. This improves opportunities for natural lighting and ultimately reduces the solar heat gain.



• Optimize Lighting.
  Utilize compact fluorescent and LED lighting to reduce the heat out put and improved efficiency. Take advantage of daylight harvesting. Consider occupancy sensors, and dimming ballasts.



• Utilize High Efficiency Motors and Variable Frequency Drives (VFD’s).
  EPA Studies have shown that VFD’s can save as much as 50% when compared to systems without them.



• Utilize Waterless Urinals and Low-Flow Plumbing Fixtures.
  On average an employee uses approximately 10 gallons of water a day. Green plumbing systems can reduce this to 2.5 gallons a day.



• Specify Recycled Content.
  Many manufacturers utilize recycled materials to reduce overall cost of raw material. There are a wide variety of products available. Incorporate a minimum % of recycled material in product specifications.

Smooth startups start with good commissioning practices

From a strategic perspective, you could say that a pharmaceutical processor’s skill at quickly expanding facilities in response to changing product, market and regulatory needs ranks right alongside research and scientific prowess.

A key factor in bringing new facilities online is commissioning, a function often misunderstood and poorly managed. Commissioning plays an invaluable role in the plant startup process by ensuring that all equipment and systems are designed, installed, tested, and fully operational in accordance with the owner’s design intent.

Commissioning covers all planning, documentation, equipment balancing, calibration and control, performance qualification and other procedures leading up to startup and turnover. Other key elements include operator training and spare parts programs.

A well planned commissioning program will:

• Accelerate project startup


• Produce superior documentation


• Improve online time


• Create a positive commercial impact


• Reduce validation effort


• Ensure a GMP-compliant facility

Though actual practices sometimes vary by project, the Commissioning Master Plan (CMP) is the nexus of an effective commissioning program. It coordinates interaction between contractors, material and equipment suppliers, and internal personnel.

In addition to road-mapping a project, the Commissioning Master Plan assigns team responsibilities and expectations to vendors, monitors performance, and establishes a basis for corrective actions needed to ensure the integrity and success of the project.

In pharmaceutical operations requiring cGMP-compliance, critical utilities and process systems must also undergo validation to satisfy FDA requirements. Occasionally, confusion arises over these terms. But, in a nutshell, all facilities must be commissioned, while only those with cGMP-critical systems undergo validation.

For GMP-compliant plants, Installation Qualification (IQ), Operation Qualification (OQ) and Performance Qualification (PQ) steps are prerequisites for validation, and monitor the following functions:

• IQ ensures installation of the proper equipment


• OQ ensures that equipment and systems operate as required, producing consistent outputs


• PQ ensures that equipment and systems perform to spec and meet process requirements

Risk management-based qualification, espoused by the FDA and incorporated into the ISPE Baseline Commissioning and Qualification Guide, empowers owners to focus primary quality and regulatory efforts on those critical design features and processes that directly impact product and patient safety. This approach ensures that all functions performed by design/contractor teams and vendors meet prescribed quality standards without overlapping or duplicating efforts. By effectively leveraging commissioning practices, owners minimize documentation and redundancy, while reducing qualification/validation time and startup costs.

From a budgetary standpoint, commissioning costs add up to a significant capital outlay, and are frequently underestimated or overlooked. Costs vary greatly according to a project’s scope, complexity and regulatory compliance factors. But it’s important for owners to properly plan and budget for all commissioning-related functions, including: planning, administration, analysis, progress monitoring and reporting.

Another decisive factor in minimizing problems during commissioning and start-up is knowing when and how to work effectively with outside vendors. Pharmaceutical plants comprise a vast network of complex equipment and infrastructure, with few owners experienced in managing renovation and expansion projects of such magnitude. As a result, many are out of their element when faced with such challenges.

To further complicate matters, cost-saving measures, like outsourcing plant engineering, maintenance and operations functions, have drained specialized technical skills from many companies.

As a result, owners could be forced to rely on untested outside contractors to manage critical commissioning and startup operations. In the absence of knowledgeable and experienced oversight, such a massive coordination effort could easily lead to planning and construction errors and delays that eat up capital, delay startup and ultimately slow a product’s speed-to-market.

For best results when establishing design/build partnerships for facility commissioning and startup, it’s important to consider a vendor’s overall project management expertise in conjunction with a high degree of technical know-how.

Finally, by integrating good commissioning practices early in the planning and design process, owners make an investment that pays dividends in time and capital savings, and supports the strategic objectives of the enterprise.

Proper planning prevents poor performance

A growing number of biotech processors are finding wisdom in this axiom taken from an old British Army training manual. They’re recognizing the many benefits of developing third-party engineering partnerships, and integrating them early-on in the master planning process; ideally, at a project’s inception stage.

Pharmaceutical processors operate in a unique environment influenced by many variables, including: capital availability, diverse market demands, complex regulatory standards, global competition, and critical compliance and commissioning requirements. As a result, they must focus assets to best achieve a competitive advantage through innovation coupled with effective cost control and speed-to-market strategies. Accomplishing that requires the highest degree of process/facility design integration driven by comprehensive master planning.

In the traditional process design model, in-house engineers and planners develop a strategic plan and define a project’s parameters. Then, independent engineering and construction specialists are called in to formalize the design and help execute the plan. But there are flaws in that approach which might seriously impact a project’s potential for successful execution.

For starters, internal, organizational dynamics can inhibit objectivity essential to developing plans and processes that support corporate-wide initiatives. To address this, master planners must rise above territorial boundaries and stay focused on key goals. In some corporate cultures, that could present political challenges for internal managers.

In addition, corporate management runs the risk of limiting creative resources at a point where innovation is most critical, during a project’s formative stage. Experience shows that incorrect assumptions made in early planning often lead to costly revisions and construction delays later in a project’s timeline.

Commercial processors who integrate design/build partnerships early in the master planning process report significant, measurable payback for their efforts. In addition to minimizing risks, alliances can help reduce capital outlay and project delays, and cut validation and commissioning costs. These advantages go a long way toward improving a processor’s ability to compete in the fast-paced, changing pharmaceutical marketplace.

For optimum results, a master plan must be aligned with a company’s strategic business goals; and the planning process should involve high level decision-makers within the organization. Management participation is essential to ensure that a master plan supports the new product pipeline, planned acquisitions, cash flow considerations and other strategic issues.

Of course, the real value of planning partnerships ultimately depends on a vendor’s knowledge and understanding of the unique character of the pharmaceutical industry. This means having the expertise and resources for dealing with virtually any facet of the business, from product development and production through quality assurance, packaging and delivery.

When evaluating a design/build partner for master planning, clients should look for comprehensive pharmaceutical experience, preferably on the corporate side. Qualified candidates should demonstrate global vision, along with a track record of providing services to technically complex, compliance-driven industries. Longevity of client relationships is another indicator of a vendor’s stability and capacity to successfully handle challenges, and deliver sound planning solutions to satisfy the needs of all stakeholders within an organization.

Taking the human factor out of aseptic processing

On average, we humans shed up to 10 million particles of dead skin and other microbial contaminants each day, making us the greatest threat to most high-purity manufacturing operations.

Since the 1970’s, clean rooms have served as a first line of defense in the pharmaceutical industry’s war against microbial contamination. To meet aseptic processing standards, clean rooms rely on specialized HVAC air handling systems, sophisticated HEPA and other filtration devices, and rigorous decontamination practices. Protecting operators from the product (and vice-versa) requires sterile clothing and time-consuming gowning procedures whenever personnel enter or leave a classified area. In addition to increasing operating costs, these factors can disrupt productivity and adversely affect a drug’s speed-to-market.

Moreover, FDA mandates that a Class 100 (ISO 5) clean room be housed in Class 1000 (ISO 7) surrounding support spaces. This increases capital outlay, along with plant footprint and operating costs. As a result, many are exploring more effective options to ensure product purity by minimizing human intervention.

Remote Access Barrier Systems (RABS); these protect operators and product by placing an aseptic filler inside a rigid-walled ISO 5 enclosure. HEPA-filtered unidirectional airflow provides an aerodynamic barrier to shield the critical process zone inside the RABS. While glove ports are employed to facilitate operator access, a RABS enclosure can also be opened for operations that cannot be performed through the glove port. Typically, RABS can be located in an ISO 7 or lower environment.

Though lower in cost than other options, like isolators, RABS are not airtight so they present some risk of contamination due to operator contact and open-door access. In addition, RABS systems need to be disinfected manually, which requires environmental monitoring of the cleaning process, placement and reassembly of sterile components. RABS are used in pharmaceutical processing, and even more widely in food and beverage applications.

Isolator systems; an isolator as defined by FDA is a decontaminated unit, supplied with Class 100 (ISO 5) or higher air quality that provides uncompromised, continuous isolation of its interior from the external environment (surrounding clean room air and personnel).

Isolators completely remove operators from the sterile area and incorporate a physical barrier along with HEPA-filtered positive airflow to seal out particulate contamination. These systems have already been proven effective in many bio-processing applications in the United States, Japan, China, India and Europe.

Initially, isolators had a reputation for high capital cost and long decontamination times. But with today’s pharmaceuticals costing as much as $1000 or more per dose, the economic picture has changed. Improvements in product throughput and speed-to-market easily offset isolator upfront costs, enhancing ROI. Consistently high sterility and safety help minimize product waste due to contamination, and reduce the risk of product recalls.

Vaporized hydrogen peroxide (VHP) cleaning/sterilization in-place (CIP/SIP) eliminates the need to dismantle, sterilize and reassemble components, and minimizes environmental monitoring requirements. As a result, decontamination cycle times can be cut to about three hours. Moreover, validated VHP sterilization is recognized by the FDA as more effective and reproducible than manual sanitation.

Since isolator systems fit into a small footprint, users are finding greater flexibility in designing critical process lines to accommodate their product development and manufacturing needs. Each module contains an interlock port for connecting to other components, so isolators may be added, deleted or combined as a user’s process evolves.

Looking to the future, as experience builds greater confidence in isolator systems, pharmaceutical and biotech manufacturers will see even more technological advancements. Currently, innovators are exploring ways to expand the use of automation and robotics for enhanced product safety, productivity and reliability. Some even envision a future in which human operators could be completely eliminated from the aseptic process.

It all started with the ancient Greeks

According to Greek mythology, scientific pharmaceutical compounding was first practiced in Greece around the seventh century BC. Pioneering the field was the goddess Hygieia, revered for her powers over health, cleanliness and sanitation, who also happened to be the granddaughter of the god, Apollo.

As the story goes, her physician father, Asklepios (Asclepius) Giver of Health, enlisted Hygieia’s aid to compound his medicines and various remedies. Hygieia also was credited with advancing early healthcare and medical hygiene; in fact, the term “hygiene” evolved directly from her name. The serpent often depicted in images of her is represented in the Rod of Asclepius, now a symbol of the American Medical Association and many other healing organizations, worldwide.

Of course, early pharmaceutical formulators didn’t have to reckon with global competition and economics, regulatory compliance and other issues we face today. They simply pressed their leaves, herbs or other raw materials into a solution, administered it, and hoped the patient survived.

But in the market-driven twenty first century, things are far more complex. To succeed, biotech innovators must address commercial as well as scientific elements of their business. As a result they must continually strive to reduce capital costs, manufacturing and operating expenses, and regulatory risks associated with bringing new products to market. Going forward, they also need to position themselves to quickly respond to the ever-changing future capacity and technology requirements of their industry.

With all of these strategic and technical considerations, it’s easy to see how the scientific side of pharmaceutical innovation has become just one facet of what began centuries ago in Hygieia’s primitive mortar and pestle.

A few thoughts on how bioprocessors can achieve their 21st century profitability and production goals:

• Single-use disposable technology; this emerging alternative enables processors to replace stainless steel vessels and piping with pre-sterilized, disposable plastic bags. These eliminate vessel cleaning and cleaning validation, along with the time and utility costs associated with these functions. Disposable technology also minimizes risk of product cross-contamination, improves process flexibility, reduces manufacturing space requirements and helps expedite product delivery to market.



• Optimizing gray space; many processors are reducing overhead through more flexible usage of costly clean room spaces. Repositioning closed equipment to less expensive unclassified spaces where it can be linked to clean areas for sampling, cuts down on the amount of clean room space needed, and helps reduce capital and operating expenditures.



• Modular fabrication; biotech manufacturers are discovering more ways to save time and capital by having critical process components and systems fabricated off-site for re-assembly in the plant. This has been used cost-effectively in assembling bioreactors, cell culture, buffer prep and hold, and clean-in-place systems, and can be easily implemented by coordinating system engineering details early-on in the fabrication process.



• Computer modeling; many drug producers are turning to early computer modeling of processes to isolate operating error at the source, improve product throughput and reduce cost of quality. This approach involves designing process configurations and operating parameters to meet commercial manufacturing and quality requirements, rather than strictly adhering to lab-based science and technology considerations. As an example, selecting buffers for compatibility with in-line dilution systems can virtually eliminate the need for large, fixed buffer vessels. In addition to enhancing product speed-to-market, this improves plant flexibility and cuts operating costs. In addition, Building Information Modeling, or BIM, is an innovative technique that facilitates seamless communications within architecture, engineering and construction. It represents a new way of working on projects that allows coordinated, consistent information for faster decision-making; provides better documentation at all levels, from concept to construction documentation; and enables modeled simulations that make it possible to predict performance before the project is constructed.



• Risk-based commissioning and validation; this concept makes validation members an integral part of the facility’s design team from the outset. In addition to facilitating regulatory compliance, the risk-based approach helps eliminate counter-productive duplication of effort while reducing validation time and expense.



• Sterile Finishing / Filling; Isolators increasingly make sense in biotech filling and finishing suites because the value of biologics per unit weight/ volume is so high.

Looking to the future, biotech processors need to recognize that successful design, construction and qualification of a facility are driven not so much by science, but by many implementation issues like the ones outlined here. This underscores the importance of building strategic partnerships with vendors and consultants who fully understand a processor’s economic, technical and scientific objectives, share in their corporate values, and have the tools and expertise to turn their visions into reality.