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.

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.