The start-up of a biopharmaceutical facility, in three acts
“Great is the art of beginning, but greater the art is of ending.” —Longfellow
 By Lauren Jean Knepley |
null
The start-up of any manufacturing facility is a complex and multileveled undertaking; however, the start up of a biopharmaceutical facility presents unique challenges beyond even the standard considerations of bringing a regulated facility to production.
It's imperative to keep in mind that there's one key organizing principle that must govern the entire process: Time-to-market is the key to success. This principal should become the touchstone for start-up decision-making as the process unfolds. The project must be staffed, planned and funded to optimize the regulatory, quality and financial aspects of the project so that the timetable can be met.
If these factors can be kept in balance, the likelihood of a successful start-up is probable. With this in mind, it's vital to be artful in the beginning of the project with careful organization and planning, but it is even more important to bring successful closure to the start-up in a timely way.
Staffing for success
Staffing is critical to the success of any endeavor, even though it may seem outdated in the age of systems and automation. Today, it's never been truer: The right people can often mean the difference between success and failure.
Every start-up should begin with a professional project manager (PM). It should be a seasoned professional, knowledgeable in biopharmaceuticals and experienced in start-up. This key player's sole responsibility will be to bring the facility up on time.
The PM cannot have dual responsibilities or any other responsibility that dilutes his/her focus from the task at hand, nor can this person be a newcomer to the industry or a newcomer to the process.
It must be someone who can be trusted to balance regulatory perspective, quality concerns, operating realities and financial considerations to make intelligent and timely decisions; otherwise, it's likely that the whole process can be mired in indecision.
The choice of a qualified PM will be the most important decision and the best value that you have in the project.
The project manager will oversee a start-up team that includes representatives from Regulatory Affairs, Quality Systems, Operations, Laboratories, Engineering and Validation. Successful start-up depends on the simultaneous and integrated activities of all these vital areas (Figure 1). They form an intricate system of interdependencies that must all be coordinated by the project manager to optimize time and resources.
For example, validation cannot happen unless it is clear from the regulatory submission what acceptance criteria should be established, unless Quality Systems has developed and implemented the document system and standard operating procedures (SOPs) have been written and approved, unless qualified personnel have been hired and trained, unless laboratory support is in place with validated methods and equipment, and unless all systems and equipment are commissioned and devices calibrated and maintained.
null
All of these things must happen at the right time and in the right order—that's where careful planning comes in.
All the planning for start-up is predicated on the assumption that the facility has been designed and constructed according to the principles of Good Engineering Practice, and that a User Requirements Specification and a Functional Design document have been developed and followed in the design of the facility.
Planning principles
The User Requirements document reflects the demands of the process as well as the regulatory commitments of all filings, production objectives, and financial considerations and constraints. This vital document forms the basis for all commissioning and validation that follows.
The Functional Design document translates those needs into a Facility Plan. Without these documents, there is nothing to verify against.
The key start-up planning document is the Master Schedule. This is analyzed and managed by the PM in concert with each of the major responsibility areas and will incorporate schedules prepared by each of these managers. This schedule can easily run to several thousand lines, and its value lies in the ability to define and track all the necessary tasks, as well as to graphically illustrate the dependencies between the various disciplines.
The schedule should be built by beginning with the agreed upon end date. This is where the art of ending becomes paramount in the process.
To achieve that launch date, tasks, resources and budget have to be allocated in the schedule, and it will become immediately apparent where the weaknesses, stumbling blocks and outright impossibilities exist. Balancing costs versus time-to-launch becomes the key metric.
The next level of critical documents includes, but is certainly not limited to, a Regulatory Strategy and Master Policies, including a Master Quality Policy and Master Validation Policy. They should include a number of plans, including a Quality Plan, a Commissioning Master Plan, a Validation Master Plan, a Document Control Plan, Cleaning and Sanitization Plan and an Environmental Control Plan.
The Environmental Control Plan is included at this juncture because environmental control and monitoring is even more critical in a biopharm operation than in a pharma operation. In a biopharmaceutical facility, you are making the active ingredient, and contamination of any intermediate destroys the whole batch. These systems consist of closed, sterilized tanks, piping, etc.
Cleaning must be fastidious inside and out. An environmental contaminant left over and not destroyed by the sterilization process means certainly at least one lost batch. The results of a wild contaminant are unpredictable, affecting not only yield but the next cleaning operation. Personnel flow, setup of gown areas, filtration operations and ion exchange columns all must be properly maintained without question.
In these operations, it's also often necessary to maintain virus control. This is particularly true if there's a blood product involved as an ingredient, intermediary or as the final product. Viral inactivation may be all-important.
Serum—particularly bovine—is somtimes used as part of the culture media, which brings in another cleaning challenge in addition to the sourcing concerns because of Bovine Spongiform Encephalitis (BSE). Many of these concerns should have been reflected in the User Requirements Specification and addressed through careful design, since biopharmaceutical operations have to be acutely aware of the cleanability of process areas. It will take a Herculean effort to succeed in environmental control if the facility design does not incorporate the specific needs of biopharmaceuticals.
One other class of documents worthy of special note is that of standard operating procedures (SOPs). At a minimum, about 400 SOPs must be in place in order to start up a biopharmaceutical facility. This covers SOPs for operations, maintenance laboratory, quality assurance, regulatory, warehousing, shipping and storage. The SOPs must be written by knowledgeable staff that are familiar with the equipment and the process. Yet, to develop these documents, this staff must be hired long before it's time to produce product. Ensuring that these documents are in place while preserving the budget is a delicate balancing act for the PM.
Budget strategies
Creation of a realistic Master Schedule should help produce a reasonably accurate price for the cost of the start-up, to which, of course, a percentage must be added for the inevitable contingencies.
This number must then be compared with the actual budget allotted for the project and a final number must be reached. Good project management will help to control costs by eliminating inefficiencies and maintaining the schedule. A sound regulatory strategy is also vital.
One element of particular importance in bringing the physical facility online is commissioning. It has been included as a budget consideration because the responsibility and the cost for these activities should lie principally with the vendor of the system or equipment. And because, done correctly, commissioning has the potential to significantly reduce the cost and the timeline for validation. Discerning and delineating what must be validated and what must only be commissioned can also have a positive impact on the budget.
As the owner, you may want to create the commissioning documents or pre-approve those submitted by the vendor. It's important to remember that commissioning is the controlled start-up and preliminary engineering assessment of facilities, utility systems and equipment in preparation for validation. Commissioning is a pre-qualification exercise designed to ensure that the system has been designed, installed, functionally tested, and capable of operating in conformance with design specifications and user requirements.
Commissioning typically occurs once the system is physically located, and includes: documentation, start-up, calibration, functional testing, tuning or balancing, and turnover. It does not substitute for validation; in fact, validation is a confirmation that commissioning has been successfully completed. Checks conducted and appropriately documented, however, may be used to support validation.
Final thoughts
It would be impossible to overemphasize that the seeds to the success for start-up of any pharmaceutical facility, but particularly for a biopharmaceutical facility, are sown in the development of the User Requirements Specification and the proper design of the facility. Given that basis, a knowledgeable, experienced PM who understands the central importance of time-to-market can orchestrate a start-up with both a beginning and an ending.
Lauren Jean Knepley is general manager at Vectech Pharmaceutical Consultants Inc. (Farmington Hills, Mich.). She can be reached at [email protected]