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Tim Roach is senior director of plant engineering at Recro Gainesville.
Careful design, planning, and record keeping are needed for cleaning and changeover in multiproduct pharmaceutical facilities.
Fixed, single-product pharmaceutical factories dedicated to a handful of blockbusters are rapidly becoming a thing of the past. Short timelines, expedited programs, a wide array of increasingly complex therapies, and frequent changeovers between small batches targeting rare diseases place flexible, highly efficient manufacturing plants in high demand.
Today’s drug manufacturers-particularly contract development and manufacturing organizations (CDMOs)-must be agile and adaptable. However, operations in modern, multiproduct facilities are complex and must be carefully laid out and orchestrated for optimal results. This article includes some best practices and considerations for the design and operation of multiproduct pharmaceutical manufacturing facilities.
In multiproduct facilities, minimizing changeover time between products and zero-defect cleaning are key. Changeover speed is a crucial factor that directly affects capacity utilization, profitability, and timely batch production.
A room or suite clean-out entails washing down and wiping down from ceiling to floor. Therefore, ensure rooms are designed with ready access to all surfaces. Smooth, slick, and sloping surfaces are ideal for quick and easy cleaning. Avoid architectural ledges and grooves. Cabinets should be sloped as well or, better yet, recessed into walls.
Ensure all conduits and piping are contained within the walls. Recess utilities such as electrical, cooling water, compressed air, and steam outlets, or even seal them off when not in use, to eliminate the need for cleaning.
As for equipment, choose automated options such as clean-in-place (CIP). Not only are automated processes more reliable and consistent than manual processes, but their associated documentation is helpful for proving this reliability to regulatory authorities.
Select equipment designed for fast and easy maintenance. Personnel should be able to perform the maintenance routine with the apparatus in place, with minimal teardown. Ideally, one should be able to complete this task during the standard changeover time.
Every cleaning or maintenance process needs a standard operating procedure as well as documentation for every time it is executed. For cleaning automated processing equipment, the record may be an electronic document download. Otherwise, it is often a notation in a tightly controlled logbook associated with that particular device.
Keep careful records for cleaning rooms. In addition to documenting actual cleaning procedures, record all loose items that enter the room on an accountability sheet. Remove every one of these mobile objects for cleaning or disposal elsewhere before stationary equipment is opened. This practice avoids exterior contamination of mobile equipment and prevents contaminants from being introduced into the stationary equipment.
Improper tracking of cleaning supplies can lead to the delayed discovery of unfortunate errors, so always be mindful that equipment is vulnerable when open. This became apparent to one API manufacturer who discovered a cleaning wipe left in a centrifuge charge chute (but not until the first batch after cleaning had been processed), leading to the batch’s rejection. Counting the wipes brought into the processing room and verifying that the same number of wipes were removed would have prevented the loss.
The choice of cleaning implements and agents is important. Sometimes, a simple oversight in this area can compromise a batch. For instance, select only non-shedding sponges and rags to wipe down equipment, or they may leave particles behind.
When changing a cleaning process, always consult the proper stakeholders and documentation to ensure your new procedure is compatible with the equipment. In one case, to achieve cleaning validation, a team switched from a detergent to a solvent-based cleaning solution. Thereafter, in a pre-run inspection, black flakes were discovered around a cover. It turned out that the equipment seals were susceptible to deterioration by the solvent. Fortunately, this problem could be solved by replacing all the seals with a higher-grade material.
At multiproduct facilities, regulatory inspectors are particularly focused on verifying the adequacy of cleaning and on the prevention of cross-contamination. CIP equipment used for CIP or wash-in-place (WIP) processes goes far to prevent the transfer of material from one batch to the next.
CIP refers to equipment designed so it can be cleaned without being opened. The benefit is speed, convenience, and the avoidance of content being transferred to nearby surfaces or into the air. Such devices have automated cleaning cycles with ports for flushing and require no disassembly. In contrast, non-CIP equipment needs to be torn down with all parts washed separately. This process is extremely time consuming and also raises the possibilities of cross-contamination and operator exposure. As an example, compared with a standard fluid bed dryer, one with well-designed CIP features can reduce changeover times from 12 hours to less than three, with minimal manual breakdown and inspection needed.
One caveat is that, despite the potential benefits of CIP designs, whether a machine can be validated in CIP mode can vary from substance to substance. While some materials are easy to wash away, other materials may be too hard to clean from CIP equipment to pass validation. Similarly, equipment with convoluted surfaces, such as mixers, may be harder to clean. Achieving validation in these situations may require that the CIP equipment be opened and re-cleaned manually as a final step in what is then termed a WIP cleaning process.
While more time-consuming than CIP, WIP is still faster and better at preventing cross-contamination than standard manual cleaning. After the automated cleaning process, it may be just one focal area that needs to be manually cleaned to achieve validation, and the concern of disseminating contaminants has been eliminated by the wash cycle that is run before the machine is opened for its final cleaning step.
Heating, ventilation, and air conditioning (HVAC) design and operation are crucial in multiproduct facilities to control the flow of air and prevent aerosolized products from being disseminated throughout. First, prevent aerosolized materials from leaving production or entry/gowning areas and contaminating the rest of the facility by implementing corridor air-handler systems that maintain air-pressure cascades. To accomplish this goal, always keep corridor air pressure slightly higher than adjacent rooms and airlocks. Equip each production area with a single-pass system that imports 100% outside air. Not only incoming air but also outgoing air must pass through high-efficiency particulate arrestance (HEPA) filters to avoid contaminating ductwork. Replace prefilters for exiting air with every product change to keep material on the filter from re-entering the room during manufacture of the next product. The right HVAC system not only provides for personnel and product safety but also for the successful operation of a multiproduct manufacturing facility.
Each step of the cleaning/changeover process offers opportunities to minimize the risk of cross-contamination. Here are some best practices:
Single-use systems (SUS) may make sense for smaller solid dosage manufacturing batch processes such as material handling and storage (bags instead of bulk containers). The efficiency requirements for research and development, for example, differ from those for large-scale manufacturing. In general, SUS offer the greatest efficiencies at R&D scale, where fewer total batches are required and cleaning methods may not be fully developed, while non-disposable (stainless-steel) components are more practical for commercial-scale manufacturing where cleaning has been validated.
Often in R&D, with a few small batches under 50 kg, no validated cleaning method exists. Time is of the essence, and cleaning validation/verification on a typical weigh-dispense isolator can take 60 to 80 hours between protocol generation, sampling, testing, and review and approval of results. In these cases, SUS are a simple, rapid means of proving equipment is clean. For example, a plastic bag could be used to transport material to a tablet press. The tote would not need to be cleaned, and scoops and other utensils can be disposable. If the batch is under 100 kg, it could even be mixed in a disposable bag.
On the other hand, in commercial solid-dosage operations with many large batches, SUS are generally impractical and not cost-effective. By the time a process has reached this stage, the CMO has usually validated a cleaning method for stainless-steel equipment. Furthermore, large single-use components are costly and would be needed in significant numbers for the many batches being run. In these situations, cleaning validation is worthwhile and stainless-steel components are often the best choice.
At multiproduct facilities, regulatory inspectors are particularly focused on verifying the adequacy of cleaning and on the prevention of cross-contamination. A facility carefully designed for multiproduct use, with easy-to-clean work areas and equipment as described above, along with appropriate cleaning validation reports, will reassure inspectors. Fundamentally, it must be shown that a cleaning procedure removed all but “an acceptable level” of the product in three out of three tests. Proper good manufacturing practice documentation is essential for approval and traceability. Knowledgeable personnel should be monitoring operations closely to guarantee compliance.
Facilities flexible enough to manufacture multiple products have become a cornerstone of the pharmaceutical industry, crucial for meeting changing market and regulatory expectations. With careful planning, they can be extremely efficient and eliminate the need to build new facilities for every new drug product. Multiproduct manufacturing allows even for drugs needed in small quantities, such as orphan drugs, to be manufactured cost-effectively.
Numerous considerations must factor into the design, equipment, and operation of these facilities, which require more space and different architecture than traditional pharmaceutical manufacturing plants. Overall, these best practices apply:
When investing in pharmaceutical products that can change lives, comprehensive, regulatory-compliant processes must be defined and adhered to for optimal operations in multiproduct facilities. No matter the phase of your project, be diligent to choose a CDMO partner that exceeds your expectations with facilities expertly designed and operated to ensure flexibility, efficiency, safety, and regulatory compliance for your products.
Tim Roach is senior director of plant engineering at Recro Gainesville.
Vol. 44, No. 2
When referring to this article, please cite it as T. Roach, “Best Practices for Design and Operation of Multiproduct Manufacturing Facilities,” Pharmaceutical Technology 44 (2) 2020.