May 29, 2018 PAP-Q2-18-CL-012
Every pharmaceutical manufacturing facility design must meet the regulatory requirements for the regions of the world where the products will be sold. All international regulatory bodies focus on product quality via Good Manufacturing Practice (GMP) regulations. In the U.S., regulations on current good manufacturing practices (cGMPs) for drug products are outlined in CFR Title 21 Parts 210 and 211.1 In Europe, good manufacturing practices for medicinal products for human and veterinary use are covered in volume 4 of EudraLex.2 Most other regulatory bodies around the world have requirements that are similar to those established by the U.S. FDA and European Medicines Agency. PIC/S (Pharmaceutical Inspection Co-operation Scheme) is a nonbinding, informal cooperative arrangement between regulatory authorities in the field of GMP. It is presently comprised of 52 participating authorities from all over the world (Europe, Africa, America, Asia and Australasia), with the aim to harmonize inspection procedures worldwide by developing common standards in the field of GMP.
The primary focus of the regulatory requirements is protecting the drug product and ensuring the highest levels of product quality. They are intended to ensure that any opportunities for cross contamination and product mix-ups are minimized. Best practice is to consider the specific needs for each OSD facility and the processes that will be performed therein. Appropriate product protection measures can then be designed into the facility, equipment and processes early in the facility design phase.
Before you can actually embark on the design of an OSD facility, it is important to determine the processing requirements and the desired output capacity (or scale) of the desired facility. A general rule of thumb for scale is that small is <1 billion units, medium is 1–4 billion units, and large is >4–5 billion units per year. The product mix must also be understood. Whether a facility will be producing a single product or multiple products will have a significant impact on the design of the plant and the choice of equipment. The opportunities for cross contamination and product mix-ups increase dramatically when multiple products are produced concurrently. The design elements of the facility can offer the added protection and control that are necessary here.
For typical OSD manufacturing operations, three primary process platforms are used: direct compression, dry granulation and wet granulation. Each involves a series of unit operations, equipment configurations and subprocesses that increase in complexity.
For example, in direct compression, the API and other dry powder formulation ingredients are basically blended into a homogenous mixture and then compressed into tablets. The main unit operations include weigh/dispense, blend and compress; these are the simplest platforms.
Granulation (dry or wet) is used when the formulation is not conducive to direct compression. Perhaps the particle characteristics, such as bulk density, particle size, flowability, etc., of the ingredients are too varied to allow for effective mixing and compressibility without some form of additional processing. Dry granulation is achieved, for instance, via roller compaction, which incorporates a shearing mechanism to alter the characteristics of the particles — aimed at creating a compressible mixture. Wet granulation involves adding a liquid to the powders. Wet granulation can be subcategorized further into low shear or high shear based on the type of granulator and process operation needed to develop the appropriate particle characteristics. The added liquid must then be removed using some type of drying process. As a result, wet granulation is the most complex process, requiring the most pieces of equipment and the greatest number of unit operations. The main unit operations include weigh/dispense, sizing/sifting, granulation, drying, blend and compress.
The size and design of the facility is heavily dependent on the processes needed and the processing platforms incorporated — in many cases, it may be one, two or all three in the requirement mix.
Subpart C of 21 CFR, Part 211 is the key FDA guidance for pharmaceutical buildings and facilities. Part 211.42 relates to design and construction features. This section states that buildings for pharmaceutical manufacturing must have adequate space to allow for proper flow of materials and operations, such that contamination and mix-ups are prevented.3 When designing new OSD facilities, “right-sizing” and “process flow” are two essential elements to address.
The GMP spaces within a facility, where products are in-process of manufacture and/or open to the environment, are the most expensive spaces in a facility both to build and to operate. Cleanable surface finishes, temperature and humidity control, air filtration, monitoring, lighting and containment aspects are among the key considerations for the design engineer. Oversizing a room leads to greater energy consumption, the need for more cleaning and additional costs.
In today’s modern facilities there is a trend to minimize square footage and maximize efficiency. As examples, blending rooms used to be as big as 20’x20’. Today they are typically 10’x10’ with the control room for the bin blender outside of the room. Similarly, modern compression rooms have separate control rooms that can be used to operate multiple compression suites with much greater efficiency.
Personnel, product, material and waste flows are also a key element of OSD facility design, with the goal of a unidirectional flow path without backtracking. Materials should move from the warehouse to the various unit ops in a process-sequential fashion (e.g., weigh/dispense to blending, granulation, compression, coating, packaging and, ultimately, back to the warehouse as finished product). This approach not only is more efficient but also by preventing backtracking, minimizes the risk of cross contamination and product mix-up.
All CRB warehouses are designed with overall efficiency in mind. The organization of the warehouse takes into consideration material flows, which start in shipping and receiving. Materials used in manufacturing processes are placed in a holding area until they can be sampled. Once it is assured that they meet quality specifications, they are moved to an area for materials that are ready for use.
In an attempt to allow manufacturers a bit more freedom in their design and operational approaches, modern guides — such as the International Society for Pharmaceutical Engineering’s OSD Baseline Guide, third edition, released in November 2016 — use a level of protection scheme based on risk assessment and mitigation of risks. It defines a matrix used for cGMP spaces that identifies three levels of protection centering on in-process materials: being open (white, Level 3), partially open (gray, Level 2) or closed (black, Level 1) to the environment and the operation.
When the process is always closed and the operation is not open to the environment, fewer controls (temperature, humidity control and uniforms) are needed to reduce the risk of contamination. In partially open systems, there is some risk of exposure, but it is typically minimal. A few additional control measures are needed, such as air filtration and overgowning. In open systems, the material is exposed to the environment and operators, and therefore a higher level of control measures is needed to minimize the likelihood of contamination. Examples include more extensive air filtration, unidirectional air flows, engineering controls and containment equipment. These areas may also be segregated with separate HVAC and air systems, as well as gowning/degowning stations.
Equipment for OSD manufacturing must be designed, sized and constructed in a fashion that is cleanable. No aspects of the equipment should provide opportunities for contamination. While much of the equipment used for OSD manufacturing has not changed extensively during the last 30 years (except with regard to equipment designed for continuous manufacturing), there have been a number of noteworthy advances.
First, OSD production equipment is now designed to be ergonomic and user-friendly. Operators today rarely climb ladders to manually feed ingredients into a process system. Instead, column lifts, manipulators and automated feed systems are employed. These automated systems minimize operator interactions with processes, reducing the potential for errors and improving the containment of OSD processes. Downflow booths, glove box isolators and split butterfly valves are additional examples of containment technologies being employed.
Second, present-day equipment is generally provided with some configuration for clean-in-place or wash-in-place capabilities via semi- to fully automated operations. Several pieces of OSD equipment no longer need to be taken apart and manually cleaned. Equipment suppliers are also working to reduce the number of components that need to be cleaned to offer further improvement.
At CRB, we specialize in providing integrated solutions. This has been our guiding force for the last 30+ years, as we have become one of the leading design and construction firms worldwide. We employ quality, honesty and technical excellence in all that we do, from the design of oral solid dose facilities and beyond, to provide best-in-class engineering from start to finish.
Dave DiProspero has 25+ years of pharmaceutical engineering experience in internationally regulated Oral Solid Dose Form manufacturing operations. He has worked as an owner's representative and as a direct employee for well-known equipment/technology suppliers and engineering firms. As an Associate/Director of Pharmaceutical Process Technology for CRB-Philadelphia, Dave is involved in front-end/back-end project consultation and planning, strategizing, design and engineering implementation/execution and is an experienced team communicator. He has a strong facility/process, design/engineering, containment, equipment, material handling and facility systems integration background