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Creating building blocks for good manufacturing practices is essential.
Laying the foundation stones for creating the right environment to be successful in solid dosage forms can sometimes come down to literally laying down the right brick and mortar building foundations and walls. Pharmaceutical Technology discussed trends and opportunities with experts for good manufacturing practice (GMP) guidance for manufacturing, testing, and quality assurance of products. This built in minimum quality management system is custodial to assure manufactured drug products are safe, both the end user, and also for those working to produce them. In the background it is useful to note that the pharmaceutical community is approaching harmonization, but key differences remain. Pharmaceutical companies must be cognizant of this if they plan to sell their products globally.
From a quality, regulatory, and facilities standpoint, what priorities need to be established to achieve optimal design for a new or existing good manufacturing practice (GMP) facility, and ensure consistent quality of the end product? Richard Anderson cleanroom specialist, of WHP Engineering diplomatically asserts it “depends on a detailed understanding of every stage of the process. WHP’s ‘inside out architecture’ is based on sizing of rooms, room adjacencies, set down areas, warehouse spaces, and packing rooms, in order to achieve the best layout and eliminate bottlenecks. Once we have the layout, we can work out the classification of cleanrooms, air flow patterns, and pressures. We then look to protect the person, product, and environment, and to maximize energy efficiency and sustainability.” So, in the descending order of priorities, at least from an engineering company’s perspective, the space itself, and the structure comes first. This makes even more sense when Anderson continues, “In general, manufacturers will continue to produce their specific product under licence using the same facility and equipment until the licence expires. Only when they need to bring new products to market, will they consider innovative approaches, for example in spray drying, compounding, granulation, or formulation.”
Anderson has seen a lot of trends in facility design come in and out of focus. “Ten to 15 years ago, we used to strip out existing facilities and put in new ones because of cross contamination issues, but we're not seeing that anymore. Instead, even Big Pharma is keeping equipment, carrying out deep cleans, and testing to ensure that there is no trace of possible contaminants, and revamping manufacturing lines. The envelope will change, or the machines might be upgraded, and new packaging lines might be introduced, but they are still able to achieve cost savings by maintaining the same facility. Historically, manufacturers have tended to favor large-scale batch production, and some of our customers choose to maintain this approach. Other manufacturers are switching to smaller batch sizes in higher value products in order to improve the quality of products and speed up the process times. The market is very diverse, and we get different messages depending which customer we talk to.”
Looking at a more global perspective, he continues, “In terms of regulations, [Europe’s] Annex 1 tells us if we need to do anything different as designers. Some fill areas are under Grade A with Grade D background, and we're now seeing Grade A with Grade C background. Open filling is done in Grade A with Grade B background. This shows that some of the classifications and cleanliness regulations are improving, depending on whether or not your process involves open filling, the type of packaging line, and whether it's a tablet or an oral dose.”
Ali Rajabi-Siahboomi, Vice President & Chief Innovation Officer from Colorcon outlines a few major trends to be aware of, saying that “new drugs coming to solid dosage formulations are more potent and have chemical sensitivities that require careful handling to ensure safety and overcome the risk of exposure as well as protect from environmental conditions such as moisture, oxygen, and temperature controls. An example is the development and manufacturing of macromolecules for oral drug delivery which require more complex and tightly monitored facilities to ensure safety and quality of the finished product.”
This thread is somewhat picked up and expanded upon by Anderson, who continues, “From an HVAC and containment, airlocks, fire and safety standpoint—everything must be considered in terms of the rising demand for certain types of solid oral dosage manufacturing modalities.”
Dave Di Prospero, associate director, Pharmaceutical Process Technology at CRB Consulting Engineers emphasizes that, “use of airlocks, both material and/or personnel, in concert with HVAC pressurization schemes, provides for the greatest flexibility when looking to future proof an oral solid dosage (OSD) manufacturing operation. Especially when considering high potent compounds. Airlocks, used as a transition between different space classifications (e.g., Controlled not classified (CNC) to Grade D) is a longtime practice that is well accepted by nearly all international regulatory agencies. This facility design configuration offers contained and controlled operations and is often the standard for multi-product facilities.”
Anderson agrees and stipulates that, for “heating, ventilation, and air conditioning (HVAC) designers, the main challenge is containment of powder, as it may be toxic or potentially explosive. Cross contamination is also an issue, and this can be reduced with air handling unit AHU zoning. Humidity control is expensive but a must when dealing with gel products, and new heat recovery systems can help to reduce the high running costs. Reflecting further on a somber tone.” He adds, “In the case of powders, liquids, and any gaseous vapor, it is vital that the substance is contained within the room, to protect both the product and the environment around it. With the clever use of bubbles and sinks, and negative pressure regimes we can minimize the risks while maintaining cGMP [current good manufacturing practice] requirements. An analogy is if you have a birthday cake, no matter how hard you try, you can’t suck the candles out. Similarly, the way to control powders is to push and pull, so you push by blowing and you pull in the right direction, and it's this push-pull approach that helps achieve containment. Due to the risk of explosion, some products require ATEX (explosive)-rated areas in case the ventilation system fails to contain the product. Fire is another potential hazard, and specified fire protection can be achieved through the use of suspended ceilings constructed from white-faced mineral fiber fissured tiles in a lay-in grid, galvanized-finish column casings, and protective fascias.”
On this score, Di Prospero, with many years of first-hand knowledge, urges anyone to keep it as simple as possible. He states clearly, “whenever possible, direct compression formulations remain the easiest and quickest processing platform for getting new products to market. Direct compression requires the fewest number of unit operations and is the least complex of the typical OSD processing platforms. Ingredients are weigh/dispensed, blended, and compressed. Depending upon the powder properties tablet coating may or may not be needed,” he concludes.
Rajabi-Siahboomi singles out a need for speed, saying “there is more and more emphasis to expedite new product developments and commercialize for not only early access by patients—FDA process supported (e.g., orphan drugs) but also to maximize the commercial exclusivity for the company. A successful and timely formulation development begins with an in-depth understanding of the critical attributes of the API such as its solubility, any structural sensitivities and incompatibilities, dose ranges to be formulated, physical attributes, and target release profile for optimum therapeutic outcome.” He continues to drill down saying, “depending on these parameters, suitable excipients and formulation enablers are selected to ensure the stability of the API in the finished dosage form during storage, as well as its stability post administration and exposure to the biological media. There are various excipients available to bring functionalities like bulking, binding, glidants, and disintegrants, and the suitability of these ingredients for specific API should be tested and understood. Modified release technologies using appropriate polymers are designed to develop different delayed or extended release profiles.”
When it comes to what matters most going forward with building designs for drug GMPs, the industry is clearly, from regulators on down,and C suite on down, encouraging , continuous manufacturing (CM) to top the list. CM is fueling rapid adoption of process analytic technologies (PAT) as a process and quality control tool. “Being able to perform real-time quality assurance and real-time release testing is essential to harvest the full benefit of CM,” says Fernando Muzzio, a professor at Rutgers University who has been leading major efforts with the US government and industry in the space. “This requires the integration of highly capable sensing systems into the manufacturing process. Moreover, once this approach becomes well-established for CM, it can be adapted for many batch processes as well,” a benefit he encourages to be more widespread.
Di Prospero, equally well known on this topic concurs. “Continuous OSD manufacturing has now secured a place in many modern manufacturing operations. If not as a stand-alone replacement to batch operations, at least as an additional processing platform in the arsenal. The benefits seen and proven in CM, as related to the elimination of scale up, improved closed and contained systems, product quality improvements via data analytics and
PAT, significant reductions in facility size, and the approaching of real-time release testing makes continuous OSD manufacturing an approach well beyond just an emerging niche.”
Anderson adds some color and crime into the picture. “The industry is changing in terms of in process monitoring and the ability to check products at every stage of the process,” he agrees. “Improvement in raw material APIs has seen an increase in quality with lower wastage and less rejected finished product. Improvements in equipment have also helped to achieve higher quality finished products. Mapping the production process from raw materials to end delivery is essential to highlight weaknesses and the potential for improvement. It may not be possible to achieve the optimum design initially, but this should be built into a strategic plan for the next phase of development following a successful product launch. Many of our customers have put fallow areas into their plants with critical utilities in place to allow future expansion to be carried out quickly and at minimum cost.”
Anderson continues. “Forward planning offers greater flexibility, and we can help to factor in potential changes to the production processes, for example, so that they will be suitable for smaller batch sizes or different end products. This means that the plant might be configured in a specific way to give larger areas, with a number of smaller suites for bespoke products. Understanding how you go through the approval process and demonstrate that a facility is fit for purpose is key. Security may become more of an issue with decentralised facilities and will depend on how attractive the product is to criminals. In the United States, pharma manufacturing facilities are under increasing threat from criminal gangs.” The more elegant of these are also on the rise, through the use cyber attacks. But sadly, Anderson is referring to smash and grab events. Something few executives would have considered only a few years back.
Chris Spivey is the editorial director of Pharmaceutical Technology.