New medicinal therapies are seeing rapid development but face many price pressures and regulatory challenges. George Wiker, VP, M+W Group and Kurt Gilson, VP, Western US, Total Facility Solutions, discuss the impact on facility design
Careful consideration of modular process and facility components integrated effectively to provide a safe and clean manufacturing operation
Image courtesey of AES Clean Technology, Inc.
A clean production environment is a critical element in the manufacturing process for pharmaceutical products. Working within a clean environment promotes better containment of the ingredients used in pharmaceutical manufacturing – a critical issue when producing antibiotics, steroids, cytotoxics, highly potent active pharmaceutical ingredients (HPAPIs) and radiopharmaceuticals – as it provides the necessary protection for workers. A clean environment is also required to protect finished drugs from environmental contaminants, and to mitigate any cross-contamination from other active pharmaceutical ingredients (APIs) being produced.
Evolution in the pharmaceutical and biotechnology industries and changes in regulatory authority standards and requirements are creating challenges across the industry
Evolution in the pharmaceutical and biotechnology industries and changes in regulatory authority standards and requirements are creating challenges across the industry. Because cleanrooms have such an important role in the drug production process, the designers and contractors who create the clean environments have an important part to play in meeting the industry’s challenges in achieving cost-effective and timely production of safe and effective drugs.
Cost is one of the key challenges facing the biopharmaceutical industry at the moment. The overall R&D costs of a drug from start to finish are very high, approaching US$1bn or more per product that makes it to the marketplace; drug developers are therefore looking to manufacturers not only to improve cost-effectiveness and net present value (NPV), but also to decrease the time to market.
As blockbuster drugs become rarer, and as the biology of disease becomes clearer and more refined, the biopharmaceutical industry is moving towards more personalised (precision) therapeutics, where targeted drugs are tailored to subgroups of patients, and therefore to smaller market populations. Immunotherapeutics and cell therapies take this a step further, potentially designing a treatment for an individual patient. Alongside this comes the trend of companies developing drugs for rare diseases, which also by definition reach only smaller markets. While the premium for these types of drugs is likely to be higher, the much smaller markets put additional pressure on companies to achieve a strong NPV for their shareholders.
Cost of goods is also important for the biosimilars industry. Biosimilars, also known as follow-on biologics, are products that are created to be as similar as possible to an originator biologic, and are produced once the originator drug’s patent has expired. Like the small-molecule generics market, the biosimilars market is driven by a need to reduce healthcare costs. Because there is arguably no difference in safety and efficacy, the biosimilars need to compete with the originator molecule and other biosimilars entirely on price. Because the development of a biosimilar is still relatively costly, the biosimilar companies need to keep their production costs as low as possible.
To maintain the safety of operators during drug substance production, and of patients in final drug products, the regulatory authorities are constantly re-evaluating good manufacturing practices (GMPs). As an example, the FDA and EU Commission are moving towards stricter separation between drugs that could be a risk in the case of contamination; for example, antibiotics that could trigger allergic reactions.
To maintain the safety of operators during drug substance production the regulatory authorities are constantly re-evaluating good manufacturing practices
In 2013, the FDA extended its existing guidance on manufacturing antibiotics, stating that penicillin and non-penicillin beta-lactam antibiotics should be manufactured separately. The aim is to prevent cross-contamination between penicillin and the non-penicillin beta-lactam antibiotics, and contamination between these drugs and other drugs manufactured in the same facility.1-3
The EU Commission has drafted similar updates to its regulations, stating that dedicated and self-contained facilities should be used to produce therapeutics such as penicillins or biologics.
Certain products, including some antibiotics, hormones, cytotoxics and HPAPIs, should not be produced in the same facilities. The EU Commission guidelines do allow these products to be manufactured in the same location ‘in exceptional circumstances’ but they must be separated by time, while precautions need to be made and the process needs to be validated.4
To run a production plant cost-effectively, manufacturers want to reduce downtime as much as possible. This may be achieved by running production lines in the same plant in parallel for different drugs, or by switching production lines from manufacturing one product to another. While this uses the space more efficiently, it does increase – even if only to a small degree – the risk of cross-contamination between production lines, either airborne or carried on equipment or on the clothing of members of staff. It also increases the cleaning costs, as lines used for different products need to be deep-cleaned in between production runs, and open areas will need to be cleaned more frequently.
And, while the aspect of redundancy may also increase capital cost, the value of maintaining manufacturing operations more than offsets the increased investment, as proven by an NPV assessment.
Facility design and construction have a key role in ensuring that the risk of cross-contamination is reduced as near to zero as possible
It may appear that the manufacturers’ desire for running projects in parallel to reduce downtime and cut costs clashes with the regulatory authorities’ need to increase segregation to maintain safety for patients and workers. However, while it will be a challenge, facility design and construction have a key role in ensuring that the risk of cross-contamination is reduced as near to zero as possible. As such, it is still possible to create a solution that meets the requirements of both the manufacturer and the regulatory authorities.
Careful specification for the build of the cleanrooms can alleviate many of these concerns. Designing and building the cleanroom to the requirements of GMPs and other guidelines such as the ASME BPE (bioprocessing equipment) standards ensures that the area is as ‘cleanable’ as possible. As an example, the choice of specification of high-purity process piping, as laid down in the ASME BPE standards, is dependent on what the pipe is going to carry. This includes mechanical and chemical properties, the external surface finish and coat, the internal product contact coating, the welds between pipes (both inside and out) and the methods of attachment.
TFS offsite hygienic piping fabrication facility with staged and separated materials
The ASME BPE standards were created as harmonised best practices across the industry with input from end-users, contractors and manufacturers to ensure the purity and safety of products.5 Other guidelines, such as the ISPE’s Baseline Pharmaceutical Engineering Guides, are very helpful and relevant.
Another solution that could both reduce costs and meet the needs of the regulatory authorities is the increasing trend in the industry to move away from open process systems – where the whole room is the primary containment and must be maintained at a high classification – to closed process systems. In closed systems, self-contained production lines are individually maintained at the specifications required for each product within a room that, while it must still meet stringent standards, need not be maintained at as high a classification level. In this case, the closed system is the primary containment and the room is the secondary containment, which can reduce costs overall (both capital (CAPEX) and operating (OPEX) together), while also maintaining segregation for individual products.
Closed systems still require fixed components, such as the high-purity process piping, but they can be combined with single-use products to create an efficient process operation. As these single-use products are disposable, and made of materials that are validated for product contact, they provide the added advantage of reducing turnaround time and staff costs, as contaminated materials are simply disposed of after use, rather than being cleaned and the whole system being validated and maintained by the operating company.
TFS cleanroom fabrication with proper lighting, gowning and project materials
With these systems, the design input becomes far more standardised, and can be efficiently integrated into the creation of three-dimensional models that are used to create fabrication drawings. The building information-modelling step incorporates the three-dimensional geometry of the building and contents, as well as building materials and components. The construction time will also be reduced, since initial setup will also be quicker, as the single-use items can be used immediately (as ‘plug-and-play’ process systems).
Capital costs are lower for systems based on single-use materials, and less investment is tied up in each site, which reduces the construction cost, and means that sites can be used more flexibly. This is likely to prove especially important for new therapeutic approaches such as cell therapies, where very clean conditions are vital for manufacture and packaging, but the products may be required in patient-specific runs.
There are still advantages to a system that combines stainless steel portions and retrofitted single-use components
While the most effective way to design and build a cleanroom is to start from scratch – building in ‘clean’ from the beginning – designers, construction teams and process-piping teams don’t always have that luxury, and may be called in to upgrade an existing facility, perhaps including single-use technologies. There are still advantages to a system that combines stainless steel portions and retrofitted single-use components. While any stainless steel portions of the system will still need to be cleaned and validated to the appropriate specifications, the single-use portions can be added off-the-shelf and used immediately. The process still needs to be modelled to ensure that it will work, and this will require close collaboration between the design team, contractor and the client.
Another approach to cutting costs and reducing the time to market is for designers and constructors to use standardised modules fabricated off-site, effectively creating a very efficient turnkey solution. This has the added advantage that the same setup can be replicated at a number of different sites, making staff training and troubleshooting easier. However, the same clean principles must be maintained throughout the process, and the quality of the construction and installation carefully monitored.
The move toward personalised medicine and to lower-cost forms of biologics will mean production lines will need to be flexible, with changeover times kept short, while maintaining high levels of cleanliness and very low risk of contamination. This will probably lead to a greater use of closed systems and single-use technologies.
Cleanroom technology will continue to evolve, in response to biopharmaceutical industry needs and regulatory guidelines and requirements, with cost and speed to market likely to remain the major drivers. The designers, construction teams and process-piping teams will need to work increasingly closely together to meet these needs in a constantly changing field.
1. ECA New FDA Guidance for the Prevention of Cross Contamination of Beta-Lactam Antibiotics. European Compliance Academy. April 4, 2013. Accessed: Sept. 9, 2014. Available from: http://www.gmp-compliance.org/ecanl_611_0_news_3666_7812,Z-PEM_n.html.
2. Gaffney, A. Antibiotics must be Manufactured Separately from Penicillin, FDA Says. Regulatory Affairs Professionals Society. April 17, 2013.Accessed: Sept. 5, 2014. Available from: http://www.raps.org/focus-online/news/news-article-view/article/3201/antibiotics-must-be-manufactured-separately-from-penicillin-fda-says.aspx.
3. CDER. Guidance for Industry – Non-Penicillin Beta-Lactam Drugs: A cGMP Framework for Preventing Cross-Contamination. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER). April 2013. Available from: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM246958.pdf.
4. EudraLex, Chapter 3: Premises and equipment (draft), in Volume 4: Good manufacturing practice (GMP) Guidelines. 2013. Available from: http://ec.europa.eu/health/files/eudralex/vol-4/pdfs-en/cap3_en.pdf.
5. ASME. Bioprocessing Equipment BPE - 2012. Available from: https://www.asme.org/products/codes-standards/bpe-2012-bioprocessing-equipment.