By Christian Dunne
Containment is key during aseptic processing and this has led to the development of new transfer methods that are both enclosed and minimize the requirement for operator intervention.
The world market for contract pharma manufacturing is expected to reach US$79.24bn in 2019 rising from US$54.54bn in 2013, with strong revenue expansion predicted up to 2025. The sterile contract manufacturing sector has experienced steady growth over the past five years with the contract manufacturing of injectables leading the sector’s growth since 2011.
There are a number of key factors that influence the sterile market. By the end of 2024, the cancer segment is projected to reach close to US$100bn in value, expanding at a CAGR of 6.5 per cent. Revenue from the cancer segment in the global sterile injectable drugs market is expected to increase 1.7X by the end of 2024compared to that in 2016. In addition, the antibiotics market was valued at US$39.8mn in 2015 and is expected to witness a CAGR of 4.0 per cent to 2025.
Global demand and the growth in specific markets, including oncology, have supported the continuous growth of the biopharma market. Consequently this is driving the need for increased development of Antibody Drug Conjugates (ADCs) in an industry that is also seeing a rise in conventional drug manufacturing using high potency active pharmaceutical ingredients (HPAPI)s. This is also driving the need for high potency handling capabilities, particularly high-containment manufacturing facilities.
With the global active pharmaceutical ingredients market expected to reach US$213.97bn by 2021 from US$157.95bn in 2016, it is growing at a CAGR of 6.3 per cent. The factors driving market growth include increasing incidence of chronic diseases, rising prevalence of cancer, technological advancements in API manufacturing, growing importance of generics, rapidly increasing geriatric population and increasing uptake of biopharmaceuticals.
The transfer of Active Pharmaceutical Ingredients (APIs) must be carried out correctly during high potency and aseptic processing to ensure highest quality of the product and complete sterility of the manufacturing processes. Containment strategies are an important component of manufacturing facilities to address these risks and adhere to the strict safety requirements associated with processing these types of products.
Traditional Methods and Challenges
There are many challenges involved in ensuring product sterility, including operator handling and the need to invest in containment equipment to protect the product from external contaminants which could come from the operator or the surrounding environment. It is, therefore, important to ensure that solutions are implemented to counter potential risks posed by human intervention.
Regulations and standards for clean room environments have gone some way to alleviating and managing the risks. Ranging from grade A to grade D, there are various approaches associated with each grade, from closed to open handling of a sterile product. In a grade A environment, less than one Colony Forming Unit (CFU) is allowable meaning there is no contamination.
The market has also already witnessed some diversification with technologies that can help minimise the risks associated with potent compounds, including isolators, Restricted Access Barrier Systems (RABS) and SBVs that are now in use to safeguard drug products throughout the manufacturing process. Closed transfers, such as the use of SBV, limit manual intervention, reducing the risk of cross contamination, and create a dust free environment to ensure operator safety.
New design technologies to remove the risk of airborne exposure have been pivotal in achieving high containment.
Isolators are an arrangement of physical barriers that provide an enclosed working space that is detached from the surrounding environment. Operators perform tasks through half-suits or glove ports, enabling manipulation to be undertaken within the space from outside the enclosure without compromising integrity. Due to the high-performance requirements for these enclosures, integrated pressure decay tests have become the norm during start up and prior to any bio decontamination phase, with the leak of the chamber being a key factor in the classification of the device.
A limitation of isolators is that they can create difficulties in transferring materials in and out of the cabinet. This can require a docking isolator to be connected and its interior sanitised before materials can be transferred. The qualification ofH202 (hydrogen peroxide) vapor systems in isolators can also be difficult. As a result, there is a need to suspend everything within the cabinet to remove any hidden surfaces.
The RABS approach offers increased flexibility for operators to interact with the process outside of the sealed area by putting a physical barrier between operators and production areas. To allow a more limited barrier to be permissible, RABS must be set-up in high-class, generally ISO 7 clean rooms. RABS contribute distinct advantages by enabling operators to maintain a distance from the process, while allowing the enclosure to be opened if significant intervention is required.
In comparison to isolators, RABS can ensure faster start-up times and improve the ease of changeover while also allowing for more operational flexibility and lower validation expenditure. Although isolators do offer the advantage of higher integrity chambers for a more robust closed solution.
Many pharmaceutical companies are finding that the use of aseptic SBV technology integrated to either the isolator or RABS for the transfer of material in or out of the enclosure is a complementary technique which works together to achieve the required sterility assurance.
Manufacturers can benefit greatly from aseptic SBV technology by its closed handling method that enables Sterility Assurance Levels (SAL) and reduces the need for operator intervention. It also reduces the need for cleaning and validating large areas which consequently leads to minimal downtime, while also increasing flow and yield from product transfers.
The technology provides a safe method for product transfer from one container, process vessel, isolator or RABS to another part of the process to ensure complete sterility of the transfer.
The unique design of the aseptic SBV enables decontamination to take place in a closed environment. Once sealed, a gap is created between the discs and hydrogen peroxide gas is flushed through this enclosure to decontaminate the space. The process of validation is done in the same manner as that of an isolator or RABS with the use of chemical indicators to ensure full coverage of the enclosure is obtained and to ensure a validated SAL of 10-6has been achieved.
Processing time varies between four and 30 minutes depending on the gassing system utilised. This is extremely fast when compared to a conventional airlock or isolator techniques which could be in the region of four to six hours. SBV can also contribute considerable cost savings in comparison to traditional approaches, being as much as three to five times cheaper than alternative methods.
The advent of sealed transfers using SBV has enabled the downgrading of the external environment as it creates an internal grade environment of its own due to the integrity of the approach. By making it possible to downgrade the surrounding clean room level, this technique has the potential to transform the environment in which drug products are manufactured. This in turn delivers cost savings and process improvements due to the less restrictive operating requirements.
The containment market is continuing to grow rapidly, driven by increasing substance potency, regulation and market dynamics such as the growth in biopharmaceuticals. Key benefit to advanced aseptic processing includes the complete elimination and control of all sources of impurities, and perhaps most importantly, those generated from human intervention. The selection of an appropriate barrier containment technique will be dependent on several factors and choosing the right contamination control platform requires considerable research into what a product needs for an effective process design.
Christian Dunne is the Global Product Manager for ChargePoint Technology for the Aseptic range of products. Over the past 15 years, Christian has been creating innovative solutions for the pharmaceutical, biotech, cell therapy and fine chemical industries in the form of high containment and aseptic process solutions.
For the past four years, Christian has been working with ChargePoint Technology on the advancement of its split butterfly range of solutions in the aseptic and containment fields, handling high potent/sterile powders and small-scale components, where both product and operator protection are paramount.
Christian is an active member of ISPE and PHSS.