Drug Product Manufacturing Science and Technology
The adoption of single-use technologies in drug product manufacturing has introduced many benefits for the pharmaceutical/ biopharmaceutical industry. It has also introduced the need for an entirely new way of thinking for a group of developing subject matter experts to deal with a fresh set of challenges. Many of the advantages of single-use technology have been well-characterized and discussed in literature, including the reduction of cross-contamination risks and cleaning validation program related resources, as well as faster changeover times on the production floor, lower capital investment costs on facility start-ups and less costs associated with routine cleaning and sterilization of product contacting parts [1-3].
Often underplayed benefits are those associated with the reduction of microbiological contamination risks and overall improvements to sterility assurance for aseptically-filled products. This article will provide an overview of several of these benefits and will also describe the inevitable concerns when outsourcing aspects of a sterility assurance program to a third party.
Microbiological Risk Management in the Process Design Phase
A well designed single-use drug product manufacturing process that is risk-educated has the ability to lower microbiological contamination potential when properly scoped, assessed and implemented. It begins at the user requirements phase when an effort of this type initiates the process and equipment validation lifecycle. It is important that the reduction of microbiological contamination risk is a pre-meditated thought when developing user requirements. This user requirement must then guide the design phase risk assessments and subsequent design review. Getting this right from the beginning of your project is vital in ensuring your end process has the greatest number of microbiological contamination risks mitigated.
Many of the risk assessment methodologies described in the International Conference on Harmonization’s (ICH) Q9, Quality Risk Management, are capable tools in identifying, assessing and mitigating risks. However, the Preliminary Hazard Analysis (PHA) and the Hazard Analysis and Critical Control Points (HACCP) are excellent tools for identifying microbiological risks in the design phase of a project where little manufacturing experience is available to educate the evaluation and prioritization of risks. These tools allow one to examine all entry points of microbial contamination including personnel, the environment, equipment, and the process. Looking past the initial pre-design scoring to understand how the design features will lower your contamination risks is an important aspect of ensuring the effectiveness of your mitigating factors.
Performing a risk assessment in the design phase must not be made into a check the box exercise where the document is created and left to collect dust on a lonely document storage room shelf. The risk assessment document must be a living one that evolves and supports your project through implementation as the output guides your design and procedural controls. Returning to this document at predefined points in your design and implementation is advised.
Design phase considerations include ensuring your product pathway is as closed as possible, leveraging integrated sampling technology, utilizing single-use connection or interface technology, and limiting the number of potential aseptic connection points. Some examples of employing these design phase considerations using single-use technologies are given in the text that follows.
Improving Microbiological Control in Bulk Handling
The initial bulk processing steps in a traditional biopharmaceutical manufacturing process offer several entry points for microbiological contamination that can potentially impact product quality and patient safety. These are non-sterile steps as they are upstream of the final sterilizing filter; however, regulatory expectations on acceptable bioburden levels at these in-process points have driven these limits down to levels that approach sterility. Improved understanding and focus on microbial control throughout the industry has also resulted in improvements in process capability, which in turn has driven down these action limits to the point where minor process aberrations can result in excursions and negative batch disposition decisions. Some examples of higher risk points in a traditional equipment bulk process are solids addition during formulation or buffer preparation steps, aseptic connections of tubing to facilitate recirculation of thawing bulk drug substance and open process bioburden sampling. Using single-use technology for the handling of bulk product can close these processes nearly completely to the environment and the humans carrying them out.
Solids addition during formulation steps or preparation of diluting buffers is traditionally an open process that carries a relatively minor risk for introduction of microbial contamination. This is of course dependent on how one performs these steps with respect to what manner and how long a traditional tank man-way is opened, the environment in which it is opened, if the prepared buffer is filtered before it is added to the product and how long the prepared buffer is held prior to addition or filtration. For a highly sensitive process, a closed system for solids addition is one single-use option that reduces microbial contamination risk. Several vendors offer powder transfer systems that either mates with other single-use systems via either a sanitary gasket type system or a proprietary closed connection system. This does require that the solids are added to the bag in some way under controlled conditions. So while this system may protect the solid from microbial contamination during the formulation step, there are upstream manipulations to consider. Bearing in mind the risk at this process step, time should be spent tightening your controls around filtration of these prepared solutions or shortening hold times while using a simpler disposable container for addition of solids.
Traditional biologics drug product manufacturing processes start with thawing of the frozen bulk drug substance in stainless steel cryovessels that are equipped with the ability to deliver warming heat transfer fluids to the tank jacket and inner coils. During the thaw step, recirculation/mixing of the bulk is required once the bulk has started to melt to ensure critical quality product attributes are met at the end of thaw. Aseptic attachment of tubing to the bottom and top of the cryo-vessel to facilitate recirculation can be required and presents an opportunity for bioburden to be introduced at the beginning of a product hold step. Even if thawed product is held at refrigerated temperatures, introduction of psychrotrophic microorganisms at this point can result in bioburden limit excursions at the end of the hold step. Several vendors now offer single-use alternatives and accompanying systems to freeze and thaw bulk drug substance in bags. When thawing in bags, alternate mixing strategies can be used that are as simple as rotating the bag following the thaw step. These alternate strategies obviate the need to make any aseptic connections to the system and allow the bulk to remain in a closed sterilized bag that it was previously filtered into at the end of the drug substance manufacturing process.
Closed system sampling for bioburden analysis is a must at these bulk process steps given that the action limits are so low. Open sampling into a sterile sampling container is not recommended because of the likelihood of sample contamination on some interval depending on the robustness of your sampling controls and proficiency of staff that take the sample. Sample contamination investigations are often not bulletproof enough to claim false positive because of the burden of proof required to point definitively at sampling as a cause.
Closed system sampling technology is not new to the industry and the ability to connect and sterilize these sampling systems in-place, while attached to traditional stainless steel systems, has existed for some time. These systems are equally as beneficial in single-use set ups and are delivered attached to your bulk processing bags pre-sterilized and ready-to-use reducing any possibility of sample contamination during collection.
Improving Sterility Assurance in Aseptic Processing
Drug products produced by aseptic processing require increased rigor and attention when it comes to reducing the risk of microbiological contamination. Once the product has passed the final sterilizing filter, the drug manufacturer must rely heavily on facility and equipment design aspects, procedural controls and personnel behaviors. Singleuse technology has the ability to design out some of these risks through the use of irradiated materials, process connection technology and clean space interface technology.
Steam sterilization using an overkill cycle design is a rigorous approach to sterilization of equipment but it does have some limitations when compared to irradiation sterilization. Steam sterilization relies on the penetration of steam into the inner surface of load items after evacuation of air from the system. This can pose challenges when sterilizing items of long length in an autoclave such as a coil of tubing attached to a filter or other assembly. This is mainly a concern for smaller scale operations where process piping is not employed and steamed in place. These steam penetration challenges often cause firms to create fragmented sections of the product contacting pathway, which subsequently requires the need for aseptic connections in the filling area. The other vulnerability of autoclave and steam-in-place sterilization is the reliance on personnel to set up, package the material and load it consistently without occluding the penetration of steam into the system. These concerns are eliminated when using single-use systems that are irradiated (typically through gamma or electron beam radiation) because of the nature of these sterilization processes and their ability to sterilize through materials completely. As a result, there is no need to fragment the process contacting path and the number of aseptic connections needed downstream of your final filter are reduced.
The market has now been flooded with a number of options for single-use connectors that allow linkages between single-use bag assemblies. This connector technology is the single greatest contributor to improved sterility assurance profiles in an aseptic operation. They also enable increased flexibility in joining together templated bag assemblies to allow for a more nimble operation [4]. It should be noted that these connectors also add a lot of value in the upstream bulk handling process and, combined with the technologies previously discussed, can create an entirely closed bulk handling system and all but eliminate microbial contamination risk at these steps. The different connector technologies have positives and negatives that must be considered. Some are universal and some have male/female connections limiting their flexibility. They come in a variety of different materials that may bring compatibility concerns with your product and will result in different extractable or leachable substance profiles. The technologies of making the connection themselves are all unique and must be evaluated for their ability to connect in an aseptic fashion and the need for personnel interaction with the device. There are certainly superior devices on the market that are backed up with vendor supplied microbial ingress data that is quite impressive. Drug manufacturers must weigh the positives and negatives of these devices and choose the best one that suits their process but at the end of the day, connector technology replaces open connections, which is one of the most risky activities in aseptic processing.
Clean space single-use interface technology provides another improvement to aseptic operations when using single-use systems. These systems are adaptations of rapid transfer port technology that existed for many years as a means of moving materials in and out of isolators or restricted access barrier systems (RABS). These interface systems can be used in several ways to improve aseptic handling of the product contacting path or sterilized drug product containers. Single-use interface systems consist of a bag that is fitted with port which mates to a complimentary device on the side of cleanroom, isolator or RABS. The mechanics of making the connection between the bag and the clean space allows for an aseptic transfer of the bag contents to the clean space by fusing together the two non-sterile surfaces at the connection interface prior to opening a small door exposing only sterilized surfaces to the clean space. These are well understood systems that replace classic interventions with the spaces through doors by gowned personnel, which introduce contamination risk. This interface technology can be used to pass through gamma sterilized tubing to a filling line as an example connecting the Grade A filling space to areas of lower classification via an entirely closed system.
Handing Over Aspects of Sterility Assurance to a Third Party
The move towards single-use technology does come with some new risks to consider. These risks have been very well characterized and front-load projects with a series of hurdles to overcome mainly around bag film compatibility and extractable substances. One significant risk to consider is that you have now passed on the responsibility of sterilizing the most critical items in your operation to a third party [5]. Single-use manufacturers outsource the sterilization of their single-use assemblies to facilities that are set up to irradiate them. It should also be noted that these irradiation facilities are not just performing work for GMP manufacturers, their understanding of the requirements can vary and GMP related work may be a small percentage of their business. As discussed, this sterilization technology is robust but passing on the responsibility of sterility assurance to an outside firm is not to be taken lightly especially given that irradiation sterilization subject matter expertise is not often a strength of parenteral drug manufacturers. Regulatory expectations hold drug manufacturers responsible for all outsourced activities and this drives the need to build considerable rigor around this program.
Drug manufacturers must build a comprehensive sterility assurance package to ensure they are under control. This program must include sterilization validation/revalidation elements, vendor qualification through sterility testing of assemblies, a sound vendor program, ongoing ISO-11137 compliance through dose auditing, single-use assembly release through review of package integrity, certificates of sterility and studies demonstrating maintenance of integrity through shipping. Keeping this in one comprehensive program package is recommended for the purposes of ensuring compliance and defending your process during regulatory inspections.
Summary
Where processes are appropriately assessed for risk, designed and implemented, single-use technology in bulk handling and aseptic processing has the capability to significantly reduce the risk of microbiological contamination and can improve sterility assurance profiles. Single-use technology by design can close systems to the greatest contamination risks present in the manufacturing environment and on the personnel carrying out the manufacturing activities. A major risk to consider with the move to these systems is handing over the sterilization of critical items in your process to a third party. This risk must be managed through implementation of a solid sterility assurance package.
References
- Petrich, M. A., “Design and deployment Strategy for Single-Use Components and Assemblies”, American Pharmaceutical Review, December 2013.
- Trotter, M., “Adoption of Single-Use Disposable Technology in Biopharma Industries – Manufacturing, Economic and regulatory Issues to Consider”, American Pharmaceutical Review, March 2012.
- Jenness, E. and Gupta, V., “Implementing a Single-Use Solution for Fill-Finish Manufacturing Operations”, BioProcess International, May 2011.
- Boehm, J., “Single-Use Connections Enable Advancements in Aseptic Processing - Improving Flexibility and Saving Money for Biopharmaceutical Manufacturers”, BioProcess International, April 2010.
- Mignot, K., “Key Factors for Validating a Disposable System” PDA Letter, October 2013.
Author Biography
Michael Hodgkinson is Associate Director of Drug Product Manufacturing Science and Technology at Genentech. He holds a Bachelor’s degree in Microbiology from the University of Guelph in Canada. He has 15 years of experience in the field of sterile products manufacturing and has held roles QC Microbiology, Quality Assurance, Manufacturing, Validation and Manufacturing Science.