Fill-finish, a critical manufacturing operation, is the processing activity related to filling a solid, semi-solid, or liquid drug product into a primary packaging component in a controlled and repeatable fashion to ensure the finished product’s quality and patient safety. Any mistakes can potentially lead to formulation issues, contamination, or improper packaging, which can have a catastrophic effect on the drug product and patients, also resulting in a costly economic impact on an organization.
Thus, the design and build of a fill-finish facility is an essential component for a compliant and efficient fill-finish operation. It is crucial to consider various environments in which you perform this activity and the equipment used, which needs to demonstrate control and the repeatability of the process.
The build or expansion of a fill-finish operation may be initiated by a pharma or biopharma organization keeping manufacturing in-house or by a contract manufacturing organization (CMO). There are different considerations when designing for these types of businesses, including different technological setups.
In-house refers to manufacturing a pharma or biopharma organization’s drug within the company. In this scenario, companies like Pfizer or GSK may have a line (or several lines) of products that are being produced, with each line dedicated to a single product. Also, the company is the owner and market authorization holder of that product.
On the other hand, CMO’s business model involves the production activities for a product that another sponsor pharma or biopharma company owns. Therefore, a CMO may need to be more flexible regarding what can be produced within the facility to meet different clients’ needs. In this scenario, CMO’s need to anticipate the business and technical requirements of multiple partners and the production process of multiple products.
While the topics covered in this blog apply to both situations, the actual choice of technologies or methods will differ based on whether the fill-finish operations are in-house or at a CMO. Also of critical importance are the product’s characteristics and whether the drug product is considered a potent active, toxic, sterile, etc. As such, some of the topics discussed might not be required or applicable for all types of processes.
In this first post of a two-part blog series on fill-finish designs, we’ll cover a few of the questions that must be asked and answered to design a compliant process that is adapted to the production and business environment of a specific facility. This blog will focus on the following three topics:
- Single-Use vs. Fixed
- Ready to Use (RTU) vs. Bulk
- Isolator vs. Restricted Access Barrier Systems (RABS)
The second part of the series to be published in the following month, will cover
- Filling technology
- Small batches vs campaign batches
- 100% In Process Check
- In process camera technology
- UV coding technology
- Robotized filling lines
Single-Use vs. Fixed
One of the first questions that will come up is “how will you handle your product”? While this is a very general topic, let’s start with whether you want to have fixed equipment that is cleaned between every batch, or if you should implement single-use technologies. This is a decision which will impact several spheres of the production environment, such as the manufacturing costs, utilities, storage considerations, and personnel workload.
With single-use technologies, you discard a material that comes in contact with the products, such as bags, tubing, or valves after each batch. For example, you may want to run single-use equipment over a large portion of your operation to discard anything that comes into direct contact with the product to avoid the need to wash and sterilize for the following equipment use, along with the required cleaning validation it entails.
With fixed stainless-steel vessels/ technology, you reuse the same tubing and formulation tank again and again after thorough cleaning and sterilization procedures. This type of technology is a significant consideration that will impact your operations in numerous ways, such as your utilities requirements and consumption—reusing equipment after washing also has an impact on cleaning validation activities, as it will be critical to demonstrate that there is no risk of contamination between the sequential batches.
On the other hand, environmentally speaking, you should be aware that single-use technology bears its burden. Therefore, an environmental impact study should be performed well when choosing one technology over the other technology. It is also advisable to consider the operational costs of single-use components, the different supply chain dynamics, and their availability versus the capital costs of multi-use systems.
So, when considering single-use vs. stainless-steel technology, you should perform a thorough risk and cost analysis to assess which method is better suited to specific processes and facilities with the best solution determined on a case-by-case basis.
Ready to Use (RTU) vs. Bulk
With the variety of drug delivery systems available in the market, the components used in a fill-finish operation could include vials, prefilled syringes, dual-chamber syringes, ampules, cartridges, pens, tubes, spray bottles, dropper bottles, pill bottles, etc. You may choose to wash and sterilize some of these components, or you can purchase RTU components that arrive at your facility already washed and sterilized that can be directly used to fill the product.
RTU components are delivered in bags within several layers of protection that you need to remove in sequence prior to usage, but on the upside, you don’t need a washing machine, a sterilization tunnel, or other cleaning systems. On the other hand, one of the disadvantages of RTU is that this format takes up more space resulting in the reduced number of products per surface area ratio than the bulk products, especially for the vials in RTU format versus vials in a bulk form. Therefore, the decision of what format to use affects the planning of your warehouse and production storage zones.
Which is more efficient and/or cost-effective? To determine that, you need to know the volume of components you will want to produce per year to make the business case. Generally speaking, with the smaller volumes, the tendency would be to go with RTU because the investment in required cleaning equipment would likely be too high. On the other hand, a very large volume supports a case for equipping yourself to perform the cleaning and sterilization in-line with your process.
Although RTU is considerably more expensive than bulk components, depending on the volume of products you make per year and other factors such as the sale price of your drug product, it may not matter whether you decide to purchase bulk or RTU format. That said, a calculation of the breakeven point needs to consider many factors, including the market dynamics of materials with the potential impact of supplies issues due to a pandemic or other problems.
Isolator vs. Restricted Access Barrier Systems (RABS)
The third technology choice you need to make is specific to the filling portion of the operation, where you fill the product in the component (primary package) and apply a closing device/lid. For sterile products, the filling of the product needs to be in a Grade A ISO 5 Classification (highest grading) environment as per regulations
There are two common methods to meet these cleanliness classification criteria: RABS or isolator technology. The choice is process-dependent. It needs to factor in the type of products you want to process and how you want to operate the equipment. You should also factor in how accustomed your team is to each technology.
You also need to consider the environment where you want to install your filling line. For example, if you have RABS technology for sterile products, ideally, you need to install it in a Grade BD background environment (ISO 7). On the other hand, if you have isolator technology for sterile products, you can install that same line in lower grade cleanroom classification (Grade C, ISO 8). The isolator technology requires a larger capital investment but a lower operational investment in the sense that the background cleanroom environment in which you operate has a lower classification demand, lower criteria, and lower costs to maintain that environment. A Grade B area is more expensive to maintain, particularly in large facilities.
The cleanability of an isolator versus the cleanability of RABS equipment is also something that must be considered. The cleaning process can be more automated in the case of an isolator, thanks to the vaporized hydrogen peroxide (VHP) system incorporated in a line isolator. On the other hand, a RABS requires a more manual cleaning process to meet the cleanliness requirements and cleaning validation endpoints.
Thus, the three topics discussed are only a few of the items you need to consider when building or expanding fill-finish capacity. Part 2 will explore further considerations to design a compliant and efficient fill-finish facility in a subsequent blog.