Filter cartridges like these are commonly used in facilities that are primarily stainless steel as well as those based on single-use technologies. PALL LIFE SCIENCES (WWW.PALL.COM)

On a holistic level, the decision regarding whether to use single-use or stainless steel equipment in a biomanufacturing plant is a significant one. It greatly influences the design, construction, layout, and operation of a plant — and consequently, the timing and cost of the overall project. And regulatory review can add an element of risk to using anything new. Disposables have been viewed as a revolutionary concept, and they are. But from a routine regulatory operational perspective, I believe it is an evolutionary change rather than a revolutionary one.

Some single-use components are found in even a modern, welldesigned facility based on stainless steel equipment. The industry uses many types of filter cartridges, tubing, and other materials that are (disposable) consumables. Many of them have a finite lifetime, being used multiple times but ultimately getting thrown away. Also, we have single-use items such as sterilizing filters for bulk manufacture (although we never claim sterility) and tubing with similar filters in filling areas. So, even so-called “stainless steel” plants incorporate plastic materials. And with such materials come challenges.

As envisioned today, a fully “single-use” biopharmaceutical plant faces size limitations on available single-use materials and still might have stainless steel materials coming into direct contact with products in manufacturing. I have seen 1,000-L buffer and media bags that fit into open stainless steel tanks. My experience has involved 500-L single-use reactors; there may be bigger ones out there, but I have not directly used them, and size still has an upper limit. So if a company wants to make 5,000 L of buffer or more — or grow a 10,000-L cell culture — it will be forced to use stainless steel tanks. As single-use technology advances, I am sure we will see larger units come to the fore.

So this is not a binary choice of “stainless steel or single use,” but rather a question of increasing the use of disposable items. Many different types of components will be coming into contact with product either directly or indirectly. The challenges of using disposables actually have been with us for quite some time. I remember working on a product in the early 1990s that used extensive singleuse materials for buffer and media preparation as well as harvest and holding. And the challenges that came up then are still at issue now. It is that the number, type, and breadth of components used are growing.

Regulatory Benefits and Challenges 
From a regulatory perspective, several elements must be in place when a company chooses to use either single-use or multiuse disposable materials and components. These basically break down into three categories:

• components leaching material into a bioprocess stream
• products binding to components
• components interacting and chemically modifying a product.

Each of those three elements must be addressed in detail, and the results will become part of the qualification process for a given component used in a given bioprocess. The well-publicized savings come with elimination of physical cleaning and holding, as well as associated validation work. For commercial products, that can represents a significant savings in operations and validations; in clinical operations, the savings are similar. However, the work necessary to address those questions requires an initial investment up front to assure materials compatibility.

Does a component leach any material into a process stream? Studies for organic leachables are well established, and the technologies for performing them are described with limits in the major pharmacopoeias. In addition, most manufacturers of single-use components are well versed in those requirements and offer their own results from tests with commonly used solvents and buffers. However, each product manufacturer must examine available data supplied by vendors and determine whether those are sufficient to support its own decision to use a given supplier’s equipment. In most cases, the product manufacturer will find some relevant conditions have not been tested and thus must be examined. Testing might be performed by the single-use vendor, if possible, or a third-party testing laboratory, or even at an in-house laboratory. You can find warning letters online (www.fda.gov/ICECI/EnforcementActions/ WarningLetters) describing failure to examine all process streams. To prevent such an experience, biomanufacturers should examine all process streams and not rely on vendors to do so.

Does product bind to a component? Binding studies cannot be performed easily by suppliers because all products are different. But the testing can be outsourced to a third-party laboratory with appropriate technology transfer. It is critical to determine that single-use materials do not bind product. I remember one case, early in my career, in which an engineer (using the “like-for-like” engineering rule) substituted a different elastomer on a fill line. It was made of the same basic material, but the plasticizer was different, with sufficiently different properties to allow a significant amount of product to adsorb onto the filling-line tubing. That caused substantial underfilling. As a result, the “like-for-like” engineering approach was modified to be more closely “identical for identical” instead.

Does a component interact to chemically modify a given product? Product stability studies are well established for primary packaging materials such as vials, stoppers, syringes, and plungers. Comparable studies to assure that product remains stable while in contact with the many other materials present in a single-use process stream have become a definite requirement. When designing these studies, companies should consider the concentration of product, period of exposure, and environmental conditions (e.g., pH buffer, composition, and temperature). Product stability can be strongly influenced by such parameters.

Supplier Qualification
Results of those studies become a key element of the vendor qualification program when a company implements single-use technology. Demonstrating material compatibility as well as an ability to deliver consistent batches of components is a measure of supplier reliability and consistency. For raw materials, it is typical to deliver three material batches and perform full testing on them as part of a vendor qualification process. Most components are visually inspected to ensure that they are the correct components ordered and properly labeled. Companies may need to check items against their own dimensional or configurational requirements, which should be defined in component specifications. Materials of construction should be checked for consistency and detailed in associated specifications.

Sterile Components: Most components are not sterile, but those that are pose a challenge: Do you perform a sterility test or not? I would recommend not. Such tests are time-consuming and fraught with problems. How many units would you use to assure sterility in general? I prefer to incorporate this topic into vendor audits, with an examination of the sterilization process a supplier uses. In most cases, single-use components are gamma irradiated, although other methods can be used (e.g., peroxide). The results of your audit of a vendor’s sterilization process should give you the confidence in its operations. This audit becomes part of vendor qualification, as well.

Remember that sterile components used in bioprocessing are typically associated with cell expansion and culture unit operations, in which a lack of component sterility can have a major impact on the overall results of a manufacturing process. But many operations have used disposables in small culture systems for decades. Cell expansion in single-use bioreactors produces inoculants for larger scale cell culture and fermentation. Other sterile components are associated with formulation and filling areas, and that is nothing new.

The vast increase in single-use technology has been in media and buffer preparation areas, in harvesting, and in downstream processing. These processes run under sanitary rather than sterile conditions, lessening associated challenges. Most companies, however, do use sterilized components here as an added safety measure. In most purification trains I have been involved with, multiple cycles of chromatography resin use are the norm because of the significant cost of such media. So single-use columns might be a long time coming.

Supplier audits are critical elements of vendor qualification. Project teams can use risk-based approaches to determine the need for in-person or paper audits. Make sure that your audit standard operating procedure (SOP) describes the use of such approaches and requires their results to be well documented in a vendor file.

Multiuse Disposables: At present, many available components are both disposable and intended for multiuse (e.g., filtration cartridges). Unless associated costs come down, I do not foresee their replacement with single-use technology. When multiuse is the norm, it is critical to determine how many cycles a given unit is good for and to have in place an assessment procedure to assure that it operates well within the limits imposed.

As more single-use components are introduced, be prepared to find somebody with a bright idea. For example, “If we keep making the same buffer day after day in a new bag and throwing it away, why can’t we make several batches consecutively?” That would convert a single-use process to multiuse. And doing so would require assessing how many cycles would be acceptable and whether residual liquids might compromise the overall system.

Supply Chain Issues: Regulators have not been vocal on component procurement and well-controlled sources. Recently, however, they have expressed concerns over associated areas of the manufacturing supply chain. Both the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) have issued guidances and regulations to supplement their good manufacturing practices (GMPs) and help protect the drug supply chain (1–4). Their focus has been on active pharmaceutical ingredients (APIs) and excipients.

In recent years, the biopharmaceutical industry has been plagued with raw materials that have been adulterated. The classic example is Baxter’s heparin incident, in which a contracted vendor supplied the company with what was purported to be “heparin” but was most likely highly sulphated chondroitin sulfate (5). Testing performed on receipt could be incapable of differentiating two given materials. Other incidents of excipient adulteration also have occurred, such as the substitution of glycerol with propylene glycol (6). In addition, several inspections by FDA and European authorities including the United Kingdom’s Medicines and Healthcare Products Regulatory Agency (MHRA) have detected data integrity issues that call into doubt some materials supplied to the European Union and United States as APIs.

That has triggered issuance of the EU’s Falsified Medicines Directive (FMD) and several others in the United States: Food and Drug Administration Safety and Innovation Act (FDASIA), the Drug Supply Chain Security Act (DSCSA), and the Secure Supply Chain Pilot Program (SSCPP) (1–4). The FMD focuses on the procurement of APIs and excipients and product transport, as well as internet sales controls and product-security measures. The FDA focuses more on enforcement and legal elements. But these developments indicate that for those areas outside your direct control, you need to have a strong working relationship with all contracted service providers. Although the documents do not specifically call out components, the coverage is implied. As is customary, the EMA describes things in more detail than does the FDA. So I definitely recommend a close read of the implemented FMD. In summary, they all point to setting up a relationship with your vendor and working  closely with that company to ensure transparency of supply. In your audit, you should examine the controls that a company has in place to ensure that what it delivers to you is what you expect to receive. The relationship goes further than a simple buyer–seller arrangement. You must be well aware of what is going on at the supplier’s operations after completing your vendor qualification program.

Covering the Component Life Cycle
The Q10 document from the International Conference on Harmonisation of Technical Requirements for the Registration of Pharmaceuticals for Human Use (ICH) talks about product life cycle, and FMD talks about API and excipient life cycles (1, 7). I think that now we must begin to consider component life cycles. When you begin to use a supplier, you perform a standard vendor qualification and approval as described above. But the work should not stop there. You need to continue to evaluate your suppliers throughout the period that you use their components.

This needs to be an element of your annual product review, but it also needs to go further than that. Clients need to be tied into their vendors’ development programs and truly work with them as they develop products and change their own manufacturing processes. In other words, you must be integrated into their change control processes. As a supplier contemplates making changes, you must be there to aid in assessing the impact of those changes on your own processes.

If you cannot be that proactive, then at least be aware of when changes are to occur so that you can monitor performance of the materials in your system. If you see a significant performance issue, then you at least will have a set of starting points to begin an investigation of the cause(s). The sooner you get integrated and truly working with your vendors, the better will be the results, and the more proactive you can be.

As the Europeans indicate, it is your product and you are responsible for it, so integrate your company into its supply chain to head off problems. This may sound like an increased amount of work, and you might ask whether your company will truly realize savings in the long run. Just remember that you do have ICH Q9 to help you prioritize what to focus on and in how much depth to consider each element (8). And that risk management may be your saving grace.

References
1 Falsified Medicines. European Commission: Brussels, Belgium, 2011: http:// ec.europa.eu/health/human-use/falsified_ medicines/index_en.htm.

2 Food and Drug Administration Safety and Innovation Act (FDASIA). US Food and Drug Administration: Rockville, MD, 2012; www.fda.gov/RegulatoryInformation/Legislation/SignificantAmendmentstotheFDCAct/ FDASIA/ucm20027187.htm.

3 Drug Supply Chain Security Act (DSCSA). US Food and Drug Administration: Rockville, MD, 2013; www.fda.gov/Drugs/DrugSafety/ DrugIntegrityandSupplyChainSecurity/DrugSupplyChainSecurityAct/default.htm.

4 Secure Supply Chain Pilot Program. US Food and Drug Administration: Rockville, MD, 2013; www.fda.gov/Drugs/DrugSafety/DrugIntegrityandSupplyChainSecurity/ ucm365626.htm.

5 Issue Brief: Heparin — A Wake-Up Call on Risks to the U.S. Drug Supply. May 2012; Pew Charitable Trusts: Philadelphia, PA, 16 May 2012; www.pewtrusts.org/en/researchand-analysis/issue-briefs/2012/05/16/heparina-wakeup-call-on-risks-to-the-us-drug-supply.

6 Coukell A. Protecting Consumers from Adulterated Drugs. Pew Charitable Trusts: Washington, DC, 1 May 2009; www.fda.gov/ downloads/NewsEvents/MeetingsConferencesWorkshops/UCM163646.pdf

7 ICH Q10: Pharmaceutical Quality Systems. US Fed. Reg. 74(66) 2009: 15990– 15991; www.ich.org/fileadmin/Public_Web_ Site/ICH_Products/Guidelines/Quality/Q10/ Step4/Q10_Guideline.pdf.

8 ICH Q9: Quality Risk Management. US Fed. Reg. 71(106) 2006: 32105–32106; www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q9/Step4/ Q9_Guideline.pdf.

BPI editorial advisor Peter H. Calcott, PhD, is president and CEO of Calcott Consulting LLC; 931 Mendocino Avenue, Berkeley, CA 94707; 1-510-316-5700; peterc@calcottconsulting.com.