Risk Assessment for Single Use Disposable Projects

By Chuck Stock, IPS | January 22, 2014

Building quality and value into manufacturing processes

Conversations about single-use disposable technology are everywhere. This transformative technology has overtaken the industry at a rapid pace. Attracted by the promise of lower facility capital costs, costs of goods sold (reduced operating costs), and increased flexibility, have put pressure on engineers and users to investigate, implement and operate applicable products using this technology as fast as possible. This change greatly impacts the configuration of the manufacturing space as well as how the process train(s) presents risk to the product. It is a paradigm shift that now puts the materials supply chain in the spotlight as a key element in the evaluation of risk, with respect to business continuity and product quality.

This shift is happening quickly — in the late ’90s and early 2000s, it looked like scaling up to bigger bioreactors was going to be the wave of the future. But with the development of cell lines that produce higher protein concentrations and new vaccine technologies that utilize cell culture approaches, the whole manufacturing scale and process balance in the biologics manufacturing plant is shifting. For upstream and downstream processing alike, these changes point to having smaller volumes, faster turnarounds and drive the need for flexibility.

The positives for single-use technology are fairly well known within the industry, and are being discussed at nearly every
pharmaceutical and biotechnology conference, as well as in most engineering and manufacturing conference rooms.

In the enthusiastic debate that has been going on over stainless vs. disposable, there is one undisputed fact; the risk profile has shifted. The movement of the risk profile from factory floor, upstream to the suppliers, may be putting product quality and patients at risk, simply because the manufacturing, quality and engineering departments now have to evaluate situations and processes outside of their current comfort zone and skill sets. When the designed process trains move beyond the well understood stainless steel-based plant and into the plastics-based process plant, the necessary skill sets in order to fully understand the product quality implications of single-use disposables may not be present.

At this point in time, the major product-related quality issues with plastics seem to have focused on the obvious compatibility and stability impact the selected materials (plastic) have on the drug product and drug product ingredients (API, co-factors, supplements and ingredients). There are areas of understanding for end users to develop that may not be within the current engineering, quality, procurement and manufacturing groups’ wheelhouse.

As more and more projects move away from the stainless steel plant based on the use of these enabling technologies, everyone from manufacturing, quality and validation managers to the C-suite needs to ask: How do we handle new supplier supply chains and ensure that we are receiving consistent, timely and quality supply, now and into the future? And how do we ensure that we have the necessary skill sets to evaluate both the single-use technology and their related supply chains?

We will outline a number of questions and approaches to allow you to be more effective with your approach with your single use suppliers. Managers should find the review of skill sets helpful in evaluating existing team and resource needs, and in understanding what to include in your supplier assessments.

Overall Risk Profile Considerations: Containers and the product
So, your engineering teams have taken the big leap! Bids are out, or perhaps you already have single-use technology at work in your processing plant. Since the process is now going to be made in a bag instead of a stainless steel tank, how does the risk profile of the container change with respect to the product?

The basic product critical quality attributes (CQAs) that we all understand are: Purity (lack of all forms of contamination), Efficacy (loss of potency due to chemical, physical or biological interaction), and Quality (cosmetic, appearance, inability to prove compliance).

We know how to address these risks in the stainless plant, as we have decades of experience. With a bioreactor or batching/holding/process tank in the stainless steel plant, in order to maintain those CQAs or mitigate those risks against them, we would take steps in the design engineering and development phase to evaluate and mitigate these well-known risks.

For example, we would make sure that the tank was made from appropriate materials that would resist corrosion and not react with the product. We would ensure that the tank(s) could withstand the rigors of the process without interacting with it. With these and other well-known design stage verifications, we can verify the outcomes of the design, certify those materials and verify the integrity of those materials. With batching tests or pressure/vacuum tests, we can verify the integrity of the system upon installation and on an ongoing basis (based on event-driven or time-driven requirements), using well established integrity tests. Years of experience, data and process knowledge — captured in procedures and practices — have given us a comfort level that once one initially qualifies one of these stainless steel tanks and keeps it in a GMP lifecycle management system (change control, maintenance, etc.), there shouldn’t be a problem.

With processing container integrity in mind, let’s now look to the plastic bags that sit at the heart of the single-use disposable solution. First and foremost, your process container to product risk profile has moved upstream to the manufacturer of the bags. With each bag being essentially your new process tank, the verification of the process container integrity is no longer a one-time event. With a stainless steel process container, one can get certifications from the fabricators, perform initial integrity testing and get the system into the plant quality system and and be “one and done” with that verification. This is simply not the case with single-use plastic bags.

Risk Profile Consideration #1: Plastics Compatibility Issues
Based on the plastic formulation(s) selected, the owner of the drug substance or product performs engineering and quality tests to show that the selected formulation is compatible with the drug substance or product. The methods to do this are fairly well known but specific expertise is needed for proper application: product compatibility tests, toxicology studies and stability studies. Once you verify that the plastic’s formulation is compatible with your product, and contains the proper quality attributes, is the verification of that material actually complete? Not really, because you no longer have a one-time verification event. The reason is that you are now relying on a supplier that gets its  film from another supplier, which in turn, gets its plastic beads from another supplier and so on. Verification of plastics compatibility has now become a level of assurance issue that the bag manufacturer is giving you the same product every time you open a new plastic “bioreactor” in your plant.

That brings in the tracking and tracing issues of plastic bead formulations, the specific polymer blends and quality control needed to attain the desired level of assurance. This assurance is now in the supplier’s hands, but it is still your responsibility is to understand, assess and monitor.

“Chain of custody” is now a key element in your container integrity quality assurance program. Some of the questions to consider are:
1. If you have an accepted and verified formulation of plastic, how is that formulation maintained by your supplier?
   a. What are the quality system elements that address and provide assurance that your suppliers will provide the traceability needed?
   b.  Do you have a Quality Agreement in place with your supplier that defines the elements (like change management) needed to assure quality from your end?
   c.  Do they have a Quality Agreement in place with their source suppliers that drives the quality assurance down to the source supplier?
   d.  What allowable variances in formulation components can occur without putting product at risk?
   e.  How are changes in formulation managed and communicated and what constitutes a change?
2. Can we understand and define the risks associated with the loss of chain of custody on the resins from a quality standpoint?
3. Do you have the necessary skill sets among your quality system auditors, and possibly procurement staff, to ask the correct questions and understand the appropriateness of the answers?
   a. What expertise in plastics, plastic formulations and the film and bag manufacturing process is needed?
4. Does the sterilization process (gamma, ETO, etc.) impact the desired properties of the formulation used?
   a. Was product based testing done with virgin film or film that was exposed to the sterilization method?

Supplier assessments need to be ongoing and you need to have personnel fully capable of understanding the technical and quality profiles of the container manufacturing process to conduct this type of deeper supplier audit.

Beyond quality system auditors, you will need members of the auditing team that understand the industrial engineering aspects of bag manufacturing, plastic resins and integrity of supply chain questions.

Risk Profile Consideration #2: Bag Integrity
Let’s take a look at the actual bag production and the physical bag integrity. Prior to performing a process run in a plastic bioreactor, a number of owners and suppliers have adopted integrity tests based on pressurizing the container with helium and testing with detectors for leaks. This provides assurance of integrity before processing for those that invest in the development, application and validation of this type of testing. Prior to this pre-use testing, there does not seem to be a practical way to inspect each bag as being physically integral. Finding a leak using a helium leak detection set up will still require tear down of the installation and re-installation and testing of a new bag. This is obviously better than a lost run, but it is still a delay and an undesired cost. In addition, other applications in the process stream may not warrant 100% testing but failed bags could impact product quality unknowingly until discovery downstream in the process or upon final product microbial results are presented. In order to develop an understanding of the quality assurance on this CQA — bag physical integrity — the owner needs understand how the bag manufacturer defines, controls and verifies the CPPs that give the respective CQAs (seam seal tear strength, welding characteristics, burst tests values, etc.). Additionally, an understanding of how handling, storage conditions and time in storage affect the maintenance of the bag’s defined CQAs needs to be developed. For example, you would need to understand the plastic film manufacturing and bag manufacturing processes to the point where you can assess if the respective suppliers have applied the appropriate statistical, industrial engineering, and process capability concepts to provide the level of assurance you need to assure that the respective processes are under control and provide a consistent and measurable quality output. Once you have this understanding, then the respective risk management, life cycle issues and processes need to be understood and applied.

1. Does the bag supplier have the respective calibration program to maintain the control of the process parameters?
   a. Is it based on a rationale aligned with process criticality and risk?
   b. What is the basis for its calibration schedules?
2. Does the bag supplier have the respective maintenance program to maintain its systems in a state of proper operational control and condition?
   a. Is it based on a rationale aligned with process criticality and risk?
   b. What is the basis for its equipment maintenance schedules?
3. What component, raw material, in-process and final assembly testing do they do to ensure the defined CQAs are being maintained at each respective process step?
   a. Does the supplier employ the respective statistically based sampling programs?
   b. What are the relevant tests? Burst testing, punch testing, seal tear testing or other types of testing?
   c.  What statistical sampling do they use to “verify” the capability and how does that align with its in-process or batch testing for release of its bags?
4. What is the sealing technology and how well can the supplier explain their knowledge of it?
5. Does the supplier have any data to support a defined storage period and set of conditions to assure that the bag CQAs are maintained?
   a. Will the supplier support you in the determination of this if needed?
   b. Are the storage conditions defined?
   c.  What are the conditions that the final bag is exposed to between final packaging at the supplier facility and your opening the bag before use in manufacturing?
   d. How long before there is a change in the characteristics (CQAs) of the bag?
  • Does it have chemical composition changes over time?
  • Does the plastic stiffen?
  • Does sterilization change the physical properties of the plastic?
Here is an example of how these issues could apply to a facility. Do you have the skill set on your supplier assessment team that understands the variety of different seal types? Thermal seals made with heated bars use a very different technology than sonic welding. This stuff can be pretty esoteric for a traditional pharmaceutical quality engineer, but understanding these technologies and the issues related to attaining a high level of assurance that each seal will be integral is important.

The same concepts carry over to the associated fittings and connections that are part of single-use systems. The bag manufacturer may use pre-molded or pre-assembled components as part of their assemblies or products. The same issues that applied to the welding of the bags themselves also apply to the welding and assembly of these components to the bag assembly or the single use product. Chain of custody on the materials used for these assemblies needs to be assessed and understood as is done for the bag films themselves.
  • Does the bag supplier have a supplier qualification program for their suppliers of key components and raw materials?
  • Are these parts covered under the supplier’s change management program?
  • Does the bag supplier have an incoming quality control program to ensure that parts, components and materials received have the defined quality attributes?
– Does the supplier identify and manage these issues according to a defined set of Critical Material Attributes (CMAs) based on their impact on the final assembly you purchase and its defined CQAs?

These components should be inspected against a defined set of CMAs before they are used in manufacturing. In the stainless steel plant, the bioreactor and critical components are qualified and managed under change control. The verification of each of these critical components is now being done in the bag manufacturing facility. If you have a fitting with a specific set of physical attributes, dimensions (opening size, a lip, etc.), then what is the supplier’s capability to assure that the CMAs are being met at an acceptable level of quality? Ask the supplier to show you their program for defining and assuring that the respective components and raw materials are meeting a set of defined CMAs. You may need to assist your supplier in defining these and managing them.

Your team will want to add skill sets that understand these industrial engineering based applications so that an effective evaluation on the reliability of a supplier’s quality and manufacturing system can be done. This is more important in the use of these single use technologies, as “every bag is your validated container.” 
Getting this skill set on your team can mean a new hire, training, or hiring a consultant. We have identified a number of areas where the drug product manufacturer now needs to have some Subject Matter Expertise applied. So far, these are in plastics manufacturing, process definition and mapping, quality systems, risk assessments and supplier relationship development.

Risk Profile Consideration #3: Business Continuity
One of the most critical considerations that goes untested with bag suppliers is that of business continuity. The ability of any one supplier to supply a critical component is currently a key element of any manufacturing organization. But given the level of technical understanding needed to properly assess the bag supplier, selecting a number of qualified suppliers can be a daunting task. Defining the desired attributes for the named supplier based on the requirements — i.e., answers to questions in previous sections of this article — should be your priority. These can be worked out with the current supplier as an immediate need, but once they are defined, you will need to get a handle on your risk in the supply chain. As you define each potential supplier from a technical standpoint, you need to consider the following from a business continuity standpoint. First up:
  • What percentage of the bag supplier’s business are you?
If your assessment team asks the supplier, “How large a piece of your business are we?” and you learn that you are at 2% and the largest customer is 75% of the supplier’s business, it should raise some flags. If the larger customer demands some formulation changes, how can you be assured that changes in the formulation will be communicated to you? Even tiny changes in formulations can alter the defined CMA (e.g. purity) and this could conceivably affect your defined product CQA that was based on that CMA being maintained. This is clearly a Business Continuity risk factor. If you didn’t know about the formulation change, and the supplier didn’t understand clearly that you wanted to know. . . that’s a problem.

There are other business continuity risks to consider. Some of the questions your assessment team should ask include:
  • Supply chain certainty: Will there be enough bags? How can the bag supplier reassure me on this?
  • If you are only minor percent of the supplier’s business, how can you be assured you won’t be last on the supply list if film supplies or scheduling gets tight?
  • What other products are run on the production line that also runs your bags?
Helping the supplier understand your concerns, risks and needs is clearly a key element of the supplier/buyer relationship. Service-oriented suppliers will ask them by design, but others may not, as they now find themselves supplying plastics to end users that have a different quality profile than their previous customers (the biopharma marketplace may be new to them).

Risk Profile Consideration #4: Facility Risk inside Bag Manufacturers
The manufacturing plant where single-use bags are made are not GMP facilities, although presumably they will be aligned with GMP standards. The FDA’s view is that it is up to the drug manufacturer to qualify their suppliers for components that come in contact with their drug products. The bag manufacturer does not make drug product but supplies components to those that do. They will not be audited by the FDA. With that said, your assessment team may need to assist your supplier in understanding how the GMPs apply to their quality and manufacturing systems. By taking the approaches defined by answering the previous questions, we have taken this approach with respect to the products and the processes that define them. However, how do these established understandings now drive requirements for the level of “qualification” of the supplier’s facility, facility systems and equipment? It would be easy to just require that the supplier provide classical IQ, OQ and PQ verifications for its respective equipment. If you take this approach, you may be blindly asking the supplier to perform tests that may not add value, end up in a quagmire of false deviations, and more importantly, not really evaluating the important variables you need to evaluate.

For this Risk Factor assessment, the key lies back in the defining of the respective CMAs for the supplier’s assembly. Based on the understanding of those respective CQAs and their respective CPPs within the bag manufacturing process, we can then assign those respective elements of the manufacturing facility, facility systems and equipment that need to be defined, managed and verified.
  • How can I make a tube welding, extrusion or CNC machine “GMP” when it is an industrial piece of equipment?
  • Do I need to have my industrial equipment running in a Classified Space? The answer to this one goes back to the issue of the respective CQAs for the assembly and how to control that CQA (particulate contamination), and if that control is best attained through facility design (environmental controls), procedural controls (washing) or a combination. This is done best through a risk assessment and then a decision process on how best to mitigate the risk.
Presumably you have removed the potential for chemical interaction during design, by choosing the correct plastic. Then bag manufacture may need to be done in a clean space to address the potential for particulate contamination. These bags are often terminally sterilized so bioburden is not an issue, but terminal sterilization does not remove particulates. So how do you appropriately assess a bag supplier’s facility? Again, you need a skill set that can assess the operation and facility of the bag manufacturer in a way that can take into account the risk factors to your product. Where will you find these skill sets? This risk management role is a true quality engineering role as well, someone who can take the manufacturing system and align it with the product to remediate risk.
  • What is the level of qualification needed or desired for the facility, facility systems and equipment? Requiring the supplier to do too much in this area will increase costs unnecessarily, waste time or eliminate a potentially good supplier.
  • How can we apply or leverage the quality engineering (or industrial engineering) studies done by the supplier to meet this need for verification? Just because the supplier has these studies in a format that may not look like biopharma protocols or reports, they may be technically applicable and correct. Repeating these for the sake of perceived quality system issues is wasteful. Locate someone with the correct skill set to assess and provide an opinion.
  • Can you provide the supplier with an understanding of what level of facility and facility system “qualifications” are really required based on a risk-based approach? Requiring the supplier to qualify systems to match what you have in your plant will most likely be wasteful, unless the requirements are based on verifying those systems as regards their impact on defined CQAs and CPPs for the respective assemblies and processes.
  • Are you willing to assist them in alignment if necessary to develop the relationship further?
Risk Profile Consideration #5: Get Them To Share!
Single-use suppliers and manufacturers typically will have the best understanding of the respective technologies and their application, but how do you get suppliers to share this expertise and knowledge? The supplier may have the knowledge you need, but because it doesn’t live in the biopharma world of regulation, where everything is documented, the knowledge may all reside within their technical staff. Encourage your team to ask the right questions — and help them to develop the skills to probe and ask follow-up questions. Questions focusing on building understanding and technical knowledge come first. How this knowledge is captured within a quality system comes next. It may be better to work with a supplier that has the right technical knowledge and understanding, but has a quality system that needs to “catch up,” than one that has a great quality system on paper, but comes up short in being able to being a technical partner. Bold and determined inquiry, with a dose of common sense, can go a long way towards knowledge sharing and creating a good working relationship and partnership with your supplier.

Risk Profile Challenge #6: Operator Training
Now, back in your facility, don’t forget that the handling of sterilized disposable bags will require a new set of skills than those required for handling stainless steel bioreactors. These bags need to be received, inspected, stored, moved and handled in a unique and focused manner. They can be heavy and unwieldy.

The issue is to consciously leverage the technical relationship you are developing with the supplier to help you understand how to procedurally control CPPs within your plant. Your operators are now actively involved in the installation of each bioreactor (the bag) and this installation directly impacts the defined CQAs for the bag and its performance. The personnel involved in the receipt, inspection and storage need to be trained in ways conducive to maintaining the assemblies in a specified manner. Questions to be asked may include:

1. What are the proper storage conditions for the assembly?
  • Can they be stacked?
  • How are they to be opened?
  • What are the physical storage conditions required to maintain the approved storage requirements?
2. What are my receipt and inspection practices required to ensure that we are receiving uncompromised assemblies?
3. How to I track and trace the assemblies within my manufacturing processes?
4. How does the unpacking, unfolding and installation of each pre-sterilized bag affect the expected performance?
5. Can the supplier help train your operators to handle these pre-sterilized bags in a manner conducive to maintaining the CQAs of the bag?
6. Is the supplier equipped to help you get set up in the plant so the bags aren’t compromised?
7. Will the supplier visit your plant and help you with logistics and qualitative issues?
8. Can the supplier train your team, and clearly define handling conditions (no sharp instruments etc.)?
9. Can it provide a template procedure or written instructions that you can use to develop your baseline SOPs?

Single-use technology has brought great innovation and promise to our ability to manufacture drug products safely and quickly. But serious consideration must be given to understanding how the end user risk profile has changed, mostly moving upstream to the supplier and in the process itself. Because the changes have occurred fairly rapidly, and much of the technology innovation is happening outside of the end-user plant, teams need to go “outside” — outside to the supplier sites, and potentially outside their own comfort zones and experiences — to ask the right types of focused questions. Getting this understanding of how the risk profile has changed and then applying this understanding may be outside your current supplier assessment team’s wheelhouse. In that case, bringing in the right SMEs from within or without your organization will be necessary. CP

Chuck Stock, CxA, MBA, is senior principal at IPS – Integrated Project Services. He has more than 33 years of process/operations and compliance experience in the pharmaceutical, biotech, and medical device industries. He has successfully started-up, commissioned and validated cell culture facilities, vaccine facilities, oral solids and liquids facilities, bulk chemical and medical device facilities. His experience encompasses facility and system design and qualifications as well as process validation and process development, including start-up and line management in the areas of aseptic processing, blood component processing, in-vitro diagnostics manufacturing, dry power processing, lyophilization processes, cell culture (small and large scale) and protein processing. He can be reached at cstock@ipsdb.com.