Considerations in Biopharmaceutical Outsourcing

Because of the complexity of the manufacturing processes for biologics, transfer of these processes to a contract manufacturer presents challenges. BioPharm International asked representatives of leading CMOs about these challenges, and about how the relationship between CMO and sponsor is evolving. Participating in the roundtable are: Kristie Zinselmeier, senior director of marketing, BioPharma Solutions, Baxter Healthcare Corporation; Vicki Wolff-Long, general manager at Cangene BioPharma; Kent Payne, PhD, vice-president and general manager of the biologics business of Catalent Pharma Solutions; and Krishnan Sampathkumar, PhD, associate director of drug product formulation and process development, Global Biologics R&D, at Hospira.

KEY CHALLENGES

BioPharm: Biologics are clearly more complex to manufacture than small-molecule drug products. What would you say are the key unique challenges associated with biopharmaceutical contract manufacturing? In your company's experience, how can a CMO best deal with unique regulatory expectations in this regard?

Zinselmeier (Baxter): Key unique requirements associated with biopharmaceutical manufacturing include:

• Product sensitivities: temperature, silicone, light, oxidation, and hydrolysis (i.e., solution stability)

• Cold-chain management: control and monitoring, frozen/refrigerated storage, and preformulated bulk (aseptic processing)

• Processing limitations: time out of refrigeration (TOR) tracking and exposure limits with regards to temperature, silicone, light, oxygen, and so forth.

Kristie Zinselmeier, Baxter

We believe that planning during the development phases helps support the unique regulatory requirements for biologics. By understanding the needs of the molecule and having the proper infrastructure, experience, and support, we strive to successfully comply with the regulatory expectations of our clients.

Wolff-Long (Cangene):

• Scale-up. In many cases, customers have only worked with bulk batches of less than 10 L, and during scale-up of the bulk, issues can be seen during fill/finish, such as precipitation.

• Time at room temperature. In many cases, customers don't have enough knowledge about stability of the bulk to support fill/finish and will require impractical processes—because they don't have the data to support a more efficient process.

• Sterile filtration. In some cases, sterile filtration of a biologic can be sensitive to flow rate and time.

• Lyophilization cycles. In some cases, no optimization work is performed on the lyophilization cycle, and it can be extraordinarily (and unnecessarily) lengthy.

Vicki Wolff-Long, Cangene

With regard to regulatory expectations, studies are required—even if the data is obtained through engineering runs. A rationale must be in place to pass the inspection—and the regulatory agencies hold both the customer and the CMO equally accountable for a well-characterized process.

Payne (Catalent): We've chosen to use single-use bioreactors to allow for greater flexibility. We also partner in various geographies to meet customer and regulatory needs, for example, our recently announced partnership with Toyobo Biologics in Japan. Another key challenge is making sure that protocols are strictly adhered to and that data are communicated to customers in a way that makes it easier for them to have complete discussions with regulatory agencies.

Kent Payne, Catalent

Sampathkumar (Hospira): Key challenges in biologics manufacturing include:

• Maintaining lot-to-lot biologic drug product consistency and reducing process heterogeneity due to raw material and process changes;

• Ensuring robustness of the process in controlling critical quality attributes (CQAs) of biologics within acceptable ranges/specifications;

• Developing capabilities to handle low (potent) and high concentration (highly viscous) stress-sensitive protein formulations. This also translates to being on top of cutting-edge technologies to ensure fill accuracy at low volumes, zero or very low air gap, or minimal material contact surface exposure.

• Controlling particulates (sub-visible and visible) to alleviate potential immunogenicity concerns

• Being involved in active discussions with regulatory agencies or be updated regarding change in regulatory expectations to plan adequately and appropriately

• Ensuring that the organization is on top of the quality-by-design (QbD) expectations and process analytical technology (PAT) development

• Voicing manufacturing concerns or current technology gaps to meet the unique expectations at public forums and to regulatory agencies.

SPONSOR EXPECTATIONS

BioPharm: How have sponsor companies' expectations for biopharmaceutical contract manufacturing changed over the past three to five years? Please provide an example or two. What do you think led to these changes?

Zinselmeier (Baxter): We have seen an increased interest in the use of disposables (i.e., single-use systems) for biopharmaceutical manufacturing. This approach has the potential to save the client time and money, but introduces a new set of challenges related to compatibility of the disposable materials and the formulation. Disposable providers have been publishing information relative to this topic and this has been very helpful. Our clients have shown interest in this technology for the advantages it potentially offers for project timelines.

Additionally, a larger trend in contract manufacturing is the standardization of processes during clinical manufacturing, which applies to biopharmaceutical manufacturing as well. Clinical manufacturing is challenging in that, generally speaking, there are many manufacturing unknowns. Much of this uncertainty is due to the timing, because process work has not been fully developed at this stage. What we have seen is an increased understanding that there is benefit to standardizing whatever you can for clinical projects, creating a tool kit so to speak. One example is identifying particular vials, stoppers, and syringes that will be used in clinical manufacturing. It seems simple, but we have found that it requires commitment from the technical teams, and there has been interest in implementing this type of system in order to reduce project timelines.

Payne (Catalent): Expectations related to the quality attributes of a facility (i.e., fit and finish and material flow) continue to rise, as do expectations related to on-time delivery. Companies like ours that have a track record of reliable delivery and that continue to invest in facility upgrades are rewarded by our customers with repeat business. Our customers' expectations vary dramatically. We add value through regulatory expertise and by helping them with risk-benefit discussions associated with their projects. We believe solutions need to be tailored to a company's needs.

Sampathkumar (Hospira): Sponsor companies have increased expectations for contract services mainly due to increased QbD and regulatory expectations in recent years. The failures or warning letters associated with commercial biologic products (even those in the market for more than a decade) as well as with manufacturing plants have led to these changes.

One specific examples of clients' expectations are having integrated sterilization and drug product filling lines. Another is that increased concerns about the immunogenicity potential of subvisible particles in biologics has led to more stringent requirements in particulate control in the drug product.

QUALITY-BY-DESIGN

BioPharm: Along these lines, have you witnessed more interest in QbD approaches from sponsor companies? Has your company applied a QbD approach to date or does it plan to?

Zinselmeier (Baxter): We are starting to see clients identify critical quality attributes of their product which we can then integrate into the manufacturing process and related validation activities. Clients have an intimate understanding of their product, and we can help them identify attributes that affect the manufacturing process and therefore implement a QbD approach.

Wolff-Long (Cangene): From the sponsor companies, no. From the regulatory agencies, absolutely. It is not feasible to fulfill the regulatory requirements without cooperation from the sponsor companies.

We are building QbD into our quality systems at this time—but more around the facility and equipment. As a CMO, we can't understand the technical details and history of the product, so it will take careful planning and more partnership when developing and defining the actual manufacturing process parameters.

Payne (Catalent): Yes, we have applied QbD for several years across our various platforms and are committed to continuing to do so.

Sampathkumar (Hospira): QbD should be an integral part of manufacturing operations at any biologic manufacturing facility. Implementation of QbD may initially require increased diligence and resources to understand process impact on product quality (especially CQAs). However the benefits to business include substantial reduction of batch failures as well as savings associated with number of successful runs; improved quality environment; and better credibility with client companies and regulatory agencies that will aid in increased business versus other CMOs.

CHANGING SERVICE PORTFOLIOS

BioPharm: There has been a trend among many large companies to consolidate suppliers. Has your company changed its offerings, or is it considering do so, as a result of this new outsourcing environment?

Zinselmeier (Baxter): We have always had what we considered to be a broad service and technology offering. We proactively looked at those services valued by our clients that enable provider consolidation. We believe there is mutual benefit and efficiency to the preferred provider model and strive to create a portfolio approach that enables clients to use BioPharma Solutions for many projects. The reduction in cost and risk for our clients has been well documented. For example, we have seen one pharma client reducing service providers from more than 60 to five during the past seven years. This has required incredible coordination and commitment to the desired benefit, and seems to be a trend that is accelerating.

Payne (Catalent): We focus on providing integrated services from gene to market and continue to invest/partner in order to expand our offerings. By providing a breadth of solutions, our customers demand we create more valuable relationships with them. Beyond our own innovation efforts, partnering with companies such as CEVEC with their CAP human cell line and Xencor's humanization technology is another way we have expanded the tools available to our customers.

BioPharm: Capacity, and specifically overcapacity of biological API manufacturing, is another hot topic in outsourcing these days. In your experience, how can a CMO best take advantage of potential overcapacity? What key considerations need to be taken into account to remain competitive in this regard?

Payne (Catalent): Our customers are looking for integrated solutions; we do not believe a business model that provides capacity alone will be successful. We have looked to leverage existing capacity in new geographies through partnership in addition to internal capacity expansion efforts.

SUPPLY AND DEMAND

BioPharm: Are there areas in which outsourced biopharmaceutical services demand continues to exceed supply?

Zinselmeier (Baxter): When considering service demand you also need to include another variant—the timing of the need for that capacity. Ideally, each party would have a robust understanding of future volume requirements and would be able to manage capacity to meet this demand. We all know that is a difficult paradigm to manage. There is often a critical need for capacity in a shortened time horizon, and this creates challenges for all parties and results in a demand imbalance. The manufacturing services space has been especially turbulent this past year, with providers exiting due to financial constraints and regulatory issues. This can create upheaval and is a recent example of the situation mentioned here.

Wolff-Long (Cangene): Areas where demand exceeds supply would perhaps include fill/finish of cytotoxics, and also medium scale syringe filling for small niche drugs, which is a core competency at CBI.

Payne (Catalent): We are expanding in order to meet the increased demand from our GPEx technology customers. Especially in the early development and manufacturing phases, there are more options and less capacity issues.

CMOS' FUTURE

BioPharm: From a CMO perspective, where do you see biopharmaceutical outsourcing in five to 10 years from now? What key changes may have occurred by then?

Zinselmeier (Baxter): As the volumes associated with biopharmaceuticals evolve, we believe we will see the need for more flexible manufacturing. New drug approvals will continue, but the volume associated with each particular molecule is decreasing. This requires a shift in capacity and services so that manufacturing resources can adapt to the new requirements and remain an efficient option for pharmaceutical clients.

Wolff-Long (Cangene): I think that large pharma will continue to outsource and provide opportunity for CMOs. One of the key challenges continues to be alignment of quality systems at the CMO and sponsor companies. In the environment of continuous improvement, change is absolutely required for compliance, but at the same time, change requires varying levels of review, documentation, and notification that can constrain implementation of new processes.

Payne (Catalent): Over the next few years, outsourcing will continue to grow as big biotechs want less risk of overcapacity in manufacturing. We will also see a stronger presence globally serving local geographies. Working with partnerships to address global needs locally is an approach we have ourselves taken, for example, our partnership with Toyobo Biologics. There will continue to be a focus on speed, which benefits from technologies like Catalent's GPEx expression platform. We expect to see further improvements in downstream processing innovation.

Sampathkumar (Hospira): The changes that I foresee in biopharmaceutical outsourcing over the next 5–10 years are:

• Low cost, high speed production of high quality biologics as margins as well as quality become important for biosimilars/biologics production.

• Mandatory requirement for implementation of key Qbd concepts (i.e., process understanding/characterization; impact on CQAs) in biopharmaceutical outsourcing.

• Increased need for process analytical technologies (PAT) and automation (e.g automated visual inspection).

• Better risk management in terms of alternate vendor assessment for raw materials.