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.
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:
Kristie Zinselmeier, Baxter
- 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.
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.
Vicki 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.
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.