Introduction: Drug Product Discussions

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On the cover: A formulator at Rentschler Biopharma (WWW.RENTSCHLER-BIOPHARMA.COM)

Quality by design (QbD), risk management, and new technologies are shaping biologics formulation work in the 21st century. We saw much evidence of this at the BioProcess International Conference and Exhibition in Boston last fall, where a wide range of talks filled the Drug Product, Fill–Finish, and Formulations track during the week after Labor Day.

Dingjiang Liu (Regeneron) offered a high-level discussion from the BioPhorum Development Group (BPDG) on “An Intercompany Perspective on Biopharmaceutical Product Robustness Studies.” Such studies ensure that drug products meet quality standards within established ranges. Liu highlighted common themes found throughout the industry, beginning with overall robustness being defined by both formulation and manufacturing processes. Integrating QbD principles, robustness is important to setting critical quality attribute (CQA) control strategies and commercial specifications. Most companies evaluate robustness and apply prior knowledge, risk assessment, and statistics to develop a drug-product design space. Three case studies illustrated study design balancing experimental complexity, statistical power, scientific understanding, and risk.

Arun Jangda (Shire) drilled a bit deeper into the topic with “A Standardized Methodology for Risk-Based Particulate Classification” from the BioPhorum Operation Group’s (BPOG’s) particulate-control workstream. Critical defects are a leading cause of recalls for parenteral drugs, he pointed out. Because regulatory guidances don’t link risk and particulate criticality, the industry is tightening specifications without scientific rationale. “Uncertainty equates to risk of regulatory exposure and challenge,” he said. After the group surveyed 15 leading global biomanufacturers about their practices, it developed a classification tool now available online.

Focus on Drug Products
The trend toward highly concentrated formulations — especially for monoclonal antibodies (MAbs) — isn’t new. But as Avind Srivastava (Avantor) pointed out in “Managing Viscosity for High-Concentration Protein Formulations,” it still comes with challenges. Viscosity is a major concern, and companies like his are developing novel excipients to reduce solution viscosity and help stabilize proteins. (See the “Talking with Thomas Palm” box for more on this topic.)

Talking with Thomas Palm (Bristol-Myers Squibb)
In BPI’s March 2015 issue, BMS authors Thomas Palm, Erinc Sahin, Rajesh Gandhi, and Mehrnaz Khossravi reported on their work in characterizing “The Importance of the Concentration–Temperature–Viscosity Relationship for the Development of Biologics.” They showed how highly concentrated protein formulations, which are increasingly common for monoclonal antibody (MAb) drugs, can present viscosity challenges especially at the lowered temperatures that are typical for intermediate and finalproduct storage/shipping. Palm is a principal scientist in drug product science and technology at BMS, and recently I asked him to revisit this topic.
We hear a lot about highly concentrated MAb formulations. Are companies exploring this approach with any other classes of biopharmaceutical product that you know of? MAbs are the most common class of biopharmaceutical products and are usually administered in a relatively high dose. Therefore, it is more common to hear about highly concentrated MAb formulations for subcutaneous administration. Because subcutaneous injection adds convenience and patient compliance, it can be viewed as a competitive advantage in a crowded marketplace. So any protein that is intended for such administration can be formulated at a concentration high enough to accommodate dose requirements. I’m sure that many companies are working on this, and soon we will hear more about high-concentration formulations of proteins other than MAbs.
You showed that “viscosity increases exponentially with decreasing temperature.“ What are the resulting effects in relation to freezing/thawing/lyophilization of highly concentrated solutions, in general? I’m not aware of any (negative) effects described for freezing, thawing, or lyophilization as a consequence of increase viscosity near the freezing point. I could imagine that cryoconcentration, for example, may be less pronounced in a more viscous solution than in a freely flowing solution — but I don’t have data to support that.
Highly viscous formulations can foul filters and make pumping difficult during manufacturing, as you described, and it can complicate administration/injection as well. Do we have a general idea of what the related limits are for highly concentrated formulations? This needs to be evaluated individually. For an injectible product, you evaluate what needle sizes, injection times, actuation forces, and so on will be acceptable. Depending on the product viscosity, tradeoffs for those factors may be needed, or a lower formulation concentration or larger injection volume may need to be considered. There is no general guidance, so companies need to evaluate what is acceptable to them and their patient populations (which may differ by disease area and competitive landscape). In manufacturing, likewise, many filter options need to be evaluated individually to develop a robust process.
Because less heat is required to change a protein solution temperature than would be required for pure water, you used water for injection (WFI) as a surrogate for temperature mapping. Can other aspects of formulation use surrogate measurements in this way? Not exactly, but surrogate solutions that match the viscosity of an active formulation — e.g., a polyethylene glycol (PEG) solution — can be used to test manufacturing unit operations or injection times and other functional aspects of delivery device development.
You described viscosity specifications around 90–110% of a set value. How is that center value determined? Are there tradeoffs between patient comfort, safety of the product, and ease of manufacturing? The center value usually is determined based on the dose required for a therapeutic protein and the maximum volume to be injected in the subcutaneous space. Generally, not much more than 1 mL can be injected comfortably without the aid of hyaluronidase or a slow-injecting patch pump. With that in mind, you try to fit the dose in that volume if formulation stability allows. For example, if a 150-mg therapeutic dose is needed, then a 150-mg/mL, 1.0-mL injection could be the design target. Safety issues and/or manufacturing problems then might require tradeoffs to be made: e.g., slightly lower protein concentration with a slightly larger injection volume.
What analytical methods are important in understanding concentration–temperature–viscosity relationships? The only test method needed to understand this relationship is a temperature-controlled viscosity measurement with samples at different concentrations. Knowing these relationships is the first step in successfully manufacturing and administering a highly concentrated protein therapeutic.
For more information, see https://bioprocessintl.com/manufacturing/monoclonal-antibodies/importance-concentration-temperature-viscosity-relationship-development-biologics.

Other speakers focused on excipients as well. In “Role of Antioxidants in Therapeutic Antibodies: Case Studies, Learnings, and Mitigation Approaches,” Ashaben Patel (Janssen R&D) provided case studies illustrating how oxidation affects biotherapeutic safety and efficacy — and how methionine can protect against it. And in “Potential Impact of Nanoparticulate Impurities from Sugars on Therapeutic Proteins,” Anant Sharma and Nats Rajagopalan (Eli Lilly) showed how those common formulation ingredients can cause protein degradation by reacting with UV light. In Lilly’s work, temperature and agitation appeared to have no effects. But the team is performing additional studies in search of a mechanistic understanding.

The box below features a conversation about excipients at the heart of a recent industry merger.

Talking with Ed Maggio (Aegis Therapeutics) and Craig Chambliss (Neurelis)
Ed Maggio is familiar to BPI readers as a proponent of alternatives to polysorbates in biologics formulations (14). Last year, his company Aegis Therapeutics was acquired by neurologically focused pharmaceutical company Neurelis. I spoke with Ed and Neurelis CEO Craig Chambliss about the merger and more.
Aegis’s Intravail technology appears to have played a big part in the recent acquisition. What interested Neurelis in this? Chambliss: “We were extremely impressed with its broad applicability in multiple clinical applications, given the need for noninvasive alternative delivery modes and rapidly acting formulations in a wide range of clinical indications.” Maggio: “Neurelis was one of the first companies to recognize the unique value of this technology for overcoming significant formulation obstacles and addressing significant unmet medical needs.”
Neurelis is focused on central nervous system treatments. Are you offering the technology to companies working in other disease areas and product modalities? Chambliss: “Neurelis remains focused on significant unmet medical needs in CNS diseases and conditions and select rare and orphan drug applications. Other disease areas, including CNS opportunities that extend beyond a targeted neurology focus, provide partnering/licensing opportunities.”
I hear that two Intravail-based formulations are poised for approval. Can you tell me more about that? Chambliss: “Tosmyra (intranasal sumatriptan) was just approved by the FDA this year. It was developed by Promius Pharma, a subsidiary of Dr. Reddy’s Laboratories. In late 2018, Neurelis filed an NDA for Valtoco (intranasal diazepam), with expected approval and launch in 2019. Both products use Intravail science for enhanced drug absorption.”
What about ProTek excipients and HydroGel technologies? Are you applying those to your own formulations, and/or do you have partnerships involving them? Maggio: “The unique ProTek stabilization agent could revolutionize the biologics industry because it affords an opportunity to eliminate or greatly reduce the need for polysorbates. Neurelis is in partnership discussions and intend to continue to offer licenses for both technologies.”
Ed, have you seen companies beginning to rethink their use of polysorbates in recent years — whether in biosimilars or new innovative drugs? Maggio: “We have not seen promotion of excipient alternatives to the polysorbates so far. Companies are interested in our technology for new products but are unlikely to change the formulation of approved products due to the high cost of new clinical studies.”
Do more concentrated formulations face more troubles related to polysorbates than less concentrated products of the past? Maggio: “Absolutely — this is a fundamental problem.”
Do excipients represent an opportunity for creating “biobetters” and/or biosimilars that can compete better with branded drugs? Maggio: “The company that develops that first biobetter with reduced or eliminated immunogenicity and anaphylaxis will own that particular space. A physician is unlikely to prescribe an alternative biosimilar with higher immunogenicity or anaphylaxis potential.”
Finally, Maggio offered a reading list of recent publications on the subject of polysorbate excipients (518).

References
1
Maggio E. Polysorbates, Immunogenicity, and the Totality of the Evidence. BioProcess Int. November 2012.

2 Maggio E. Biosimilars, Oxidative Damage, and Unwanted Immunogenicity. BioProcess Int. June 2013.

3 Maggio E. Alkyl Mono- and Diglucosides: Highly Effective, Nonionic Surfactant Replacements for Polysorbates in Biotherapeutics — A Review. BioProcess Int. March 2016.

4 Maggio E. Polysorbates, Biotherapeutics, and Anaphylaxis: A Review. BioProcess Int. September 2017.

5 Singh SK, et al. Are Injection Site Reactions in Monoclonal Antibody Therapies Caused By Polysorbate Excipient Degradants? J. Pharm. Sci. 107(11) 2018: 2735–2741.

6 Perino E, et al. Xolair-Induced Recurrent Anaphylaxis Through Sensitization to the Excipient Polysorbate. Ann. Allergy Asthma Immunol. 120(6) 664–666.

7 Stark C, et al. Injection Site Reactions to PCSK9i Monoclonal Antibody Therapies Are Caused By Polysorbates in the Products. J. Clin. Lipidology 12, 2018: 562–564.

8 Mridula D, et al. Polysorbate Degradation in Biotherapeutic Formulations: Identification and Discussion of Current Root Causes. Int. J. Pharmaceutics 552(1–2) 2018: 422–436.

9 Buecheler JW, et al. Oxidation Induced Destabilization of Model Antibody–Drug Conjugates. J. Pharm. Sci. October 2018.

10 Yarbrough M, et al. Edetate Disodium (EDTA) As a Polysorbate Degradation and Monoclonal Antibody Oxidation Stabilizer. J. Pharm. Sci. November 2018.

11 Zhang L, et al. Degradation Mechanisms of Polysorbate 20 Differentiated By 18 O-Labeling and Mass Spectrometry. Pharm. Res. 34(1) 2017: 84–100.

12 Martos A, et al. Trends on Analytical Characterization of Polysorbates and Their Degradation Products in Biopharmaceutical Formulations. J. Pharm. Sci. 106(7) 2017: 1722–1735.

13 Gopalrathnam G, et al. Impact of Stainless Steel Exposure on the Oxidation of Polysorbate 80 in Histidine Placebo and Active Monoclonal Antibody Formulation. PDA J. Pharm. Sci. Tech. 72(2) 2018: 163–175.

14 Zhang L, et al. Dual Effect of Histidine on Polysorbate 20 Stability: Mechanistic Studies. Pharm. Res. 35(2) 2018: 33.

15 Hampl V, et al. A Newly Identified Impurity in Polysorbate 80, the Long-Chain Ketone 12-Tricosanone, Forms Visible Particles in a Biopharmaceutical Drug Product. J. Pharm. Sci. 107(6) 2018: 1552–1561.

16 Jones MT, et al. Considerations for the Use of Polysorbates in Biopharmaceuticals. Pharm. Res. 35(8) 2018: 148.

17 Dahotre S, et al. Novel Markers to Track Oxidative Polysorbate Degradation in Pharmaceutical Formulations. J. Pharm. Biomed. Analysis 157, August 2018: 201–207.

18 Majjoubi N, et al. Effect of Nonionic Surfactants (Dodecyl Maltoside and Polysorbate 20) on Prevention of Aggregation and Conformational Change of Recombinant Human IFNbeta_1b Induced By Light. Iran J. Pharm. Res. 16(1) 2017: 103–111.

Keeping Patients in Mind: Highly concentrated formulations present unique questions related to patients’ treatment experience as well — particularly when subcutaneous (SC) injection is the goal. In “Subcutaneous Injection Physiology Research to Improve Biologics Delivery and the Patient Experience,” Michael Harrison (Eli Lilly) showed how the full potential of SC delivery could improve patient care and disease management. But such drugs must be formulated for increased bioavailability as well as safety and efficacy, and they must be delivered with patient tolerability in mind. Harrison emphasized that drug products must “deliver an experience that integrates with patients’ and caregivers’ lives.”

That’s the goal of combination drug–device products, as described by Jeffrey Givand and Steven Persak (Merck Research Labs) in “The Interplay Between User Requirements, Target Product Profile (TPP), and Delivery Device Design Inputs.” Connecting back to higher-level QbD discussions, they showed how a traditional TPP is insufficient to define delivery device requirements when it ignores user capabilities pertaining to the device interface. “Robust collaboration between drug, formulation, and device development teams is critical early (and throughout) product development,” Givand said. Companies need to put the necessary time into innovating or developing required device functionality, especially for highly viscous, large-volume, or lyophilized products.

Focus on Manufacturing Processes
Support technologies are key to the new era in biopharmaceutical manufacturing. In “Advances in Fill–Finish and Drug Product Manufacturing,” Mark Yang (Sanofi) provided an excellent overview of disposables (e.g., vials and fill–finish assemblies), multiformat fillers and isolator technologies, lyophilization with process analytical technology (PAT), drug-product inspections, and modular facilities. And two more speakers highlighted individual process technologies: Frankie Petoskey (Seattle Genetics) with “Impact of Closed-System Transfer Devices (CSTDs) to Drug-Product Quality: The Importance of Comparability Testing,” and Yuh-Fun Maa (Genentech) with “Filling in VaporPhase Hydrogen Peroxide (VPHP) Sanitized Isolators: Uptake and Impact on MAb Drug Product Quality.”

Petoskey’s case study illustrated the need for comparability testing especially when CSTDs are used with potentially hazardous drugs such as antibody–drug conjugates. “CSTD materials of contact are common,” she said. “However, the combination of silicone oil and mechanistic properties of the device can lead to particle generation.”

VPHP increasingly is used for sanitizing fill lines, but companies are realizing that residual presence of the substance could affect product quality. The Genentech group used risk assessment to address it. “Silicone tubing associated with peristaltic pumps is highly permeable to H2O2,” Maa cautioned, “but its uptake behaviors are reversible pending processing conditions and ultimately residual VPHP concentration in the isolator.” Contact time figured heavily into the equation.

Finally, Jia Sun (Genentech) featured a new sample-preparation method with “Progress and Challenges in Automation-Assisted Formulation Development.” The team used an automated liquid handler for design of experiment (DoE) formulation studies. In a case study, they investigated the identities and activities of leachables from containers used in stability studies. “Automation systems bring true benefits to formulation development in both formulation preparation and analytical assays,” Sun said.

Continuing the Discussion
In a sponsored contribution to this special insert on page 10, Rentschler Biopharma reports on its recent market research collaboration with Leukocare that showed the underestimated importance of (but increasing investment in) early stage formulation work, a growing trend toward SC than intravenous (IV) delivery of biopharmaceuticals, and the value of highly concentrated formulations. The authors include a case study featuring a Leukocare formulation platform technology.

At the BPI Conference, Jeremy Duboeuf (Roche) illustrated one trend revealed in those survey results — moving from IV to SC delivery — with his presentation, “Coformulation Development of MAbs and Recombinant Human Hyaluronidase.” Roche added hyaluronidase as a permeation enhancer to assist in SC administration of a highly concentrated MAb formulation, then showed that it did not compromise quality or stability of the robust liquid product that resulted. “Coadministration and coformulations provide patient benefit by reducing treatment time,” said Duboeuf, “and they are less invasive than IV delivery.” His team will be coadministering two different MAb products using the same permeation enhancement technology in future work.

And on page 5, authors from Merck highlight another coformulation project — and the analytical approaches that can assist in development of such products. “Coformulating two or more protein therapeutics into a fixed-dose, single drug product is an emerging strategy for delivering biologics to patients,” they write in their abstract. “Mixing proteins into fixed-dose combinations brings multiple benefits to patients, healthcare providers, and biomanufacturers. Coformulated products do raise additional complexity, however, in terms of formulation and analytical development, product characterization, and immunogenicity assessment. Analytical methods originally developed for individual products need technical advancement for them to adequately evaluate multiple active ingredients in coformulated products. New approaches are required to answer additional questions regarding the mechanisms of degradation, aggregation pathways, and the possible formation of mixed aggregated species in coformulated products. Characterization of fixed-dose combinations of protein therapeutics is a rapidly evolving field that includes defining analytical strategies, developing appropriate analytical assays and tools, and understanding and managing potential product stability risks.”

BPI looks forward to your thoughts and future contributions on these formulation topics and more to keep the discussion going.

Cheryl Scott is cofounder and senior technical editor of BioProcess International, PO Box 70, Dexter, OR 97431; 1-646-957-8879; cscott@bioprocessintl.com.

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