From the Editor: Drug Product

This special summer issue serves as an “expression platform” for as many different industry voices as we could squeeze in between our front and back covers. To get even more points of view than our authors could provide, we used a reader survey. The results elucidated in this Drug Product section continue to outline broadly the current working environment of some 200 readers who responded with a focus on formulation, fill–finish, drug-delivery, characterization, analysis, and other drug-product concerns.

After our survey results, authors from the Indo US Organization for Rare Diseases and Jeeva Clinical Trials highlight the need for governments, industry leaders, and advocacy groups to work together in allocating resources and streamlining regulatory processes for developing effective treatments for patients with rare diseases. BPI managing editor Brian Gazaille explores the coming together of therapeutics and diagnostics for cancer immunotherapy with Ofer Sharon of OncoHost.

BPI often makes a distinction between drug-substance and drug-product manufacturing. Even though much analytical work applies to the former, we are including that part of our survey results here for balance and to reflect the continued importance of the substance itself once it goes into formulation, fill and finish. Product quality — which is inextricably tied to safety and efficacy — remains a central concern from beginning to end.

Your Voice Here

Just over a fifth of our survey respondents chose the analytical, quality, and product-development path in our survey. Demographically, nearly 10% reported working in each of the following areas: quality assurance and/or quality control (QA/QC), analysis, formulation, and drug discovery — indicating some overlap among those fields. It is often the case that the smaller the company, the more varied are the analytical functions performed by each of its scientists; alternatively, larger companies devote whole laboratories and departments to specific types of analysis. We summarize the associated survey questions and answers below and thank respondents for their participation in this “expression platform.” Note that percentages are rounded off to the nearest whole number, and some questions allowed respondents to “check all that apply.”

Which analytical methods are most important in your analytical laboratory? Based on weighted averages, polymerase chain reaction (PCR) and immunoassays seem to be the most vital techniques in biopharmaceutical laboratories. Over 2/3 of respondents marked the latter as very important; reliance on the former was most widespread, with less than 10% of respondents marking it as unimportant. Liquid chromatography and spectroscopic systems are tied for a close second place, with another tie for third among gel electrophoresis, analytical filtration, and high-throughput screening. Despite the many interesting conference presentations we’ve seen on the topic, microfluidics and lab chips were listed as no more important than gas chromatography, which typically sees little use outside raw-materials analysis.

What are your biggest challenges in assay development? Respondents indicated that by far (70%), the main difficulty they encounter is a lack of available control/reference materials. Other key challenges include assay validation (47%) and limited sample-volume availability (40%). Reagent variability and assay robustness were tied at 30%, with reproducibility (27%) and variability across users (23%) close behind. Trending and data drift trailed with just 13% of respondents highlighting them.

What types of testing/analysis does your company outsource? We expected clinical-trials management to be outsourced, but fully 60% of responses somewhat surprisingly indicate that more companies manage their own trials. Over a third (37%) do outsource clinical trials analysis. Tied at 33% were preclinical testing, viral safety, and process validation; tied at 23% were formulation, product characterization, and “none.” Only 20% of respondents reported outsourcing raw-materials testing.

What materials still are most affected by supply-chain concerns? Nearly half of our survey participants (46%) reported trouble sourcing chemicals and buffers. Over a third (39%) reported supply issues with instrumentation and formulation excipients/adjuvants, and nearly as many with laboratory reagents (36%). Of less concern were drug-product containers (e.g., vials) (32%), labware and accessories (25%), filling hardware 14%, and “other” (7%). Filters were highlighted most in that final miscellaneous category.

Is your company working with alternative drug presentations? Although nearly half of respondents (47%) said that their companies work exclusively on liquids for injection/infusion, that was the minority if you consider all the others together. About a third of represented companies have lyophilized products. Nearly a third (30%) are working with prefilled syringes; nearly a quarter (23%) with combination products/devices. Less prominent were “other devices” (17%) and coformulations (13%). Development of combination products with bespoke devices is widely understood to be one of the most complicated endeavors that a small innovator can embark upon.

Is your company investigating alternative formulations? Related to the above, a majority of participants (68%) said “none.” The remainder of responses were a bit surprising, with oral delivery coming ahead of the others at 19%. Nasal and ophthalmic routes were tied at 13%, transdermal and inhaled formulations tied at 10%, and buccal delivery tied at 6% with “other” (topical being called out specifically). We find that niche formulations tend to be applied only to certain products for site-specific delivery, whereas systemic delivery of biologics continues to require infusion or injection.

Which activity represents the biggest challenge for your company’s formulation work? Stability studies — a perennial subject of regulatory concern — unsurprisingly accounted for most respondents (62%). Well behind them in the rankings were preformulation testing, excipient/adjuvant availability and compatibility, and outsourcing expertise with new modalities in a three-way tie at 38%. Just behind those was contract development and manufacturing organization (CDMO) availability at 31%.

How much are automation/robotic technologies used in your analytical laboratories? We see automation in most labs now. Nearly half (48%) of respondents reported some use (e.g., for plate handling/reading), and nearly another quarter combined said either “quite a bit (e.g., robotic liquid handlers, automated assays)” or “a great deal (most work involves automated assistance).” Only 28% reported no automation, with their laboratories exclusively using manual assays and liquid handling.

Is your company working to develop companion diagnostics? We found that a slim majority are doing so. Often, that work is performed for particular products based on internal capabilities (15%) or through partnerships (26%), although 11% of respondents’ companies were developing companion diagnostics for all of their products (and all based on collaborations). No one seems to be going it alone to create diagnostics for every therapeutic program. However, nearly half (48%) said that their companies were not pursuing companion diagnostics at all.

Editors’ Perspective

Look for discussions of assay development and product-related impurities analysis in our upcoming eBooks this fall and winter. And our November–December issue and featured report together will cover aspects of product development and formulation and fill–finish. We know that stability is key in formulation of biopharmaceutical products, no matter their presentation or delivery method. Risk management based on data and prior knowledge figures strongly into decision-making. Whether developing processes or products, you can’t manage risks without well-interpreted information on which to base your assessments. Analytical laboratories and scientists are essential to biopharmaceutical development.