5 Step Strategy to Accelerate Biologics Manufacturing and Ensure Robust Scale-Up Process

June 17, 2019

By Biologics Team at AbbVie Contract Manufacturing

“Speed to milestone” – “Speed to Market” – “Speed to Patient” is the universal rally cry and well known for all BioPharmaceutical drug developers.  Companies ranging from small Biotech to large Pharma are constantly driving to shorten development time and gain faster approval for their high quality, lifesaving therapies.  Biologics, such as monoclonal antibodies, fusion proteins, and antibody drug conjugations, present unique and time-consuming challenges when balanced against our collective goal to accelerate development and regulatory approvals.    Biologics add an extra level of complexity, whereby factors such as cell line and analytical development, biologic instability, scale up, and limited capacity may negatively impact time to market and budget outcomes.    

Biologics are defined by their manufacturing process, which requires complete understanding through formal process characterization.1  Process characterization is an essential component of process validation and represents a critical area of importance, yet an opportunity in prompt milestone achievement. Process characterization provides an in-depth understanding of a drug product to establish effective process control strategies and it defines the critical product and process parameters for determining the proven acceptable ranges for efficient manufacturing.

Even a small change to the structure of a biologic during the manufacturing process can result in a significant impact on safety, efficacy and function. Something as simple as a deviation in pH, a temperature fluctuation, a variation in the method of thawing a vial or the switch to a different consumable supplier can affect a biopharmaceutical’s identity, purity or potency. By knowing in advance, the influence of different manufacturing events on a biologic and being able to provide supporting data to back up these occurrences through process characterization, the risk of manufacturing failures and regulatory time delays is significantly reduced.

Process characterization involves the determination of acceptable ranges for many hundreds of parameters to ensure manufacturing consistency by providing a thorough understanding of the process. One approach to the analysis of process characterization data is statistical in nature, yet this requires a significant amount of work and can dramatically extend timelines if the necessary expertise and equipment are not available in-house. Risk-based and failure-mode approaches are also feasible however the former can be limiting since it treats each possible source of failure in isolation, while the latter may be flawed if a potential failure mode is omitted

By establishing a platform approach to process characterization, which has supported the successful approval of several marketed biologics, AbbVie scientists ensure the entire process is robust, right first time, and results in a highly consistent product to facilitate efficient BLA filing. AbbVie’s five-step process below offers a thorough understanding of the biologic and process control strategies to help accelerate time to a robust and reliable commercial scale process.

Step 1: Draft a Master Plan

A detailed master plan describes the manufacture and evaluation of the biologic from start to finish, including strategy and rationale for approaches to small-scale characterization and full-scale validation. Also defining the efforts which will be made to implement and complete the various activities according to current Good Manufacturing Practices (cGMP), the master plan ensures a well thought-out, justified and complete process characterization.

Step 2: Perform Risk Assessments

Risk assessments are performed on process characteristics and product quality attributes to generate a prioritized list of parameters to be evaluated during process characterization. Duplication of work can be prevented by referring to risk assessments carried out for a previous process characterization project.

Step 3: Characterize the Cell Culture and Purification Processes

mAbs are typically produced by cultured cells in bioreactors, from which they are subsequently harvested and purified. Characterization of these processes is broken down into five activities:

Laboratory scale-down models

According to ICH guidelines, small scale models can be used to provide a representation of the commercial process and to support process development studies2. Laboratory bioreactors, chromatography columns and, where feasible, filtration steps are run under conditions that simulate manufacturing as closely as possible. Comparison of scale-down model performance with manufacturing process performance determines the suitability of the scale-down model for subsequent characterization activities.

Process mapping

By using appropriate analytical methods, the quality attributes of the in-process material and bulk drug substance (BDS) are measured and tracked. These include critical quality attributes (CQAs), which are known or highly likely to impact safety or efficacy. Potential CQAs can also be identified.

Proven Acceptable Range (PAR) studies

PAR studies are performed to determine the impact of deliberate variations in relevant operating parameters on unit operation performance (e.g. the effect of bioreactor temperature on cell growth). Most PAR data are generated in bench-scale experiments, although in some cases it is derived from analysis of historical manufacturing data.

In-process sample stability

The stability of in-process samples at anticipated holding steps is investigated to determine the impact of extended hold time on product yield and quality, using relevant assays.

Impurity clearance

Impurities such as DNA, host-cell proteins and process chemicals are undesirable for many reasons (e.g. the presence of HCPs can cause the development of adverse toxic or immunological reactions in a patient). In-process mapping of impurities is conducted to assess the impurity clearance capability of the process.

Step 4: Post-Characterization Risk Assessment

A second round of risk assessments is performed on the process parameters, based on the data generated from process characterization studies. The outcome is a listing of critical and non-critical parameters, as well as a ranking of the critical process parameters.

Step 5: Process Justification Report

Summarizing the overall control strategy for manufacturing the biologic, this report provides justification of the proven acceptable ranges for manufacturing operating parameters. It also represents a basis for process validation. As well as using process characterization data, the process justification report draws on historical manufacturing data.

CMOs as Process Characterization Partners

Stakeholders involved in the clinical development of a Biologic are wise to partner with an experienced CMO, who has the biologics expertise, resource and facilities to handle this important stage of a drug’s lifecycle. Successful process characterization is a critical factor in driving faster progression to regulatory approval and market.

Experienced CMOs offer many advantages. Having performed many process characterization studies on a range of Biologic candidates offers a well-established platform for planning, assessment, analytical studies, data analysis, and review to support market approval. Additionally, an experienced CMO will have in place the necessary, and often costly equipment required for biopharmaceutical testing, accompanying this with a pool of highly experienced personnel.

Access to specialized instrumentation, administered by experts, can streamline process characterization by preventing the need to out-source to different service providers and can also substantially reduce testing time. AbbVie offers wide-ranging expertise in scale-down models, high throughput systems and experimental design.

Thorough process characterization provides a full understanding of the biopharmaceutical and the processes under which it can be efficiently, compliantly manufactured for safety, purity, and potency. This benefits the biologics manufacturer, the regulatory agencies and ultimately the patient. In contrast, process characterization that has not been performed correctly can lead to issues with regulatory compliance or manufacturing performance. These can force costly re-work and substantial time delays in getting to market or can result in tight tolerances for the proven acceptable ranges, greatly restricting manufacturing.

Employing operational excellence and experienced clinical Biologics development teams provide opportunities to compress the development timeline while minimizing the risk profile.  To assist in compressing client timelines and milestone achievement, AbbVie incorporates a proven pharmaceutical methodology using a holistic risk assessment and project needs assessment to construct a flexible project plan and timeline.   Experienced Project Managers and Science &Technology teams familiar with all stages of Biological development are engaged early on during project initiation and Technology Transfer stages.  While time to GMP manufacturing depends greatly upon the stage of development; in general, a typical Tech Transfer to GMP timeline can be accelerated to only five months.  A typical Biologics project may proceed directly from 200 or 500L in Process Sciences directly to 3,000L GMP for clinical and commercial production allowing the client to further reduce time to milestone.2     

AbbVie has commercialized several Biologics based therapeutics and continues to leverage its innovator know-how, expertise, and resources to help our third-party partners meet and exceed their goals:

1. AbbVie Bioresearch Center (ABC) Worcester, MA (1,000L, 3,000L, 6,000L Configurations)

2. AbbVie Bioresearch Ltd (ABL) Barcoloneta, Puerto Rico (6,000L, 12,000L Configurations)

Learn more about AbbVie’s Operations Contract Manufacturing  at Abbvie supports a broad range of contract services including Antibody Drug Conjugations (ADCs), sterile fill finish (lyophilization for potent and biological compounds), fermentation and oral solid dose, contact us to discuss your needs further at 1-847-938-8524 or