Continuous Processing and Single-Use Systems

2019 BPSA International SummitPRODUCTION DEPLOYMENT COLLABORATIONBIOTHERAPEUTICS

Continuous Processing and Single-Use Systems:

A synergistic tandem


Single-Use Solutions result in a Paradigm Shift

• The combination of the possibility for supporting closed operations with the high frequency of introductions of new single-use solutions designed for continuous processing has inspired a paradigm shift in biopharmaceutical facility design.

• Morten Munk, Global Technology Partner, NNE www.pqri.org


SUS and Continuous Bioprocessing offers a number of synergetic advantages

• Fit for flexibility• Limited clean-up• Reduced room classification

requirements• A leaner footprint


“ Right now, manufacturing experts from the 1950s would easily recognize the pharmaceutical manufacturing processes of today. It is predicted that manufacturing will change in the next 25 years as current manufacturing practices are abandoned in favor of cleaner, flexible, more efficient continuous manufacturing.”

Dr. Janet Woodcock, AAPS Annual meeting, October 2011

Pharmaceutical Manufacturing: The Path Ahead..


Definition

What is continuous manufacturing?Batch manufacturing involves multiple discrete steps. After each step in the process, production typically stops so samples can be tested offline for quality, resulting in hold times.

Continuous manufacturing involves material fed through an assembly line of fully integrated components, moving nonstop within the same facility, eliminating hold times between steps.


21 CFR 210.3

Batch -a specific quantity of a drug or other material that is intended to have uniform character and quality, within specified limits, and is produced according to a single manufacturing order during the same cycle of manufacture

Batch refers to the quantity of material and does not specify the mode of manufacture

Lot - a batch, or a specific identified portion of a batch, having uniform character and quality within specified limits; or, in the case of a drug product produced by continuous process, it is a specific identified amount produced in a unit of time or quantity in a manner that assures its having uniform character and quality within specified limits.

Definitions for both “batch” and “lot” are applicable to continuous processes

FDA definitions of “Batch” and “Lot”


Laboratory determination of final specifications for release

21 CFR 211.165(a): For each batch of drug product, there shall be appropriate laboratory determination of satisfactory conformance to final specifications for the drug product….. prior to release

Documentation of Manufacturing

21 CFR 211.188 Batch product and control records shall be prepared for each batch of drug product produced and shall include complete information relating to the production and control of each batch

Extended investigations of unexplained discrepancies

21 CFR 211.192: The investigation shall extend to other batches…that may have been associated with the specific failure of discrepancy.

Recall situation

21 CFR 211.150(b): Distribution procedures shall include… a system by which the distribution of each lot of drug product can be readily determined to facilitate its recall if necessary

Defining a “Batch” and “Lot”

Why does it matter under GMP?


Regulatory Perspective

Potential Advantages of Continuous Pharmaceutical Manufacturing


• No major regulatory hurdles for implementing continuous manufacturing

• Supportive to the implementation of continuous manufacturing using a science and risk-based approaches

• Steady state operation – a key advantage (consistent quality, reduced heterogeneity)

• Lessons learned by small molecule/Pharma to be applied by Biotech

Continuous Processing GuidanceListening to FDA feedback


FDA EMA PMDAThe 21st Century Cures Act, enacted in December 2016, authorized grants to support studying CM and recommending improvements to the process of continuous manufacturing of drugs and biological products.

FDA’s Emerging Technology Team (ETT) assists companies that want to implement innovative technology, including Continuous Manufacturing, for manufacturing both new and existing drugs. FDA encourages adoption of this technology by engaging with firms interested in using Continuous Manufacturing.

Innovation Task Force (ITF)-platform for early dialogue scientific (Q, NC, clinical), regulatory and legal

CHMP Scientific Advice- official advice from the CHMP on appropriate tests and studies

PAT team-support of PAT and QbDactivities in the EU

EMA SME office – dedicated support to small pharmaceutical companies

PMDA Innovative Manufacturing Technology Working Group - The purpose of this WG is to discuss regulatory issues related to quality assessment and GMP inspection to facilitate the introduction of innovative manufacturing technologies while ensuring appropriate quality.Continuous manufacturing is our primary target.

Regulatory Bodies Support Continuous Manufacturing

ICH Q8, Q9, Q10 and Q11, and PtC: principles apply to enhanced development, manufacturing and controlstrategy approaches including continuous manufacturing

https://www.gpo.gov/fdsys/pkg/PLAW-114publ255/pdf/PLAW-114publ255.pdf


• Raw material properties (and lot to lot variability)à Specifications!• Process dynamics: Residence Time Distribution (RTD)• Material traceability

• State of control, Detection of disturbances

• Segregation of material• Design spaces – potential interaction between steps• Scalability (equipment design)

Continuous Pharmaceutical Manufacturing

Scientific Challenges - Drug Development considerations

Some traditional concepts might need to be further explored and process description may look different


• Systems and controls: automated valves, feed-back and feed-forward controls

• Flow rate of process

• In-process controls and sampling considerations different from batch process

• Routine use of PAT tools

• Use of models (first principles, empirical): intention and relevant for routine production?

Continuous Pharmaceutical ManufacturingScientific Challenges – Manufacturing and Control Strategy

The definition of a batch should be stated prior to manufacture

ICH Q7 “A specific quantity of material produced in a process or series of processes so that it is expected to be homogeneous within specified limits. In the case of continuous production, a batch may correspond to a defined fraction of the production. The batch size can be defined either by a fixed quantity or by the amount produced in a fixed time interval”.


• Procedures for start up/shut down and interruption

• Control strategy is product and process specific, may be different to that for batch model

• Procedures for handling deviations and non-conforming material (segregation points, how is segregation decided?)

• Real-Time Release Testing (RTRT): Parallel testing and plan for end product testing when PAT data is not available (back-up/redundancy)?

• Process validation strategy: traditional process validation or Continuous Process Verification (CPV), based on data rich environment of PAT-enabled continuous manufacturing

Continuous Pharmaceutical ManufacturingScientific Challenges – Manufacturing and Control Strategy


Continuous Pharmaceutical ManufacturingScientific Challenges – Equipment

EquipmentLocation of diverting valves

Potential fouling?

Design/ engineering: larger contact surface

Plans for maintenance?

Strategy for cleaning validation?

Location of PAT tools

Indicators of equipment failure?

Potential for microbial growth?

Mainly discussed during pre-approval inspection in Europe


• 20 biologic drug products produced in perfusion cell culture processes have been approved

• Three molecule classes dominate this group: 30% are enzymes, 30% are antibodies, and 20% are coagulation factor VIII variants

Perfusion processes

FDA approved drugs


Widely used today for commercial manufacturing of complex/labile proteins, such as enzymes, blood factors and, in some cases, mAbs

Mab Production

Upstream Continuous, Downstream Batch


Recently explored at development and pilot scale

Mab Production

Upstream Batch, Downstream Continuous


Advantages:

1. Elimination of large hold tankage (including clarification unit operations) between the bioreactor and the capture step.

2. The implementation of continuous capture results in 1-2 orders of magnitude reduction in column size and lowers buffer utilization, which is particularly important when the capture step employs columns of large diameter.

Mab ProductionContinuous bioreactor and capture followed by batch (post-capture) downstream


Additional efforts are required:• Viral inactivation and clearance systems• Robust UF/DF system• Interfaces between unit operations

Mab Production

Fully integrated Continuous Process


• Regulators are supportive of innovative biopharmaceutical manufacturing, including continuous manufacturing (CM). However, there is a lack of experience

• Regulators encourage the implementation of continuous manufacturing using a science and risk-based approach

• Current regulatory framework is adequate to allow CM. No specific guideline currently available, but existing guidelines are supportive.

• CM offers advantages over batch manufacture. Additional considerations may need to be explored.

• Regulators need to understand the product and process development, manufacturing and process control strategy (and decision making).

Concluding Thoughts


What’s Next?

• How can BPSA help?• What are the single-use challenges, gaps, education to address?• Examples: Robustness of systems, automated systems, sensors…

• Initiation of Project with interested team members• Definition of Project Charter (Scope)• Start Work for Deliverables

Documents

Continuous Processing and Single-Use Systems