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Non-GMP Pilot Production

WuXi Biologics non-GMP pilot plant (NPP) was established in September 2011. Located in the Waigaoqiao Pilot Free Trade Zone, Shanghai, it has 1,400m2  clean suite space and offers the following capabilities:

 

  • Material generation, for drug feasibility studies process and method development and early R&D client material requirements (e.g., preliminary toxicology or PK studies)
  • IND-enabling toxicology study material generation and process evaluation for scaling up to GMP 
  • 1 to 3 lots non-GMP Drug Substance (DS) production for NMPA filing, including, process scalability and robustness evaluation 
  • Process scale-up and GMP manufacturing support, including optimization of scale-up strategy, risk assessment and mitigation for eventual GMP production 
  • Late-stage PC study support
  • Non-GMP EOPC cell bank creation
  • Non-GMP formulation buffer preparation

 



The NPP Shanghai site (NPP-SH) has 600m2 upstream non-GMP clean suites and 800m2 downstream non-GMP clean suites. It is equipped with a variety of state-of-the-art process equipment including:

 

  • 7 × 20L/50L WAVE & RM bioreactors for seed culture
  • 5 × 50L + 7 × 200L + 1 × 500L for fed-batch production
  • 50L + 200L bioreactors for perfusion production; 4 × ATF6

 

100% disposable/single-use elements from the seed train to production at all scales.

 

  • Clarification: 

 

    • Alfa Lava Centrifuge x 2
    • Millipore DF Holder: 11m2 x 1, 5.5m2 x 8 and 2.2m2 x 3;

 

  • Chromatography: AKTA Process x 4, AKTA Ready x 1, AKTA Pilot x 3
  • UF/DF: 

 

    • Millipore Smart UF/DF System x 1
    • Millipore UF/DF Holder: 0.1 m2 x 4, 0.5 m2 x 7

Upstream equipment and instruments


Downstream equipment and instruments


 

Since its foundation, the NPP Shanghai site has successfully completed over 500 batches of non-GMP  drug substance for over 260 projects with over a 99% success rate. The pilot plant  has a demonstrated production  capacity of 100 to 120 batches per year.


2014-2020 historical batches and Project number

  • Since its establishment, the NPP Shanghai site has delivered over 500 batches of drug substance for over 260 projects with the successful rate of over 99%.  


 

NPP-SH has delivered over 260 projects with  the  products covering a variety of molecule types. Besides monoclonal antibodies, which comprise the majority of products produced at the site, and increasing number of other products are being manufactured that include mAb intermediates for ADC drugs, bi-pecific antibodies and Fc-fusion proteins. Moreover, the downstream technical platform is capable of handling a wide variety of recombinant proteins, including polypeptides, Fabs, membrane proteins and enzymes.


Molecule type and distribution in all projects at NPP-SH

 

 

  • NPP is capable of handling a variety of biopharmaceutical molecule types.


 

Process scale-up is one of the key roles of the non-GMP pilot plant. At WuXi Biologics, factors including consistent power over volume (P/V), oxygen transfer/utilization rate (OTR and  OUR) and alignment on the timing of turning on the micro-sparger between different scales etc.,  are taken into consideration during cell culture process scale-up. Empirical platform experience, together with scale-up calculation tools built upon kLa  models of various bioreactors, are employed to ensure smooth technology transfer and successful scale-up  of processes from PD scales to 50 L and up to 500 L scale. In addition, comparability of  productivity and product quality attributes between the two scales are evaluated.


 

  • N-1 perfusion in Rocking Motion (RM)  and WAVE bioreactors : 

 

Using  perfusion in N-1 seed expansion is widely used in the industry to realize process intensification and different modes of the production culture. Using a rocking bioreactor for N-1 perfusion process has additional benefit over a stirred-tank reactor coupled with a cell retention device.

 

Advantages include:

 

    • Reducing  the use of disposable stirred tank reactors in the seed train.
    • Supporting the high seeding density in fed-batch and perfusion cultures.

N-1 perfusion to support inoculation of bioreactors at a broad

  • N-1 perfusion provides a high transfer cell density to support inoculation of production bioreactors at different scales, thus a wide range of seeding density can be realized.  

Two stirred-tank reactors can be saved in the seed train of 2000 L production, with N-1 perfusion

 

  • With a rocking bioreactor for N-1 perfusion culture, the last few stages in a typical seed train can be combined into one and some stirred-tank reactors can be saved.


  • PAT: implementation of Raman spectroscopy for automatic control in pilot scale production

 

Raman spectroscopy offers non-destructive, continuous, real-time measurements to monitor the performance during cell culture, thus providing a good PAT tool for biologics manufacturing. At the NPP, multiple case studies have demonstrated that Raman spectroscopy can be utilized together with existing bioreactor controllers to  realize automatic control of a perfusion culture.  

Advantages include:

 

    • Automatic control of VCD stably at 40 × 106 cells/mL in a 45-day perfusion culture, at 50 – 150 L culture volume;
    • Precise and easy-to-operate process in combination with one-point calibration of Delta V controller system.

application of raman spectroscopy in process monitoring and controls

 

  • This case demonstrated that with a Raman spectroscopy probe, the VCD of a perfusion culture can be automatically maintained and remain stable at 40 e6 for  up to 35 days.

  • In-line dilution with ÄKTA 

 

In-line dilution with ÄKTA is widely used in the biopharmaceutical industry, to enable easier purification processes and buffer preparation and improve efficiency.

This technology can also help to improve capacity, realize cost saving and easier buffer delivery. 

 

    • to reduce the demand of disposable bags and tanks in buffer preparation
    • to reduce the space for buffer storage
    • less buffer filtration time

 

conventional Process