Classifications

• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
  • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
  • C12Q1/70—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving virus or bacteriophage
  • C12Q1/701—Specific hybridization probes
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
  • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
  • C12Q1/02—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving viable microorganisms
  • C12Q1/22—Testing for sterility conditions
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
  • C07K1/14—Extraction; Separation; Purification
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
  • C07K1/14—Extraction; Separation; Purification
  • C07K1/16—Extraction; Separation; Purification by chromatography
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
  • C07K1/14—Extraction; Separation; Purification
  • C07K1/36—Extraction; Separation; Purification by a combination of two or more processes of different types
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
  • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
  • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
  • C12Q1/6806—Preparing nucleic acids for analysis, e.g. for polymerase chain reaction [PCR] assay
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
  • A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
  • A61L2/0011—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using physical methods
  • A61L2/0029—Radiation
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
  • A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
  • A61L2/0082—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using chemical substances
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
  • G01N2333/005—Assays involving biological materials from specific organisms or of a specific nature from viruses

Definitions

• the invention achieves this object by provision of a method for validation of continuous viral clearance comprising the steps of:
• step d sampling the spiked probe, and e) analyzing the sample of the spiked probe of step d).
• This method has the advantage that it allows for a simple and inexpensive validation of continuous viral clearance.
• validation refers to the process of establishing evidence or a high degree of assurance that a specific process, method, or system will consistently produce a result meeting pre-determined acceptance criteria.
• a continuous process refers to the fact that the validation is carried out continuously as the probe is processed. In contrast in a "batch" method, a complete charge of a probe, e.g. a product, would be validated at a given time point.
• a continuous process refers to a process for carrying out at least two process steps in series, whereby the second process step starts processing the probe before the first process step is completed.
• yield refers to the removal of viral particles or inactivation of viral particles.
• the step of performing viral clearance results in less viral particles being present in the probe and/or the viral particles are no longer capable of infecting cells especially host cells, i.e. they are inactivated.
• probe refers to a substance potentially containing viruses.
• spiking refers to deliberately increasing the amount of viral load substantially.
• virus is used interchangeably with the term “viral particle” and refers to an agent that is smaller than a bacterium and that can only reproduce after infecting a host cell.
• concentration of viruses in a given sample is extremely low.
• low levels of impurity may be negligible, but because viruses are infective impurities, even one viral particle may be enough to ruin an entire process chain. It is for this reason that special measures must be taken to determine the appropriate removal or inactivation method for whatever type of virus is being extracted from whatever type of probe.
• Spiking studies were created specifically for this purpose.
• a spiking study is a study done in order to determine the possible methods of viral removal, i.e. clearance or inactivation. They rely on the principle that increasing the viral count (or level of activity) of a probe by a factor of 10 4 or 10 5 of the original will only change the virus removal/inactivation ratios by one order of magnitude. From this knowledge, spiking studies known in the state of the art have been created in which the virus number (or level of activation) is increased or "spiked" by a factor of 10 4 or 10 5 of the original probe. A probe with this new high number or level of activity is then typically subjected to the clearance method of choice.
• VI volume of spiked feedstock prior to the clearance step
• Tl virus concentration of spiked feedstock prior to the clearance step
• ⁇ V2 volume of material after the clearance step
• T2 virus concentration of material after the clearance step.
• valid manner refers to the fact that the spiking needs to be carried out reproducibly and the desired level of viral particle load has to be always ensured.
• the viral clearance method needs to take the special features of a continuous process into account, e.g. varying pH levels, residence time, temperature, additive concentrations, homogeneity of the solution and conductivity.
• the probe is a stream and/or a product stream.
• stream refers to a continuous flow of liquid and/or gas.
• product stream refers to a stream comprising a product.
• the probe is a product stream.
• This product stream for example flows from one unit operation to another unit operation until the product has reached the desired characteristics.
• the probe is a stream. This stream may for example be a stream entering a production process.
• the same production process may comprise both the method for validation described herein, wherein the probe is a product stream and the method for validation described herein wherein the probe is a stream.
• the reduction factor needed for a certain stream and/or a product stream is dependent on many different factors, some of which include:
• the step of spiking the probe in a valid manner is carried out using a connector e.g. a Y junction and/or a T junction.
• no mixing unit is used to mix the stream and/or product stream and the spiking material.
• a static mixer and/or a mixing vessel or vessel without mixing is used to mix the stream and/or product stream and the spiking material.
• the step d) of sampling the spiked probe comprises sampling for a predetermined period of time.
• This embodiment is advantageous as in takes into account that in a continuous production process the product stream can be subject to periodically fluctuating conditions in different unit operations e.g. with regard to the pH value, conductivity or product concentration.
• the product stream is an eluate of a continuous chromatography and a coiled flow inverter (CFI) is used for viral inactivation.
• CFI coiled flow inverter
• the sampling for predetermined period of time i.e. a fixed sampling duration has the effect that influences of the fluctuating pH resulting from the continuous chromatography are excluded.
• the sampling duration is set to one switch time.
• switch time refers to the time in which the continuous chromatography elutes a specific column before switching to the next column for elution.
• switch time Via setting the sampling duration to one switch time, the complete collection of the expected pH levels resulting from the continuous chromatography is collected. In other words, via sampling over a predetermined period of time, e.g. a switch time, the periodically fluctuating conditions are taken into account.
• the result may be falsified or not reproducible depending on whether a sample is taken at a moment in time when the product stream leaving the continuous chromatography is at a high pH level compared to a moment in time when the product stream leaving the continuous chromatography is at a low pH level.
• the step of sampling the spiked probe comprises sampling for a predetermined period of time, e.g. a switch time, whenever the unit operation preceding the viral inactivation has periodically fluctuating conditions.
• the probe comprises at least one component selected from the group consisting of a peptide, protein, a small molecule drug, a nucleic acid.
• peptide refers to a polymer of amino acids of relatively short length (e.g. less than 50 amino acids).
• the polymer may be linear or branched, it may comprise modified amino acids, and it may be interrupted by non-amino acids.
• the term also encompasses an amino acid polymer that has been modified; for example, by disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation, such as conjugation with a labeling component, such as but not limited to, fluorescent markers, particles, biotin, beads, proteins, radioactive labels, chemiluminescent tags, bioluminescent labels, and the like.
• protein refers to a polypeptide of amino acids.
• the term encompasses proteins that may be full-length, wild-type, or fragments thereof.
• the protein may be human, non- human, and an artificial or chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non- naturally occurring amino acid polymer.
• the protein is a therapeutic protein.
• therapeutic protein refers to a protein that can be administered to an organism to elicit a biological or medical response of a tissue, an organ or a system of said organism.
• the protein is an antibody.
• antibody refers to a binding molecule such as an immunoglobulin or immunologically active portion of an immunoglobulin, i.e., a molecule that contains an antigen-binding site.
• small molecule drug refers to a low molecular weight ( ⁇ 900 daltons) compound that may help regulate a biological process.
• nucleic acid refers to deoxyribonucleotides or ribonucleotides and polymers thereof in either single- or double-stranded form. Unless specifically limited, the terms encompass nucleic acids containing analogues of natural nucleotides that have similar binding properties as the reference nucleic acid and are metabolized in a manner similar to naturally occurring nucleotides. Unless otherwise indicated, a particular nucleic acid sequence also implicitly encompasses conservatively modified variants thereof (e.g. degenerate codon substitutions) and complementary sequences as well as the sequence explicitly indicated.
• a coiled flow inverter (CFI) was used for viral inactivation. It was constructed to deliver a defined minimum residence time.
• minimum residence time refers to the time which a single virus/viral particle at least remains in a given device, e.g. the CFI.
• the step of spiking the sample in a valid manner comprises spiking the sample after homogenization.
• the term "homogenization” refers to a unit operation which ensures that the one or more characteristics of the probe that is important for viral clearance is consistent within the probe. For example, if the probe is a product stream, the unit operation prior to viral clearance is a continuous chromatography and the characteristic of the probe that is important for viral clearance is a pH value the homogenization ensures that the entire product stream when leaving the homogenization is at the same pH level. In a preferred embodiment the homogenization is conducted in a homogenization loop.
• homogenization loop refers to a continuous stirred tank reactor (CSTR) constructed from tubing.
• CSTR continuous stirred tank reactor
• the homogenization loop does not consist of one large tank with a stirring device but rather of an circular arrangement of tubings through which the stream is pumped. Since the internal volume flow is higher than the inlet and outlet flow, a good mixing of the incoming stream is achieved.
• the viral clearance of step c) is a viral inactivation.
• This viral inactivation is preferably carried out at a pH level ⁇ 4. Viral inactivation at these conditions has the effect that given a suitable residence time it reliably inactivates large enveloped viruses.
• the viral clearance is a viral inactivation, which is carried out in a coiled flow inverter (CFI).
• CFI coiled flow inverter
• This viral inactivation is for example carried out at a pH level ⁇ 4 in a CFI.
• Using the CFI is advantageous since it ensures that the residence time needed for viral inactivation is reliable and reducibly ensured.
• the viral inactivation is carried out at a pH level ⁇ 4.
• viral inactivation may also be achieved using solvents and/or detergents such as tri(n-butyl)phosphate and Tween or Triton X-100 or other inactivating chemicals such as iodine or beta-propiolactone.
• solvents and/or detergents such as tri(n-butyl)phosphate and Tween or Triton X-100 or other inactivating chemicals such as iodine or beta-propiolactone.
• viral inactivation using the CFI may also be achieved via irradiation and/or precipitation, e.g. using caprylic acid.
• a combination of viral inactivation via low pH treatment and using solvents and/or detergents and/or irradiation and/or precipitation may be employed.
• step c) the viral clearance of step c) is carried out in a plugged flow reactor, a straight tube and/or a straight helix in addition or instead of a CFI.
• the step of sampling the spiked probe comprises back to front sampling.
• back to front sampling refers to a method in which sampling is started at the end of a process and then progresses towards the start of said process.
• back to front sampling means that the first samples are taken at or near the outlet of the CFI, then sampling progresses towards the inlet of the CFI, i.e. against current flow in the CFI.
• sampling within the CFI leads to a disturbance of the internal flow patterns. Therefore, the sampling method had to be chosen carefully in order to guarantee valid results also for this reason. Thus, in the example described below sampling was started at XM18 and ending with XM12 (cf. FIG 3).
• the step of sampling the spiked probe comprises immediately neutralizing each probe drop when it enters a sampling container.
• the feature of immediately neutralizing each probe drop when it enters a sampling container can be achieved via filling the container with a buffer that immediately shifts the pH value to ⁇ pH 7, for example 2 M Tris buffer.
• samples are taken via threeway stopcocks.
• any method of withdrawing a sample may be used which allows to take samples without interrupting the process, e.g. T junctions may be used or the tube of the CFI may be successively shortened.
• the step d) analyzing the sample of the spiked probe comprises determination whether viral particles are present.
• This determination can be carried out via and method that allows the increase in numbers of viral particles and their determination for example using standard methods known in the art such as next generating sequences and/or other PCR-based methods in combination with sequencing methods.
• step d) - analyzing the sample of the spiked probe - comprises quantification of the viral particles.
• virus quantification involves counting the number of viruses in a specific volume to determine the virus concentration via methods such as plaques assay, focus forming assay, endpoint titration - also termed endpoint dilution assay - protein-based virus quantification assays, transmission electron microscopy, tunable resistive pulse sensing, quantitative PCR and/or large volume plating.
• said quantification of viral particles is achieved via endpoint titration and/or large volume plating.
• Endpoint titration also termed endpoint dilution assay - quantifies the amount of virus required to kill 50% of infected hosts or to produce a cytopathic effect in 50% of inoculated tissue culture cells.
• tissue culture Infective dose TCID50
• TCID50 tissue culture Infective dose
• host cells are plated and serial dilutions of the virus are added. After incubation, the percentage of cell death (i.e. infected cells) is manually observed and recorded for each virus dilution, and results are used to mathematically calculate a TCID50 result.
• Two methods commonly used to calculate TCID50 are the Spearman- Karber and the Reed-Muench method.
• LVP Large volume plating
• the cleared virus is a large enveloped viruses.
• disposable equipment is employed.
• the present invention relates to the use of the method for validation described herein in a continuous process for the production of therapeutic proteins.
• CFI coiled flow inverter
• the overall plant setup can be seen in Figure 1.
• the low pH viral inactivation step is placed after the chromatography unit.
• the elution profile of the Tarpon BioSMB chromatography unit shows a periodically fluctuating pH level between the elution buffer (pH 3.1) and the wash buffer (pH 7.0).
• the homogenization loop can be understood as a continuous stirred tank reactor( CSTR) leading to pH levels constantly below 4.
• CFI coiled flow inverter
• the concentration measurements were normalized to 1 and limited to values between 0.5% and 99.5% of the maximum value.
• the average residence time was determined by numerical integration using the trapezoidal rule. The residence time was then normalized to one with the help of the average residence time.
• the relative width Rw was calculated according to equation 1. ⁇ 0.005 and ⁇ 0.995 hereby represent the dimensionless time points were 0.5% and 99.5% of the maximum dimensionless concentration is reached. The relative width therefore shows how narrow the RTD is. :3 ⁇ 4.005
• the CFI After the first 2.5 h of continuous chromatography the CFI had to fill completely with spiked chromatography eluate for 3 h in order to reach the steady state. The necessary duration of 3 h was determined from the corresponding RTD experiments. After the first virus experiment, the CFI was CIPed with 5 M NaOH for at least 1 h.
• a novel spiking procedure for a continuous process had to be developed.
• 230 ⁇ 7 ⁇ spiking material had to be added to the 4.6 mL/min chromatography eluate stream.
• a Gilson Minipuls 3 pump was used to add the spike stream to the chromatography eluate stream via a connector. No internal mixing unit was used. The spiking point was set after the homogenization loop.
• each sampling container was filled with 4.13 mL of 2 M Tris buffer prior to sampling. With the help of this method, the pH of each drop of sample was neutralized immediately when entering the sampling container. This prevented inhomogeneous residence times at low pH levels within the samples.
• the sampling duration was set to one switch time (17.3 min) of the continuous chromatography. This leads to a complete collection of the expected pH levels from the continuous chromatography.
• the CFI was designed to deliver a minimum residence time of 120 min. Prior to the performed experiments, cytotoxicity and interference assays were performed. The necessary final dilution of the sample was determined to be 1:54. With this dilution factor, no effect on cell growth and virus replication could be observed.
• FIG 1 shows a schematic overview of a process scheme for a pre-viral study.
• FIG 2 shows the experimental setup for RTD measurements
• FIG 3 shows a schematic overview of the sampling points as well as the final CFI.
• FIG: 4 depicts the results of the residence time distribution characterization
• the upper left diagram of FIG 4 shows the RTD characterization results for the CFI.
• the average residence time was determined at 145 min with a relative width Rw of 0.819. Consequently, every arm out of the 10 arms realized within the CFI provides a residence time of 14.5 min.
• the RTD within the CFI is very narrow, leading to a minimized residence time of every single fluid element, i.e. viral particle.
• the lower left diagram of FIG. 4 shows the results for the HL. It shows the typical CSTR RTD behavior. The average residence time are 8.12 min, the Rw is 0.027.
• the upper right diagram FIG. 4 shows the measurement for the combination of HL and CFI. In comparison to the CFI results shown in the upper left diagram, the average residence time increases to 154 min, the relative width decreases to 0.739.
• the lower right diagram FIG. 4 shows the overall comparison of the experimental results as well as calculated graphs for laminar straight tubes and laminar straight helixes.
• the combination of HL and CFI leads to a visibly wider residence time distribution than using solely the CFI. Nevertheless, both constellations show a significantly better RTD than the alternatives, the laminar straight tube and the laminar straight helix.
• FIG. 5 depicts the results of the pre-viral study continuous process
• the virus titer and LRV results of two experiments can be seen in FI. 5.
• the upper part of the diagram shows the results of the single sampling with mode A of continuous chromatography.
• the first two columns represent the virus titer results for the load and hold sample.
• process conditions e.g. temperature and buffer composition
• mAB test item itself
• the middle and the lower diagram of FIG 5. show the results of the two samplings with mode B of ProtA chromatography.
• the sampling procedure was started with 3M18 for 17.31 min. After a pause of 8.66 min, sample 4M18 was drawn. The further sampling was done pair wise as well.
• FIG: 6 shows a schematic diagram of the log reduction value (LRV) of viral titer against the residence time in the CFI, which in the case of the CFI is equal to a specific location in the CFI.
• LRV log reduction value

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Citations (2)

• 2016
  • 2016-10-21 EP EP16194959.9A patent/EP3141611A3/en not_active Withdrawn
• 2017
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  • 2017-10-19 EP EP17791896.8A patent/EP3529367A1/en not_active Withdrawn
  • 2017-10-19 JP JP2019520956A patent/JP2019537435A/ja not_active Ceased
  • 2017-10-19 AU AU2017345412A patent/AU2017345412A1/en not_active Abandoned
  • 2017-10-19 WO PCT/US2017/057298 patent/WO2018075716A1/en not_active Ceased
  • 2017-10-19 KR KR1020197010823A patent/KR20190066017A/ko not_active Ceased
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