Practical Points in Method Tech Transfers: Three Savory Scenarios
Nadine M. Ritter, Ph.D.
President and Analytical Advisor
www.GlobalBiotechExperts.com
© N.M. Ritter, Ph.D. 2016 1
http://psychology.wikia.com/wiki/Amino_acids
Cozzone, A. J. Proteins: fundamental chemical properties. in Enc.of Life Sciences (Nature Publ
Group, London, 2001)
Protein Tertiary Structure Prediction; D Xu, Y Xu; in Current Protocols in Protein
Science (May, 2001)
P. Rudd, et. al; J. Immunology, 2004, 173: 6831-6840
Biological/Biotechnology/Biosimilar Products = Diversity in Molecules and Diversity in Methods
E Padron et al, J Virol 2005; 5047-5058
Diversity Among Molecular Entities
Midwest Stem Cell Therapy CenterUniv of Kansas
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Diversity in Methods: Monoclonal Antibodies
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Diversity in Methods: Viral Vaccines and Gene Therapy
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Where is it Coming From? Where is it Going To?
Significant Differences In:
• Deliverables• Unique vs Consistent
• Procedures• Custom vs Constrained
• Turnaround time• Hours vs minutes
• Cost of Goods• Higher vs Lower
• Training• Years vs Days
• Scale of Operations• Small vs Large
• Source of Reagents• Custom vs Commercial
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Assay Transfer* Protocol -R&D to QC, Site to Site, Sponsor to CMO, CMO to Sponsor
Exact replication of validated method with identical systems?
Transfer protocol could be similar to a intermediate precision study
* I personally do not favor co-validation between labs unless (1) identical systems and (2) same QA food chain; too many fist fights between organizations! ICHQ2R1 Reproducibility…
DON’T ASSUME – VERIFY!
Implementation of validated method with similar systems?
Transfer protocol should contain repeat of key parameters
Adaptation of validated method to new instrument systems?
Transfer protocol might have to be re-validation protocol
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• What type of technology forms the basis of the method? [spectroscopy, chromatography, chemiluminescence, surface plasmon resonance, etc…?]
• What instrumentation is directly utilized in the method?[spectrometer, HPLC, plate reader, cell sorter, etc…?]
• How is the primary measurement generated?[The total path: signal generation, detection, translation to raw values]
• How are the raw data analyzed?[e.g. against standard curves, identity standards, nothing?]
• What is the reportable result for the test method?[numerical value, ‘conforms’, pass/fail statement?]
• How are the critical assay materials stored, handled, and prepared before, during and after testing? [e.g. test samples, reference standards, assay controls, critical reagents?]
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Define the Key Procedural Elements of the Method
• Which material will be analyzed with the method? [raw material, intermediate, bulk, finished?]
• Which form of the material will be used? [liquid, lyophilized, tablet, powder, patch?]
• What is the material parameter being evaluated? [identity, composition, concentration, impurities?]
• Will the method be for both release and stability?
• What specifications will this method support? [qualitative or quantitative?]
• What phase of product development is it for? [“Qualification” vs validation?]
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Define the COMPLETE Intended Uses of the Method
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Post Approval Change: Analytical Testing Lab Site(FDA Guidance for Industry: PAC-ATLS, 1998)
Analytical testing laboratories include those performing physical, chemical, biological, and microbiological testing to monitor, accept, or reject materials as well as those performing stability testing.
Prior to submitting analytical testing laboratory site change supplements, an applicant should determine that the laboratory has the capability to perform the intended testing. The supplement should also contain the name and address of the new analytical testing laboratory site and a full description of the testing to be performed by the new facility.
Information to support the capability of a laboratory to perform the intended testing (e.g., comparative data, CGMP history of performing the test, appropriate standard operating principles (SOPs), equipment and personnel in place) should be available for FDA investigator review.
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Post Approval Change: Analytical Testing Lab Site(FDA Guidance for Industry: PAC-ATLS, 1998)
An analytical testing laboratory site change can be submitted as a Changes Being Effected (CBE) supplement if
(1) the test method(s) approved in the application or methods that have been implemented under 21 CFR 314.70(d) are used
(2) all postapproval commitments made by the applicant relating to the test method(s) have been fulfilled (e.g., providing methods validation samples)
(3) the new testing facility has the capability to perform the intended testing,
and
(4) the new testing facility has had a satisfactory current good manufacturing practice (CGMP) inspection within the past 2 years.
When submitting a supplement for a change in an analytical testing laboratory site, the applicant should confirm in a written statement why a PAC-ATLS CBE supplement is appropriate (i.e., the four circumstances listed above exist).
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Post Approval Change: Analytical Testing Lab Site(FDA Guidance for Industry: PAC-ATLS, 1998)
Method Technology Transfer Protocol and Report
PROTOCOL Method transfer protocol should include ALL of the intended test sample
types: Multiple lots of each sample type intended for testing (DS, DP,
intermediates) QA policy on re-testing of lots: Make blended or composite ‘lots’ Impurity methods [Upstream samples (less purified); Spiked samples
(enriched impurity)] Stability methods [Aged samples from ICH stability pull points (target
and accelerated); force-degraded samples of method’s stability-indicating claims]
The amount of data needed (number of samples, number of runs) depends on type of assay, product specification requirements and stage of development (pre vs post approval)
Degree of statistical data analysis will depend upon the type of method technology (eg separation methods vs colorimetric) and the specifications for the method’s intended use (specificity, selectivity)
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Method Technology Transfer Protocol and Report
REPORT Copy of TT protocol (study plan) prior to transfer exercise
Copy of SOP from sending lab and copy of SOP from recipient lab (compare degree of operational differences; note any modifications made)
Some include copies of training exercises to show recipient lab proficiency (feasibility runs), or statement of audit of training program
TT protocol as executed (with all deviations or adjustments clearly documented and justified)
Summary of data compared to performance acceptance criteria (justification/remediation of failures)
Fully annotated representative images of raw data (gels, chromatograms, binding curves, etc..)
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Agitation
DeamidationHydrolysis Oxidation
A B C D E F G H
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- - - + - - - -
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- - - + - - - -
- - - + - - - -
+ - - + - - - -
A = Appearance B= pH C = SDS-PAGE D= SEC-HPLCE = RP-HPLC F = IEF G = Peptide Map H = Potency
Freeze-Thaw Photodegradation
A B C D E F G H
- - - - - - - -
- - - - + - - -
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A B C D E F G H
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A B C D E F G H
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A B C D E F G H
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A B C D E F G H
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Force Degradation Results: Stability-Indicating Profile
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Agitation
DeamidationHydrolysis Oxidation
A B C D E F G H
- - - - - - - -
- - - + - - - -
- - - + - - - -
- - - + - - - -
- - - + - - - -
+ - - + - - - -
A = Appearance B= pH C = SDS-PAGE D= SEC-HPLCE = RP-HPLC F = IEF G = Peptide Map H = Potency
Freeze-Thaw Photodegradation
A B C D E F G H
- - - - - - - -
- - - - + - - -
- - - - + - - -
- - + - + - - -
- - + - + + - -
+ - + + + + - +
0
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A B C D E F G H
- - - - - - - -
- - - - - - - -
- - + - - - + -
- - + + - + + -
- - + + + + + +
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A B C D E F G H
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- - - - - - + -
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A B C D E F G H
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A B C D E F G H
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- - - - - - - -
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Tech Transfer of SEC-HPLC Rationale for FD Samples
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Agitation
DeamidationHydrolysis Oxidation
A B C D E F G H
- - - - - - - -
- - - + - - - -
- - - + - - - -
- - - + - - - -
- - - + - - - -
+ - - + - - - -
A = Appearance B= pH C = SDS-PAGE D= SEC-HPLCE = RP-HPLC F = IEF G = Peptide Map H = Potency
Freeze-Thaw Photodegradation
A B C D E F G H
- - - - - - - -
- - - - + - - -
- - - - + - - -
- - + - + - - -
- - + - + + - -
+ - + + + + - +
0
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A B C D E F G H
- - - - - - - -
- - - - - - - -
- - + - - - + -
- - + + - + + -
- - + + + + + +
- - + + + + + +
A B C D E F G H
- - - - - - - -
- - - - - - + -
- - - - - - + -
- - - - - - + -
- + - - - + + -
- + - - - + + -
A B C D E F G H
- - - - - - - -
- - - - - - - -
- - - - - - - -
- - - - - - - -
- - - - - - + -
- - - + + - + -
A B C D E F G H
- - - - - - - -
- - - - - - - -
- - + + - - - -
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- - + + + + - +
Tech Transfer of Potency Assay Rationale for FD Samples
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Points to Consider in the TT Testing Scheme
Ideally: transfer test samples should be split and analyzed side-by-side in each lab
Transfer data should be compared within – not between! – sample types
Comparing new data from the recipient lab to historical data from the sending lab may not be suitable to assess method performance
Age and condition of test samples can change over time, even if stored frozen
Method performance acceptance criteria should not be tighter BETWEEN sending and recipient labs than WITHIN sending lab (Check intermediate precision capabilities in the sending lab)
Assess comparability of system suitability performance capabilities between laboratory sites for the technology (How many times is the method aborted/invalid in sending lab?)
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Instrumentation: When is Comparable Really Comparable?
• Verify that instruments utilize the same type of technologye.g. gel scanning image analysis CCD vs laser vs VIS
• Determine if they are capable of the same performance parameterse.g. plate washers, cell sorters
• Check for any ‘default’ instrument settings that can affect
the test results e.g. integration parameters, scanner settings, plate washer flow rates
• Confirm that they utilize the same data analysis algorithmse.g. averaging, SD, curve fitting
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Are these test results comparable?
A = 15.6%B = 35.8%C = 48.6%
A = 5.6%B = 25.8%C = 28.6%
A = 15.2%B = 31.8%C = 39.5%D = 7.9%
A = 48.2%B = 51.8%
A = 10.4%B = 41.2%C = 44.5%
A = 5.4%B = 4.3%C = 21.2%D = 14.5%E = 54.5%
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A = 15.6%B = 35.8%C = 48.6%
A B C
A = 5.6%B = 25.8%C = 28.6%
A B C
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A = 48.2%B = 51.8%
A B
A = 5.4%B = 4.3%C = 21.2%D = 14.5%E = 54.5%
A B C D E
Method Tech Transfers: Practical Lessons Learned
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Capture the method procedure in EXQUISITE detail – assess the differences
Compare the operations in the receiving lab to that of the sending lab (instruments, reagents, documentation, system suitability practices)
Define the full intended use of the method (reportable results, types of test samples, form of test materials, stage of development)
Allow recipient lab to run several feasibility and training runs (even if they use the same methodology all the time)
Design an appropriate tech transfer study design (sample types, number of runs, side-by-side testing)
Establish appropriate transfer acceptance criteria (no tighter than intermediate precision within a lab)
Critically evaluate the raw data (even if the processed results look good!)
Continue to track/trend method performance after transfer
