method validation...• one company had method, validation results and change history as part of...

Manufacturing Breakout Session I Michael Coutant (Pfizer), Pete Yehl (Genentech),

Zhanna Yuabova (Boehringer-Ingelheim)

Method Validation

IQ GMPs in Early Development

• Defining the terms: should try to harmonize but no agreement harmonization industry wide

• We should at least be harmonized on what we do at each stage if we can’t define terms consistently

– Qualification: reliable; scientifically sound – Validation: performance and accuracy verified by experimental approach – View from 2 companies:

• Validation: ICHQ2 definition: used for release of product for phase III and beyond • Qualification: limited subset of validation against a protocol and fit for purpose, early

development through Phase IIa: cur point is pre-registration stability. • Characterization: methods suited for IPC controls, i.e., mutagens in upstream intermediates.

Not protocol driven.

– Company X: Long term stability studies: Company Y time that validation is completed

• Validation often dependent on the state of the formulation or process • Some companies call it a staged approach (Stage 1, stage 2 validation etc. Or call

this fit for purpose (FFP) validation – Dependent on the way analytical groups are organized in the development space? BMS

• Terminology should be aligned with what is defined in regs for qualification and validation


• Paper guidance by IQ as guide • Linearity not necessarily required: accuracy/precision may be

more important • Using system suitability (SS) to address lots of validation

parameters as being built into the method was discussed, however no consensus was reached. This could avoid specific protocols and validations for things like linearity and precision: – Acceptable to use system suitability definition as part of validation – SS Could encompass linearity, precision, specificity, LOQ, even solution

stability and accuracy


• Test in acceptance criteria in final specification: validated method; upstream methods (not specified in reg docs: this would be qualified based on risk assessment)

• Company X: for filed specs, all methods are scientifically robust, actual validation is a box check. Early methods or controls not in reg specs have equal scientific rigor but are not formally validated.


• i.e. GC: validated for each solvent, not necessarily for different API matrices

– One company: no specific validation of solvents in different API’s, rely on the bulk validation data

– Some companies: standard additions and/or recovery from API matrix, though recovery issues are rare

– If recovery is poor, evaluate the impact of the result; ie. Trace solvents recovery may be more important than high level solvent (i.e methanol, not uniformity, etc)

• Compendial methods – Most companies do not validate individual KF, ROI methods, but rather qualifies them.


• Generally Not formal validation; not protocol driven


• The concept of validation as a continuous process every time you run the method (i.e. it is not necessarily a one time event) was discussed.

Manufacturing Breakout Session II Michael Coutant (Pfizer), Pete Yehl (Genentech),

Zhanna Yuabova (Boehringer-Ingelheim)

Method Validation


• Pros: – traceability of records; Reviewability, data sharing, one searchable

repository, elimination of the need for reports; finding data when someone leaves, generated templates can take the place of reports

– Chemometric mining of “meta” data associated with particular lots or excipient, which instruments were used, etc to gain additional info on a particular result:

– Knowledge management tool; installed with vendors and CMO

• Cons: – downtime can be paralyzing to organization – Too much customization can make it burdensome – Potentially need to train auditors on a system could be difficult, – access to entire notebook vs. specific question (audit concern?)


• Method specific: many companies do validations at CMOs instead of transfers

• Decision depends on the stage of the program, state of the method, perceived complexity of the method, comfort of company with method.


• Validation protocols: companies have an approved plan or protocol for early development as a guidance document

– This could be an SOP: defines the validation protocol/plan, data format is built into an ELN template and integrated into CMC templates directly by copy and paste

• Several companies integrate ELN to automatically generate reports and dossier sections via template approach

• One company had method, validation results and change history as part of same document, so changes were monitored through a single document.


• Some companies supported the use of system suitability data being used as a surrogate for formal validation

• Validation criteria at early stage: how to document and how strict are criteria in early vs. late?

– Validation parameters set in alignment with specs, which can be rigorous even early

• Non qualified, non-GMP instruments: can you do validation on this? – Most companies: GMP instruments delineated from non-GMP at some companies, only

validation and GMP on some instruments. Development only on development instruments

– More rare: GMP releases vs. validations: sometimes delineated instruments – Some companies Development instruments vs. GMP instruments: validation in

development instruments since they are maintained the same way, though this could be an issue if they are not documented as calibrated

• In this case, development all done on development instruments, GMP and validation done on another set

– Some companies chose to qualify all instruments because its easier business process and improve lab flexibility


• Formal validation reports are not necessary in early development.

• Validation summary sheets are common and okay for early development


• What is appropriate QA oversight in Early Dev? – Most companies: only Analytical sign off for reports and protocols, no

QA signature needed. Regular internal audit by QA eases the concerns – Industry variability: QA looking at either final reports or raw data prior

to lot release, though not approving reports themselves – Formal feedback mechanism of report check off for partner CMO’s:

• Analytical responsibility to communicate change. sometimes QA is in the loop to do this, some companies have the change/revision history documented built into method document

– If change impacts a reg doc, formal change control is needed. Other changes captured in revision history

– Some companies have formal change control for early development method changes

method validation...• one company had method, validation results and change history as part of...

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