Replacing Analytical Methods for Release and Stability Testing A Regulatory Perspective

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1 Replacing Analytical Methods for Release and Stability Testing A Regulatory Perspective Presentation at The IVT s 12 th Annual Analytical Procedure and Method Validation Conference Dec 12, 2016 Lokesh Bhattacharyya Lab Chief, DBSQC FDA/CBER/OCBQ

2 Introduction 2

3 Outline Regulations and Guidance Categories of change Submission Requirements Concerns (Perceived) Comparability Study Two Case Studies Changing Method During Stability Study 3

4 Regulations 21 CFR (a)(1) An applicant must inform the FDA, through submission of a supplement to the original license application, about changes in the product, production process, quality controls or labeling established in the approved license application. (2) Before distributing a product made using a change, an applicant must assess the effects of the change and demonstrate through appropriate validation and/or other clinical and/or non-clinical laboratory studies the lack of adverse effect of the change on the identity, strength, quality, purity, or potency of the product as they may relate to the safety or effectiveness of the product. 4

5 Regulations The reporting categories for changes to an approved application are based on the probability of the changes to have a substantial, moderate or minimal potential to adversely affect the identity, strength, quality, purity and potency of the product as they may relate to the safety or effectiveness of the product. Risk Based (b) (1) Major Changes Substantial potential for adverse effect on the product - Prior Approval Supplement (c) (1) Potential for Moderate Change - Supplement Changes Being Effected in 30 Days (CBE-30) or Changes Being Effected (CBE) (under certain circumstances) (d) (1) Minor Changes - Annual Report 5

6 Guidances FDA Guidances Demonstration of Comparability of Human Biological Products, Including Therapeutic Biotechnology-Derived Products, 1996 Changes to Approved Applications: Biological Products, 1997 Changes to an Approved Application for Specified Biotechnology and Specified Synthetic Biological Products, 1997 Comparability Protocols - Protein Drug Products and Biological Products-Chemistry, Manufacturing, & Controls Information, 2003 Changes to an Approved NDA or ANDA, 2004 ICH Q2(R1) Validation of Analytical Procedures, 2005 ICH Q5E - Comparability of Biotechnological/Biological Products Subject to Changes in Their Manufacturing Process,

7 FDA Guidance : Major Changes Changes requiring Prior Approval Supplement (PAS) submission and approval prior to distribution of the product made using the change (major changes) (b) Any change in manufacturing processes or analytical methods that, Involves change in source materials or cell line Results in change(s) of specification limits or modification(s) in potency, sensitivity, specificity, or purity Establishes a new analytical method Deletes a specification or an analytical method (except as required by USP/NF) Eliminates tests from the stability protocol Alters the acceptance criteria of the stability protocol 7

8 FDA Guidance : Major Changes New lot of, new source for, or different in-house reference standard or reference panel (panel member) resulting in modification of reference standard specifications Changing the test method. This is a critical issue for many biochemical, immunochemical and biological assays, e.g., clotting assay for FVIII potency (changing the reagent) Extension of the expiration dating period and/or a change in storage temperature, container/closure composition, or other conditions, other than changes based on real time data in accordance with a stability protocol in the approved license application. 8

9 FDA Guidance : Major Changes Prior Approval Supplements Content Detailed description of the proposed change The intermediates/drug substances/products involved The manufacturing or testing site(s) or area(s) affected Detailed description of the new/revised method Description of studies performed to evaluate the effect of the change comparability report Describe the statistical method of evaluation in detail The data derived from those studies (report) Relevant validation protocols and data (report) A reference list of relevant standard operating procedures (SOPs) and validation reports 9

10 FDA Guidance : Moderate Potential Changes requiring supplement submission at least 30 days prior to distribution of the product made using the change (c) (CBE-30) Change in the site of testing from one facility to another From the license holder to a new contract lab From an approved contract lab to a new contract lab From a contract lab to the license holder Every thing else should remain the same assay procedure, standard, same/equivalent reagents and equipment, same qualification criteria, etc. CBE under certain circumstances Based on FDA experience with the particular type of change 10

11 FDA Guidance : Moderate Potential Submission requirements : At least 30 days prior to distribution Same as PAS (Major Change) Submission should include adequate comparability data 11

12 FDA Guidance : Minor Changes Changes to be described in an annual report (minor changes) (d) Submission requirements A list of all products involved A full description of the changes The manufacturing site(s) or area(s) involved The date each change was made A cross-reference to relevant validation report(s) and/or SOPs Relevant data from studies and tests performed to evaluate the effect of the change on the identity, strength, quality, purity, or potency of the product as they may relate to the safety or effectiveness of the product 12

13 FDA Guidance : Minor Changes Changes that can be reported in the annual report (d) Modifications in analytical procedures with no change in the basic test methodology or existing release specifications provided the change is supported by validation data Tightening of specifications of an existing reference standards to provide greater assurance of product purity, identity, and potency Establishment of an alternate test method for reference standards or release panels qualification A change in the stability test protocol to include more stringent parameters (e.g., tightened specifications) 13

14 FDA Guidance : Minor Changes Addition of time points to the stability protocol Change in the storage conditions of in-process intermediates based on data from a stability protocol in an approved license application, which does not affect labeling, except for changes in storage conditions which are specified by regulation Relocation of equipment within an approved operating room or rearrangement of the operating area However, the equipment must be qualified after relocation 14

15 Change in Analytical Method Change in basic methodology change in the basic principle of operation or mechanism of action SE-HPLC to RP-HPLC : Major (both chromatography but operates through altogether different mechanisms) Potency assay from a clotting to a chromogenic method : Major (different mechanisms) C 8 to C 18 column : Moderate (interaction of sample components with column altered) Replacement of an equipment by another can be moderate or minor A qualified functionally dissimilar equipment (moderate) coulometric vs potentiometric titration A qualified functionally similar equipment (minor) Assay transfer can be moderate or minor All personnel relocated to the new lab; functionally similar equipment (minor) New personnel at the different location and/or dissimilar equipment (moderate) 15

16 Concerns (Perceived) What if I find something new in an approved product (after changing to a new and improved method)? What will happen after opening Pandora s Box? This something has been in your product all the time your previous methods just did not see it Your manufacturing method is still the same you product composition is still the same Your product has been used and proven safe and efficacious Characterize this new thing (impurity) If it is really something that has safety issues or suspected to have safety issues, you rather want to know it now before it is too late FDA may request additional studies to show that new-found component is safe 16

17 Comparability Study : Design Different assays or at different locations Analysis of the same samples by multiple analysts using both methods Multiple analysis of the same lot vs analysis of multiple lots How many lots or replicates? Statistical considerations statistical power Case by case Clear understanding of what is changing/being compared Performance characteristics of the two assays Ability to perform assay in a comparable manner Comparability of analysts ability, equipment performance, reagents, etc. May be downgraded if there is a previously approved comparability protocol 17

18 Comparability Study Selection of appropriate statistical method(s) for the evaluation of results What is the question you are asking? Understanding the purpose of the comparability study Appropriate null hypothesis Selection of samples How many factors do you want to vary at a time? Use of DOE Can your statistical method handle multivariate analysis? Number of samples/replicates should be large enough to have adequate statistical power Explain your statistical method in details 18

19 Comparability Case Study 1 A SEC HPLC method is replaced by a RP-HPLC method for an impurity assay in a drug product Submitted as an annual report Justification : Same basic methodology HPLC New method was stated as validated, however no validation or comparability data included This change should be submitted as a PAS a new analytical method Necessary validation and comparability data should be included 19

20 Comparability Case Study 2 A potency method is transferred from Lab A to Lab B Data Submitted: Intermediate precision in each lab Three lots, three analysts in each lab Reportable results : %RSD in each lab Met acceptance criteria ( 20%) Comparability data for 6 lots, each analyzed by three analysts in each lab Data analyzed by paired t-test F > F crit at 95% CI but < F crit at 99% CI (?) Sponsor s conclusion : Pass (based on 99% CI results) However, Lab B greater than Lab A for all 6 six lots; Ratio of results between two labs for 6 lots from 1.5 to 3.4 We concluded H 0 is incorrect 20

21 Changing Method During Stability Study Changing a method in the middle of an ongoing stability study presents many questions and uncertainties, which need to be adequately addressed Is the new method stability indicating? Is the validation of the new method (as a stability indicating method) alone sufficient to introduce the new method in the middle of an ongoing stability study? How to compare results from both methods? What statistical method to use? How do you ascertain power of the statistical method, particularly if you are monitoring an impurity Should you run a pilot to make a prior assessment? 21

22 Changing Method During Stability Study Accelerated stability study evaluated using both old and methods? May often involve significant amount of additional work My personal thought (not CBER s position) avoid if you can If you plan to do so, draft your study-plan and discuss with FDA review staff for concurrence before introducing the new method in the stability program 22

23 Thank you Questions? 23

Replacing Analytical Methods for Release and Stability Testing CBER Perspective

Replacing Analytical Methods for Release and Stability Testing CBER Perspective Presentation at the CMC Strategy Forum January 27, 2014 Lokesh Bhattacharyya Chief, Lab of Analytical Chemistry and Blood