US FDA post approval changes

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1. US Post Approval Changes By, CHANDRA MOHAN

2. INTRODUCTION Types of Post Approval Changes Major (PAS ) Moderate (CBE-30 and CBE-0 ) Minor (AR ) Examples for Post Approval Changes SUPAC

3. In this presentation, I am going to discuss about the post approval changes and their reporting categories. After the approval of NDA or ANDA, the applicant may make post approval changes, provided the changes are reported to the FDA under the appropriate categories . Section 506 A of the Federal Food, Drugs and Cosmetics act and  21 CFR 314.70 provide for 4 reporting categories of the post approval changes which are listed below- 21 CFR 314.70 (b) – PAS 21 CFR 314.70 (c) (3) – CBE-30 21 CFR 314.70 (c) (6) – CBE-0 21 CFR 314.70 (c) (7) – Disapproves of CBE-0 and CBE-30 21 CFR 314.70 (d) (3) – Annual Reports Introduction

4. Major Changes - PAS A major change is a change that has a  substantial potential  to have an adverse effect on the identity, strength, quality, purity, or potency of a drug product as these factors may relate to the safety or effectiveness of the drug product. A major change requires the submission of a supplement and approval by FDA prior to distribution of the drug product made using the change. This type of supplement is called and should be clearly labelled as  Prior approval supplement . An applicant may ask FDA to expedite its review of a prior approval supplement for public health reasons like drug shortage or in case if there is a delay would impose an extraordinary hardship on the applicant.   

5. Moderate Changes A moderate change   is a change that has a  moderate potential  to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product as these factors may relate to the safety or effectiveness of the drug product. The moderate change is categorized into 2 types based on the type of supplement being filed -         a ) Supplement - Changes Being Effected in 30 Days This type of change requires submission of supplement to FDA at least 30 days before the distribution of drug product made using the change.   This type of supplement is called, and should be clearly labelled, a  Supplement - Changes being effected in 30 Days. The drug product made using moderate changes cannot be distributed if the FDA informs the applicant to file a prior approval supplement for the changes made or if FDA informs that the information is missing or if FDA disapproves the changes being affected in 30 days.

6. Moderate Changes b ) Supplement - Changes Being Effected This type of supplement contains changes for which distribution can occur when FDA receives the supplement. FDA may order the manufacturer to cease distribution of the drug products made using the disapproved change, If, after review, FDA disapproves a changes-being effected.

7. Minor changes - AR A minor change   is a change that has  minimal potential  to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product as these factors may relate to the safety or effectiveness of the drug product . Does not require FDA approval prior to distribution of the drug product made using the change.

8. Reporting changes Each change should be described in enough detail in the cover letter or summary section of the Annual Report to allow FDA to determine whether the appropriate reporting category has been used.

9. The following information must be contained in a Prior Approval Supplement 1) A detailed description of the proposed change 2) The drug product(s) involved 3) The manufacturing site(s) or area(s) affected 4) A description of the methods used and studies performed to assess the effects of the change 5) The data derived from such studies 6) For sterilization process and test methodologies related to sterilization process validation, relevant validation protocols and a list of relevant standard operating procedures must be provided in addition to the requirements in 3) and 4)

10. Types of Changes for Prior Approval Supplements 1.) Changes in the qualitative or quantitative formulation of the drug product, including inactive ingredients or in the specifications Examples : • changes in specification of drug concentration, pH, chemical purity ( EtOH , Acetonitrile, K222), NaCl concentration, BET concentration limit, deleting any part of a specification, etc. • Establishing a new analytical procedure or a change in an analytical procedure that does not provide the same or increased assurance of the identity, strength, quality, purity, or potency of the material being tested as described in the approved application.

11. Types of Changes for Prior Approval Supplements 2.) Changes that may affect drug product sterility assurance , such as changes in drug product sterilization method(s) or an addition, deletion, or substitution of steps in an aseptic processing operation Examples: • Addition to an aseptic processing line of new equipment made of different materials • Deletion of equipment from an aseptic processing line • Changes in the sterilization method (e.g., filtration, chemical , irradiation ) • Changes in materials or pore size rating of filters used in aseptic processing

12. Types of Changes for Prior Approval Supplements 3.) Changes in the manufacture of the drug substance that may affect the impurity profile and/or the physical , chemical, or biological properties of the drug substance Examples: • Changes in solvents (e.g., acetonitrile to tetrahydrofuran) • Changes in the precursor (e.g., mannose triflate to mannose tosylate ) • Changes in the resins of the purification columns • Changes in the hydrolysis method (e.g., acid vs. base , hydrochloric acid to sulfuric acid or phosphoric acid) • Changes of the crown ether used to complex the cation

13. Types of Changes for Prior Approval Supplements 4.) Labelling changes Examples: • Changes based on post-marketing study results, including, but not limited to, labelling changes associated with new indications and usage. • Revision ( expansion or contraction) of population based on data. • Claims of superiority to another drug product.

14. Types of Changes for Prior Approval Supplements 5.) Changes in container closure system Examples: • Changes in a drug product container closure system that controls the drug product delivered to a patient. • Changes in the type (e.g., glass to high density polyethylene ( HDPE), vial to syringe) or composition (e.g., one HDPE resin to another HDPE resin) of a packaging component that may affect the impurity profile of the drug product

15. Types of Changes for Prior Approval Supplements 6.) Site change to different manufacturing site which doesn’t have satisfactory GMP status within 2 yrs. 7.) Replacement of equipment with another equipment which has different design & different operating principle. 8.) Fundamental change in the process ( eg . Wet granulation to dry granulation or vise versa) 9.) Change in the route of the synthesis for a drug substance. 10.) Changing an analytical procedure for the finished product if the change is not compendial .

16. The following information must be contained in a CBE-30 Supplement 1) Full explanation of the basis for the change. 2) The date on which the change is to be made. • The applicant must wait 30 days after submission of the CBE-30 Supplement before distributing the drug product made using the change • If the FDA informs the applicant within 30 days of the submission that any information is missing, the applicant must not distribute the drug product made using the change until the supplement has been amended to provide the missing information • The FDA may inform the applicant that the change needs to be resubmitted as a Prior Approval Supplement

17. Types of Changes for CBE-30 Supplements 1.) Any change in process and/or process parameters. Examples: • Changes in concentration of reactants, reaction times , reaction temperatures and pressures. • Changes in the order of addition of reactants. • Changes in reaction pH. • Changes in final distillation temperatures (e.g., water content of anhydrous steps ).

18. Types of Changes for CBE-30 Supplements 2.) A change in the container closure system that does not affect the quality of the drug product. Examples: • Changes in the size or shape of a container for a sterile drug substance (The new container having the same quality glass , septum and crimp.)

19. Types of Changes for CBE-30 Supplements 3.) Relaxation of an acceptance criterion or deletion of a test to comply with an official compendium that is consistent with FDA regulatory requirements. Examples : • Relaxing an acceptance criterion or deleting a test for raw materials used in drug substance manufacturing ( e.g., increasing the melting point range for mannose triflate , deleting the appearance acceptance criteria for mannose triflate or K222) • Making a change to an analytical procedure used for testing raw materials or drug substance intermediates that does not provide the same or increased quality assurance as the analytical procedure described in the approved application.

20. Types of Changes for CBE-30 Supplements 4.) Addition of new PET manufacturing sites. • Additional facilities are required to be shown to operate identical to currently approved sites. • A product comparability protocol is required by the FDA to be submitted with the CBE-30 supplement for the addition of new sites.

21. Types of Changes for CBE-30 Supplements 5.) Labeling changes. Examples: • Addition of an adverse event due to information reported to the applicant or Agency. • Addition of a precaution arising out of a post-marketing study.

22. Types of Changes for CBE-30 Supplements 6.) Site change to different manufacturing site for DP, DS which has satisfactory GMP status within 2 yrs. 7.) Replacement of equipment with another equipment which has different design & same operating principle. 8.) Change in analytical procedure with an equivalent procedure ( eg . Method change from HPLC to UV)

23. Submission of CBE-0 Supplements For certain types of changes, the holder of an approved application may commence distribution of the drug product upon receipt by the agency of a supplement for the change ( i.e., there is no waiting period) • If, after reviewing a CBE-0 supplement, FDA disapproves the change , FDA may order the manufacturer to cease distribution of the drug product made using the change. • If FDA informs the applicant that any information is missing , the applicant must cease distributing the drug product made using the change until the supplement has been amended to provide the missing information.

24. Types of Changes for CBE-0 Supplements 1.) Addition to a specification or changes in the methods or controls to provide increased assurance that the drug substance or drug product will have the characteristics of identity, strength, quality, purity, or potency that it purports or is represented to possess. Examples: • Adding a new test and associated analytical procedure and acceptance criterion. • Improving an HPLC or GC method to increase the peak resolution. • Increase the frequency of CIDG impurity testing.

25. Types of Changes for CBE-0 Supplements 2.) Changes in the labeling to reflect newly acquired information to accomplish any of the following: • To add or strengthen a contraindication, warning , precaution , or adverse reaction. • To add or strengthen an instruction about dosage and administration that is intended to increase the safe use of the drug product. • To delete false, misleading, or unsupported indications for use or claims for effectiveness.

26. Types of Changes for CBE-0 Supplements 3.) Change in manufacturing site for the final intermediate of drug substance. 4.) Change in test method or controls for assuring better product quality. 5.) Change or addition/deletion of a desiccant.

27. Annual Report Changes in the drug substance, drug product, production process , quality controls, equipment, or facilities that have a minimal potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product do not need to be reported to the FDA immediately , but can be reported in the submission of the next scheduled Annual Report.

28. Types of changes reported in Annual Reports 1.) Any change made to comply with a change to an official compendium that is consistent with FDA regulatory requirements. Example: • Change of USP CIDG specification from 1.0 mg/dose to 0.125 mg/mL

29. Types of changes reported in Annual Reports 2.) Replacement of equipment with that of the same design and operating principles Example: • Replace Agilent GC with a Bruker GC using the same column and detector

30. Types of changes reported in Annual Reports 3.) The addition or revision of an alternative analytical procedure that provides the same or increased assurance of the identity, strength , quality , purity, or potency of the material being tested as the analytical procedure described in the approved application. Example: • Add PTS as an alternative to the gel-clot test for BET

31. Types of changes reported in Annual Reports 4.) Tightening of acceptance criteria. Examples: • Reduce acceptance criteria concentrations for acetonitrile , K222 and BET • Increase radiochemical purity criteria.

32. Types of changes reported in Annual Reports 5.) A change in the labeling concerning the description of the drug product or in the information about how the drug product is supplied, that does not involve a change in the dosage strength. Examples: • Changes in the layout of the package or container label that are consistent with FDA regulations without a change in the content of the labelling. • Editorial changes , such as adding a distributor's name. • Labelling changes made to comply with an official compendium.

33. Types of changes reported in Annual Reports 6.) Minor structural modifications with in an approved manufacturing facility. 7.) Batch size up to 10 folds 8.) Change in equipment of same design and operating principle. 9.) Non automated equipment to automated 10.) Site change for labeling operation or secondary packaging. 11.) Addition or deletion of embossing/debossing in tablet dosage form. 12.) Extension of expiration dating based on complete shelf life data.

34. Types of changes reported in Annual Reports Components And Composition: Elimination or reduction of an overage from the drug product manufacturing batch formula. Change in coating formulation, if the coating material have been approved for another similar product and the change does not alter release of the drug, specification or stability. The supplier of an inactive ingredient was specified in an approved application, change to a new supplier of that inactive ingredient (e.g., change from one drug master file (DMF) holder to other DMF holder or change to a new qualified supplier). This is applicable only if the inactive ingredient’s specification remains unchanged.

35. Manufacturing Sites Minor structural modifications made in an approved manufacturing facility. Manufacturing Process, Batch Size, and Equipment Addition of a sieving step(s) Changes in mixing times (for blending powders, granules) Changes in drying times. Manufacturing batch size within 10 folds. Equipment replacement with that of the same design and operating principle. Decrease in the number of open handling steps or manual operation procedures. Types of changes reported in Annual Reports

36. Specifications Addition of a new test to the specification for an excipient. Change to the specification for a drug substance, drug product, or pharmacopeial excipient that is made to comply with the official compendia.(Specification changes not suitable for documentation in an annual report include changes to an assay, tests for impurities, degradation products, product-related substances, or biological activities that are approved in NDAs and ANDAs. Such changes should be submitted in a supplement.) Change in the approved analytical procedure if the revised method maintains the original test methodology and provides equivalent or increased assurance that the drug substance or drug product. Addition of an in-process test. Revision of tablet hardness if there is no change in the approved dissolution Addition of a test for packaging material Tightening of an approved acceptance criterion for a drug substance, a drug product, drug product formulation components, and in-process material. Types of changes reported in Annual Reports

37. Container/Closure System A change in the container/closure system for the storage Transfer to a contract manufacturing organization (CMO) for the washing, drying, or/and siliconization of a drug product stopper or any part of a container closure system For solid oral dosage forms, when the change is to use another suitable primary packaging component used in any other CDER-approved drug product: Change in type of desiccant to another desiccant that was previously used in another approved product and is suitable for its intended use. Elimination of a bottle filler, such as a fibrous material (e.g., suitable type of cotton, rayon, polyester, etc.) that is used to fill empty or void space in the finished product container. Change to delete the company trademark or other markings on the crimp cap Types of changes reported in Annual Reports

38. Labeling Changes Revision in drug product labeling to reflect the qualitative change in inactive ingredient(s) of coating formulation, A change in the drug product labeling to revise information related to CMC changes. Miscellaneous Changes Extension of the drug substance retest dating period or drug product expiration dating period based on real-time stability data For immediate release solid oral dosage forms, if a dissolution test is performed, elimination of a test for identity or hardness from an approved stability protocol. Types of changes reported in Annual Reports

39. SUPAC- Scale-Up and Post Approval Changes

40. Level of changes Likelihood of impact on formulation quality and performance Level 1: Unlikely to have detectable Level 2: Could have significant impact Level 3: Likely to have significant impact

41. SUPAC These guidelines provide recommdation for post approval changes in The component or composition The site of manufacture The scale up of manufacture , and The manufacturing ( process and equipment)

42. THANK YOU! Questions ?