ZA CTD

1. ZA CTD IMPLEMENTATION DATE: 31 May 2011 >9 MONTHS LATER…

2. SOME THINGS TO DISCUSS • INTEGRATION OF EXPERIENCES OF TRANSITION TO CTD • MANAGING THE HYBRID DOSSIER: CHALLENGE OR OPPORTUNITY • WHAT SHOULD GO INTO AN AMENDMENT REQUEST? • UNDERSTANDING OPERATIONAL PROCESSES MAY HELP! • QUESTIONS ON API AMENDMENTS • OTHER QUESTIONS

3. SUBJECT TO INTERPRETATION WHAT IS 5X5? =25 ARE YOU SURE?

4. SUBJECT TO INTERPRETATION cont…. IS IT NOT =14? YOU HAVE AN OPPORTUNITY TO JUSTIFY OR CLARIFY YOUR REASONING USING VARIOUS MATHEMATHICAL PRINCIPLES

5. SUBJECT TO INTERPRETATION cont…. JUSTIFICATION THAT 5X5=14

6. EXPERIENCES • INTERPRETATION OF THE REQUIREMENTS • APPLICATIONS OF VARIOUS REQUIREMENTS • UNDERSTANDING SOME OF THE OPERATIONAL CHALLENGES • HYBRID FORMAT • POST REG EXPECTATIONS • APPLICATIONS REJECTED • HOW TO DO AN AMENDMENT IN CTD? • HOW CAN A FOLLOW UP BE DONE? POST REG UNIT APPLICANTS

7. POSTREG EXPECTATIONS • GRANULARITY OF THE ZA CTD • CODING OF SUBMISSIONS • THE AMENDMENT SUBMISSION • COVER PAGE OF SUBMISSION • COVER LETTER (Module 1.0) • COMPREHENSIVE TABLE OF CONTENTS (Module 1.1) • APPLICATION FORM (1.2.1) • ANNEXES TO APPLICATION FORM (1.2.2) • CLASSIFICATION OF AMENDMENTS • AMENDMENT SCHEDULE (1.5.2.1) • MANAGING THE FORMAT/HYBRID DOSSIER FORMATION

8. GRANULARITY OF ZA CTD • A characteristic of the ZA CTD format is the granularity of the format. See GUIDANCE FOR THE SUBMISSIONOF THE SOUTH AFRICAN CTD /eCTD -GENERAL & MODULE 1, pages 14-16. • Post Reg have been receiving documents • With page /plastic sleeve separators and no tabs • With only module separators: inadequate

9. GRANULARITY OF ZA CTD cont… • Tabs with long names and numbers not visible. See notes on comprehensive TOC • Tabs of same size & location: separation is provided but difficult to navigate • Tabs are not sequential, eg tabbing of a submission starts at 1.5.2.3 then followed by 1.2.1 and then 1.1 • Tabs that are attached to the page as separator, which falls off during handling • Some hand written tabs are not legible, e.g 3 and 5 cannot be deciphered • Examples

10. CODING OF SUBMISSIONS • Applicants submitting any request to MCC should be appropriately coded. See General information Guidelines for correct codes, section 13 page 25 onwards. • Post Registration codes start with the letter “V”

11. CODING OF SUBMISSIONS cont… with exception of : • VAC* =Applicant transfer, name and address change of the applicant • VAA* =Address only change for the HCR only • VNC =Updates following a proprietary name change approval • VCR =Cancellation of registered medicine • VCO =Withdrawal of an application for registration of a medicine THESE ARE NOW FUNCTIONS OF OP’s & ADMIN DIRECTORATE

12. CODING OF SUBMISSIONS • INCORRECT CODING RESULTS IN YOUR SUBMISSIONS NOT REACHING THE APPROPRIATE UNIT. • COMMON PROBLEMS ARE VPI’S CONFUSED WITH CPA’S. Please note that a VPI =Package insert changes involving the Composition, Identification, Presentation and Storage conditions only, while CPA =Package insert amendments for clinical aspects of registered/ old medicines

13. COVER PAGE OF THE SUBMISSION • Company letterhead • Name of Product and application or registration number • Address to Post Registration Unit • Include the codes of the amendment e.g. VRS, VCA… • Volume identifier e.g. Volume 1 of 1 • This volume contains: • An example of the cover of an amendment submission

14. COVER LETTER (1.0) • All amendment requests must have a cover letter as per section 6 of the amendments guideline. • Not the same as the letter of application. See requirements of letter of application in Part B Module 1 of the Guidance for submission of the ZA CTD • In the case of amendments submitted the cover letter should be placed in module 1.0

15. COMPREHENSIVE TABLE OF CONTENTS (1.1) • A comprehensive TOC (cTOC) is required with amendment submissions to monitor transition in format to ZA CTD. • The use of cTOC was a pre-requisite for accepting Hybrid dossier formation. • How is this done? By adding columns to the cTOC that would reflect the transition status of the various modules of the entire dossier. • See example of cTOC for MBR1 to CTD transition. • See example of cTOC for MRF1 to CTD transition with page and volume reference • In cases where full updates have been done then only the CTD Module and volume number would be used. • The role of the TOC will be clarified further under HYBRID DOSSIER FORMATION

16. APPLICATION FORM 1.2.1 • Must be submitted with all amendment requests. • All fields in Application form 1.2.1 must be completed. • Inclusion of the CV of the qualified person for Pharmacovigilance (e) need not be attached if previously submitted and remains unchanged. Indicate date of submission. • The Amendment history (f) must include all amendments submitted, including type A’s implemented

17. ANNEXES TO APPLICATION FORM 1.2.2 • 1.2.2.1-Proof of Payment (if applicable) • 1.2.2.2-Authorisation to communicate of behalf of the applicant (All except if responsible pharmacist) • 1.2.2.3-Dossier product batch information (full updates) • 1.2.2.4-Electronic copy declaration- (if applicable) • 1.2.2.5-CV of person responsible for Pharmacovigilance-first update/changes (reference date of submission is sufficient) • 1.2.2.6-API change control (if applicable) • 1.2.27-8- VAMF-PMF (if applicable)

18. CLASSIFICATION OF AMENDMENTS • Amendments Guideline provides a list of Type A, B and C amendments. • Some changes may not fall entirely within any of the listed amendments, if uncertain use Type C unclassified. If for instance a change in the order of addition of ingredients in modified or slow release formulation, this may alter the release characteristics and should be classified as a Type C unclassified. Provide evidence that the release profile of the formulation has not changed/remains within parameters. • Currently a list of frequent amendments that are not listed in the Amendments Guideline are being compiled which includes amongst others classification of an update to existing CEP, addition of a new API source where the current and proposed sources have CEP’s .

19. CLASSIFICATION OF AMENDMENTS cont… • Remember incorrect classification of Amendments into Type A and B may result in implementation of changes which may have to be reversed when evaluated. • Note that Type A amendments may only be submitted with the next Type B or C amendment for that product (Except Biological Medicines) • If there is ten or more Type A amendments to the product, the applicant is requested to submit an application for a full update which includes these Type A amendments

20. AMENDMENT SCHEDULE (1.5.2.1) • As per Amendments Guideline, the Amendment Schedule (AS) must be completed for all amendment requests. • The current and proposed information must be reflected as well as the reason for change • In the case of changes in formulation or production processes it is necessary to include a column for effect of these amendment/s on the product.

21. AMENDMENT SCHEDULE (1.5.2.1) cont… • Please note internal codes and references given to procedures and processes are not permissible on the AS e.g. (existing) Test method Q123 changed to (proposed) Test method Q456 is meaningless to the evaluator. Details of the test must be included in the existing column and the details of the proposed test method must be included in the proposed column so that the evaluator has adequate information to evaluate such a change. Remember to provide reason for change • Declaration on the AS must be completed and signed (Original)

22. AMENDMENT SCHEDULE (1.5.2.1) cont… • In the case of full updates with format change to CTD the AS should reflect all annexures / parts that are existing in the current format. • The corresponding module and section of the CTD must be reflected in the proposed column. • Example AS,

23. APPLICANTS EXPERIENCES • POST REG EXPECTATIONS • WHAT HAPPENS IF NOT MET? • HOW TO DO AN AMENDMENT SUBMISSION? • HOW CAN A FOLLOW UP BE DONE?

24. WHAT HAPPENS IF THESE ARE NOT DONE? • NO TABS OR INADEQUATE TABBING=REJECTED AT PRE-SCREENING • NO COVER PAGE OF SUBMISSION =DELAY(CALL APPLICANT) • NO COVER LETTER =DELAY(CALL APPLICANT) • NO COMPREHENSIVE TABLE OF CONTENTS (Module 1.1)= REJECT AT TECHNICAL SCREENING • NO APPLICATION FORM =REJECT TECHNICAL SCREENING

25. WHAT HAPPENS IF THESE ARE NOT DONE?Cont….. • NO ANNEXES TO APPLICATION FORM (1.2.2) =DELAY- CALL APPLICANT • CLASSIFICATION OF AMENDMENTS= DELAY OR REQUEST TO UPLIFT AND SUBMIT RELEVANT DATA. • AMENDMENT SCHEDULE (1.5.2.1)=REJECTED AT TECHNICAL SCREENING. • HYBRID DOSSIER SUBMITTED:=REJECTED AT TECHNICAL SCREENING.

26. HYBRID DOSSIER PROBLEM! A matter of INTERPRETATION where the applicants have confused the concept of Hybrid dossier FORMATION and Hybrid dossier SUBMISSION What is the difference???

27. HYBRID DOSSIER PROBLEM cont…. • Dossiers that are Old Medicines or are Registered medicines are existing in either MBR1 or MRF1 formats. • After the date of implementation (31/05/2011) of CTD the MCC no longer accepted amendments in MBR1 or MRF1 formats. • All amendments and updates are to be submitted in CTD format. • This would result in the FORMATION of a HYBRID dossier with the existing/remaining annexures or parts when filed.

28. HYBRID DOSSIER PROBLEM cont…. • The Post Registration Unit has received applications in which applicants are SUBMITTING HYBRID files. • These files include the updated modules as well as copies of the existing format. • Some HYBRID dossiers submitted are TRIPLE HYBRID…what does this mean?

29. HYBRID DOSSIER PROBLEM cont…. • This is when the applicant has some information existing in MBR1; some in MRF1 and the newer amendments in CTD. • It was communicated that only the following Hybrid files were allowed to be FORMED (note NOT Submitted) • MBR1-CTD and • MRF1-CTD

30. HYBRID DOSSIER PROBLEM cont…. • So what if an applicant SUBMIT a Hybrid file? • It will not be evaluated…and returned • WHY? • The time and resources involved in looking at information in obsolete formats is wasted! • This may result in the formation of a triple hybrid…which cannot be managed

31. HYBRID DOSSIER PROBLEM cont…. • Help us and yourselves by investing the time and resources it takes to SUBMIT a Hybrid file into rather updating the entire file to CTD…i.e do a full update to CTD. • In this way the evaluators will be using their time evaluating a relevant format and the applicant achieves a full update. • Yes, full updates in CTD format are accepted at any time, however full updates are classified as a Type C change as it can only be accepted that a full update is done when the MCC provides a letter communicating that the format change has been accepted. • The time it takes to evaluate a full update is much more than a partial update or an amendment.

32. HYBRID DOSSIER PROBLEM cont…. • The importance of the cTOC in assuring that there are no other hybrids e.g. MBR1 –MRF1 existing • That in such cases where the applicant managed to mix their formats, they are advised to do a full update to CTD immediately • The cTOC is able to provide both MCC and applicant on the status of transition to CTD… • Remember…01 June 2016 all files should be in CTD ☺

33. HOW TO DO AN AMENDMENT SUBMISSION? Example : Change in applicant, packer and FPRC (VAC,VPC,VLC) • Cover Page of Submission indicates all sections in the module affected • Cover letter (1.0) • cTOC (1.1) • Application form (1.2.1) • Annexes (1.2.1) Payment • 1.5.2.1 Tabulated schedule of amendments • 1.5.2.2 Medicines Register Details • 1.5.2.3 Affidavit by Responsible Pharmacist • Very important 1.7 details to be submitted

34. HOW CAN A FOLLOW UP BE DONE? • Call at least 6-8 weeks after submission (only if necessary) • Call Post Reg Unit for all P&A Amendments only • Contact details are: BennetteLovemore on 012 395 9313 or email: Lovemb@health.gov.za AlinahDiale on 012 395 9271 or email: Dialea@health.gov.za SilveraniPadayachee on 012 395 9316 MCC website MCCZA.com

35. What you need to have handy • If submission enquired on is older than 3 months then have the following information at hand to enable tracking of your document • Proprietary name • Registration/Application number • Date of cover letter • Variation code: e.g VAC, VPC,VLC • Proof of submission • Provide your contact details

36. POST REG OPERATIONAL PROCESS • Amendment submissions received via Ops & Admin after being serialised & logged into system • Pre-Screening: • Administrative screening for all “V” codes • VRR are recorded and allocated immediately • VGC and VSB screened out recorded and handled by supervisor • Re-submissions identified by Re-submission codes are verified by code number and recorded for allocation • All documents thereafter are screened for tabs

37. Re-submissions • Do not re-submit any document without contacting the unit to obtain a re-submission reference number. • Disadvantage of not obtaining a re-submission number is that document rejected at screening and if passes then document enters normal queuing system • What is the benefit of a re-submission ref number • Enables priority allocation • Prevents duplication (verification done apriori)

38. Question of Backlog! • Unit receives on average 250 applications per month (>3000pa) • 1560 done in 2010; 1849 done in 2011 (with half staff complement) • Documents received into unit is > 8 weeks old or older • Queries telephonic and email reached 160 per month (CTD) • Technical screening of Amendments enable Type C administrative to be processed from Post Reg on screening • Technical Type C amendments follow queue system (Now evaluating July-August 2011 submissions) • Administrative Type C without technical evaluations are processed on screening (±2weeks from entry), acknowledgement letter generated and submission transferred to Inspectorate for evaluation and then transfer to Ops and Admin for certificate generation.

39. Process flow for Certificate Amendment • Entry into Ops & Admin (serialised, logged and payment verification) • To Post Reg Unit; letter generated and document transferred to Inspectorate • In the case of Biological Medicines they are transferred to the Biological Unit • Inspectorate evaluation and transfer to Ops & Admin • Ops & Admin generate Amended Certificate • Certificate signed by Registrar • NB- Amended Certificate will not be generated until verified that document signed off by Post Reg (Biological) and Inspectorate…so don’t submit duplicates it just congests an already congested system

40. ACHIEVING PERFECT TRANSITION Are we there yet?

41. Some challenges experienced with API amendments • Majority of the technical amendments received are for changes in the API source • Requests for once-offs for API sources are channeled to Post Reg Unit for evaluation…so important to plan ahead • Many requests for API source changes are not approved as report as outlined in P&A guideline is not submitted

42. Some challenges experienced with API amendments cont… • Circulars are obsolete, applicants are to comply with current guidelines. • Obtain DMF’s; APIF’s or CEP’s from manufacturer, contracts with manufacturers to advise timeously of changes and plan ahead. • Literature and motivation must be submitted to support claims that API’s are well known chemical entities • Minor changes in the route of synthesis of API is considered a Type C8b (guideline) • Is there an error in the bullet points numbering for point 3.1.5 of P&A guideline June 2011? Yes, one point was omitted. Identified by P&A Committee and will be corrected with next update. • Type C, category 8 c amendment for an additional API source. The final product comparative dissolution study report in support of product efficacy - should this appear under 32R141 (pharmaceutical availability studies) or 32R42 (comparative results for multiple API manufacturers). 32R141

43. API amendments and Guidelines • The Amendments guideline point 5.2   “In the case of a general change in the manufacturer or specification of an active pharmaceutical ingredient (API), affecting more than one product (same dosage form), the updated PART 3A / Module 3.2.S of the product dossiers involved should be submitted only upon approval of the general change.   • The expected interpretation of this was that, if a change in API source or method of synthesis was evaluated and approved it would imply that the new source or method of synthesis was evaluated, however to retain the shelf life of the product with the change the stability (b) or (c) and efficacy requirements met. Note that a stability commitment for stability (c) is not accepted. • Outcome is that this statement will be reworded to exclude or reduce chances of misinterpretation.

44. Some other questions • Is declaring talc, asbestos-free still applicable as the guideline (2.02 PA Jun11 v6, dated June 2011) no longer requests this to be declared. A declaration is required. • When can we expect the Post Registration Amendment Guideline be updated to be aligned with the CTD? Was updated to include “CTD”. A guidance for transition into CTD is in-process. Amendment guideline itself has many proposed changes, one major change involves the classification of the Biological Amendments. • Location of stability data in CTD: 32P81(Tabulated Summary and Conclusion and 32P83 (Stability data)

45. Some other questions • During the MRF 1 phase for Part 3D we had to submit supplier specifications, finished product manufacturer specifications and COAS from the supplier and finished product manufacturer for the container. Please clarify what exactly is required of us do we still submit both supplier and finished product manufacturer specifications and COAs or do we submit only 1 and from which one . The focus is generally on the FFP manufacturer/applicant specifications, however if parenterals/eye drops then comply with the pharmacopoeial specifications. • Deadlines for P&A responses: 3 months • If are submitting a CEP and no DMF, please specify what additional requirements on parts of a DMF are needed to be submitted? The P&A guideline states you need module 3.2.S.1.3 and stability data if there is no retest period on the CEP. Do we need to submit a module 3.2.S.4 . For stability 3.2.S.7

46. Some Pointers from Post Reg Evaluations • Please consult current Amendment guidelines. Amendments submitted based on old guidelines will be rejected. • Type A amendment submissions on its own are not accepted. Full update with 10 implemented type A’s will be accepted. • Post Reg screening will reject documents that do not include an Amendment history, adequately completed amendment schedules and relevant authorisation letters. • The Amendment history is to include all amendments approved and pending since the date of registration, except the one currently applied for. • In the amendment schedule, indicate why change is made in the reason column. • For changes in API source refer to P&A guideline 3.1.7 (3.2.S & 3.2.R.4). A signed and dated report of the comparative study from the common laboratory must be submitted. The results should also be presented in tabular format. Comparison of CoA’s are not sufficient.

47. Responses (VRR) • Responses should only address requests as per the MCC communication. Do not make additional amendment requests in responses • Include MCC communication relevant to the response. Refer to Amendments guideline 1.1 & 1.2 on format of responses. • Code your responses as VRR only and not the initial amendment code. Remember wrong code results in delayed responses

48. Re-submission of Post Reg Amendments • Please do not re-submit amendment requests without prior consultation and approval. • This results in unnecessary duplication of work, waste of resources, waste of paper and filing space.

49. From this we gather that not everything has been COOL with the transition to CTD …. but we getting there!

50. Questions