Transcript Post Registration Strategy

ZA CTD
IMPLEMENTATION DATE: 31 May 2011
>9 MONTHS LATER…
SOME THINGS TO DISCUSS

INTEGRATION OF EXPERIENCES OF TRANSITION
TO CTD

MANAGING THE HYBRID DOSSIER: CHALLENGE
OR OPPORTUNITY

WHAT SHOULD
REQUEST?

UNDERSTANDING
MAY HELP!

QUESTIONS ON API AMENDMENTS

OTHER QUESTIONS
GO
INTO
AN
AMENDMENT
OPERATIONAL PROCESSES
SUBJECT TO INTERPRETATION
WHAT IS 5X5?
=25
ARE YOU SURE?
SUBJECT TO INTERPRETATION
cont….
IS IT NOT =14?
YOU HAVE AN OPPORTUNITY TO
JUSTIFY OR CLARIFY YOUR
REASONING
USING VARIOUS MATHEMATHICAL
PRINCIPLES
SUBJECT TO INTERPRETATION
cont….
JUSTIFICATION THAT 5X5=14
EXPERIENCES
POST REG UNIT




INTERPRETATION OF
THE REQUIREMENTS
APPLICATIONS OF
VARIOUS
REQUIREMENTS
UNDERSTANDING
SOME OF THE
OPERATIONAL
CHALLENGES
HYBRID FORMAT
APPLICANTS




POST REG
EXPECTATIONS
APPLICATIONS
REJECTED
HOW TO DO AN
AMENDMENT IN CTD?
HOW CAN A FOLLOW
UP BE DONE?
POST REG 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
GRANULARITY OF ZA CTD

A characteristic of the ZA CTD format is the
granularity of the format. See GUIDANCE
FOR THE SUBMISSION OF 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
GRANULARITY OF ZA CTD cont…
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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
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”
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
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
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

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
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
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
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)

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 .
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
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.
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)
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,

APPLICANTS EXPERIENCES

POST REG EXPECTATIONS
WHAT HAPPENS IF NOT MET?
 HOW TO DO AN AMENDMENT
SUBMISSION?
 HOW CAN A FOLLOW UP BE DONE?

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
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.
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???
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.
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?
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
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

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.
HYBRID DOSSIER PROBLEM
cont….
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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
☺
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
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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:
Bennette Lovemore on 012 395 9313 or email:
[email protected]
Alinah Diale on 012 395 9271 or email:
[email protected]
Silverani Padayachee on 012 395 9316
MCC website MCCZA.com

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
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
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)
Question of Backlog!
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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.
Process flow for Certificate Amendment
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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
ACHIEVING PERFECT TRANSITION
Are we there yet?
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

Some challenges experienced with API
amendments cont…

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
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
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.
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)
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
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.
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
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.
From this we gather that not everything
has been COOL with the transition to
CTD ….
but we getting there!