Case Study Session

1
Case Study Session

• BROMI VARIATIONS.

2
PLAN

• How this session will work.
• A presented example (Case Study 1) to give you an
  idea of what you should be looking for.
• Then there will be up to 3 further case studies
  for you to work through
• More complex than first example.
• Time for discussions answer questions.
• Try to work out how you would do it.
• BROMI or not and highlighting potential issues.

3
PLAN

• Model answers to all four case studies will be
  provided in the delegate pack to allow you to
  train others.
• Set-up for round-table discussions.
• Please nominate a table leader to feedback
  answers to questions during this session.
• Any questions please ask the industry or MHRA
  support on hand.

4
CASE STUDY 1.
5
PROBLEM.

• Company A sells pain reliever tablets
• Section 6.5 of the SPC describes the current
  packaging as
• Blister strips consisting of a base layer of 250
  micron PVC with lidding foil of 20 micron
  aluminium foil, in packs of 8 or 16 tablets
• The company wishes to add a pack size of 12
  tablets.

6
QUESTIONS.

• Could this be a BROMI change, if so which one?
• What conditions are there for the change and do
  we meet them?
• What documentation would be required?
• Do we have sufficient information available to
  submit this application as a BROMI change? If
  not what additional data would we need to
  provide?
• Is there anything additional we would submit?

7
ANSWERS.

• Could this be a BROMI change, if so which one?
• Yes, before the BROMI variations this would have
  been a Type IA now it could be a BROMI Self
  Certification category 41.a.1

8
ANSWERS.

• What conditions are there for the change and do
  we meet them?

9
ANSWERS.

• What documentation would be required?
• Cover Letter
• Completed Portal Application Form.
• Completed BROMI variations guideline page
• Proof of Payment (according to company
  procedures)
• PLUS

10
APPLICATION FORM.
11
APPLICATION FORM.
12
APPLICATION FORM.
13
APPLICATION FORM.
14
BROMI GUIDELINE PAGE.
15
ANSWERS.

• Do we have sufficient information available to
  submit this application as a BROMI change? If
  not what additional data would we need to
  provide?
• Yes. As the required pack size is within the
  current range this can be submitted as a BROMI
  Self certification. No stability declaration is
  required.
• Is there anything additional we would submit?
• No

16
DISCUSSION / QUESTIONS

• Any questions on first case study example?

17
CASE STUDY 2.
18
PROBLEM

• Company A sells Pain Reliever Tablets.
• Section 6.5 of the SmPC describes the current
  packaging as
• Blister strips consisting of a base layer of 250
  micron PVC with lidding foil of 20 micron
  aluminium foil containing 8 tablets, in pack
  sizes of 8 or 16 tablets.
• The company wishes to change the lidding foil to
  a thicker material which consists of 20 micron
  aluminium foil and 15 micron PVC.
• A specification for the new packaging material is
  available.
• The company has also done some work to compare
  the permeability of the new packaging with the
  old packaging to show that the product does not
  interact with either PVC or Aluminium foil.
• Stability studies with the new packaging have
  been started this week

19
QUESTIONS

• Could this be a BROMI change, if so which one?
• What conditions are there for the change and do
  we meet them?
• What documentation would be required?
• Do we have sufficient information available to
  submit this application as a BROMI change? Is
  there anything additional we would submit?
• Fill in blank Portal Application form (pertinent
  sections only)

20
ANSWERS

• Could this change be a BROMI change, and if so
  which one?
• Yes, it could be a BROMI Type IB change, code no.
  29.c
• Change in the qualitative and/or quantitative
  composition of the immediate packaging material -
  All other pharmaceutical forms change concerns
  more resistant packaging and stability data are
  not yet available

21
ANSWERS

• What conditions are there for the change and do
  we meet them?
• The product concerned is not a biological or
  sterile product.
• The change only concerns the same packaging type
  and material (e.g. blister to blister).
• The proposed packaging material must be at least
  equivalent to the approved material in respect of
  its relevant properties.
• The proposed packaging is more resistant than the
  existing packaging e.g. thicker blister packaging
  and three months stability data are not yet at
  the disposal of the applicant. Assurance is
  given that these studies will be initiated and
  finalised and that the data will be provided
  immediately to the competent authorities if
  outside specifications or potentially outside
  specifications at the end of the approved shelf
  life (with proposed action).

22
ANSWERS

• What documentation would be required?
• Cover Letter
• Completed Portal Application Form
• Completed BROMI variations guideline page
  (checklist)
• Proof of payment (according to company procedure)
• Revised dossier pages (Module 3.2.P.7).
• Justification for the omission of stability data
  and stability commitments. In module 3 or as a
  separate statement)
• Comparative permeability data.
• Discussion of the original interaction data and
  its relevance to the new packaging.
• Revised SmPC section 6.5
• Present and Proposed Specification

23
ANSWERS

• Do we have sufficient information available to
  submit this application as a BROMI change?
• Yes, sufficient information is available.

24
CASE STUDY 3.
25
PROBLEM

• Overview of the proposed changes to be made
• Change in the name and address of the MA holder
• Change in the name of the manufacturing site
• Addition of a new pack size
• Impacted Licences
• ParaTabs Childrens Tablets
• ParaTabs Adults Tablets

26
PROBLEM

• Change 1 - Change the name and address of the MA
  holder from
• ABC Pharmaceuticals
• 1 High Street
• Pharmatown
• UK
• Company number 1234
• to
• XYZ Pharmaceuticals
• 1 The Business Park
• Pharmatown
• UK
• Company number 1234

27
PROBLEM

• Change 2 - Change the name of the manufacturing
  site from
• ABC Pharmaceuticals
• Pharmaplant
• Paris
• France
• to
• XYZ Pharmaceuticals
• Pharmaplant
• Paris
• France

28
PROBLEM

• Change 3 - Addition of a new pack size
• New pack size 4 tablets for each licence
• Current pack sizes on licence 2 6 tablets
• Packaging material remains the same

29
QUESTIONS

• Can these changes be submitted as BROMI
  applications?
• What conditions are there for each change and do
  we meet them all?
• What documentation would be required?
• Do we have sufficient information available to
  submit these applications as BROMI changes? If
  not what additional data would we need to
  provide?
• What strategy would you use?
• Fill in blank Portal Application form (pertinent
  sections only)

30
ANSWERS.

• CHANGE 1
• Could this be a BROMI change, if so which one?
• Yes as Company remains the same legal entity
• Self certification BROMI No. 1 Change in the
  name and/or address of the marketing
  authorisation holder.
• What conditions are there for the change and do
  we meet them?
• MA holder must remain the same legal entity
• The changes are the only changes to be made,
  other than those stated which are being submitted
  in parallel.

31
ANSWERS.

• CHANGE 1(Cont)
• What documentation would be required?
• Cover Letter
• Completed Portal Application Form
• Completed BROMI variations guideline page
  (checklist)
• Proof of payment (according to company procedure)
• Companies House Certificate
• Proposed SPC (and fragment) and artwork (as
  appropriate) in this case carton, foil and
  joint PIL for each product
• Do we have sufficient information available to
  submit this application as a BROMI change?
• Yes.
• Is there anything additional we would submit?
• No.

32
ANSWERS.

• CHANGE 2
• Could this be a BROMI change, if so which one?
• Yes as this remains the same company submit
  under
• Self certification BROMI No 5 Change in the name
  and/or address of a manufacturer of the finished
  product.
• What conditions are there for the change and do
  we meet them?
• Manufacturing site remains the same
• The change is the only change to be made, other
  than those stated which are being submitted in
  parallel.

33
ANSWERS.

• CHANGE 2 (Cont)
• What documentation would be required?
• Cover Letter
• Completed Portal Application Form
• Completed BROMI variations guideline page
  (checklist)
• Proof of payment (according to company procedure)
• Formal document with new name (in this case a GMP
  certificate)
• Updated CTD pages
• Updated artwork as appropriate
• Do we have sufficient information available to
  submit this application as a BROMI change?
• Yes.
• Is there anything additional we would submit?
• No.

34
ANSWERS.

• CHANGE 3
• Could this be a BROMI change, if so which one?
• Yes, the new pack size to be added is within the
  current range so can be submitted as
• Self certification BROMI No. 41, a 1 Change in
  pack size of finished product within the
  currently approved range (By referencing the SPC
  you can see that 2 tablet and 6 tablet pack sizes
  are currently registered).
• What conditions are there for the change and do
  we meet them?
• The new pack size is consistent with the posology
  
• Primary packaging remains the same
• The smallest and largest pack sizes remain on the
  licence
• The change is the only change to be made, other
  than those stated which are being submitted in
  parallel.

35
ANSWERS.

• CHANGE 3 (Cont)
• What documentation would be required?
• Cover Letter
• Completed Portal Application Form
• Completed BROMI variations guideline page
  (checklist)
• Proof of payment (according to company procedure)
• Proposed SPC (and fragment)
• Proposed carton, foil leaflet for each product
• Updated CTD pages
• Stability data is not required as the stability
  parameters are not affected.
• Do we have sufficient information available to
  submit this application as a BROMI change?
• Yes.
• Is there anything additional we would submit?
• No.

36
ANSWERS.

• CHANGE 3 (Cont)
• STRATEGY
• The 3 changes can be submitted in parallel

37
CASE STUDY 4.
38
PROBLEM

• Company A sells pain reliever tablets
• It would like to use paracetamol manufactured by
  Active P Supplier Inc in their tablets. This is a
  new supplier.
• Active P Supplier Inc has a European
  Pharmacopoeia Certificate of Suitability (CEP)
  for paracetamol.
• It has a number of suppliers of paracetamol on
  its licences, however it would also like to
  remove Paracetasupply Ltd from the licence.
• Paracetasupply Ltd is listed as an API (Active
  Pharmaceutical Ingredient) manufacturer on three
  other of company As licences.

39
QUESTIONS

• Could the above changes be handled as BROMI
  changes, if so which one(s)?
• What conditions are there for the changes and do
  we meet them?
• What documentation would be required?
• Do we have sufficient information available to
  submit relevant applications?
• If not what additional data would we need to
  provide?
• What is the most efficient way of removing
  Paracetasupply Ltd from all three licences?
• Fill in blank Portal Application form (pertinent
  sections only)

40
ANSWERS

• Could this be a BROMI change, if so which one?
• The addition of a new CEP could be submitted as a
  BROMI Self Certification change code 15 a 2 if
  the manufacturer is currently approved (Updated
  CEP) but in this case the manufacturer is not
  currently approved and so the variation should be
  submitted via the standard Type I A route, change
  code 15 b 2.
• The deletion of Paracetasupply Ltd on the 3
  licences can be done as a BROMI change code 9a.

41
ANSWERS

• What conditions for the changes and do we meet
  them?
• Type I A Code 15 b
• The finished product release and end of shelf
  life specifications remain the same.
• The finished product release and end of shelf
  life specifications remain the same.
• The active substance will be tested immediately
  prior to use if no retest period is included in
  the European Pharmacopoeia certificate of
  suitability or if data to support a retest period
  is not provided.
• The manufacturing process of the active
  substance, starting material/reagent/intermediate
  does not include the use of materials of human or
  animal origin for which an assessment of viral
  safety data is required.
• BROMI Change code 9a
• An appropriately authorised site remains
  registered on the authorisation to undertake the
  manufacturing operation concerned.

42
ANSWERS

• What documentation would be required?
• Type I A Code 15 b
• Copy of the current (updated) European
  Pharmacopoeia certificate of suitability.
• Amended page(s) of Part IIC and IIF (old Part
  IIE) or equivalent in the CTD format, if
  applicable
• Where applicable, a document providing
  information of any materials falling within the
  scope of the Note for Guidance on Minimising the
  Risk of Transmitting Animal Spongiform
  Encephalopathy Agents via Human and Veterinary
  Medicinal Products including those which are used
  in the manufacture of the active substance. The
  variation application form should clearly outline
  the present and proposed manufacturers as
  listed in section 2.5 of the (Part IA)
  application form.
• A declaration by the Qualified Person (QP) of
  each of the manufacturing authorisation holders
  listed in the application where the active
  substance is used as a starting material and a
  declaration by the Qualified Person (QP) of each
  of the manufacturing authorisation holders listed
  in the application as responsible for batch
  release. Cover Letter
• Proof of payment (according to company procedure)
• Completed application form
• Completed variations guideline page (checklist)
• Cover Letter

43
ANSWERS

• What documentation would be required?
• BROMI Change code 9a
• Cover letter
• Completed BROMI variations guideline page
  (checklist)
• Completed Portal Application Form
• Proof of payment (according to company procedure)
• The present and proposed manufacturers should
  be clearly stated on the variation application
  form.
• Updated Module 3 pages in CTD format

44
ANSWERS

• Do we have sufficient information available to
  submit this application as a BROMI change? If
  not what additional data would we need to
  provide?
• No, for the addition of the API supplier. We
  have the current European Pharmacopoeia
  certificate of suitability but we require a
  signed QP declaration before submission.
• Yes to remove the API manufacturer,
  Paracetasupply Ltd . The licences still include
  an API supplier Paracetamol Supplies Ltd.
• Is there anything additional we would submit?
• No

45
ANSWERS

• What is the most efficient way of removing
  Paracetasupply Ltd from all three licences?
• As with standard, non-BROMI variations bulk
  applications are acceptable.