Page 1 of 7

Fictional sample submission of a Biologics MIV-1:

Product Name: Healmenow50mg/mL
Dosage form: Liquid in glass vial for injection

APPENDIX 10A: CHECKLIST FOR MINOR VARIATION APPLICATIONS
(MIV-1 & MIV-2) FOR BIOLOGICS (PRISM #: 1234567A)

The following items are mandatory in the checklist for each submission:
1. Compulsory documents;
2. *Copy of the dossier requirement of relevant changes with the relevant boxes for
conditions and documentations ticked (except for MIV-1 change(s) which is/are not listed
in the Guideline on Minor Variation Applications for Biologics);
3. Declaration of the applicant for MIV-1 or MIV-2.

*Note:
In case of an MIV-1 application, delete the complete list of MIV-2 changes and those
MIV-1 changes which are not applicable;
In case of an MIV-2 application, delete the complete list of MIV-1 changes and those
MIV-2 changes which are not applicable.

Compulsory documents for MIV-1 applications (please tick):
The on-line PRISM application form Amendment to a License of Western Drug
Product, where the Section 0.4 is appropriately filled;
The MAV/MIV: Table of Summary of Changes form (download via the link in PRISM
titled Please provide details of variation(s));
The relevant CTD section(s) of the currently registered version with the proposed
change(s) clearly highlighted, underscored, or otherwise indicated.

DOSSIER REQUIREMENTS FOR BIOLOGICS MIV-1

B1 Change of Manufacturing Site

For any change, including addition to or replacement, of currently registered manufacturing
site(s) of drug substance, drug product, process intermediates, and/or primary packager.

Documents Required In Addition to MIV-1 Compulsory Documents
1) Official letter authorising the proposed site to perform the related activity;
2) GMP certificate;
3)
Validation study reports and/or summaries of the manufacturing process at the
proposed manufacturing site;

4) Release and/or shelf life specifications;
5)
Batch analysis data (in a comparative tabular format) of at least three batches
manufactured at the currently registered and proposed site;

6)
Results of appropriate stability studies of at least three batches produced at the
proposed manufacturing site in accordance with the relevant stability guidelines.

B4 Change of Test Procedure

For any change of test procedure of drug substance, drug product, in-process tests, product
release tests, and/or stability tests.

Documents Required In Addition to MIV-1 Compulsory Documents:
1) Validation study reports and/or summaries of the proposed test procedure.


Page 2 of 7
B5 Change of Specifications

For any change of release and/or shelf life specifications of drug substance, drug product, in-
process tests, product release tests, and/or stability tests.

Documents Required In Addition to MIV-1 Compulsory Documents:
1) Scientific and/or historical data used to support the change;
2)
Currently registered version of the release and/or shelf life specifications with the
proposed change(s) clearly highlighted, underscored, or otherwise indicated.

B6 Change of Container Closure System

For any change of the container closure system that is in immediate contact with the drug
substance, drug product, process intermediates, and/or diluent used for reconstitution.

Documents Required In Addition to MIV-1 Compulsory Documents:
1)
Information on construction materials and design features of the proposed container
closure system;

2)
Study reports and/or summaries on compatibility, leaching materials, leak tests, etc. for
demonstrating the suitability of using the proposed container closure system;

3) Release and shelf life specifications;
4)
Results of appropriate stability studies of at least three batches produced with the
proposed container closure system in accordance with the relevant stability guidelines.

B9 Change of Product Label

For any change of product labelling of the package insert (PI), patient information leaflet
(PIL), unit carton label, inner label, and/or blister strips which cannot be classified as an MAV
or an MIV-2.

Documents Required In Addition to MIV-1 Compulsory Documents:
1)
J ustification for the proposed change(s) and supporting clinical documents, where
applicable;

2)
Currently registered product label with the proposed change(s) clearly highlighted,
underscored, or otherwise indicated;

3) Proposed product label with all change(s) incorporated;
4)
Approved PI/SmPC/PIL from a reference regulatory agency containing the proposed
changes.



Declaration of the applicant for MIV-1
I hereby submit an application for the concerned product to be varied in accordance with the
proposals given above. I declare that (please tick the appropriate declarations)

There are no other changes than those identified in Section 0.4 Amendment Details;
All conditions as set for the change(s) concerned are fulfilled;
The required documentations as specified for the change(s) have been submitted.



Peter Tan 15 J an 2007
Applicants Name: Applicants Signature: Date:




Page 3 of 7
Fictional sample submission of a Biologics MIV-1:

Product Name: Healmenow50mg/mL
Dosage form: Liquid in glass vial for injection


0.4 Amendment Details: 1. PRISM updates.
2. Inclusion of additional DS manufacturer to allow alternative
and back-up site.
3. Change of DS specification as well as testing methods.
4. Addition of a 10 ml pack size.



Page 4 of 7
A. MAV/MIV: Table of Summary of Changes HEALMENOW 50MG/ML

DETAILS OF VARIATION TO EXISTING PRODUCT LICENCE
Specify the precise present and proposed wording or specification. For changes to package insert or Patient Information Leaflet, please highlight changes in the proposed version.
Section in Original
Dossier Affected by
Change
Present Proposed Reason for change
Status of proposed change in
other countries i.e. whether
approved, pending decision
or rejected
Status date
(MAV-1 onl y)
PRISM updates
2. Applicant Particulars
(Name and NRIC)

4.3b Animal-derived
material

4.7 Storage condition


Person X
A7654321B

no


Store at room temp.


Peter Tan
G1234567Q

Yes, Bovine serum cell
culture Australia

Store at or below 30C
(approved previously by
HSA on 15 J an 2004)


New personnel

Not captured previously

To better define storage
conditions
NA NA
ACTD Part I 1.1
ACTD Part II S2, S4, S7


Current DS manufacturing,
DP primary packaging site:
Company A
New York, NY 10128 USA

DS manufacturing site:
(MIV1 B1)
Company A
New York, NY 10128 USA
&
Company B
55 Performance Rd
Erehwon, CA 92128 USA
To provide an additional DS
manufacturing site to
increase production capacity
and to provide a back-up site.

Approved: USA, Belgium
Canada: Notification
Pending: UK

NA








Page 5 of 7
Section in Original
Dossier Affected by
Change
Present Proposed Reason for change
Status of proposed change in
other countries i.e. whether
approved, pending decision
or rejected
Status date
(MAV-1 onl y)
ACTD Part II S4.1, S4.2,
S4.3, S4.5, S7.3
Current DS specification is
attached in encl. S4.1_A.

New DS specification is
attached in encl. S4.1_B.
Main changes are:
1) Replaced specific
activity assay
method for DS to
comply with 2006
Ph. Eur.
(MIV1 B4)
2) Added specification
for the % of
glycosylation (MIV1
B4 & B5)
Detailed changes are
highlighted in comparison
table in encl. S4.1_C.
Changes are due to
scientific reference and
historical data. Please refer
to details in comparison
table in encl. S4.1_C.


Approved: USA, Belgium
Canada: Notification
Pending: UK
NA
ACTD Part I 1.4

ACTD Part II P2.3, P3.3,
P3.4, P3.5, P5.1, P5.2,
P5.3, P5.4, P5.6, P7
Pack size 50mg/mL, 1mL

Pack size: (MIV1 B6, B9)
50mg/mL, 1ml
&
50mg/mL, 10ml
Detailed changes of labels are
highlighted in comparison
table in encl. tab1.4.
Additional pack size due to
the nature of the disease
and common physician
usage practices.
Pending: UK NA



Page 6 of 7
MIV-1 Compulsory Document for HEALMENOW50MG/ML
Comparative ACTD Sections with changes indicated
CURRENT DOSSIER PROPOSED DOSSIER
HIGHLIGHT
ACTD Part II S4.1
Table S4-1: Test Methods and
Specifications of Healmenow

DS

Potency:
Test Method Specification
Activity by XX
Colormetric Assay
70-130 units/mL
In vitro Uptake Assay maximal uptake at
2.5 nM
Strength:
Test Method Specification
Total Protein by UV 0.80- 1.10 mg/mL



= Changed

ACTD Part II S4.1
Table S4-1: Test Methods and
Specifications of Healmenow

DS

Potency:
Test Method Specification
Activity by ZZ
Fluorescence Assay
80-120 units/mL
In vitro Uptake Assay maximal uptake at
2.5 nM
Glycosylation:
Test Method Specification
FACE Analysis Similar to reference
Strength:
Test Method Specification
Total Protein by UV 0.80- 1.10 mg/mL
= Modified
= New
UNDERSCORE
ACTD Part II S4.2 Analytical Procedures
S4.2.1 Activity by XX Colormetric Assay

The purity of

The activity of Healme DS is determined by
measuring the rate of the conversion pre-XX to
XX in the presence of Healme DS. XX has
maximum absorption at 470nm.


The strength of

ACTD Part II S4.2 Analytical Procedures
S4.2.1 Activity by ZZ Fluorescence Assay

The purity of

Pursuant to 2006 European Pharmacopeia
(Ph. Eur.), the activity of Healme DS should be
determined by measuring the release of a
fluorescent molecule from a non-fluorogenic
substrate in the presence of enzyme. The
assay uses an artificial substrate xyzXX

The strength of
OTHERWISE INDICATED
e.g. TRACKED CHANGES (MS WORD)



ACTD Part II P2.3
P2.3.6 Finished Product

Final fill volume of the product is 1.0 mL and
10 mL. Development of different fill volume is
currently underway.
OTHERWISE INDICATED
ACTD Part II P3.3
P3.3.7 Manufacturing Process of 10 mL
product
Not present

ACTD Part II P3.3
P3.3.7 Manufacturing Process of 10 mL
product
Finished bulk drug product transported to
Room 234 via protocol YM#55. FILLER model
1000 is used for both fill volumes.



Page 7 of 7
MIV-1 B1 1


Vandelay Industries
100 Vandelay Park Blvd.
New York, NY 10128 USA





J anuary 15, 2007

Re: Healmenow50 mg/ml MIV-1 B1-1

To Whom It May Concern:

I represent Vandelay Industries in authorizing the following site for the proposed action:

Site address Proposed activity/responsibility
Company B
55 Performance Rd
Erehwon, CA 92128
USA
Healmenow50 mg/ml drug substance
manufacturing

Thank you.

Best regards,



J ohn Smith
Regional Manger
Vandelay Industries