....................................-...................................., ...................................., ....................................

- IRAN
.................................... Production Transfer Protocol

15 July 2012

PRODUCT TRANSFER PROTOCOL

PRODUCT TO BE TRANSFERRED (Stages include tabletting, coating, packaging):

.................................... tablet

.................................... (....................................s, ....................................)

Approved by:
.................................... .................................... Industrie
30-36, ....................................
37100 ....................................s, ....................................
Quality Assurance:
Signature & Date

Technology Transfer Manager:

Signature & Date

.................................... (.................................... is appointed as the .................................... representative

and MAH)
(Tehran, Iran)
....................................
39, Alvand Ave., Argantin Sq.
Tehran 1516673115, Iran

Quality Assurance (Responsible Pharmacist):

Signature & Date

Receiving site: .................................... Pharmaceutical Laboratories (Tehran, Iran)

.................................... Bld.,
Tehran, Iran

Plant Logistic & Purchasing:

Signature & Date
Quality Assurance:
Signature & Date
Quality Control:
Signature & Date
Quality Operations:
Signature & Date

Date Version Written by Checked by Status

24 April 2012 01 Sayeh Majzoob (Technology

Transfer, ....................................
Iran)

-----------------------------
Signature & Date

TABLE OF CONTENTS
1/13
....................................-...................................., ...................................., ....................................- IRAN
.................................... Production Transfer Protocol

15 July 2012

SERIAL CONTENTS PAGE NUMBER

NUMBER
-- APPROVALS 1

-- TABLE OF CONTENTS 2

1 SUMMARY 3

2 RESPONSIBILITIES 3

3 PRODUCTS AND TRANSFERRED ACTIVITIES 3

4 ENVIRONMENT - HYGIENE – SAFETY 5

5 PRODUCT REVIEW BEFORE TRANSFER 5

6 ANALYTICAL TRANSFER 5

7 MANUFACTURING PROCESS TRANSFER 6

8 RAW MATERIAL AND SUPPLIERS 9

9 PACKAGING MATERIAL 9

10 REGULATORY 10

11 STABILITY 10

12 PLANNING 11

13 RELEASE CONDITIONS 11

14 LOGISTICS 11

1.SUMMARY

2/13
....................................-...................................., ...................................., ....................................- IRAN
.................................... Production Transfer Protocol

15 July 2012

1.1. This document defines the tasks to be realized to perform the transfer and the
responsible unit for each task.
1.2. This document summarizes the feasibility study of the transfer realized by the receiving
site, .................................... based on the transfer file prepared by the donor site.

2.RESPONSIBILITIES

2.1. .................................... is hereby appointed as ....................................’s representative

to manage Quality issues and Finished Product recall with regard to the Processing
and Packaging Operations performed by .....................................
2.2. Overall responsible people in the receiving site, .................................... are defined in
the following table:

Activities in
Responsible
....................................
Project leader
R &D and Product development
QA
RSO
Production
Control laboratory
HSE

2.3. Detailed responsibilities and obligations of the parties with regard to the Processing
and Packaging Operations are defined Quality agreement of this product.
2.4. The donor site (...................................., ....................................s) is responsible of the
market supply until the release of the 1st batch from the receiving site (Receiving entity:
..................................../...................................., Iran; Receiving site:
....................................), it gives the necessary assistance to the receiving site until the
end of the transfer.
2.5. A central coordination is done by the project coordinators in ....................................
....................................s (....................................)- .................................... Iran (Sayeh
MAJZOOB)- .................................... (....................................)- ....................................
(Amir MINOONESHAN).

3.PRODUCTS AND TRANSFER ACTIVITIES

3.1. Reasons of the transfer:

.................................... Tablet ( & ....................................) was launched in

Iranian market on Feb. 2009. .................................... sales have achieved significant
upside during the first year of launch [149%]. Availability of ....................................
tablet in Iranian market through local manufacturing will provide following
advantages:

3/13
....................................-...................................., ...................................., ....................................- IRAN
.................................... Production Transfer Protocol

15 July 2012

 Protect the product against other possible entries/importations in the future.

It is unlikely to register another brand product if local brand is available in the
market.
 Imported products, if granted to be imported based on new regulations
introduced by MOH, are subject to local taxes (65% rate) whereas local
products are exempted from Tax.

3.2. Operations to be transferred:

 Tablet compression from granules received from ....................................s

(with assistance from ...................................., ....................................S)
 Coating of the tablets (with assistance from ....................................,
....................................S)
 Packaging (artwork templates and specifications provided by
...................................., ....................................s)
 Quality control (methods and specifications provided by
...................................., ....................................s, no analytical transfer is
needed)

3.3. Knowledge of the receiving site, ....................................:

.................................... already has experience in manufacturing and packaging of

solid dosage forms. The secondary packaging of .................................... is already
done in ..................................... .................................... has experience in Quality
control aspects of .....................................

3.4. Major Investments needed:

Tablet press toolings

Blistering size parts

3.5. Classification of the product:

.................................... tablets and its ingredients ingredient are not psychotropic,

from a biological origin, hormone, antibiotics, …

3.6. Specific constraints

cGMP guidelines for solid dosage form manufacturing

Workshops

acceptable conditions

Temperature: 15-25°C

RH : ≤ 70%
4/13
....................................-...................................., ...................................., ....................................- IRAN
.................................... Production Transfer Protocol

15 July 2012

For storage of granulate

Temperature: 15-25°C

4.ENVIRONMENT – HYGIENE - SAFETY

4.1. The preliminary risk analysis linked to the transfer on the receiving site,
...................................., will be realized before the start of validation batches by the HSE
responsible of the receiving site, .................................... in collaboration with the HSE
responsible of the donor site, if necessary, according to the guideline:
4.2. The risk analysis should consider different aspects: product/process/machine and
environment work place.
4.3. According to the results of this analysis (OK to start without any actions/ OK to start
with actions), Time to set up the necessary HSE requirements would be determined
and implemented.

5.PRODUCT REVIEW BEFORE TRANSFER

5.1. .................................... Tablet (120 & ....................................) was launched in Iranian

market on Feb. 2009. .................................... sales have achieved significant upside
during the first year of launch [149%]. Availability of .................................... tablet in
Iranian market through local manufacturing will provide following advantages:

 Protect the product against other possible entries/importations in the future. It is

unlikely to register another brand product if local brand is available in the market.
 Imported products, if granted to be imported based on new regulations introduced
by MOH, are subject to local taxes (65% rate) whereas local products are exempted
from Tax.

5.2. .................................... .................................... and .................................... tablets are

currently being imported in Bulk blisters to Iran and the secondary packaging is done
in .....................................
5.3. The receiving site, .................................... has experience on the QC and analytical
methods of .................................... Tablets (Generic form containing the same API as
....................................).
5.4. The local production in .................................... site will begin from compression of
received .................................... Granules (from ....................................,
....................................s), due to the cGMP status of manufacturing facilities in
.....................................

6.ANALYTICAL TRANSFER/ REVALIDATION (VERIFICATION)

6.1. The receiving site, .................................... has experience on the QC and analytical
5/13
....................................-...................................., ...................................., ....................................- IRAN
.................................... Production Transfer Protocol

15 July 2012

methods of .................................... tablets (Generic form containing the same API as

....................................). The .................................... method is identical to compendial
methods. Therefore analytical transfer is not needed for .................................... tablets.
A re-validation (verification) would be done on the analytical methods in
...................................., before the manufacturing of the 1st validation batch.
6.2. The following specifications and methods of analysis have to be provided by the donor
site, ...................................., ....................................s to the receiving site:
...................................., (in case the methods are pharmacopoeial the reference to the
respective pharmacopoeia should be made):

 .................................... granules
 .................................... tablet .................................... core tablet
 .................................... tablet .................................... coated tablet
 .................................... tablet .................................... core tablet
 .................................... tablet .................................... coated tablet

Coating material:
 Opadry # 06A93131
 Polyethylene Glycol 400

7.MANUFACTURING PROCESS TRANSFER / VALIDATION

7.1. Specific conditions for manufacturing/storage:

Workshops

acceptable conditions

Temperature: 15-25°C

RH : ≤ 70%

For storage of granulate

Temperature: 15-25°C

7.2. Describe the critical stages of the process: Tablet compression, Tablet coating

7.3. Comparative table with the different steps of the process and equipment used by the
receiving and donor site:

6/13
....................................-...................................., ...................................., ....................................- IRAN
.................................... Production Transfer Protocol

15 July 2012

7/13
....................................-...................................., ...................................., ....................................- IRAN
.................................... Production Transfer Protocol

15 July 2012

Batches of 550 kg granules in drums will be supplied by the donor site,

....................................s to the receiving site, .................................... (the number of
drums and the granule net weight in each drum to be determined later).

7.4. Donor site Receiving site

(...................................., (....................................)
....................................s)

Process step Granule mixing with lubricant Granule mixing with

(Soneco (1800L)) lubricant (remixing after
receiving the lubricated
granules form Donor site,
....................................s)
Batch size 550 kg 100-110 kg ~ 208 L (Bulk
density 0.48 g/mL), in case
the 240 L drum mixer is used
(0.86% of drum filled)
Or
2 sub-batches of 50-55 kg ~
104-114.5 L (0.43%-0.47% of
drum filled)

Process step Tablet compression Tablet compression

Batch size 550 kg 100-110 kg
(Fette 3090 or (IMA- Kilian S250 Smart,
Courtoy RS190/290/292) equipped with vacuum
transfer AZO
And de-duster Advantec and
metal check MET 300)

Process step Tablet coating Tablet coating

Batch size 550 kg 100-110 kg
(Driam or Bohle) (Coating machine Sejong SFC
130 FH digitally controlled with
CIP with laser measure for the
T of the core tablets bed
-peristaltic pump Watson
Marlow, 2 airspray guns in
fixed space (25cm), 1mm
diameter)

Process step Blistering/Cartoning Blistering/Cartoning

Batch size IMA blistering machine Continuous

blistering machine IMA TR
200
Batch size: Tabletting and coating batch size in ....................................s: 550 kg

Tabletting and coating batch sizes in ....................................: 100-110 kg

7.5. The process transfer will be validated on the basis of realization: 1 technical batch of
25 kg of granules will be first supplied by ....................................s to
8/13
....................................-...................................., ...................................., ....................................- IRAN
.................................... Production Transfer Protocol

15 July 2012

.................................... to test the quality during the transport (start of transport

validation), compressibility, flow properties, …. Thereafter 3 batches of granules will be
supplied by ....................................s to .................................... for validation batches
(exact shipment amounts to be deteremined later).

7.6. Validation:

 The process validation protocol will be written by the receiving site,

.................................... and reviewed and approved by the
.....................................

The critical points to be validated are:

 Tablet compression: Granule compressibility, Flow properties,

Uniformity of granules, Particle size distribution
 Coating: uniform coating
 Quality and Stability studies: Initial acceptable tablets quality, and
acceptable tablet quality during the stability studies

 .................................... validation master plan relating to

....................................:

.................................... is responsible for writing, implementing and reporting

all validation aspects of all utilities, equipment, analytical equipment, …
involved in the warehousing and manufacturing and packaging of the
.................................... tablet, together with the cleaning validation protocols.

 Cleaning validation of equipments:

Cleaning process should be done for tablet press machine (some of the
components should be dedicated such as drum for mixing granules, tube
which transfers granule to the hopper, connecting tubes of metal detector
and tube of vacuum cleaner). The other components should be cleaned and
cleaning validation should be done.

Coating suspension transfer tubes to coating pan are dedicated, the other
parts should be cleaned and cleaning procedure should be validated.

Cleaning procedures should be done for hopper of blistering machine.

Total cleaning validation should be done for all surfaces of the equipments
which are in contact with .................................... granules and tablets.

7.7. Assistance:

Depending on the “criticality of the process”, “Donor Site or Industrial Development

9/13
....................................-...................................., ...................................., ....................................- IRAN
.................................... Production Transfer Protocol

15 July 2012

of ....................................” can be implied in the realization of the technical batches

and the 3 validation batches in the receiving Site, .....................................

8.RAW MATERIAL AND SUPPLIERS

To reduce the risks linked to the transfer, the material for the 3 validation batches will
be sourced from the suppliers of the donor site, or by .....................................

Material Donor Site Supplier Receiving Site

Supplier
....................................
N.A. (Granule ....................................,
Granule manufactured in donor ....................................s
site)
Tablet Coating suspension

Opadry # 06A93131 An in-house coat is Colorcon

used in Donor site,
....................................s;
However In other
....................................
sites such as
Compiegne, Opadry #
06A93131 (Colorcon) is
used
Polyethylene Glycol Clariant Clariant
400 Dow Dow
Univar Univar

However for routine production receiving site. .................................... will use other existing
suppliers where appropriate, ensuring materials of the same quality are used and will set up
the necessary validations. Prior to any change of supplier for excipient,
.................................... must be informed in order to check if the supplier has been audited
and qualified by .....................................

9. PACKAGING MATERIAL

9.1. All primary packaging materials used at receiving site, .................................... will be in
agreement with the specifications described in the Marketing Authorization dossier (MA
holder in Iran is ....................................).

 PVC PE PVDC 290 MICR. (Donor site supplier: KLOCKNER)

 ALU (Donor site supplier: LAMP)

10/13
....................................-...................................., ...................................., ....................................- IRAN
.................................... Production Transfer Protocol

15 July 2012

9.2. If there are some dimension modifications of the carton (if significant), of the tablets
number per blister, or the elements of groupage, the agreement of each subsidiary
concerned has to be obtained.

9.3. In all cases of multi-sourcing production, the standard dimension of the donor site will
be imposed.

9.4. Packaging material size :

DIMENSION
Packaging component Donor site Receiving site
Blister for: Blisters of 15 tablets Blisters of 15 tablets
.................................... Size: 60 x 120 mm Size: 60 x 120 mm
.................................... and
....................................
....................................
Cardboard box for: Each cardboard box Each cardboard box contains 1
.................................... contains 1 blister of 15 blister of 15 tablets
.................................... and tablets Size: 65 x 22 x 125 mm
.................................... Size: 66 x 23 x 127 mm
....................................
Shipper box: each shipper box Each shipper box contains 100 boxes
.................................... contains 100 boxes;
.................................... and Size: 340 x 240 x 260
.................................... mm
....................................

9.5. On-going projects & rules implemented

Implementation date of braille, data matrix, etc.: No

Is the packaging child resistant? No
Is the packaging anti-counterfeiting type? No

10. REGULATORY

Marketing Autorisation dossier in force:

Reg-P-2008-5590 in 2008

11/13
....................................-...................................., ...................................., ....................................- IRAN
.................................... Production Transfer Protocol

15 July 2012

Variation: CMC-FP-2010-02633 in August 2011

Variation: Reg-P-2010-099 in November 2011

Variation : DOSS IN 2011 06678 (dated October 2011), submitted to Iran’s MoH on
April 2012

11. STABILITY

11.1. For .................................... granules a stability study (holding time validation) for
one year will be performed by ....................................s. The same data will be used by
receiving site, .....................................
11.2. The stability results of the finished product (Blistered coated
.................................... .................................... and .................................... tablet)
obtained by the donor site shows: 3 years shelf life in 30° C away from humidity.
11.3. A new stability study for finished product (Blistered coated ....................................
.................................... and .................................... tablet) according to ICH conditions
will be done by the receiving site, ...................................., based on the stability study
protocol.

12. PLANNING

Step Date
Analytical verification July 2012
Technical batch July/August 2012
Validation batches (3 batches) November 2012
Stability (beginning of study on finished November 2012
product)
Stability results T3 months January 2012-February 2013
Stability results T6 months (if needed) April-May 2013
Variation dossier availability (Site transfer May 2013
from ....................................
....................................s to
...................................., from steps after
granulation step)
Variation dossier registration in Iran MoH June-July 2013
(Site transfer form ....................................
....................................s to
...................................., from after
granulation step)
12/13
....................................-...................................., ...................................., ....................................- IRAN
.................................... Production Transfer Protocol

15 July 2012

Launch (Start of commercial batches in Iran) July-August 2013

13. RELEASE CONDITIONS

Validation batches will be approved if all of the conditions in Granule transfer process,
manufacturing process, packaging process and all QC results in all steps of manufacturing
meet the requirements who have been defined by Pharmacopeia and
....................................s specifications.

14. LOGISTICS

14.1. The preparation of the transfer planning has to be done according to the “best
practice 7-05 product transfer logistic management”.
14.2. Depending on the shelf life of the granules and the regulatory lead-time, the
granules for validation batches will be allocated to «Iran». (Based on the holding time
studies time-line, by August 2012, 3 months expiry date can be assigned to the
granules, and the granules for validation batches can be shipped).
14.3. Final stock coverage will be defined together by donor site,
....................................s/ receiving site, .................................... in collaboration with CD
and .................................... Iran/ Pharma Solids transfer coordinator.
14.4. According to the above planning, the availability of the 1st batch for the following
SKUs could be available in the following times:

.................................... SKUs Granules batch availability

GMID Code Date (in receiving site,
....................................)
438464 ....................................  Granules for technical
(....................................) studies (25 kg): August-
granules (for September 2012
....................................  Granules (for validation
.................................... and batches): November 2012
.................................... tablets) (due to holding time
studies, see item 14.2)

13/13