CollaGenex
pharmaceuticals [GRAPHIC OMITTED]
June 26, 2001
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President, PMRS, Inc.
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Dear ▇▇. ▇▇▇▇▇▇▇▇:
This letter serves to clarify Exhibits A, B, and C in the PMRS/CollaGenex
Services and Supply Agreement, amended December 1, 2000
Section 2.4 (a) shall now read:
PMRS shall provide a BULK PRODUCT COA and such other documents as may
be requested or required by regulatory bodies, whether domestic or
foreign, to COLLAGENEX, prior to shipment as set forth in EXHIBITS B.1
(US TABLETS) AND B.2 (EU TABLETS).
Section 2.4 (f), formerly the second 2.4 (e), shall now read:
Final Product Testing: PMRS shall provide COLLAGENEX with a FINAL
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PRODUCT COA and such other documents as may be requested or required by
regulatory bodies, whether domestic or foreign, to COLLAGENEX, prior to
shipment as set forth in EXHIBIT C.1 (100 COUNT BOTTLES) AND C.2
(BLISTERS). If the FINAL PRODUCT does not conform to the Specification,
PMRS will immediately notify COLLAGENEX and the parties will consult
with each other, regarding the nonconformity with a view towards
resolving the nonconformity.
Exhibits A, B.1, B.2, C.1, and C.2 are attached.
All other terms and conditions remain as per the PMRS/CollaGenex Services and
Supply Agreement, amended December 1, 2000.
For PMRS, Inc:
/s/ ▇▇▇▇▇ ▇. ▇▇▇▇▇▇▇▇
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▇▇. ▇▇▇▇▇ ▇. ▇▇▇▇▇▇▇▇
President
For CollaGenex Pharmaceuticals, Inc.
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▇▇. ▇▇▇▇ ▇▇▇▇▇▇▇▇▇▇
Director of Manufacturing
CollaGenex Pharmaceuticals, Inc., ▇▇ ▇▇▇▇▇▇▇▇▇▇ ▇▇▇▇▇, ▇▇▇▇▇ ▇▇▇,
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EXHIBIT A:
BULK PRODUCT DESCRIPTION:
White to off-white, round, film-coated tablets engraved on one side with a "PS
20" monogram, containing doxycycline hyclate equivalent to 20 mg doxycycline,
and delivered in 300 kg lot sizes (approximately 1.5 million tablets per lot) in
polyethylene-lined fiber drums with desiccant pouches.
FINAL PRODUCT DESCRIPTION:
White to off-white, round, film-coated tablets engraved on one side with a "PS
20" monogram, containing doxycycline hyclate equivalent to 20 mg doxycycline,
and delivered in HDPE bottles with desiccant pouches, induction seal liners,
and CRC caps as 60 and 100 count packages; or in HDPE bottles with desiccant
pouches, induction seal liners, and screw caps as 1000 count packages; or in
blisterpacks composed of aluminum foil PVC/ACLAR.
BULK TABLET RELEASE AND STABILITY SPECIFICATIONS (US TABLETS):
As contained in NDA 50-783, Section 3.2.7.2 (Page 1.5 - 029)
Exhibit A, Attachment 1
BULK TABLET RELEASE AND STABILITY SPECIFICATIONS (EU TABLETS):
As contained in the MCA "Grant of Marketing Authorisation", PL 17096/0002,
Section B., Page 1
Exhibit A, Attachment 2
EXHIBIT A - ATTACHMENT 1
NDA 50-783
Periostat(R)(doxycycline hyclate tablets), 20 mg
Section 3 - CMC
The following specifications pertain to Periostat(R) (doxycycline
hyclate tablets), 20 mg:
Test Limit Method
---- ----- ------
Appearance/ description White to off-white, round, Visual
film-coated tablet with
"PS 20" monogram
Identification (release only) Conforms to standard USP, Doxycycline
tablets
Odor Practically odorless See PMRS 80061
Hardness Report See PMRS 80061
Friability NMT 1% USP <1216>
Assay 90.0% to 120.0% label claim See PMRS 80061
Uniformity of dosage units/ Conforms USP <905>
content uniformity (release
only)
Total impurities/degradant NMT 5.0% See PMRS 80061
(area %)
Water NMT 8.5% USP <921>
Dissolution Q: 85% in 90 minutes USP <711>
3.2.7.3 Analytical Methods
The methods listed above for the uncoated and film-coated tablets
are provided in PMRS analytical monographs 80070 and 80061,
respectively. Copies of the current versions of these documents,
designated by numeric suffixes (.01 and .06, respectively),
follow.
EXHIBIT A - ATTACHMENT 2
PL 17096/0002
LICENCE DETAILS
Finished Product Specification-
TEST DESCRIPTION SPECIFICATION SPECIFICATION
(RELEASE) (END OF SHELF LIFE)
Description White to off-white, round, White to off-white, round,
film-coated tablet with PS-20 monogram film-coated tablet with PS-20
monogram
Identification Main peak retention time by HPLC Main peak retention time by HPLC
conforms to that of doxycycline conforms to that of doxycycline
hyclate standard hyclate standard
Odour Practically odourless Practically odourless
Content of doxycycline 95-105% label claim 95-105% label claim
Identity of colour Positive for Titanium dioxide by Positive for Titanium dioxide by
hydrogen peroxide colour test hydrogen peroxide colour test
Uniformity of content Of ten tablets, each individual Of ten tablets, each individual
content is from 85-115% of mean content is from 85-115% of mean
content. If one individual content content. If one individual
is outside these limits but within content is outside these limits
75-125% of the mean determine the but within 75-125% of the mean
individual content of 20 further determine the individual content
tablets. The sample complies if not of 20 further tablets. The sample
more than 1 tablet is outside the complies if not more than 1 tablet
limits of 85-115% of the mean and is outside the limits of 85-115%
none is outside 75-125% of the of the mean and none is outside
mean./ (Ph. Eur. 2.9.6) 75-125% of the mean./ (Ph. Eur.
2.9.6)
Related substances
6-epidoxycycline NMT 1.6% NMT 1.6%
Methacycline NMT 1.0% NMT 1.0%
Unidentified related NMT 0.4% NMT 0.4%
substances (individual)
Total related substances NMT 3.0% NMT 3.0%
Light-absorbing impurities <0.2% <0.2%
Hardness 13.5-21.5 kp 13.5-21.5 kp
Friability NMT 1% NMT 1%
Dissolution (Ph. Eur. 2.9.3)1 NLT 70% released in 45 minutes NLT 70% released in 45 minutes
Dissolution (in-house test)2 NLT 85% released in 90 minutes NLT 85% released in 90 minutes
Disintegration3 NMT 30 mins NMT 30 mins
Water content NMT 5% w/w NMT 8.5% w/w
Microbial contamination
Total aerobic count <=1000 cfu/g <=1000 cfu/g
Fungi <=100 cfu/g <=100 cfu/g
E. coli absent in 1 g absent in 1 g
1Tested on import into the EC;
2Tested at manufacturing site in USA
3Carried out only as part of in-process control
EXHIBIT B.1 BULK PRODUCT COA (US TABLETS):
Page 1 of 1 R15287
PMRS [GRAPHIC OMITTED]
PHARMACEUTICAL MANUFACTURING RESEARCH SERVICES, INC.
FINISHED PRODUCT CERTIFICATE OF ANALYSIS AND DISPOSITION
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ITEM DESCRIPTION: PERIOSTAT DOXYCYCLINE 20 MG FILM COATED TABLET (US MARKET)
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ITEM CODE: 70206 CONTAINERS: 4 Drum DISPOSITION NUMBER: QAD04978
RECEIVING NUMBER: R15287 QUANTITY: 317.311 Kg EXP. DATE: 10/2001
MANUFACTURER: PMRS DATE TESTED: 05/16/2001 JOB NUMBER: 656
MANUFACTURER LOT NO: B01159 DISPOSITION: APPROVED PMRS BATCH NUMBER:
DATE MANUFACTURED: 05/09/2001 DISPO DATE: 05/23/2001 B01159
DISPOSITION BY: pmcnally
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Test: Reference: Lower Spec: Upper Spec: Result: Units: Analyst: Report Result Ref:
---- --------- ---------- ---------- ------ ----- ------- ------ ----------
Description 80061.07 conforms --- Conforms --- RL 05/15/2001 PMRS-258/55
Identification 80061.07 conforms to --- Conforms --- SS 05/16/2001 PMRS-130/185
standard
Odor 80061.07 practically --- Odorless --- RL 05/15/2001 PMRS-258/58
odorless
Hardness 80061.07 report --- 17.8 kp JCM 05/11/2001 PMRS-260/2
results
Friability 80061.07 --- 1 0 % JCM 05/11/2001 PMRS-259/11
Assay 80061.07 90.0 120.0 100.4 %LC RL 05/15/2001 PMRS-258/67
Uniformity of Dosage Units/ 80061.07 85.0 115.0 99.7 %LC RL 05/15/2001 PMRS-258/68
Content Uniformity (Range) (93.6-
101.6)
Uniformity of Dosage Units/ 80061.07 --- 6.0 2.3 %RSD RL 05/15/2001 PMRS-258/68
Content Uniformity (% RSD)
Total Impurity/Degradant- 80061.07 --- 5.0 1.0 %w/w RL 05/15/2001 PMRS-258/83
Total
Total Impurity/Degradant- 80061.07 report --- 0.0 %area RL 05/15/2001 PMRS-258/64
Unknown 1
Total Impurity/Degradant-4- 80061.07 report --- 0.1 %w/w RL 05/15/2001 PMRS-258/83
epidoxycycline
Total Impurity/Degradant- 80061.07 report --- 0.1 %w/w RL 05/15/2001 PMRS-258/82
metacycline
Total Impurity/Degradant- 80061.07 report --- 0.8 %w/w RL 05/15/2001 PMRS-258/82
6-epidoxycycline
Water 80061.07 --- 8.5 4.3 % SCC 05/14/2001 PMRS-262/2
Dissolution (90 minutes) 80061.07 85 --- 99 %LC(Q) SCC 05/11/2001 PMRS-264/4
Identification (HPLC) 80061.07 conforms --- Conforms --- RL 05/15/2001 PMRS-258/68
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SAMPLE NUMBERS:
COMMENTS: 1,474,834 Tablets (215.2 mg/tab)
PERIOSTAT DOXYCYCLINE 20 MG FILM COATED TABLET (US MARKET), BATCH/LOT: B01159
WAS MANUFACTURED AND ANALYZED ACCORDING TO UNITED STATES CURRENT GOOD
MANUFACTURING PRACTICE REQUIREMENTS AND MEETS ALL REQUIREMENTS FOR HUMAN USE.
THE ABOVE RESULTS HAVE BEEN CHECKED AGAINST AND ARE CERTIFIED TO BE A TRUE COPY
OF THE ACTUAL REPORTED ANALYTICAL RESULTS.
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▇▇▇▇▇▇▇ ▇. ▇▇▇▇▇▇▇
Director, Quality Management
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PMRS [GRAPHIC OMITTED]
EXHIBIT B.2 BULK PRODUCT COA (EU TABLETS):
While a COA for EU tablets has not been issued as of the date of this document,
the COA for EU tablets will contain the test results as required by the MCA
"Grant of Marketing Authorisation", PL 17096/0002, Section B., Page 1 and will
use a format similar to the COA for US Tablets (Exhibit B.1).
EXHIBIT C.1 FINAL PRODUCT COA (100 COUNT BOTTLES):
Page 1 of 1 R15420
PMRS [GRAPHIC OMITTED]
PHARMACEUTICAL MANUFACTURING RESEARCH SERVICES, INC.
FINISHED PRODUCT CERTIFICATE OF ANALYSIS AND DISPOSITION
ITEM DESCRIPTION: PERIOSTAT 20 MG 100 TABLETS / BOTTLE
ITEM CODE: 80247 CONTAINERS: 3 Bottle DISPOSITION NUMBER: QAD05105
RECEIVING NUMBER: R15420 QUANTITY: 300 tabs RETEST DATE: 04/2003
PO NUMBER: DATE TESTED: 06/21/2001 JOB NUMBER: 656
SUPPLIER: PCI Services DISPOSITION: APPROVED - ID ONLY PMRS BATCH NUMBER:
MANUFACTURER: PMRS DISPO DATE: 6/26/2001 B01163A
MANUFACTURER LOT NO: B01163A DISPOSITION BY: pmcnally
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Test: Reference: Lower Spec: Upper Spec: Result: Units: Analyst: Report Result Ref:
---- --------- ---------- ---------- ------ ----- ------- Date: ----------
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Description 80095.00 conforms --- Conforms --- RL 06/21/2001 PMRS-263/7
Identification 80095.00 conforms --- Conforms --- RL 06/21/2001 PMRS-263/9
(Doxycycline Hyclate)
SAMPLE NUMBERS: S41030
COMMENTS: None
Periostat 20mg 100 Tablets / Bottle, Batch/Lot: B01163A was manufactured and
analyzed according to United States current Good Manufacturing Practice
requirements. Finished product testing is the responsibility of the client.
The above results have been checked against and are certified to be a true copy
of the actual reported analytical results.
/s/ ▇▇▇▇▇▇▇ ▇. ▇▇▇▇▇▇▇ 06/26/2001
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▇▇▇▇▇▇▇ ▇. ▇▇▇▇▇▇▇
Director, Quality Management
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[GRAPHIC OMITTED]
EXHIBIT C.2 FINAL PRODUCT COA (BLISTERS):
R15412
PMRS [GRAPHIC OMITTED]
PHARMACEUTICAL MANUFACTURING RESEARCH SERVICES, INC.
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Certificate of Analysis and Disposition
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ITEM DESCRIPTION: PERIOSTAT 20MG 2 X 2 BLISTER CARD
ITEM CODE: 80245 GRADE: no grade
RECEIVING NUMBER: R15412 MFG RETEST DATE: 04/03 DISPOSITION: Approved
PO NUMBER: CONTAINERS: 1 Carton DISPO DATE: 06/18/2001
SUPPLIER: PCI Services QUANTITY: 72 each DISPO BY: jmeltzer
MANUFACTURER: PMRS DATE TESTED: 06/15/2001 DISPO NUMBER: QAD05089
MFG LOT NO: B01159B RETEST DATE: 04/2003 JOB NUMBER: 656
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R15412 SAMPLE NUMBERS: S41020
Test: Reference: Lower Spec: Upper Spec: Result: Units: Analyst: Report Date Result Ref:
---- --------- ---------- ---------- ------ ----- ------- ----------- ----------
Description 80095.00 conforms --- conforms --- RL 06/15/2001 PMRS 263/4
Identification 80095.00 conforms --- conforms --- RL 06/15/2001 PMRS 263/6
(Doxycyline Hyclate)
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Comments: None
The above results have been checked against and are certified to be a true copy
of the actual reported analytical results.
/s/ ▇▇▇▇▇▇▇ ▇. ▇▇▇▇▇▇▇ 06/18/2001 [GRAPHIC OMITTED]
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▇▇▇▇▇▇▇ ▇. ▇▇▇▇▇▇▇
Manager, Quality Assurance
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