การประชุมวิชาการเรื่อง Analytical Method Validation for FDA Compliance

สมาคมเภสชั กรอุตสาหการ (ประเทศไทย) 197

NEUTRALISATION/REMOVAL OF
ANTIMICROBIAL ACTIVITY

If growth is inhibited(reduction by factor greater than 2) modify
procedure

1. Increase volume of diluent or culture medium
2. add neutralizing agent into the diluent or culture medium
3. membrane filtration
4. combination of the above measures

Table 2: Common neutralizing agents for interfering substance

Interfering Substance Potential Neutralizing
Agents/Method

Glutaraldehyde, mercurials Sodium hydrogen sulfite
(Sodium bisulfite)

Phenolics, alcohol, aldehydes, sorbate Dilution

Aldehydes Glycine

Quaternary ammonium compounds (QACs), Lecithin

parahydroxybenzoates (parabens), bis-biguanides

QACs, iodine, parabens Polysorbate

Mercurials Thioglycollate

Mercurials, halogens, aldehydes Thiosulfate

EDTA (edetate) Mg or Ca ions

REF: USP 42-NF37 <61> MICROBIOLOGICAL EXAMINATION OF NON-STERILE PRODUCTS: MICROBIAL ENUMERATION TESTS

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EX. MODIFICATION

Pour plate method

• BSP TSA or SDA > 20 ml (Larger plate)

TSA or SDA + Neutralizing agent

• NZF TSA or SDA 15-20 ml

TSA or SDA > 20 ml(Larger plate)

TSA or SDA + Neutralizing agent

EX. MODIFICATION

Spread plate method

• BSP TSA or SDA + Neutralizing agent

• NZF TSA or SDA + Neutralizing agent

สมาคมเภสชั กรอุตสาหการ (ประเทศไทย) 199

RESULTS AND INTERPRETATION

• If the criteria cannot be met one or more of the organisms
tested with any of the described methods, the method and
test conditions the come closest to the criteria are used to
test the product.

• If a change in testing performance or change in the product
that may affect the outcome of the test

Suitability must be confirmed

TEST FOR
SPECIFIED MICROOGANISMS

Test for absence

• Bile-tolerant gram negative bacteria
• Escherichia coli
• Salmonella
• Pseudomonas aeruginosa
• Staphylococcus aureus
• Candida albicans

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TEST STRAINS FOR GROWTH PROMOTING
AND INHIBITORY PROPERTIES OF MEDIA

TEST STRAINS

Staphylococcus aureus ATCC 6538, NCIMB 9518, CIP 4.83, or
Pseudomonas aeruginosa NBRC 13276
Escherichia coli
ATCC 9027, NCIMB 8626, CIP 82.118, or
NBRC 13275

ATCC 8739, NCIMB 8545, CIP 53.126, or
NBRC 3972

Salmonella enterica subsp. ATCC 14028
ent3e9rica serovar

Typhimurium or, as an alternative

Salmonella enterica subsp. NBRC 100797, NCTC 6017, or CIP 80.39
enterica serovar Abony

Candida albicans ATCC 10231, NCPF 3179, IP 48.72, or
NBRC 1594

REF: USP 42-NF37 <62> MICROBIOLOGICAL EXAMINATION OF NON-STERILE PRODUCTS: TESTS FOR SPECIFIED MICROORGANISMS

TEST STRAINS FOR GROWTH PROMOTING
AND INHIBITORY PROPERTIES OF MEDIA

• Test each batch of
- ready-prepared medium
- medium prepared from dehydrate
- medium prepared from ingredients
• Compare the result with a previously tested and approved

batch of medium

40

สมาคมเภสชั กรอุตสาหการ (ประเทศไทย) 201

TEST STRAINS FOR GROWTH PROMOTING AND
INHIBITORY PROPERTIES OF MEDIA

• Test for growth promoting properties : Incubate the shortest
period of time
o Liquid media : Inculate ≤ 100 cfu
o Solid media : Surface spread ≤ 100 cfu

• Test for inhibitory properties : Incubate the longtest period of
time
o Liquid media : Inculate ≥ 100 cfu
o Solid media : Surface spread ≥ 100 cfu

• Test for indicative properties :
o Solid media : Surface spread ≤ 100 cfu

41

GROWTH PROMOTING AND INHIBITORY
PROPERTIES OF MEDIA

Medium Property Test strains

Test for bile- Enterobacteria Growth promoting E.coli, P.aeruginosa
S.aureus
tolerant gram- enrichment broth- Inhibitory
Mossel
negative
bacteria

Violet red bile Growth E.coli, P.aeruginosa
glucose agar
promoting+indicative

Test for MacConkey broth Growth promoting E.coli
S.aureus
Escherichia coli Inhibitory

MacConkey agar Growth E.coli

promoting+indicative

REF: USP 42-NF37 <62> MICROBIOLOGICAL EXAMINATION OF NON-STERILE PRODUCTS: TESTS FOR SPECIFIED MICROORGANISMS

42

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GROWTH PROMOTING AND INHIBITORY
PROPERTIES OF MEDIA

Medium Property Test strains

Test for Rappaport Growth promoting Salmonella enterica
Salmonella subsp. Enterica serovar
Vassiliadis Typhimurium or
Salmonella enterica
Salmonella subsp. Enterica serovar
enrichment broth Abony

Inhibitory S.aureus

Xylose lysine, Growth promoting + Salmonella enterica
deoxycholate agar indicative subsp. Enterica serovar
Typhimurium or
Salmonella enterica
subsp. Enterica serovar
Abony

43 REF: USP 42-NF37 <62> MICROBIOLOGICAL EXAMINATION OF NON-STERILE PRODUCTS: TESTS FOR SPECIFIED MICROORGANISMS

GROWTH PROMOTING AND INHIBITORY
PROPERTIES OF MEDIA

Test for Medium Property Test strains
Pseudomonas Cetrimide agar Growth promoting P.aeruginosa
aeruginosa Inhibitory E.coli
Mannitol salt agar S.aureus
Test for Growth promoting +
Staphylococcus Reinforced Indicative E.coli
aureus medium for Inhibitory Cl. sporogenes
Clostridia Growth promoting
Test for Clostridia Columbia Agar Cl. sporogenes
Growth promoting

REF: USP 42-NF37 <62> MICROBIOLOGICAL EXAMINATION OF NON-STERILE PRODUCTS: TESTS FOR SPECIFIED MICROORGANISMS

44

สมาคมเภสชั กรอุตสาหการ (ประเทศไทย) 203

GROWTH PROMOTING AND INHIBITORY
PROPERTIES OF MEDIA

Medium Property Test strains

Test for Candida Sabouraud Growth promoting C.albicans

albicans dextrose broth

Sabouraud Growth C.albicans
dextrose agar
promoting+indicative

REF: USP 42-NF37 <62> MICROBIOLOGICAL EXAMINATION OF NON-STERILE PRODUCTS: TESTS FOR SPECIFIED MICROORGANISMS

45

TESTING OF PRODUCT

Bile-tolerant gram-negative bacteria : Test for absence

Sample 10 g or ml + TSB 90 ml 20-25 0C 2-5 hours
Transfer 10 ml to EEB 100 ml 30-35 0C 24-48 hours
Subculture on VRBG 30-35 0C 18-24 hours
No growth

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TESTING OF PRODUCT

• Salmonella spp.: Test for absence

Sample 10 g or ml + TSB 90 ml 30-35 0C 18-24 hours

Transfer 0.1 ml to RVS 10 ml 30-35 0C 18-24 hours
Subculture on XLD 30-35 0C 18-48 hours
No growth

47

TESTING OF PRODUCT

• Escherichia coli : Test for absence

Sample 10 g or ml + Diluent 90 ml

Transfer 10 ml to TSB 100 ml 30-35 0C 18-24 hours
Transfer 1 ml to MCB 100 ml 42-44 0C 24-48 hours
Subculture on MCA
No growth 30-35 0C 18-72 hours

48

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TESTING OF PRODUCT

• Staphylococcus aureus: Test for absence

Sample 10 g or ml + Diluent 90 ml

Transfer 10 ml to TSB 100 ml 30-35 0C 18-24 hours
Subculture on MSA 30-35 0C 18-72 hours
No growth

49

TESTING OF PRODUCT

• Pseudomonas aeruginosa: Test for absence

Sample 10 g or ml + Diluent 90 ml 30-35 0C 18-24 hours
Transfer 10 ml to TSB 100 ml 30-35 0C 18-72 hours
Subculture on CET
No growth

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TESTING OF PRODUCT

• Candida albicans: Test for absence

Sample 10 g or ml + Diluent 90 ml

Transfer 10 ml to SDB 100 ml 30-35 0C 3-5 days
Subculture on SDA 30-35 0C 24-48 hours
No growth

51

SUITABILITY OF THE TESTS

• Preparation of the sample
• Add each test strain at the time of mixing in the prescribed

growth medium
• Inoculate the test strain not more than 100 cfu individually
• Using the shortest incubation period
• The specified microorganisms must be detected with the

indication reaction
• Any antimicrobial activity of the product necessitates a

modification of the test procedure

52

สมาคมเภสชั กรอุตสาหการ (ประเทศไทย) 207

SUITABILITY OF THE TESTS

Bile-tolerant gram-negative bacteria : Test for absence

E.coli ≤ 100 cfu

Sample 10 g or ml + TSB 90 ml 20-25 0C 2-5 hours
30-35 0C 24-48 hours
Transfer 10 ml to EEB 100 ml 30-35 0C 18-24 hours

Subculture on VRBG
Pink to red colonies, bile

precipitate

53

SUITABILITY OF THE TESTS

• Salmonella spp.: Test for absence Salmonella ≤ 100 cfu

Sample 10 g or ml + TSB 90 ml 30-35 0C 18-24 hours

Transfer 0.1 ml to RVS 10 ml 30-35 0C 18-24 hours
30-35 0C 18-48 hours
Subculture on XLD

Red colonies, with or without
black center

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SUITABILITY OF THE TESTS

• Escherichia coli : Test for absence E.coli ≤ 100 cfu

Sample 10 g or ml + Diluent 90 ml

Transfer 10 ml to TSB 100 ml 30-35 0C 18-24 hours
42-44 0C 24-48 hours
Transfer 1 ml to MCB 100 ml
30-35 0C 18-72 hours
Subculture on MCA
Pink to red colonies, bile

precipitate

55

SUITABILITY OF THE TESTS

• Staphylococcus aureus: Test for absence

Sample 10 g or ml + Diluent 90 ml S.aureus ≤ 100 cfu

Transfer 10 ml to TSB 100 ml 30-35 0C 18-24 hours
30-35 0C 18-72 hours
Subculture on MSA

Yellow colonies, bright yellow
zone

56

สมาคมเภสชั กรอุตสาหการ (ประเทศไทย) 209

SUITABILITY OF THE TESTS

• Pseudomonas aeruginosa: Test for absence

Sample 10 g or ml + Diluent 90 ml Ps.aeruginosa ≤ 100 cfu

Transfer 10 ml to TSB 100 ml 30-35 0C 18-24 hours
Subculture on CET 30-35 0C 18-72 hours

Green-yellow to dark green

57

SUITABILITY OF THE TESTS

• Candida albicans: Test for absence C.albicans≤ 100 cfu

Sample 10 g or ml + Diluent 90 ml

Transfer 10 ml to SDB 100 ml 30-35 0C 3-5 days
Subculture on SDA 30-35 0C 24-48 hours
Growth of white colonies

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NEUTRALIZATION/REMOVAL OF
ANTIMICROBIAL ACTIVITY

If growth is inhibited modify procedure
1. Increase volume of diluent or culture medium
2. add neutralizing agent into the diluent or culture medium
3. membrane filtration
4. combination of the above measures

If the antimicrobial activity can not be neutralized assumed that
the inhibited microorganisms will not be present in the product

Table 2: Common neutralizing agents for interfering substance

Interfering Substance Potential Neutralizing
Agents/Method

Glutaraldehyde, mercurials Sodium hydrogen sulfite
(Sodium bisulfite)

Phenolics, alcohol, aldehydes, sorbate Dilution

Aldehydes Glycine

Quaternary ammonium compounds (QACs), Lecithin

parahydroxybenzoates (parabens), bis-biguanides

QACs, iodine, parabens Polysorbate

Mercurials Thioglycollate

Mercurials, halogens, aldehydes Thiosulfate

EDTA (edetate) Mg or Ca ions

REF: USP 42-NF37 <61> MICROBIOLOGICAL EXAMINATION OF NON-STERILE PRODUCTS: MICROBIAL ENUMERATION TESTS

สมาคมเภสชั กรอุตสาหการ (ประเทศไทย) 211

NEGATIVE CONTROL

• Use the chosen dilution in place of the test preparation
• Verify testing and also testing the products
• There must be no growth of microorganisms
• A failed negative control requires an investigation

61

POSITIVE CONTROL

• Use the chosen diluent in place of the test preparation and
add each test strain

• Verify testing
• There must be growth of microorganism

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INTERPRETATION

Positive Product Negative Testing
Control Control Product
Positive
Control

Test Strains Acceptance Limit Conclusion
Result

Acceptance Limit
Result

Acceptance Limit
Result

Acceptance Limit
Result

Escherichia  Suitable
Escherichia coli  Unsuitable

coli

63

DOCUMENTS

• Requirement, Acceptance limit
• Method
• Analytical procedures

– Inoculation and dilution
– Preparation of the product
– Negative control
– Positive control
– Positive Product control
– Testing of the product
• Result and Interpretation

64

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ภญ. นพวรรณ องั กรู ศนั สนีย

การศึกษา
• เภสชั ศาสตรบ์ ณั ฑติ จฬุ าลงกรณ์มหาวทิ ยาลยั
• วศิ วกรรมศาสตรม์ หาบณั ฑติ สาขาวศิ วอตุ สาหการและ

การผลติ มหาวทิ ยาลยั เทคโนโยลพี ระจอมเกลา้ ธนบรุ ี
ตาํ แหน่งปัจจบุ นั : รกั ษาการในตาํ แหน่งผอู้ าํ นวยการกองบรหิ าร

ระบบคณุ ภาพ การประกนั คณุ ภาพโรงงานผลติ ยารงั สติ 1 องคก์ าร
เภสชั กรรม
ประวตั ิการทาํ งาน
• เภสชั กรประจาํ แผนกมาตรฐานวตั ถุดบิ 1 กองมาตรฐานวตั ถุดบิ ฝ่าย
ประกนั คณุ ภาพ องคก์ ารเภสชั กรรม (เมษายน 2546 – กนั ยายน 2550)
• เภสชั กรประจาํ โครงการ Fast Track ฝ่ายประกนั คณุ ภาพ องคก์ ารเภสชั
กรรม (ตลุ าคม 2550 – กรกฎาคม 2553) รบั ผดิ ชอบการควบคมุ คณุ ภาพวตั ถดุ บิ
และยาสาํ เรจ็ รปู
• รกั ษาการในตาํ แหน่งผอู้ าํ นวยการกองการควบคมุ คณุ ภาพ การประกนั
คณุ ภาพโรงงานผลติ ยารงั สติ 1 องคก์ ารเภสชั กรรม (สงิ หาคม 2553 – 15
พฤษภาคม 2562) รบั ผดิ ชอบงานควบคมุ คณุ ภาพทกุ กระบวนการ
• รกั ษาการในตาํ แหน่งผอู้ าํ นวยการกองบรหิ ารระบบคณุ ภาพ การประกนั
คณุ ภาพโรงงานผลติ ยารงั สติ 1 องคก์ ารเภสชั กรรม (16 พฤษภาคม 2562–
ปัจจบุ นั ) รบั ผดิ ชอบงานบรหิ ารระบบคณุ ภาพทกุ กระบวนการ
• เป็นผปู้ ระเมนิ ทางวชิ าการ (Technical Assessor) ตามมาตรฐาน มอก.
17043 (ISO/IEC 17043) ใหก้ บั สาํ นกั งานมาตรฐานผลติ ภณั ฑอ์ ตุ สาหกรรม
(ตลุ าคม 2560 – ปัจจุบนั )
• เป็นผตู้ รวจประเมนิ GMP Self - inspection ของโรงงานผลติ ยารงั สติ 1
(กมุ ภาพนั ธ์ 2561 - ปัจจุบนั )
• เป็นผตู้ รวจประเมนิ Supplier audit วตั ถดุ บิ ยาและบรรจภุ ณั ฑ์

สมาคมเภสชั กรอุตสาหการ (ประเทศไทย) 215

Challenges in
Analytical Method

Transfer

Noppawan Angkulsansanee
13 November 2019

1

GMP Guidelines

• GUIDE TO GOOD MANUFACTURING
PRACTICE FOR MEDICINAL
PRODUCTS PART I, PE 009-14 (Part I),
1 July 2018 (PIC/S)

• Chapter 6 – Quality Control

• Technical transfer of testing methods

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Technical transfer of testing methods (PIC/S)
=1=

6.37 Prior to transferring a test method, the transferring site
should verify that the test method(s) comply with those as
described in the Marketing Authorisation or the relevant
technical dossier. The original validation of the test method(s)
should be reviewed to ensure compliance with current
ICH/VICH requirements. A gap analysis should be performed
and documented to identify any supplementary validation that
should be performed, prior to commencing the technical
transfer process.

3

Technical transfer of testing methods (PIC/S)
=2=

6.38 The transfer of testing methods from one laboratory
(transferring laboratory) to another laboratory (receiving
laboratory) should be described in a detailed protocol.

4

สมาคมเภสชั กรอุตสาหการ (ประเทศไทย) 217

Technical transfer of testing methods (PIC/S)
=3=

6.39 The transfer protocol should include, but not be limited to, the
following parameters:
i. Identification of the testing to be performed and the relevant

test method(s) undergoing transfer;
ii. Identification of the additional training requirements;
iii. Identification of standards and samples to be tested;
iv. Identification of any special transport and storage conditions of

test items;
v. The acceptance criteria which should be based upon the current

validation study of the methodology and with respect to
ICH/VICH requirements.

5

Technical transfer of testing methods (PIC/S)
=4=

6.40 Deviations from the protocol should be investigated prior to
closure of the technical transfer process. The technical transfer
report should document the comparative outcome of the process and
should identify areas requiring further test method revalidation, if
applicable.

6.41 Where appropriate, specific requirements described in other
guidelines should be addressed for the transfer of particular testing
methods (e.g. Near Infrared Spectroscopy).

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Participating Laboratories

Sending / Transferring Receiving
Laboratory
Laboratory
(RU)
(SU)
“VALIDATED

ANALYTICAL

PROCEDURE”

Development unit QC unit/Intracompany facility/
Another company/Contract lab

7

AMT Guidelines

• Validation of Analytical Procedures PA/PH/OMCL (13) 82
2R, OMCL Network/EDQM of the Council of Europe
(OMCL: Official Medicines Control Laboratory)

• USP General Chapters <1224> Transfer of Analytical
Procedures

• WHO Technical Report Series, No. 961, 2011 Annex 7
WHO guidelines on transfer of technology in
pharmaceutical manufacturing

8

สมาคมเภสชั กรอุตสาหการ (ประเทศไทย) 219

OMCL/EDQM
CATEGORIES OF ANALYSIS

“Method transfer check
(verification of suitability)
has to be done to show that under actual
conditions of use in the individual laboratories
the method is adequate (fit for use).

9

OMCL/EDQM
Transfer of Analysis (1)

• It is assumed that a certain amount or elements of
validation data for this particular analysis is already
available

• No or only a few validation characteristics need to be
considered

• In an ideal situation, this can be done by comparison of
the results of two laboratories performed on the same
sample

10

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220 TIPA | Thai Industrial Pharmacist Association

OMCL/EDQM
Transfer of Analysis (2)

“No formal validation required”
indicates that the respective validation characteristics

have already been considered by others.
However

a verification of suitability under conditions of use
(=method transfer check)
has to be done.

11

OMCL/EDQM
Method Types to be Transferred

1.1 Pharmacopoeial (compendial) method
1.2 Method of a manufacturer
1.3 Non compendial published method
1.4 Method of a first manufacturer to be used for a

product of a 2nd manufacturer
1.5 Method for an active substance to be used for a

medicinal product
1.6 Methods validated to reduce, refine or replace

animal use

12

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USP General Chapters <1224>
Transfer of Analytical Procedures

“The documented process that qualifies a laboratory
(the receiving unit) to use an analytical test

procedure that originated in another laboratory (the
transferring unit), thus ensuring that the receiving

unit has the procedural knowledge and ability to
perform the transferred analytical procedure as

intended.”

13

USP General Chapters <1224> Types

of Transfer of Analytical Procedures

• Comparative testing

– Most common
– Receiving unit meeting the predetermined acceptance

criteria = assure receiving unit is qualified to run the
procedure

• Covalidation between two or more laboratories

– Assessment of reproducibility

• Revalidation / Partial validation
• Transfer waiver

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USP General Chapters <1224>

Transfer waiver >> appropriate justifications document
• New product’s composition

– Comparable to existing product
– Concentration of API is similar to existing product
– Analyzed by procedures that RU already has experience

• Analytical procedure transferred = same or very
similar to a procedure already in use

• USP-NF unchanged method

– Verification

• Personnel are moved to the receiving unit!

15

USP General Chapters <1224>
Elements recommended

• Receiving unit run the procedure to identify any
issues

• Issues need to be resolved before the transfer
protocol is signed

• Documented training

16

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Responsibilities

(SU) (RU)

• Providing • Providing

 Analytical procedure  Qualified staff
 Reference standards  Calibrated/qualified
 Validation reports
 Training facilities & instruments
 Assist in analysis of  GLP system

results • Review & approve

• Review & approve transfer protocol and

transfer protocol and report

report

17

USP General Chapters <1224>

Samples to be used

• Homogeneous lots of the target material from standard production
batches

• Sample intentionally prepared (spiking known impurities)
• A single lot may be used (Because the aim is not related to the

manufacturing process)

• Normally use 3 lots (to confirm consistency)
• Additional expired, aged, or spiked samples are recommended to be

carefully chosen and evaluated to identify potential problems (from
differences in sample preparation or equipment) and to evaluate the
impact of potential aberrant results on marketed products.

18

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USP General Chapters <1224>

Transfer acceptance criteria

• Comparability criteria

• %RSD for each site
• Intermediate precision %RSD of the RU

• For assay and content uniformity testing: Statistical method
for the comparison of the means

• For impurity testing: A simple descriptive approach can be
used

• For dissolution: comparison of the dissolution profile (f2) or
comparison of data at specified time points

19

WHO TRS No. 961, Annex 7

6. Quality control: analytical method transfer

Table 1

Possible experimental designs and acceptance
criteria for analytical testing

st. dev., standard deviation.
Note: numbers in the table are given as examples only and should not
be considered as recommendations.

20

สมาคมเภสชั กรอุตสาหการ (ประเทศไทย) 225

WHO TRS No. 961, Annex 7
=1=

21

WHO TRS No. 961, Annex 7
=2=

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WHO TRS No. 961, Annex 7
=3=

23

WHO TRS No. 961, Annex 7
=4=

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WHO TRS No. 961, Annex 7
=5=

25

WHO TRS No. 961, Annex 7
=6=

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228 TIPA | Thai Industrial Pharmacist Association

Documented Process

Executed

Preapproved transfer Transfer report
protocol

27

Preapproved transfer protocol (1)

– Objective
– Scope
– Sending unit and receiving unit requirements
– Sending unit and receiving unit responsibilities
– The details of the procedure
– Additional training requirements
– The standards, samples and instruments/parameters to be

used

28

สมาคมเภสชั กรอุตสาหการ (ประเทศไทย) 229

Preapproved transfer protocol (2)

– Identification of any special transport and storage conditions
of test items

– The analytical procedure/experimental design
– Identification of specific analytical performance characteristics
– The predetermined acceptance criteria including acceptable

variability (for comparative testing)
– Example of report form (worksheet) to ensure consistent

recording of results

29

Example contents of transfer protocol (1)

TABLE OF CONTENTS
REVISION HISTORY
1. Purpose
2. Scope
3. Responsibilities
4. Definitions
5. Procedure

5.1 Personal Identification List
5.2 Protocol Corrections
5.3 Principle
5.4 Work Instruction Verification

5.4.1 Work Instruction Verification For Sending Unit
5.4.2 Work Instruction Verification For Receiving Unit
5.5 Test Instrument And Equipment
5.5.1 Test Instrument and Equipment of Sending Unit
5.5.2 Test Instrument and Equipment of Receiving Unit

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230 TIPA | Thai Industrial Pharmacist Association

Example contents of transfer protocol (2)

5.6 Materials
5.7 Sampling Procedure
5.8 Reporting
5.9 Protocol Approvals
6. Technology Transfer Notes
7. Analytical Methods Transfer Procedure And Acceptance Criteria
8. Summary Report
9. Attachments
10. Deviation

10.1 Deviation List
10.2 Deviation Report
11. Reference
12. Conclusion
POST-EXECUTION APPROVAL

31

USP General Chapters <1224>
Analytical procedure

• Sufficient detail and explicit instructions
• Pretransfer meeting between SU and RU to clarify

any issues and answer any questions
• Complete or partial data along with technical details

from SU should be available to RU
• SU personnel to be on site during the transfer
• LC or GC: clearly express the number of replicates

and injection sequences
• Dissolution: specify the number of individual dosage

units

32

สมาคมเภสชั กรอุตสาหการ (ประเทศไทย) 231

Transfer report

• SU and RU should compare and discuss data to address any
corrections or updates to the final report.

• Deviations from the protocol should be investigated prior to
closure of the technical transfer process.

• The technical transfer report should document the
comparative outcome of the process and should identify areas
requiring further test method revalidation, if applicable.

33

Analytical Method Transfer
Conclusion

YES Acceptance NO
criteria met?


Transfer successful Transfer unsuccessful
& &

RU is qualified to run Investigation and
the process remedial needed

34

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AMT Guidelines (Scope)

• Validation of Analytical Procedures PA/PH/OMCL (13) 82 2R,
OMCL Network/EDQM of the Council of Europe (OMCL:
Official Medicines Control Laboratory)
>> Guidance on verification of suitability

• USP General Chapters <1224> Transfer of Analytical
Procedures
>> General explanation

• WHO Technical Report Series, No. 961, 2011 Annex 7 WHO
guidelines on transfer of technology in pharmaceutical
manufacturing
>> Guidance on comparative testing

35

THANK YOU

36

สมาคมเภสชั กรอุตสาหการ (ประเทศไทย) 233

ภญ. เกศินี แสงจนั ทร์

Position : QC Manager , บรษิ ทั อารเ์ อก็ ซ์ แมนูแฟคเจอรง�ิ จาํ กดั

Education :
2548 – จบการศกึ ษาปรญิ ญาตรี จากคณะเภสชั ศาสตร์ มหาวทิ ยาลยั ศลิ ปากร

Experience :
2548 – ���� QC Pharmacist, บรษิ ทั คาวาซมู ิ ลาบอราทอร�ี (ประเทศไทย)

จาํ กดั เป็นบรษิ ทั ผลติ เวชภณั ฑท์ างการแพทย์ และผลติ ภณั ฑ์
Blood bag (ถุงบรรจเุ ลอื ด) ซง�ึ จดั เป็นยาปราศจากเชอ�ื
2553 – ���� QA Pharmacist, บรษิ ทั อารเ์ อก็ ซ์ แมนูแฟคเจอรง�ิ จาํ กดั
���6 – ปัจจบุ นั QC Manager, บรษิ ทั อารเ์ อก็ ซ์ แมนูแฟคเจอรง�ิ จาํ กดั

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234 TIPA | Thai Industrial Pharmacist Association

Method Validation
for Elemental Impurities

according to
USP requirements

Kesinee Saengjun 13 November 2019

1

Outline

 Elemental impurities : Basics
 Introduction USP General Chapters <232> and <233>
 Implementation USP General Chapters <232> and <233>
 Elemental impurities procedures

 Understand your sample/product/material
 Which elemental impurities should be measured
 Calculating target limit or target concentration

and the “J” value from the PDE
 Sample preparation for ICP technique
 Instrument technique to be used
 Validation procedures

2–

สมาคมเภสชั กรอุตสาหการ (ประเทศไทย) 235

Elemental impurities : Basics

3

Elemental impurities : Basics

 ICH Q3D Guideline for Elemental impurities

 Focus is on the final product - The fishbone diagram
assists by advising on the components for consideration :
all potential sources of elemental impurities should be
considered and evaluated for their contribution to
the drug product

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Elemental impurities : Basics

 ICH Q3D Guideline for Elemental impurities

 Establishes Permitted Daily Exposures (PDEs) for
24 elements for Oral, Inhalation and Parenteral Routes

 Concepts can be used for other routes of administration
 Training modules provide further guidance on calculations

and risk assessment

5

Notable Differences between ICH Q3D and

USP Elemental Impurities Chapters

Notable Differences between ICH Q3D and USP <232>,<233>

ICH Q3D USP <232>, <233>

Guideline Enforceable standards

Includes 24 elements and PDEs - Includes 24 elements and PDEs outlined
outlined in three delivery categories in three delivery categories

Analytical methods not provided (published in USP 40-NF35, First supplement,
(delegated to pharmacopeias) official from December 1, 2017)

- Includes 15 elements [Not included : Ti, Au,

Se, Co, Ba, Sn, Li, Sb, Ag]
(published before December 1, 2017)

Provides analytical methods and
validation criteria

Includes Total Parenteral Nutrition Excludes Total Parenteral Nutrition
(TPN) products (TPN) products

6

สมาคมเภสชั กรอุตสาหการ (ประเทศไทย) 237

Elemental impurities : Basics

 Element Classifications – ICH Q3D/USP

Class Elements Toxicity

Class 1 As, Cd, Hg and Pb Significantly toxic across all administration

routes and have limited or no use in
pharmaceutical manufacturing

Class 2 Toxicity based on administration route
Class 2A Co, V and Ni
Relatively high probability of toxicity
based on administration route

Class 2B Ti, Au, Pd, Ir, Os, Rh, Relatively low probability of toxicity
Ru, Se, Ag and Pt based on administration route

Class 3 Li, Sb, Ba, Mo, Cu, Sn Relatively low toxicity (high PDEs)
and Cr by the oral route of administration,
but may require consideration in
risk assessment for the inhalation
and parenteral routes

7

Introduction
USP General Chapters

<232>, <233>

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Introduction USP General Chapters
<232>, <233>

 Made applicable through

USP General Notices Section 5.60.30 Elemental
Impurities in USP Drug Products and Dietary
Supplements (official as of 1-May-2019)

9

Introduction USP General Chapters
<232>, <233>

USP General Chapters

<232> <233> <2232>
Elemental Elemental
Impurities – Impurities – Elemental
Procedures Contaminants
Limits
(official as of 1-May-2018) in Dietary
(official as of 1-Aug-2017) Supplements

(official as of 1-Dec-2014)

10

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<232> Elemental Impurities - Limits

Tablet 1 :
Permitted daily exposures (PDEs)
for elemental impurities in
drug products

11

<232> Elemental Impurities - Limits

Tablet 2 :
Elements to be
considered in the
risk assessments

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<232> Elemental Impurities - Limits

Tablet 3 :
Permitted
concentrations of
elemental impurities
for individual
component options
for product with a
maximum daily dose
of ≤ 10 g/day

13

<232> Elemental Impurities - Limits

Summary ICH/USP
Elements and Limits

14

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<232> Elemental Impurities - Limits

 Speciation

 The determination of the oxidation state, organic complex, or
combination is termed “speciation”. Each of the elemental impurities
has the potential to be present in differing oxidation or complexation
states. However, arsenic and mercury are of particular concern
because of the differing toxicities of their inorganic and complexed
organic forms

 The arsenic limits are based on the inorganic (most toxic) form.
Arsenic can be measured using a total-arsenic procedure under
the assumption that all arsenic contained in the material under test
is in the inorganic form

 The mercury limits are based upon the inorganic (2+) oxidation state.
The methyl mercury form (most toxic) is rarely an issue for
pharmaceuticals. Thus, the limit was established assuming the most
common (mercuric) inorganic form

15

<232> Elemental Impurities - Limits

 Speciation

 If total arsenic or mercury result exceeds the PDE limit, a speciation
analysis may be performed to check level

 If speciation analysis results for inorganic form is less than the PDE
limit, the drug product is in compliance

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<233> Elemental Impurities - Procedures

 This chapter describes

 analytical procedures (ICP-AES/ICP-OES, or ICP-MS)
 guidelines on sample preparation
 criteria for alternative procedures as long as the

meet the validation requirements laid-out in this
chapter
 No speciation methods described in this chapter

17

Implementation
USP General Chapters

<232>, <233>

18

สมาคมเภสชั กรอุตสาหการ (ประเทศไทย) 243

Implementation USP General Chapters
<232>, <233>

 As of January 1, 2018

 USP <231> Heavy Metals was omitted

 USP General Chapters <232> and <233>
was officially implemented

 Implementation through General Notices
 No reference to <232> will be in monographs

19

Elemental impurities -
Procedures

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Elemental impurities - Procedures

1. Understand your sample/product/material

2. Which elemental impurities should be measured
3. Calculating target limit or target concentration and
the “J” value from the PDE
4. Sample preparation for ICP technique

5. Instrument technique to be used

6. Validation procedures

21

Elemental impurities - Procedures

1. Understand your sample/product/material

 Route of administration of drug product
• Oral
• Parenteral
• Inhalation

 Drug product component
• API
• Excipient
• Etc.

22

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Elemental impurities - Procedures

2. Which elemental impurities should be measured

23

Elemental impurities - Procedures

2. Which elemental impurities should be measured

Class 1 and Class 2A
elements must be
assessed in all
products

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Elemental impurities - Procedures

2. Which elemental impurities should be measured

Class 3 elements
(Li, Sb and Cu)
should be considered
for Parenteral routes
of administration

25

Elemental impurities - Procedures

2. Which elemental impurities should be measured

Class 3 elements (all)
should be considered
for Inhalation routes
of administration

26