Evaluation of Differences between Chinese Pharmacopoeia and...

Evaluation of Differences between Chinese Pharmacopoeia and ICH Q4B Standard and Consideration of Harmonization Strategies

Chinese Pharmacopoeia Commission

Hong XiaoxuOctober 30, 2018 Beijing

Confidential for restricted use only

Main Contents

• Relevant background

• Difference evaluation

• Harmonization strategies


ICH Q4 Background

ICH is a technical non-governmental international organization jointly established by the drug administration institutions and industry associations of the US, European Union and Japan.

Its basic aim is to coordinate and establish the international technical standards and norms about drug safety, efficacy and quality in the field of drug registration.

QQuality

ICHQuality

SSafety

Efficacy MMultidisciplinary


Application and Implementation of ICH Q4 in China

In June 2017, International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) officially approved China Food and Drug Administration (CFDA) as the 8th member of its regulatory authority.

On June 7, 2018, CFDA was elected a member of the management committee of ICH.


ICH Harmonization Purpose

Coordinate and establish the international technical standards and norms about drug safety, efficacy and quality in the field of drug registration

International harmonization of pharmacopeia aims to establish common standards and norms, avoid repeated drug tests when the drug registration applicant applies for registration in different countries or regions and avoid the potential legal risks during result determination.

Reduce the legal adjustment procedures when drug administration institutions apply the method of pharmacopeia in other countries or regions in registration approval


Q4A pharmacopeia harmonization

Evaluation of Q4B pharmacopeia and recommendation to be used in ICH regions (parent

document)

Q4B appendix 1-14

Q4B Q/A

Forewo

rd Guideli

ne Terms

Annex


Organizational Structure of Q4 Guideline

Q4 pharmacopeia

Q4B

ICH Q4 Work Flow

ICH No. Name and issued time of guidelines No. of general rules of EP 9.0/JP 17/USP 40 coordinated

Q4B appendix work flow

Q4

Q4A

Pharmacopeia

Pharmacopeia harmonization

Evaluation of Q4B pharmacopeia and recommendation to be used in ICH regions 2007.11.1

Q4B 1R1

Q4B 2R1

Q4B 3R1

Residue on ignition/sulfated ash test method 2010.9.27

Injection filling volume test method 2010.9.27

Particulate matter test method 2010.9.27

2.4.14/2.44/ <281>

2.9.17/6.05/<1>

2.9.19/6.07/<788>

PDG work flow

PDG document submission

Regional pharmacopeia implementation

Inter-regional acceptance

ICH Q4B work flow Q4B EWG evaluation and

establishment of appendix ICH signed Q4B appendix

draft Appendix supervision and

consultation ICH SC adopted the appendix Regional supervision and

implementation

Q4B 4AR1

Q4B 4BR1

Q4B 4CR1

Q4B 5R1

Q4B 6

Q4B 7R2

Q4B 8R1

Microbiological test of non-sterile products: microorganism count method 2010.9.27

Microbiological test of non-sterile products: control bacteria test 2010.9.27

Microbiological test of non-sterile products: determination criteria for drug substance and its preparation 2010.9.27

Disintegration time test method 2010.9.27

Content uniformity test method 2013.11.13

Dissolution test method 2010.11.11

Sterility test method 2010.9.27

2.6.12/4.05(I) /<61>

2.6.13/4.05(II)/<62>

5.1.4/4.05/<1111>

2.9.1/6.09/<701>

2.9.40/6.02/<905>

2.9.3/6.10/<711>

2.6.1/4.06/<71>

Q4B 9R1

Q4B 10R1

Q4B 11

Q4B 12

Q4B 13

Confidential for restricted use only Q4B 14

Tablet friability test method 2010.9.27

Polyacrylamide gel electrophoresis method 2010.9.27

Capillary electrophoresis method 2010.7.9

Sieving method 2010.7.9

Powder bulk density test method 2012.7.7

Bacterial endotoxin test method 2012.10.18

2.9.7/G6/ <1216>

2.2.31/G3/<1056>

2.2.47/G3/<1053>

2.9.38/3.04/<786>

2.9.34/3.01/<616>

2.6.14/4.01/<85>

Relevant content of Q4B

Main Contents





Item

Q4B 1R1 Residue on Ignition Test Method

ChP general rules （0841） ICH EP 2.4.14/JP 2.44/USP <281>

Sulfuric acid addition

Ignition temperature after adding sulfuric acid

Test end condition

700~800℃ (If the residue needs to be subject to heavy metal examination, the ignition temperature shall be 500~600℃)

600±50℃

Incinerate the test piece completely and move it to a dry container; cool it down and weigh it precisely. Then ignite it to a constant weight. The second weighing after it's ignited to the constant weight shall be conducted after 30 minutes' ignition.

Incinerate the test piece completely and move it to a dry container; cool it down and weigh it precisely. Calculate the remaining residue amount. If it's unqualified, ignite it for 30 minutes again, till the deviation of remaining residue doesn't exceed 0.5mg or comply with the limit.


0.5~1ml A little amount (usually 1ml)

Item

/

/

/

Q4B 2R1 Injection Filling Volume Test Method

ChP general rules (0102) (0942) ICH EP 2.9.17/JP 6.05/USP <1>

Test article filling volume

Take 5 pieces (bottles) of test articles if the filling volume is not bigger than 2ml; take 3 pieces (bottles) of test articles if the filling volume is 2ml~50ml.

Take 1 piece if the filling volume is 10ml and above. Take 3 pieces if the marked volume is above 3ml and below 10ml. Take 5 pieces if the marked volume is 3ml or below.

Dose Single dose/multiple dose/mass intravenous infusion; 1 piece of test article is taken for the latter two.

Test specificationCheck the syringe volume: The syringe volume shall not be 3 times bigger than the volume drawn out; use a 21# syringe needle, of which the length is at least 2.5cm (1 inch). Take adequate containers and combine their contents to reach the volume required for determination, and a dry syringe shall be used to draw the content from each container respectively.If the filling volume is 10ml and above, after the container is opened, all contents shall be directly poured to a graduated cylinder or weighing beaker.

Multiple dose test article of biological

product

1. The injection above 50ml and concentrated solutions for injection shall be tested according to the minimum filling volume test method (general rules 0942 Filling Volume Test Method)

2. Weight divided by relative density (for the small specification filling volume measured based on volume)

Q4B 3R1 Particulate Matter Test Method (1)

Item ChP general rules (0903) ICH EP 2.9.19/JP 6.07/USP <788>Method Light obscuration method/microscope counting method Light obscuration method/microscope counting method (confirm which is the

method after harmonization)

Water for particulate examination

Light obscuration method: take 50ml for determination. Requirement: in each 10ml, the number of particulate matters of 10μm and above shall be less than 10; the number of particulate matters of 25μm and above shall be less than 2.Microscope counting method: take 50ml for determination. Requirement: the number of particulate matters of 10μm and above shall be less than 20; the number of particulate matters of 25μm and above shall be less than 5.

Take 5 test water samples, each being 5ml, and test the particulates according to the following method.In 25ml water, the number of particulates of 10μm and above shall not exceed 25.

Sampling amount(below 25ml)

No requirement about the total amount; at least 4 test articles Take 10 or more packages and transfer the contents to a clean container to make the total volume not less than 25ml. Or mix the contents in an appropriate amount of penicillin bottles, and dilute it to 25ml with particulate-free water or other particulate-free solvents.

Determination

Result determination(Light obscuration method)

1. For the intravenous infusion injection with a marked filling volume of 100ml or above, in each 1ml, the number of particulates of 10μm and above shall not be bigger than 25, and the number of particulates of 25μm and above shall not exceed 3, unless otherwise specified.

2. For the intravenous infusion injection, sterile powder for intravenous infusion, concentrated solutions for injection, and sterile drug substances for injection with a marked volume of 100ml and below, in each test article container (piece), the number of particulates of 10μm and above shall not exceed 6000, and the number of particulates of 25μm and above shall not exceed 600, unless otherwise specified.

Test 1A (Intravenous infusion injection or injection preparation with a marked filling volume of above 100ml) In each 10ml, the number of particulates of 10μm and above shall not be bigger than 25, and the number of particulates of 25μm and above shall not exceed 3. Test 1B (Intravenous infusion injection or injection preparation with a marked filling volume of below 100mL) In each test article container, the number of particulates of 10μm and above shall not be bigger than 6000, and the number of particulates of 25μm and above shall not exceed 600.

Q4B 3R1 Particulate Matter Test Method (2)

/

ChP general rules（0903） ICH EP 2.9.19/JP 6.07/USP <788>Item

Test environmentClean workbench: high efficiency particle air filter, hole diameter: 0.45μm

No particulates can be introduced during the determination. It's better to perform the test in a laminar flow cabinet.

Result determination (microscopic

method)

(1) For the intravenous infusion injection with a marked filling volume of 100ml or above, in each 1ml, the number of particulates of 10μm and above shall not exceed 12, and the number of particulates of 25μm and above shall not exceed 2, unless otherwise specified.

(2) For the intravenous infusion injection, sterile powder for intravenous infusion, concentrated solutions for injection, and sterile drug substances for injection with a marked volume of 100ml and below, in each test article container (piece), the number of particulates of 10μm and above shall not exceed 3000, and the number of particulates of 25μm and above shall not exceed 300, unless otherwise specified.

Test 2A (Intravenous infusion injection or injection preparation with a marked filling volume of above 100ml) In each 1mL, the number of particulates of 10μm and above shall not exceed 12, and the number of particulates of 25μm and above shall not exceed 2. Test 2B (Intravenous infusion injection or injection preparation with a marked filling volume of below 100mL) In each test article container, the number of particulates of 10μm and above shall not exceed 3000, and the number of particulates of 25μm and above shall not exceed 300.

Particulate matter test method of ophthalmic

solution

In accordance with the particulate matter test method (standard)

Q4B 4BR1 Microbiological Purity Test of Non-sterile Products: Control Bacteria Test

Strain name ChP general rules（1106） ICH EP 2.6.13/JP 4.05(II)/USP <62>

Staphylococcus aureus

Pseudomonas aeruginasa

Escherichia coli

Salmonella paratyphi B

Candida albicans

Clostridium sporogenes

ATCC 6538、NCIMB 9518、CIP 4.83、NBRC13276


CMCC(B)64 941

CMCC (B) 26 003

CMCC (B)10 104

CMCC(B)44 102

CMCC(B)50 094

CMCC(F)98 001

ATCC 10231、NCPF 3179、IP 48.72、NBRC1594

ATCC 9027、NCIMB 8626、CIP 82.118、NBRC 13275

ATCC 8739、NCIMB 8545、CIP 53.126、NBRC 3972

ATCC 14028

NCIMB 100797、NCTC 6017、CIP 80.39

Q4B 4BR1 Microbiological Purity Control Bacteria Test - Test Article Preparation and Pre-incubation

Sampling amount Incubation time

ChP ICH ChP ICH

Bile~Tolerant Gram-Negative Bacteria

Take the test article. Take at least 1g test article. About 2 hours Incubated in tryptic soy broth at 20 ~ 25℃; the incubation time is usually controlled within 2 ~ 5 hours.

Escherichia coli Take the test article.Take the test solution equivalent to 1g or 1ml test article.

Take at least 1g test article.Take 10mL test solution or the test solution equivalent to 1g or 1ml test article.

Mixed evenly in the tryptose soya broth, incubated for 18 ~ 24 hours at 30 ~ 35℃

Mixed evenly in the tryptic soy broth, incubated for 18 ~ 24 hours at 30 ~ 35℃

SalmonellaTake 10g or 10ml test article. Take at least 1g test article.

Take 10mL test solution or the test solution equivalent to 1g or 1ml test article.


Incubated for 18 ~ 24 hours at 30 ~ 35℃ in the tryptic soy broth

Pseudomonas aeruginosa Take the test article.Take the test solution equivalent to 1g or 1ml test article.




Staphylococcus aureusTake the test article.Take the test solution equivalent to 1g or 1ml test article.


Incubated for 18 ~ 24 hours at 30 ~ 35℃ in the tryptose soya broth


ClostridiaTake the test article.Take 2 pieces of test solution equivalent to 1g or 1ml test article.

Divide at least 20mL (at least 2g or 2mL test article) into two parts, each having at least 10ml.

Place one part at 80℃ and insulate the heat for 10 minutes and then cool it down rapidly.

Heat one part at 80℃ for 10min and then cool it rapidly; the other part won't be heated.

Candida albicans Take the test article.Take the test solution equivalent to 1g or 1ml test article.

Take 10mL test solution or the test solution equivalent to 1g or 1ml test article.

Incubated for 3~5 days at 30~35℃in the Sabouraud Dextrose Broth

Mixed evenly in the Sabouraud Dextrose Broth, incubated for 3~5 days at 30~35℃

General requirement and classification

3

4

5

Q4B 4CR1 Microbiological Test of Non-sterile Products: Determination Criteria for Drug Substance and Its Preparation

Item ChP general rules （1107） ICH EP 5.1.4/JP 4.05/USP<1111>1

2

6


The preparations and raw materials and excipients required and marked to be sterile under the preparation general rules and variety: conform to the sterility test rules.

NA

NATopical administration preparation for operations, serious burns and serious traumas: conform to the sterility test method.Non-sterile chemical preparation, biological preparation, TCM preparation containing no initial powder of crude drug

Non-sterile preparation

Non-sterile TCM preparation containing the initial powder of crude drug

NA (relevant contents in the pharmacopeia of different countries are not coordinated)USP: Botanical preparation<2023>EP: Herbal medicinal products for oral use<5.1.8>JP: Crude drugs

Non-sterile raw materials and excipients for pharmaceutical use Non-sterile raw materials for pharmaceutical useTCM extract and processed TCM NA

Q4B 4AR1 Microbiological test of non-sterile products: microorganism count method (I)

Route of administration Total aerobes Total fungus and microzyme Control bacteriacfu/g，ml，10cm2 cfu/g，ml，10cm2 ChP general rules （1105）EP 2.6.12/JP 4.05(Ⅰ) /USP<61>）

ChP ICH ChP ICH ChP ICH

Oral administration-solid preparation

Preparation for gingiva administration

Aural preparation

No Escherichia coli detected out (1g or 1ml);No salmonella shall be detected out from the preparation containing viscus extract (10g or 10ml); No salmonella shall be detected out from the chemical preparations and biological preparations that contain unextracted components and mineral substances from animals and plants (10g or 10ml).

No Escherichia coli detected out (1g or 1ml)

Oral administration-liquid preparation

Preparation for oral mucosa administration

No Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa shall be detected out (1g, 1ml or 10cm2).

No Staphylococcus aureus and Pseudomonas aeruginosa shall be detected out (1g or 1ml).

No Staphylococcus aureus and Pseudomonas aeruginosa shall be detected out (1g, 1ml or 10cm2).

No Staphylococcus aureus and Pseudomonas aeruginosa shall be detected out (1g or 1ml).

Preparation for transdermal administration

103103 102

101

102102

102

102

101

101

101

102

102102 101 101

-

/ /

* /

Q4B 4AR1 Microbiological test of non-sterile products: microorganism count method (II)

Route of administration Total aerobescfu/g，ml，10cm2

Total fungus and microzyme cfu/g，ml，10cm2

Control bacteriaChP general rules （1105） EP 2.6.12/JP 4.05(Ⅰ) /USP<61>）

ChP ICH ChP ICH ChP ICH

Inhalation administration preparation

102 102 101 101

Preparation for vagina and urethrae administration 102 102 101 101

103

102

/

103

102

102

102

/

102

101

Raw materials and excipients for pharmaceutical use 103 103 102 102


No Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, and Bile~Tolerant Gram-Negative Bacteria shall be detected out (1g or 1ml).

No Staphylococcus aureus, Pseudomonas aeruginosa, and Bile~Tolerant Gram-Negative Bacteria shall be detected out (1g or 1ml).

No Staphylococcus aureus, Pseudomonas aeruginosa and Candida albicans shall be detected out (1g, 1ml or 10cm2). Clostridium shall also not be detected out in TCM preparation (1g, 1ml or 10cm2).

No Staphylococcus aureus, Pseudomonas aeruginosa, and Candida albicans shall be detected out (1g or 1ml).

Rectal administration-solid (liquid) preparation


Other topical administration preparations


Transdermal patch No Staphylococcus aureus and Pseudomonas aeruginosa shall be detected out (1 patch).

Item

/

/

Q4B 5R1 Disintegration Time

ChP general rules（0921） ICH EP 2.9.1/JP 6.09/USP <701>

Scope of application Tablets, capsules and dropping pills Tablets and capsules

Complete disintegration refers to

Except the insoluble coating materials or shells left on the screen mesh or stuck to the baffle plate bottom (if used), the preparation shall be completely softened without a hard core.

Instrument and deviceThe instrument and device also include a heating unit that can heat the solution to 35~39℃.

The circulating frequency is 30~32 times P.M.The circulating frequency is 29~32 times.

Inner diameter 21.5mm, wall thickness 2mm Inner diameter 20.7~23mm, thickness of pipe 1.0~2.8mm

Test methodWater temperature 37℃±1℃ 37±2℃

Take 6 test articles and all shall be totally disintegrated within 15min. If one can't be totally disintegrated, test another 6 pieces again, and all shall meet the requirement.

Take 6 test articles. If 1~2 can't be completely disintegrated, test another 12. Among 18 pieces, if at least 16 pieces are completely disintegrated, the result is qualified.

Test method description Tablet: Chinese medical extract tablets, semi-extract tablets and total powder tablets; film-coated tablets (including TCM film-coated tablets); sugar-coated tablets (TCM / chemical drug); enteric-coated tablets; colon-specific enteric-coated tablets; lozenges; sublingual tablets; soluble tablets; effervescent tablets; orally disintegrating tablets;Capsule: hard capsules or soft capsules; enteric capsules; colon-specific enteric capsules;Dropping pill

Common coated tablets, enteric coated tablets, lozenges, sublingual tablets, hard capsules, soft capsules

Dosage form

/

/

/

Enteric-coated tablets

/

Lozenges

/

/

/

/

/

Q4B 5R1 Test Parameters of Various Dosage Forms within the Disintegration TimeChP general rules （0921） ICH EP 2.9.1/JP 6.09/USP <701>

Chinese medical extract tablets, semi-extract tablets Note: uncoated-common tablets: （37±2）℃， the specified time

Tested for 2h in hydrochloric acid solution (9→1000). No cracks, disintegration or softening. Take out the gondola and wash it with some water. Add 1 baffle plate to each tube, and test it according to the above method in phosphate buffer solution (pH6.8). All shall be disintegrated within 1h.

Soak the gondola in water for 5min and test it in simulated gastric fluid at (37±2)℃. 1h later, take out the gondola and observe the sample. There shall be no disintegration, cracks or softening. Then test it in simulated intestinal fluid at (37±2)℃ using the above method. At the end of the time specified in the text under the variety item, take out the gondola and observe the sample. All shall be completely disintegrated.

Colon-specific enteric-coated tabletsThere shall be no cracks, disintegration or softening in hydrochloric acid solution (9→1000) and phosphate buffer solution below pH6.8, and all shall be disintegrated within 1h in PH7.5 ~ 8.0 phosphate buffer solution.

Totally disintegrated or melted within 10min

Add a baffle plate to each tube. Total powder tablets shall be totally disintegrated within 30 minutes; extract (semi-extract) tablets shall be totally disintegrated within 1h.

Film-coated tablets Tested in hydrochloric acid solution (9→1000); chemical film-coated tablets shall be totally disintegrated within 30 minutes. For TCM film-coated tablets, add 1 baffle plate to each tube. Each tablet shall be totally disintegrated within 1h.

Sugar-coated tablets Chemical sugar-coated tablets shall be totally disintegrated within 1h. For TCM sugar-coated tablets, add 1 baffle plate to each tube. Each tablet shall be totally disintegrated within 1h.

Take out the gondola 4h later and observe the sample. All shall be disintegrated.

Sublingual tablets Totally disintegrated and melted within 5min Take out the gondola at the end of the time specified in the text under the variety item.

Soluble tablets Totally disintegrated and melted within 3 min when the water temperature is 20℃±5℃.

Effervescent tablets In 20±5℃ water, gas stops escaping. The tablets shall be dissolved or dispersed in water, without remaining particles.

Orally disintegrating tabletsTested in a detached instrument or device

Hard capsules or soft capsules Hard capsules shall be totally disintegrated within 30 min. Soft capsules shall be totally disintegrated within 1h.

Hard capsule: use the same method for fixing a screen mesh to the gondola bottom to fix another screen mesh with 1.8 ~ 2.2mm hole diameter and 0.60 ~ 0.655mm steel wire diameter to the circular plate on the top surface.

Enteric capsules Test it in hydrochloric acid solution for 2h without using a baffle plate and no shells shall have cracks or disintegration. Add a baffle plate to each tube and test it in simulated intestinal fluid. It shall be totally disintegrated within 1h.

Colon-specific enteric capsulesTest it in hydrochloric acid solution for 2h and no shells shall have cracks or disintegration. Test it in phosphate buffer solution (ph6.8) for 3h and no shells shall have cracks or disintegration. Add a baffle plate and test it in phosphate buffer solution（ph7.8). It shall be totally disintegrated within 1h.

x11,xx12x x 30 30

Item

20

Q4B 6R1 Content Uniformity (I)

1. Test method typeIncluding the content uniformity (CU) test methodWeight (volume) difference (WV) is not included herein and is listed under the general rules of each preparation.

ICH EP 2.9.40/JP 6.02/USP <905>

Including the content uniformity test method (CU) and weight (volume) difference (WV) test method

2. Scope of application (dosage form, sub-dosage form)

Plain tablet WV CU WV CU

WV

/

WV

CU

WV

WV

WV1/CU2

WV

WV1/CU2

CU

CU

CU

CU

WV

WV

WV1/CU2

WV

WV1/CU2

WV

CU

WV

CU

WV

WV

CU

WV

CU

CU

CU

CU

CU

WV

WV

CU

WV

CU

Note: 1. At present, ChP applies to the powder, Dry suspension, Granules, and spray packed on a single dose basis. 2. ChP is the sterilized powder for injection adopting the mixed powder technology.


Different methods (CU or WV method) are adopted according to the labeled amount of single dosage of different dosage forms and the proportion of main drug content in each single dosage.≥25mg and ≥25% <25mg or＜25% ≥25mg and ≥25% <25mg or＜25%

Tablet Coated tablet

Film coat

Others

Capsule

Hard capsule

Soft capsuleSuspension, emulsion or gelatinSolution

Solid preparation packed on a single dose basis

Prescribed preparation

Freeze-dried

Others

Complex prescription

Freeze-dried

Others

ChP general rules（0941）

x11,xx12x x 30 30

Item

WV WV

Qualified

Confidential for restricted use only 21

Q4B 6R1 Content Uniformity（II）

ChP general rules（0941） ICH EP 2.9.40/JP 6.02/USP <905>Different methods (CU or WV method) are adopted according to the labeled amount of single dosage of different dosage forms and the percentage of main drug content in each single dosage.≥25mg and ≥25%

Oral solution CU; others/

WV3

<25mg or ＜25%

Oral solution CU; others/

WV3

≥25mg and ≥25%

CU

<25mg or ＜25%

CU

Important statistical parameters disagree with ICH. Preliminary test n=10Preliminary test n=10

A+2.2S≤L qualified ∣M-X ∣+2.4S≤15.0

Re-test n=30Qualified

A+S＞L Unqualified ∣M-X ∣+2.0S≤15.0 andA+2.2S＞L，and A+S≤L Re-test 0.75M ≤ Xi ≤1.25M

Re-test n=30 Failed to meet the above conditions Unqualified 3. CU method criterion

When A≤0.25L, if A2+S2≤0.25L2 , it is qualified. If A2+S2＞0.25L2 , it is unqualified. When A＞0.25L, if A+1.7S≤L, it is qualified. If A+1.7S＞L, it is unqualified.

X<98.5 ：98.5≤X≤101.5：X>101.5：

M=98.5M=XM=101.5

Unless otherwise specified, L=15.0For oral constituted suspension packed on a single dose basis, soft capsules filled with non-homogeneous phase solution, dry powder inhalation in the form of capsules or vesicle, ophthalmic, otic and nasal suspension packed on a single dose basis, and solid or semisolid preparations, L=20.0; for transdermal patches and suppositories, L=25.0

4. When the content uniformity and assay methods are different

The specific correction method is given. No specific correction method is given.

2. Scope of application (dosage form and sub-dosage form)

Soft capsule packed on a single dose basis

Others

Test method

Q4B 7R2 Dissolution Rate and Releasing Rate Test Method（I）

Item ChP general rules（0931） ICH EP 2.9.3/JP 6.10/USP <711>

Result determination

Method I (basket method), method II (paddle method), method III (small glass method), method IV (paddle over disk), method V (cylinder method)

Method 1 (basket method), method 2 (paddle method), method 3 (reciprocating cylinder method), method 4 (Flow-through cell method )

Ordinary preparation

Consolidated sample limit table

Q4B 7R2 Dissolution Rate and Releasing Rate Test Method（II）

Item ChP General rules（0931） ICH EP 2.9.3/JP 6.10/USP <711>Sustained release preparation or controlled release preparation

(1) Among six tablets (pills), the dissolution amount of each tablet (pill) at each time point doesn't exceed the specified scope when calculated according to the labeled amount.

(2) Among six tablets (pills), the dissolution amount of 1~2 tablets (pills) exceeds the specified amount at each time point, but it doesn't exceed 10% of the specified scope, and the average dissolution amount measured at each time point doesn't exceed the specified scope.

(3) Among six tablets (pills), if the dissolution amount of 1~2 tables (pills) measured at each time point exceeds the specified scope, and only the dissolution amount of one tablet (pill) exceeds 10% of the specified scope, but it doesn't exceed 20% of the specified scope, and its average dissolution amount doesn't exceed the specified amount, another 6 tables (pills) shall be taken for a re-test. Among the 12 tablets (pills) in the preliminary test and re-test, the dissolution amount of 1~3 tablets (pills) measured at each time point exceeds the specified scope, and the dissolution amount of only 1 tablet (pill) exceeds 10% of the specified scope, but it doesn't exceed 20% of the scope, and the average dissolution amount doesn't exceed the specified scope.


Q4B 7R2 Dissolution Rate and Releasing Rate Test Method（III）

Item ChP General rules（0931） ICH EP 2.9.3/JP 6.10/USP<711>Enteric-coated preparation

(1) Among 6 tablets (pills), the dissolution amount of 1~2 tablets (pills) is bigger than 10%, but the average dissolution amount is not bigger than 10%.Dissolution amount in the buffer solution （1 ) Among six tablets (pills), the dissolution amount of each tablet (pill) is not lower than the specified limit (Q) when calculated according to the labeled amount. Unless otherwise specified, Q shall be 70% of the labeled amount. (2) Among six tablets (pills), the dissolution amount of only 1~2 tablets (pills) is lower than Q, but it's not lower than Q-10%, and the average dissolution amount is not lower than Q.(3) Among six tablets (pills), if the dissolution amount of 1~2 tablets (pill) is lower than Q, and the dissolution of only 1 tablet (pill) is lower than Q-10%, but it's not lower than Q20%, and its average dissolution amount is not lower than Q, another 6 tablets (pills) shall be taken for another test. Among the 12 tablets (pills) in the preliminary test and re-test, the dissolution amount of 1~3 tablets (pills) is lower than Q, and the dissolution amount of only 1 tablet (pill) is lower than Q-10%, but it's not lower than Q-20%, and its average dissolution amount is not lower than Q.


25

ChP2020 Application of Different Dissolution Methods in Two Pharmacopeia

Tablet

175

234

42

0

0

Capsule

106

73

11

0

0

Granule

2

10

1

0

0

Dry suspension

0

9

0

0

0

Patch

0

0

0

1

0

Pill

0

1

0

0

0

Total

283

327

54

1

0

Remarks: For some tablets and granules, two methods in the general rules 0931 are quoted. Data in this table are not suitable for calculating the number of varieties of tablets and granules in dissolution rate test.


Method

Method 1 Basket method

Method 2 Paddle method

Method 3 Small glass method

Method 4 Paddle over diskMethod 5

Cylinder method

Confidential for restricted only

Q4B 8R1 Sterility Test Method（I）

Item ChP General rules（0542） ICH EP 2.6.1/JP 4.06/USP <71>

Staphylococcus aureusATCC 6538， CIP 4.83， NCTC 10788， NCIMB 9518， NBRC 13276

Bacillus subtilis

Pseudomonas aeruginosa

AnaerobesClostridium sporogenes

FungiCandida albicans

ATCC 6633， CIP 52.62， NCIMB8054， NBRC 3134

ATCC 9027， NCIMB 8626， CIP82.118， NBRC 13275

ATCC 19404， CIP 79.3， NCTC533 or ATCC 11437， NBRC 14293

ATCC 10231， IP 48.72， NCPF3179， NBRC 14293

ATCC 16404， IP 1431.83， IMI

Culture medium for the test

Thioglycollate MediumTryptose Soya Broth

Thioglycollate MediumTryptose Soya Broth

Strains for sensitivity test

Staphylococcus aureus[CMCC (B) 26 003]

Bacillus subtilis [ CMCC(B)63 501]

Pseudomonas aeruginosa[CMCC (B)10 104]

Clostridium sporogenes[CMCC(B)64 941]

Candida albicans [CMCC(F)98 001]

Aspergillus niger [CMCC(F)98 003] Aspergillus brasiliensis

Q4B 8R1 Sterility Test Method（II）


Culture medium preparation

Thioglycollate MediumTryptose Soya BrothCulture medium for neutralization or inactivation0.5% Glucose Broth (for the sterility test of antibiotics like streptomycin sulfate)Tryptose Soya AgarSabouraud Dextrose BrothSabouraud Dextrose Agar

Thioglycollate MediumSoybean Casitone Digest Medium◆ Culture medium for penicillin and cephalosporin test

Dilute solution, washing solution

0.1% sterile peptone water solutionpH7.0 sterile sodium chloride - peptone buffer solutionOther recognized solutions (0.9% sterile sodium chloride solution etc.)

Diluent A: Dissolve 1g stomach enzyme digest of animal tissue in 1L water, pH7.1±0.2, add adequate beta-lactamase of which there are residual antibiotics on the inactivated filter membrane.Diluent D: Add 1mL Polysorbate 80 to each liter of diluent A and regulate the pH value to 7.1±0.2. This liquid is used for the samples containing lecithin or grease.Kiluent K: Dissolve 5.0g stomach enzyme digest of animal tissue, 3.0g beef extract, and 10.0g polysorbate 80 in 1L water. Regulate the pH to be 6.9±0.2 ◆

Test article examination

Active control and negative control are required. Negative control is required.

Test article culture The Thioglycollate Medium container to inoculate the biological test article shall be divided into two equal parts. One shall be placed at 30 ~ 35℃ for culture and the other 20 ~ 25℃. Tryptose Soya Broth medium shall be placed at 20 ~ 25℃.

The other Tryptose Soya Broth medium shall be placed at 22.5+2.5℃. Glycolate Fluid Culture Medium shall be placed at 30 ~ 35℃.

Result determination

Q4B 8R1 Sterility Test Method （III）


After 14 days of culture, if it's hard to determine the microbes from the appearance, transfer an appropriate amount of the culture fluid to the same fresh culture medium and continue culturing for 3 days.

After culturing for 14 days, transfer several parts (each part shall be at least 1ml) of the culture medium to the container which contains the same fresh culture medium and continue culturing for at least 4 days.


Item

Instrument and device

Q4B 9R1 Tablet Friability Test Method (I)

ChP general rules（0923） ICH EP 2.9.7/JP G6/USP <1216>

Scope of application

In compliance with ICH

Test method and judgment criterion

Friability test of uncoated compressed tablets and a supplement of other physical stress tests

Rotating cylinder: inner diameter 286.0±0.2; outer diameter 305.0±1.0; depth 39.0±0.3 (mm)

Rotating cylinder: inner diameter 287.0±4.0; outer diameter 302.5±4.0; depth 38.0±2.0 (mm)

Arc septum: inner diameter 80.0±1.0 (mm) Arc septum: inner diameter 80.5±5.0 (mm)

Center ring of rotating cylinder: inner diameter 10.0±0.1; outer diameter 25.0±0.25 (mm)

Center ring of rotating cylinder: inner diameter 10.0±0.1; outer diameter 25.0±0.5 (mm)

Drop height 155.5 (mm) Drop height 156.0±2.0 (mm)

Diversity of the instruments on sale: not consideredDiversity of the instruments on sale: if the cylinder is provided with two septa or the instrument is provided with more than one cylinder, the test of several batches of samples can be conducted at one time.

The same as ICH If the per tablet weight is 0.65 g or below, take several tablets to make the total weight about 6.5g; if the per tablet weight is bigger than 0.65g, take 10 tablets. Weigh the sample precisely and place it in the rotating cylinder; rotate the cylinder for 100 times and take out the tablets. Remove the powder dropping from the tablet surface and weigh the tablets again precisely. The weight lost shall not exceed 1%. If the sample has obvious breakage, cracks, and smashed pieces after turning, the sample is not qualified. Usually, this test is only performed once. If it's hard to determine the result, or the lost weight exceeds 1%, perform another two tests. The average lost weight in the three tests shall not exceed 1% and there shall be no breakage, cracks and smashed pieces.

Item

30

Q4B 9R1 Tablet Friability Test Method (II)

ChP general rules （0923） ICH EP 2.9.7/JP G6/USP <1216>

Requirements for special dosage forms

Ambient humidity The relative humidity is smaller than 40%.

If the tablet of which the shape or size may cause serious irregular rolling in the cylinder or the tablet made through special processes can't be tested using this method, it can be exempted from friability test.

During the friability determination of effervescent tablets and chewable tablets, different standards may be adopted.

The ambient humidity shall be well controlled.


Item

/

/

Q4B 10R1 Polyacrylamide Gel Chromatography

ChP general rules（0541） ICH EP 2.2.31/JP G3/USP <1056>Introduction to the

method and principleSimple There are detailed introductions to the principle, nature, type, and

preparation.

Nature Compulsory 1056 is a recommended method.

Electrophoresis Current and voltage are confirmedNo special requirement, determined according to the instruments of different manufacturers and the optimal separation effect they can reach; more flexible.

Reagents for the test Coomassie brilliant blue staining solution, destaining solution, stationary liquid; silver nitrate solution, color development solution, stop buffer

Test method Simple Detailed

Test verification Protein molecular weight distribution

Impurity assay Validation required


Test instruments and equipment

System suitability

Q4B 11 Capillary Electrophoresis Method

Item ChP General rules（0542） ICH EP 2.2.47/JP G3/USP <1053>

Separation pattern(1) Capillary zone electrophoresis (CZE)(2) Capillary isotachophoresis (CITP)(3) Capillary Isoelectric Focusing (CIEF)(4) Micelle electrokinetic chromatography (MEKC)(5) Affinity capillary electrkphoresis (ACE)(6) Capillary gel electrophoresis (CGE)(7) Capillary Electrochromatography (CEC)(8) Capillary array electrophoresis (CAE)(9) Chip-based capillary electrophoresis (Chip CE)

Capillary zone electrophoresisCapillary gel electrophoresisCapillary Isoelectric FocusingMicelle electrokinetic chromatography (MEKC)

1. Capillary Elastic quartz capillary; the capillaries with 50μm and 75 μ m inner diameter are most frequently used (sometimes, the capillaries with a bigger inner diameter is used in Capillary Electrochromatography)

2. DC high voltage supply 0~30kV (or about) adjustable DC power supply; it can provide about 300 μ A current.

3. Electrode and electrode groove 4. Washing and sampling system5. Detection system Ultraviolet and visible spectrophotometer, laser-

induced fluorescence detector, electrochemical detector, mass spectrometry detector, nuclear magnetic-resonance detector, chemiluminescence detector, LED detector, resonance Rayleigh scattering detector, etc.

Fundamental specifications are made to relevant parameters of the detection instrument, including the voltage, polarity, temperature, capillary and electrolyte solution parameter, buffer solution type and concentration, buffer solution PH and organic solvent, and separation additives. No precise experimental parameters are given. The optimal test parameters are determined according to the optimization of test separation conditions on the basis of validation.

Suitability consideration: The test items and method of system suitability are the same as those of high-performance liquid chromatography or gas chromatography. Repeatability (relative standard deviation, RSD), capacity factor (K'), capillary theoretical plates (n), resolution (R), tailing factor (T), linear range, limit of detection (LOD) and limit of quantitation (LOQ)

Besides ChP, symmetry factor (As) (tailing factor), apparent theoretical plate number, and SNR (sensitivity) shall also be considered.

Q4B 12 Sieving Method

Sieving method


Manual sieving method (single sieving method, dual sieving method)Mechanical sieving methodAir spray method

Mechanical vibration method, air purge method, (acoustic wave sieving method); the vibration method and vibration parameters shall be pointed out (if adjustable).

Sieve diameter 200nm, unless otherwise specified Besides 200nm, there were also requirements for the test of the test sample amount tested using the sieve 76nm in diameter. The least test drug amount shall be 5g.Impact of humidity and static electricity on samples

Table of sieve hole diameter

NA Standard sieve hole diameter ISO 3310 - 1 (as shown in the figure below)

Re-test requirement No special requirements If the particle weight on the mesh exceeds 50% of the sample's total weight, the test needs to be performed again unless otherwise specified in the text part of the variety.

Test record requirement No special requirements Besides the particle weight on each sieve mesh and base plate, the raw data

shall also include the sample weight, total sieving time, precise sieving examination method, and the set value of each adjustable parameter.


Standard Sieve Hole Diameter ISO 3310-1


Q4B 14 Bacterial Endotoxin Test Method

Item ChP general rules （1101） ICH EP 2.6.14/JP 4.01/USP <85>

Method classification 1. Gel method (quantitative gel test, semi-quantitative gel test)2. Photometry

1. Gel method 2. Quantitative method3. Photometry

Gel method interference test

When the result of solution B meets the re-test requirement of TAL sensitivity, the test article is considered having no interference under such a concentration level.

When the sensitivity of solution B is within the scope of 0.5λ~2.0λ (0.5λ and 2.0λ included), the test article is considered having no interference under such a concentration level.

Result determination of gel method

If the parallel pipes of negative control solution D are negative, the parallel pipes of active control solution B are positive, and the parallel pipes of active control solution C are positive, the test is effective.

If two parallel pipes of solution A are negative, the test article is considered to be qualified. If two parallel pipes of solution A are positive, the test article is considered to be unqualified.

If one of the two parallel pipes of solution A is positive, and the other pipe is negative, the test needs to be performed again. During the re-test, solution A needs 4 parallel pipes. If all parallel pipes are negative, the test article is considered to be qualified; otherwise, the test article is considered to be unqualified.

If the parallel pipes of negative control solution D are negative, the parallel pipes of active control solution B are positive, and the parallel pipes of active control solution C are positive, the test is effective.If two parallel pipes of solution A are negative, the test article is considered to be qualified. If two parallel pipes of solution A are positive, the test article is considered to be unqualified.

If one of the two parallel pipes of solution A is positive, and the other pipe is negative, the test needs to be performed again.During the re-test, if two parallel pipes of solution A are negative, the test article is considered to be qualified. During the re-test, if 1 or 2 test articles are positive, the test article is considered to be unqualified.

Main Contents






1 ●

2 √

3 √

4 √

5 √

6

7 ●

Overall Evaluation

No. Test method

Residue on ignition test method

harmonization state

Basically the same

Main problems

Ignition temperature and test finish condition

Coordinability Harmonization content

The unity of detection temperature needs substantive experimental data. Revision of bacteriostat standard is difficult.

Particulate matter test method

Basically the same Grouping of sampling amount and result determination 100ml

A test is needed to confirm whether it can be coordinated and unified.

Disintegration time test method

Basically the same ○√ A test is needed to compare and validate the methods.

Content uniformity test method

With basically the same general structure

There is big difference between Chinese Pharmacopoeia and ICH in determining the disqualification of batch products.

Needing systematic adjustment

Basically the same

Basically the same

Basically the same

Microbiological test of non-sterile products: microorganism count method

The test amount is slightly different. There is slight supplement to the method suitability test and the fungi counting culture medium.

Needing validation

Microbiological test of non-sterile products: control bacteria test

Only the strain source and pre-incubation time of Bile~Tolerant Gram-Negative Bacteria are slightly different. ChP includes the biochemical test of part control bacteria.

Conformity of the strains of different sources needs validation.

Microbiological test of non-sterile products: determination criteria for drug substance and its preparation

Besides the standard for non-sterile chemical preparations, biological preparations, chemical materials and pharmaceutical excipients in ICH harmonization method, Chinese Pharmacopoeia also includes the standard for microbiological purity of TCM preparations, TCM extracts and some processed traditional Chinese medicines.

Text standard harmonization; some need experimental verification.

The control temperature, gondola lifting times, relevant test parameters and result determination are slightly different.

8 √

9

10 √

12 ○

13 ○

14 √

Overall EvaluationNo. Test method harmonizatio

n state Main problems harmonization content Coordinability

Sterility test method Basically the same

The strains, test quantity, and washing amount are slightly different. There is slightly supplement to the sterility test method of biological products.

Conformity of the strains of different sources needs validation.

Tablet friability test method

Determination method of granule size and distribution of granulesize, method 2: sieving method

Basically the same

Basically the same

√

Needing text revision, and when necessary, experimental verification

11 Basically the same

Partially the same

√

Injection filling volume test method

Basically the same

Make method comparison and validation.

Polyacrylamide gel electrophoresis method

Basically the same

For the description of the test method, ICH is more principled and flexible.

To be more flexible in test method description; giving more definite regulations in varieties to improve the suitability

15 Capillary electrophoresis method

Basically the same

As above √ As above


The device size and result determination are slightly different.

Compared with Chinese Pharmacopoeia Ver. 2015, ICH has more detailed regulations about different mesh sizes, how to choose an appropriate sieve according to the granule size of the sample, and selection of sample weight.

Bacterial endotoxin test method

There is only slight difference in method representation. Text revision

Dissolution rate and releasing rate determination method

There is difference in the test method and result judgment, including basket method and paddle method.

Needing method validation, corroboration of relevant test parameters, and collection of product suitability dataThe draft standard for flow-through cell method has been basically finished and it will keep in line with ICH method.

The filling volume of test article is more detailed. The test needs to be detailed.

Harmonization Strategies (Ⅰ)

• ChP and ICH Q4B are basically the same in technical requirements and have no big difference in implementation.

• The pharmacopeia of different countries also varies in terms of Q4B implementation. The pharmacopeia of different countries also has relevant requirements established according to the country's drug quality control nature. Not all of the contents are perfect and consistent with each other, but in the standard, the differences have been marked out and clearly specified.

• In ICHQ4B method, the four test methods of USP implementation are numbered with the digit bigger than 1000, and in principle,the methods are recommended and flexible, instead of being compulsory.

• During the establishment and revision of the test methods of ChP, constant attention has been paid to the experience of international universal test methods. At present, studies on the following test methods have been performed according to Q4B analysis method, and the unity and harmonization with the method specified in ICHQ4B is the key of the methodology.

• Those with the greatest difference are the residue on ignition test method and content uniformity test method, which need further studies.

• ICHQ4 also provides that the harmonization standard needs to be confirmed after evaluating whether it's enforceable in different regions, so there shall be a comprehensive evaluation on the impact on implementation in terms of relevant harmonization methods of Chinese Pharmacopoeia, so as to ensure the smooth transition of the revisions.


Harmonization Strategies (Ⅱ)

• Considerations of harmonization of relevant methods:

• The methods shall be coordinated based on the drug characteristics and existing quality standards and detection limit standards in China. In the meanwhile, there shall also be sufficient evaluation about whether the harmonization is executable.

• If there are differences in terms of wording, the words need to be standardized. If there are differences in terms of text description, but the differences won't affect comprehension, the former description will be kept but need to be standardizedaccording to relevant descriptions in Q4B.

• If there are differences in terms of contents, relevant parameters and test results, a comparative study shall be carried out to the methodology. In the meanwhile, drug assays need to be organized, and manufacturers shall provide more comprehensive validation and accumulate related data.

• Methodological studies shall be carried out about the missing test methods, and the methods need to be established according to the international requirements and Q4B methods.

• If there are big differences between the methods, further comparison between the methodologies is recommended. There can alsobe new methods for new products, and gradual transition to the methods applicable to marketed products.


//

2

/

2

Disintegration Time (Comparison of Major Parameters of the Disintegration Instrument Used in the Pharmacopeia in Different Countries)

Instruments

Pharmacopeia

Ch P 2015 USP 38BP 2016

Below 18mm Above18mm① ②

EP 8.0Below18mm Above 18mm

① ②JP 16

Beaker

Temperature （℃）

Lifting times/min

Height (mm)Inner diameter (mm)

Length (mm)

37±130~32

77.5±2.5

138~16097~11537±229~32

Glass tube

Sieve mesh

Inner diameter(mm)

Wall thickness(mm)Mesh inner diameter (mm)

Wire diameter (mm)

21.5

2/0.42

21.85±1.15

1.9±0.91.8~2.2

0.615±0.045

21.85±1.15

1.9±0.91.8~2.2

0.615±0.045

33.0±0.5

2.5±0.51.8~2.2

0.63±0.03

21.85±1.15

1.9±0.91.8~2.2

0.615±0.045

33.0±0.5

2.5±0.51.8~2.2

0.63±0.03

21.85±1.15

1.9±0.91.8~2.2

0.615±0.045

Diameter (mm)Thickness (mm)

20.7±0.159.5±0.15

20.7±0.159.5±0.15

20.7±0.15 31.4±0.139.5±0.15 15.3±0.15

20.7±0.159.5±0.15

31.4±0.13 20.7±0.1515.3±0.15 9.5±0.15

Baffle plate Hole numberHole diameter(mm)Hole spacing center (mm)

5

6

52±0.16±0.2

52±0.16±0.2

73.15±0.1

4.2

52±0.16±0.2

73.15±0.1

4.2

52±0.16±0.2


Application and Implementation of ICH Q4 in China

Carry out experimental studies, validation and researches

2019

Collect opinions about the draft standard and finalize it.

2021

2022

2018Translation of the text part, and evaluation and comparison between the text part of ICH Q4B and relevant general rules of Chinese Pharmacopoeia Ver. 2015

2020Relevant committees of Chinese Pharmacopoeia Commission reviews and evaluates the necessity of uniformity and forms a draft standard.

Formally implemented together with Chinese Pharmacopoeia after release

Proposed line map and time schedule for the implementation of Q4 guidelines


Summary

ICH harmonization aims to ensure the drug safety, efficacy, quality and harmonization of international drug standards. Q4-related test methods in the pharmacopeia of different countries have been applied to the quality control of relevant drugs and validated in practice. The methods are feasible. Implementation of ICH Q4 is of more importance for the harmonization of international drug quality control methods.

Chinese Pharmacopoeia is established and revised by reference to relevant requirements of European and American pharmacopeia, and tends to be consistent with the national standard. The Pharmacopeia 2020 has been further harmonized with the international standard in terms of relevant methods.

There are greater challenges for the harmonization of Chinese Pharmacopoeia with the standards, because there are too many varieties (TCM, chemical drugs, biological products), standards (the standards included in the pharmacopeia, the standards not included in the pharmacopeia released by relevant departments, and standards for enterprise registration), and enterprises.

At present, although China's relevant drug administration institution has become a member of ICH management committee, it's still not a member of PDG workgroup. There are no effective ways and a sound work mechanism for information exchange for ICHQ4B standard harmonization, and the number of units involved is small. Experts from international organs and relevant international enterprises still need to provide more supports and help.

There is a need for comprehensive understanding of the meaning of ICH Q4B standard harmonization and implementation, and implementation of common standards and retention of individual characteristics shall be balanced.

The comprehensive evaluation between Chinese Pharmacopoeia and ICH Q4B needs to be further improved, and work strategies for future standard harmonization need to be established.

Chinese Pharmacopoeia 2020 will be further unified with ICH Q4 standard. China would like to participate in the harmonization between Chinese Pharmacopoeia and ICH Q4 guidelines, including the harmonization of relevant

standards of PDG. China's drug administration institutions and industry will also make more contributions in this respect.


Acknowledgement:


• Professor Xu Yuhua, Division of General Affairs, Chinese Pharmacopoeia Commission

• Doctor Xu Xinyi, Division of General Affairs, Chinese Pharmacopoeia Commission

• Associate Investigator Liu Zhen, Jiangxi Institute for Drug Control

• Zhang Zhen, China Pharmaceutical University

Your comments and advice are welcome！


Date post:	27-Feb-2021
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