Click to edit Master title style Microbial Limits Test Applicability Study and

Consideration Points on the Pathogenic Bacteria Testing:

Testing Methods Validation Study

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Benoît RAMOND (Sanofi)

Click to edit Master title style Regulations

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Pharmacopoeias

Monographs •Harmonized

Chapters (EP/USP/JP)

•Chinese Ph.

Comparison •Chinese Ph.

Vs. Harmonized Chapters

Impact on Tests Performance •Harmonized

Chapters (EP/USP/JP)

•Chinese Ph.

Harmonised Chapters – ICH Q4b

ICH Q4b Chinese Pharmacopoeia Commonality Major Difference

USP<62> EP 2.6.13 JP 4.05 Part 2

1106 – Microbiological Examination of non-sterile products: Tests for Specified Microorganisms

Both describe teast for E. coli, S. aureus, P. aeruginosa, C. albicans, Salmonella spp. & bile-tolerant Gram-negative bacteria

Use of triple sugar iron agar as indicative for Salmonella spp. (ChP), Use of Candida chromogenic agar as indicative for C. albicans (ChP)

Microbial Limit Tests

Click to edit Master title style

• Pharmacopoeias in the chapter Microbiological Testing Methods applied to Pathogens (Specified Microorganisms) request the following: – Test for Bile-tolerant Gram Negative Bacteria – Test for Candida albicans – Test for Clostridia spp. – Test for Escherichia coli – Test for Pseudomonas aeruginosa – Test for Salmonella spp. – Test for Staphylococcus aureus

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Click to edit Master title style Bile Tolerant Gram Negative Bacteria Qualitative Test

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Bile Tolerant Gram - Bacteria

Dosage Form ICH Q4b Ch. P.

Oral Solid No No

Oral Liquid No No

Oromucusal, Gingival, Nasal use No No

Cutaneous, Auricular use No No

Inhalation use Absence in 1g

Absence in 1g

Rectal use No No

Vaginal use No No

Click to edit Master title style Bile Tolerant Gram Negative Bacteria Qualitative Test

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Test for Bile Tolerant Gram Negative Bacteria - Qualitative Media and Tests

Batch N°

(1) Incubation date: Examination date: Incubation Temp.: Incubator Reference:

(2) Incubation date: Examination date: Incubation Temp.: Incubator Reference:

Batch N°

(1) Incubation date: Examination date: Incubation Temp.: Incubator Reference:

(2) Incubation date: Examination date: Incubation Temp.: Incubator Reference:

Batch N°

(1) Incubation date: Examination date: Incubation Temp.: Incubator Reference:

(2) Incubation date: Examination date: Incubation Temp.: Incubator Reference:

With product Without product With product Without product With product Without product (1) Mossel Broth Growth: Growth: Growth: Growth: Growth: Growth:

(2) Violet Red Bile Glucose Agar

Colonies description:

Colonies description:

Colonies description:

Colonies description: Colonies description:

Colonies description:

Gram stain Identification Method Ref.:

Result: Profile Ref.:

Method Ref.: Result: Profile Ref.:

Method Ref.: Result: Profile Ref.:

Method Ref.: Result: Profile Ref.:

Method Ref.: Result: Profile Ref.:

Method Ref.: Result: Profile Ref.:

Conclusion Conform / Not conform

Click to edit Master title style Bile Tolerant Gram Negative Bacteria Quantitative Test

Confidential for restricted use only

Bile Tolerant Gram - Bacteria

Click to edit Master title style Staphylococcus aureus

Staphylococcus aureus

Dosage Form ICH Q4b Ch. P.

Oral Solid No No

Oral Liquid No No

Oromucusal, Gingival, Nasal use

Absence in 1g

Absence in 1g

Cutaneous, Auricular use

Absence in 1g

Absence in 1g

Inhalation use Absence in 1g

Absence in 1g

Rectal use No Yes

Vaginal use Absence in 1g

Absence in 1g

Click to edit Master title style Staphylococcus aureus

Confidential for restricted use only

Test for Staphylococcus aureus Media and Tests

Batch N°

(1) Incubation date: Examination date: Incubation Temp.: Incubator Reference:

(2) Incubation date: Examination date: Incubation Temp.: Incubator Reference:

Batch N°

(1) Incubation date: Examination date: Incubation Temp.: Incubator Reference:

(2) Incubation date: Examination date: Incubation Temp.: Incubator Reference:

Batch N°

(1) Incubation date: Examination date: Incubation Temp.: Incubator Reference:

(2) Incubation date: Examination date: Incubation Temp.: Incubator Reference:

With product Without product With product Without product With product Without product

(1) CSB Growth: Growth: Growth: Growth: Growth: Growth: (2) Mannitol agar Colonies

description: Colonies description:

Colonies description:

Colonies description: Colonies description:

Colonies description:

Gram stain Identification Method Ref.:

Result: Profile Ref.:

Method Ref.: Result: Profile Ref.:

Method Ref.: Result: Profile Ref.:

Method Ref.: Result: Profile Ref.:

Method Ref.: Result: Profile Ref.:

Method Ref.: Result: Profile Ref.:

Conclusion Conform / Not conform

Click to edit Master title style Pseudomonas aeruginosa

Pseudomonas aeruginosa

Dosage Form ICH Q4b Ch. P.

Oral Solid No No

Oral Liquid No No

Oromucusal, Gingival, Nasal use

Absence in 1g

Absence in 1g

Cutaneous, Auricular use

Absence in 1g

Absence in 1g

Inhalation use Absence in 1g

Absence in 1g

Rectal use No Yes

Vaginal use Absence in 1g

Absence in 1g

Click to edit Master title style Pseudomonas aeruginosa

Confidential for restricted use only

Test for Pseudomonas aeruginosa Media and Tests

Batch N°

(1) Incubation date: Examination date: Incubation Temp.: Incubator Reference:

(2) Incubation date: Examination date: Incubation Temp.: Incubator Reference:

Batch N°

(1) Incubation date: Examination date: Incubation Temp.: Incubator Reference:

(2) Incubation date: Examination date: Incubation Temp.: Incubator Reference:

Batch N°

(1) Incubation date: Examination date: Incubation Temp.: Incubator Reference:

(2) Incubation date: Examination date: Incubation Temp.: Incubator Reference:

With product Without product With product Without product With product Without product

(1) CSB Growth: Growth: Growth: Growth: Growth: Growth: (2) Cetrimide agar

Colonies description:

Colonies description:

Colonies description:

Colonies description: Colonies description:

Colonies description:

Gram stain Identification Method Ref.:

Result: Profile Ref.:

Method Ref.: Result: Profile Ref.:

Method Ref.: Result: Profile Ref.:

Method Ref.: Result: Profile Ref.:

Method Ref.: Result: Profile Ref.:

Method Ref.: Result: Profile Ref.:

Conclusion Conform / Not conform

Click to edit Master title style Escherichia coli

Escherichia coli

Dosage Form ICH Q4b Ch. P.

Oral Solid Absence in 1g

Absence in 1g

Oral Liquid Absence in 1g

Absence in 1g

Oromucusal, Gingival, Nasal use No Yes

Cutaneous, Auricular use No No

Inhalation use No Yes

Rectal use No No

Vaginal use No No

Click to edit Master title style Escherichia coli

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Test for Escherichia coli Media and Tests

Batch N°

(1) Incubation date: Examination date: Incubation Temp.: Incubator Reference:

(2) Incubation date: Examination date: Incubation Temp.: Incubator Reference:

(3) Incubation date: Examination date: Incubation Temp.: Incubator Reference:

Batch N°

(1) Incubation date: Examination date: Incubation Temp.: Incubator Reference:

(2) Incubation date: Examination date: Incubation Temp.: Incubator Reference:

(3) Incubation date: Examination date: Incubation Temp.: Incubator Reference:

Batch N°

(1) Incubation date: Examination date: Incubation Temp.: Incubator Reference:

(2) Incubation date: Examination date: Incubation Temp.: Incubator Reference:

(3) Incubation date: Examination date: Incubation Temp.: Incubator Reference:

With product Without product

With product Without product

With product Without product

(1) CSB Growth: Growth: Growth: Growth: Growth: Growth: (2) MacConkey Broth

Growth: Growth: Growth: Growth: Growth: Growth:

(3) MacConkey agar

Colonies description:

Colonies description:

Colonies description:

Colonies description:

Colonies description:

Colonies description:

Gram stain Identification Method Ref.:

Result: Profile Ref.:

Method Ref.: Result: Profile Ref.:

Method Ref.: Result: Profile Ref.:

Method Ref.: Result: Profile Ref.:

Method Ref.: Result: Profile Ref.:

Method Ref.: Result: Profile Ref.:

Conclusion Conform / Not conform

Click to edit Master title style Candida albicans

Candida albicans

Dosage Form ICH Q4b Ch. P.

Oral Solid No No

Oral Liquid No No

Oromucusal, Gingival, Nasal use No No

Cutaneous, Auricular use No No

Inhalation use No No

Rectal use No No

Vaginal use Absence in 1g

Absence in 1g

Click to edit Master title style Candida albicans

Confidential for restricted use only

Test for Candida albicans Media and Tests

Batch N°

(1) Incubation date: Examination date: Incubation Temp.: Incubator Reference:

(2) Incubation date: Examination date: Incubation Temp.: Incubator Reference:

Batch N°

(1) Incubation date: Examination date: Incubation Temp.: Incubator Reference:

(2) Incubation date: Examination date: Incubation Temp.: Incubator Reference:

Batch N°

(1) Incubation date: Examination date: Incubation Temp.: Incubator Reference:

(2) Incubation date: Examination date: Incubation Temp.: Incubator Reference:

With product Without product With product Without product With product Without product

(1) Sabouraud Dextrose Broth

Growth: Growth: Growth: Growth: Growth: Growth:

(2) Sabouraud Dextrose agar

Colonies description:

Colonies description: Colonies description:

Colonies description: Colonies description:

Colonies description:

Gram stain Identification Method Ref.:

Result: Profile Ref.:

Method Ref.: Result: Profile Ref.:

Method Ref.: Result: Profile Ref.:

Method Ref.: Result: Profile Ref.:

Method Ref.: Result: Profile Ref.:

Method Ref.: Result: Profile Ref.:

Conclusion Conform / Not conform

Click to edit Master title style Salmonelle spp.

Salmonella spp.

Dosage Form ICH Q4b Ch. P.

Oral Solid No No

Oral Liquid No No

Oromucusal, Gingival, Nasal use No No

Cutaneous, Auricular use No No

Inhalation use No No

Rectal use No No

Vaginal use No No

Dosage Form ICH Q4b Ch. P.

Preparation containing raw material of natural origin

Absence in 10g

Absence in 10g

Click to edit Master title style Salmonelle spp.

Confidential for restricted use only

Test for Salmonelle spp. Media and Tests

Batch N°

(1) Incubation date: Examination date: Incubation Temp.: Incubator Reference:

(2) Incubation date: Examination date: Incubation Temp.: Incubator Reference:

(3) Incubation date: Examination date: Incubation Temp.: Incubator Reference:

Batch N°

(1) Incubation date: Examination date: Incubation Temp.: Incubator Reference:

(2) Incubation date: Examination date: Incubation Temp.: Incubator Reference:

(3) Incubation date: Examination date: Incubation Temp.: Incubator Reference:

Batch N°

(1) Incubation date: Examination date: Incubation Temp.: Incubator Reference:

(2) Incubation date: Examination date: Incubation Temp.: Incubator Reference:

(3) Incubation date: Examination date: Incubation Temp.: Incubator Reference:

With product Without product With product Without product

With product Without product

(1) CSB Growth: Growth: Growth: Growth: Growth: Growth: (2) Rappaport Vassiliadis Salmonella Broth

Growth: Growth: Growth: Growth: Growth: Growth:

(3) XLD agar Colonies description:

Colonies description:

Colonies description:

Colonies description: Colonies description:

Colonies description:

Gram stain Identification Method Ref.:

Result: Profile Ref.:

Method Ref.: Result: Profile Ref.:

Method Ref.: Result: Profile Ref.:

Method Ref.: Result: Profile Ref.:

Method Ref.: Result: Profile Ref.:

Method Ref.: Result: Profile Ref.:

Conclusion Conform / Not conform

Click to edit Master title style Objectionable Microorganisms?

USP<1111>: «Table 1 includes a list of specified microorganisms for which acceptance criteria are set. The list is not necessarily exhaustive, and for a given preparation it may be necessary to test for other microorganisms depending on the nature of the starting materials and the manufacturing process.» CP 1107: «The specified microorganisms listed in Tables above are not necessarily exhaustive. Thus, raw material, excipients and some special preparations may be necessary to control other potential hazardous microbes depending on nature, usage, manufacturing process and so on.»

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Click to edit Master title style Objectionable Microorganisms?

USP<1111>: «In addition to the microorganisms listed in Table I, the significance of other microorganisms recovered should be evaluated in terms of the following:

• The use of the product: hazard varies according to the route of administration (eye, nose, respiratory tract).

• The nature of the product: – Does the product support growth? – Does it have adequate antimicrobial preservation?

• The method of application. • The intended recipient: risk may differ for neonates,

infants, the debilitated. • Use of immunosuppressive agents, corticosteroids. • The presence of disease, wounds, organ damage.»

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Click to edit Master title style Objectionable Microorganisms?

CP 1107: «In addition to the specified microorganisms required above, the significance of other microorganisms recovered should be evaluated in terms of the following:

• Administration route, hazards vary according to the route of administration,

• The nature of the product: – Whether the product supports growth? – Whether it has adequate antimicrobial preservation,

• The use of the product, • The intended recipient, risk may differ for neonates,

infants, the debilitated, • Use of immunosuppressive agents, corticosteroids. • The presence of disease, wounds, organ damage, and

so on.»

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Click to edit Master title style Objectionable Microorganisms? Examples of recalls with presence of « OTHER MICROORGANISMS »

(FDA – Review of recalls 2004-11 for non-sterile products Objectionable microorganisms):

Examples of Objectionable Microorganisms:

– Burkholderia cepacia complex known to induce respiratory infection in persons with cystic fibrosis & chronic granulomatous disease.

– Pseudomonads that can proliferate in the presence of common antimicrobial preservatives in a topical cream, nasal spray or oral liquid.

– Molds that can grow on the surface of tablets if exposed/stored to high humidity environment.

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34

21 15

11

9 5 4 1 Recall (%) Burkholderia cepacia

Fungi

Other Pseudomonads

Enterobacteiaceae

Bacillus cereus

Click to edit Master title style Objectionable Microorganisms?

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Non Sterile Products

Objectionable Microorganisms

Microorganisms of Concern

Product / Process Risk Evaluation •Product Characteristics • Route of Administration •Microbial growth

inhibition (Yes/No)

Microorganism Risk Evaluation •Habitat / Origin •Pathogenicity •Growth conditions •Susceptibility to

products / disinfectants •Population

Patient Risk Evaluation •Microbial risk factors •Infection risk evaluation •Patient category

• Total Number of Organisms 1

• Microorganism’s Characteristics 2

• Product’s Characteristics 3

• Route of Administration 4

• Potential Impact on Patients 5

Click to edit Master title style Objectionable Microorganisms?

Point of interest: Objectionable Microorganisms should be considered in the control strategy for non-sterile product including validation of the methods (TAMC / TYMC / or Specific Tests).

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Click to edit Master title style

Confidential for restricted use only

Thank you

Click to edit Master title style

微生物限度方法适用性确认及致病菌控制考虑要点

方法适用性确认

Confidential for restricted use only

Benoît RAMOND (Sanofi)

Click to edit Master title style 法规介绍

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药典

各论

•协调一致的章节(EP/USP/JP)

•中国药典

比较

•中国药典Vs. 协调一致的章节

测试性能的影响

•协调一致的章节(EP/USP/JP)

•中国药典

协调一致的章节– ICH Q4b

ICH Q4b 中国药典 共性 Major Difference

USP<62>

EP 2.6.13

JP 4.05

第二部分

1106 – 非无菌产品微生物限度检查：控制菌检查法

两者都描述了大肠杆菌，金黄色葡萄球菌，铜绿假单胞菌，白色念珠菌，沙门氏菌属和耐胆盐革兰阴性菌的测试

使用三糖铁琼脂作为沙门氏菌的指示剂（ChP），

使用假丝酵母生色琼脂作为白色念珠菌的指示（ChP)

微生物限度测试

Click to edit Master title style 法规介绍

• 用于病原体（特定微生物）的微生物测试方法在药典要求如下：

– 测试耐胆盐革兰氏阴性菌

– 测试白色念珠菌

– 测试梭菌

– 测试大肠埃希菌

– 测试铜绿假单胞菌

– 测试沙门氏菌

– 测试金黄色葡萄球菌

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Click to edit Master title style 耐胆盐革兰阴性菌定性试验

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耐胆盐革兰氏阴性菌 – 细菌

剂型 ICH Q4b Ch. P.

口服固体制剂 No No

口服液体制剂 No No

口腔黏膜、齿龈、 鼻腔给药

No No

耳用制剂 皮肤给药制剂

No No

吸入给药 Absence

in 1g Absence

in 1g

直肠给药 No No

阴道给药 No No

Click to edit Master title style 耐胆盐革兰阴性菌定性试验

Confidential for restricted use only

耐胆盐革兰氏阴性菌的检验 - 定性 培养和测试

批次 N°

(1) 培养时间: 检测时间: 培养温度： 恒温箱编号:

(2) 培养时间: 检测时间: 培养温度： 恒温箱编号:

批次 N°

(1) 培养时间: 检测时间: 培养温度： 恒温箱编号:

(2) 培养时间: 检测时间: 培养温度: 恒温箱编号:

批次 N°

(1) 培养时间: 检测时间: 培养温度: 恒温箱编号:

(2) 培养时间: 检测时间: 培养温度: 恒温箱编号:

有产品 没有产品 有产品 没有产品 有产品 没有产品

(1) 培养基

生长: 生长: 生长: 生长: 生长: 生长:

(2) 紫红

胆盐葡萄糖琼脂

菌落描述: 菌落描述: 菌落描述: 菌落描述: 菌落描述: 菌落描述:

革兰氏染色

鉴定 方法编号：

结果:

参考编号：

方法编号：

结果:

参考编号：

方法编号：

结果:

参考编号：

方法编号：

结果:

参考编号：

方法编号：

结果:

参考编号：

方法编号：

结果:

参考编号：

结论 符合/不符合

Click to edit Master title style 耐胆盐革兰阴性菌定量试验

Confidential for restricted use only

耐胆盐革兰氏阴性菌 – 细菌

Click to edit Master title style 金黄色葡萄球菌

金黄色葡萄球菌

剂型 ICH Q4b Ch. P.

口服固体制剂 No No

口服液体制剂 No No

口腔黏膜、齿龈、 鼻腔给药

Absence in 1g

Absence in 1g

耳用制剂 皮肤给药制剂

Absence in 1g

Absence in 1g

吸入给药 Absence

in 1g Absence

in 1g

直肠给药 No Yes

阴道给药 Absence

in 1g Absence

in 1g

Click to edit Master title style 金黄色葡萄球菌

Confidential for restricted use only

金黄色葡萄球菌的检验 培养和测试

批次 N°

(1) 培养时间: 检测时间: 培养温度： 恒温箱编号:

(2) 培养时间: 检测时间: 培养温度： 恒温箱编号:

批次 N°

(1) 培养时间: 检测时间: 培养温度： 恒温箱编号:

(2) 培养时间: 检测时间: 培养温度： 恒温箱编号:

批次 N°

(1) 培养时间: 检测时间: 培养温度： 恒温箱编号:

(2) 培养时间: 检测时间: 培养温度： 恒温箱编号:

有产品 没有产品 有产品 没有产品 有产品 没有产品

(1) CSB 生长: 生长: 生长: 生长: 生长: 生长:

(2) 甘露醇琼脂 菌落描述: 菌落描述: 菌落描述: 菌落描述: 菌落描述: 菌落描述:

革兰氏染色

鉴定 方法编号：

结果:

参考编号：

方法编号：

结果:

参考编号：

方法编号：

结果:

参考编号：

方法编号：

结果:

参考编号：

方法编号：

结果:

参考编号：

方法编号：

结果:

参考编号：

结论 符合/不符合

Click to edit Master title style 铜绿假单胞菌

铜绿假单胞菌

剂型 ICH Q4b Ch. P.

口服固体制剂 No No

口服液体制剂 No No

口腔黏膜、齿龈、 鼻腔给药

Absence in 1g

Absence in 1g

耳用制剂 皮肤给药制剂

Absence in 1g

Absence in 1g

吸入给药 Absence

in 1g Absence

in 1g

直肠给药 No Yes

阴道给药 Absence

in 1g Absence

in 1g

Click to edit Master title style 铜绿假单胞菌

Confidential for restricted use only

铜绿假单胞菌的检验 培养和测试

批次 N°

(1) 培养时间: 检测时间: 培养温度： 恒温箱编号:

(2) 培养时间: 检测时间: 培养温度： 恒温箱编号:

批次 N°

(1) 培养时间: 检测时间: 培养温度： 恒温箱编号:

(2) 培养时间: 检测时间: 培养温度： 恒温箱编号:

批次 N°

(1) 培养时间: 检测时间: 培养温度： 恒温箱编号:

(2) 培养时间: 检测时间: 培养温度： 恒温箱编号:

有产品 没有产品 有产品 没有产品 有产品 没有产品

(1) CSB 生长: 生长: 生长: 生长: 生长: 生长:

(2) 溴化十六烷

基三甲铵琼脂培养基

菌落描述: 菌落描述: 菌落描述: 菌落描述: 菌落描述: 菌落描述:

革兰氏染色

鉴定 方法编号：

结果:

参考编号：

方法编号：

结果:

参考编号：

方法编号：

结果:

参考编号：

方法编号：

结果:

参考编号：

方法编号：

结果:

参考编号：

方法编号：

结果:

参考编号：

结论 符合/不符合

Click to edit Master title style 大肠埃希菌

大肠埃希菌

剂型 ICH Q4b Ch. P.

口服固体制剂 Absence

in 1g Absence

in 1g

口服液体制剂 Absence

in 1g Absence

in 1g

口腔黏膜、齿龈、 鼻腔给药

No Yes

耳用制剂 皮肤给药制剂

No No

吸入给药 No Yes

直肠给药 No No

阴道给药 No No

Click to edit Master title style 大肠埃希菌

Confidential for restricted use only

大肠埃希菌的检验 培养和测试

批次 N°

(1) 培养时间: 检测时间: 培养温度： 恒温箱编号:

(2) 培养时间: 检测时间: 培养温度： 恒温箱编号:

批次 N°

(1) 培养时间: 检测时间: 培养温度： 恒温箱编号:

(2) 培养时间: 检测时间: 培养温度： 恒温箱编号:

批次 N°

(1) 培养时间: 检测时间: 培养温度： 恒温箱编号:

(2) 培养时间: 检测时间: 培养温度： 恒温箱编号:

有产品 没有产品 有产品 没有产品 有产品 没有产品

(1) CSB 生长: 生长: 生长: 生长: 生长: 生长:

(2) 麦康凯液体培养基

生长: 生长: 生长: 生长: 生长: 生长:

(3) 麦康凯琼脂培养基

菌落描述: 菌落描述: 菌落描述: 菌落描述: 菌落描述: 菌落描述:

革兰氏染色

鉴定 方法编号：

结果:

参考编号：

方法编号：

结果:

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方法编号：

结果:

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方法编号：

结果:

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结果:

参考编号：

方法编号：

结果:

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结论 符合/不符合

Click to edit Master title style 白色念珠菌

白色念珠菌

剂型 ICH Q4b Ch. P.

口服固体制剂 No No

口服液体制剂 No No

口腔黏膜、齿龈、 鼻腔给药

No No

耳用制剂 皮肤给药制剂

No No

吸入给药 No No

直肠给药 No No

阴道给药 Absence

in 1g Absence

in 1g

Click to edit Master title style 白色念珠菌

Confidential for restricted use only

白色念珠菌的检验 培养和测试

批次 N°

(1) 培养时间: 检测时间: 培养温度： 恒温箱编号:

(2) 培养时间: 检测时间: 培养温度： 恒温箱编号:

批次 N°

(1) 培养时间: 检测时间: 培养温度： 恒温箱编号:

(2) 培养时间: 检测时间: 培养温度: 恒温箱编号:

批次 N°

(1) 培养时间: 检测时间: 培养温度: 恒温箱编号:

(2) 培养时间: 检测时间: 培养温度: 恒温箱编号:

有产品 没有产品 有产品 没有产品 有产品 没有产品

(1) 沙氏葡萄糖液体培养基

生长: 生长: 生长: 生长: 生长: 生长:

(2) 沙氏葡萄糖琼脂培养基

菌落描述: 菌落描述: 菌落描述: 菌落描述: 菌落描述: 菌落描述:

革兰氏染色

鉴定 方法编号：

结果:

参考编号：

方法编号：

结果:

参考编号：

方法编号：

结果:

参考编号：

方法编号：

结果:

参考编号：

方法编号：

结果:

参考编号：

方法编号：

结果:

参考编号：

结论 符合/不符合

Click to edit Master title style 沙门菌

沙门菌

剂型 ICH Q4b Ch. P.

口服固体制剂 No No

口服液体制剂 No No

口腔黏膜、齿龈、 鼻腔给药

No No

耳用制剂 皮肤给药制剂

No No

吸入给药 No No

直肠给药 No No

阴道给药 No No

剂型 ICH Q4b Ch. P.

含有天然来源原料的制剂

Absence in 10g

Absence in 10g

Click to edit Master title style 沙门菌

Confidential for restricted use only

沙门菌的检测 培养和测试

批次 N°

(1) 培养时间: 检测时间: 培养温度： 恒温箱编号:

(2) 培养时间: 检测时间: 培养温度： 恒温箱编号:

批次 N°

(1) 培养时间: 检测时间: 培养温度： 恒温箱编号:

(2) 培养时间: 检测时间: 培养温度： 恒温箱编号:

批次 N°

(1) 培养时间: 检测时间: 培养温度： 恒温箱编号:

(2) 培养时间: 检测时间: 培养温度： 恒温箱编号:

有产品 没有产品 有产品 没有产品 有产品 没有产品

(1) CSB 生长: 生长: 生长: 生长: 生长: 生长:

(2) RV沙门菌增菌液体培养基

生长: 生长: 生长: 生长: 生长: 生长:

(3) 木糖赖氨酸

脱氧胆酸盐琼脂培养基

菌落描述: 菌落描述: 菌落描述: 菌落描述: 菌落描述: 菌落描述:

革兰氏染色

鉴定 方法编号：

结果:

参考编号：

方法编号：

结果:

参考编号：

方法编号：

结果:

参考编号：

方法编号：

结果:

参考编号：

方法编号：

结果:

参考编号：

方法编号：

结果:

参考编号：

结论 符合/不符合

Click to edit Master title style 致病菌？

USP<1111>:

«表1列出了控制菌所设立的接收标准。该清单不一定穷举。另外，对于给定的制剂，可能需要根据起始物料的性质和生产过程来测试其他微生物菌。»

CP 1107:

«上表中列出的控制菌不一定是穷举。 因此，根据性质，用途，生产过程等，可能需要原料，辅料和一些特殊制剂来控制其他潜在的有害微生物菌。»

Confidential for restricted use only

Click to edit Master title style 致病菌？

USP<1111>:

«除了表1列出的控制菌外，药品中若检出其他可能具有潜在危害性微生物，应从以下方面进行评估：

• 产品的使用：给药途径不同，其危害不同 （眼，鼻，呼吸道）

• 产品的特性：

– 药品是否促进微生物生长？

– 药品是否有足够的抑制微生物生长能力？

• 药品的使用的方法

• 用药人群：用药人群不同，如新生儿、婴儿及体弱者，疯险可能不同

• 患者使用免疫抑制剂和甾体类固醇激素等药品的情况

• 存在疾病、伤残和器官损伤等等

Confidential for restricted use only

Click to edit Master title style 致病菌？

CP 1107:

«除了列出的控制菌外，药品中若检出其他可能具有潜在危害性微生物，应从以下方面进行评估：

• 产品的使用：给药途径不同，其危害不同

• 产品的特性：

– 药品是否促进微生物生长？

– 药品是否有足够的抑制微生物生长能力？

• 药品的使用的方法

• 用药人群：用药人群不同，如新生儿、婴儿及体弱者，疯险可能不同

• 患者使用免疫抑制剂和甾体类固醇激素等药品的情况

• 存在疾病、伤残和器官损伤等等

Confidential for restricted use only

Click to edit Master title style 致病菌？

存在《其他微生物菌》的召回事例

(FDA – 对于非无菌药品

致病菌2014-11的回顾):

致病菌的举例:

– 洋葱伯克霍尔德菌群可引起囊性纤维化和慢性肉芽肿病患者的呼吸道感染

– 假单胞菌可以在常见的抗菌防腐剂存在下在局部乳膏、鼻喷雾剂或口服液中增殖

– 如果暴露/储存在高湿温度环境中，霉菌可在片剂表面生长

Confidential for restricted use only

34

21 15

11

9 5 4 1

召回 (%) Burkholderia cepacia

Fungi

Other Pseudomonads

Enterobacteiaceae

Bacillus cereus

Click to edit Master title style 致病菌？

Confidential for restricted use only

非无菌产品

致病菌

微生物菌的关注

产品 / 风险流程评估

•产品特性

•给药方式

•微生物生长

•抑制 (是/否)

微生物风险评估

•来源/ 起源

•致病性

•生长条件

•对产品/消毒剂的敏感性

•人口

患者风险评估

•微生物危害因素

•感染风险评估

•患者类别

• 生物总数 1

• 微生物的特性 2

• 产品特点 3

• 给药路径 4

• 对患者的潜在影响 5

Click to edit Master title style 致病菌？

兴趣点：

在非灭菌产品的控制策略中应考虑致病菌，包括方法验证

（总需氧微生物数量/总酵母和霉菌数量/或特定测试）

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Confidential for restricted use only

谢谢