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X. RETURNED DRUG PRODUCTS (21 CFR 211, SUBPART K)

X. RETURNED DRUG PRODUCTS (21 CFR 211, SUBPART K)

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12



Handbook of Pharmaceutical Manufacturing Formulations: Over-the-Counter Products



APPENDIX: GMP Audit Template, EU Guidelines

(http://pharmacos.eudora.org/F2/eudoralex/vol-4/home.html)

Compliance

1 2 3*



Remarks



EU-Guide



1



PERSONNEL



1.1



Qualified personnel available?



□□□



2.1



1.2



Organisation charts available?



□□□



2.2



1.3



Job descriptions available?



□□□



2.2



1.4



Responsibilities clearly defined?



□□□



2.2



Key personnel

Responsible persons designated for:

1.5



• Production?



□□□



2.5



1.6



• Quality control?



□□□



2.6



1.7



Are they independent from each other?



□□□



2.3



1.8



Are joint functions clearly defined?



□□□



2.7



1.9



Are the responsible persons working full time?



□□□



2.3



1.10



Have the responsible persons the appropriate formation, knowledge and

experience?



□□□



2.1/2.2



1.11



Have the relevant departments enough personnel?



□□□



2.1



Training

1.12



Continuous training programmes for the production and QC staff?



□□□



2.8



1.13



Initial job training for all employees?



□□□



2.9



1.14



Teaching aids (videos, slides, brochures) available?



□□□



2.9



1.15



External training courses for the staff?



□□□



2.9



1.16



Training records?



□□□



2.9



1.17



Special training in sensitive areas? (sterile prod., toxic subs.)



□□□



2.10



1.18



Information for visitors to the manufacturing area?



□□□



2.11



2



HYGIENE

Personnel Hygiene

Detailed written hygiene programmes for:



2.1



• clothing?



□□□



2.13



2.2



• use of washrooms?



□□□



2.13



2.3



• behaviour in production areas?



□□□



2.13



□□□



2.14



2.4



Precautions against sick or personnel with open wounds in production?

Medical examination:



2.5



• on recruitment?



□□□



2.15



2.6



• regular re-examinations?



□□□



2.15



* 1. Fulfilled or available; 2. partially fulfilled; 3. not fulfilled or not available.



© 2004 by CRC Press LLC



Good Manufacturing Practices in Over-the-Counter Drug Product Manufacturing



Compliance

1 2 3*



13



Remarks



EU-Guide



Duty of notification after:

2.7



• trips to tropical countries?



□□□



2.15



2.8



• cases of contagious illness in the family?



□□□



2.15



2.9



Instructions for appropriate working clothes?



□□□



2.16



2.10



Absence of food and drinks (chewing gum!) in the working area?



□□□



2.17



2.11



Measures against contact with open product (gloves etc.)?



□□□



2.18



2.12



Instructions for hand washing in production?



□□□



2.19



2.13



Change of clothes when entering and leaving the production area?



□□□



5.19



2.14



Change rooms and toilets easily within reach?



□□□



3.31



2.15



Toilets and restrooms sufficiently separated from production areas?



□□□



3.30/3.31



2.16



Work shops separate from production areas?



□□□



3.32



2.17



Laboratory animal rooms totally segregated from production rooms?



□□□



3.33



3



WAREHOUSE



□□□



3



Rooms, general:

3.1



Suitable for the intended use?



3.2



• adequate size?



□□□



3



3.3



• clean?



□□□



3



3.4



Located and designed to exclude external contamination?



□□□



3.1



3.5



Appropriate level of maintenance?



□□□



3.2



3.6



Maintenance works possible without contamination risk?



□□□



3.2



3.7



Appropriate lighting and air conditioning?



□□□



3.3



3.8



Recording of temperature and humidity?



□□□



3.9



Protection against the entry of insects or other animals?



□□□



3.4



3.10



Controlled access for authorised personnel only?



□□□



3.5



Rooms, special requirements

Type of warehousing:



.........



3.11



Separation of goods sufficient?



□□□



3.18



3.12



Provision for different storage temperatures?



□□□



3.19



3.13



Goods receiving zone weather protected?



□□□



3.20



3.14



Cleaning zone for incoming goods?



□□□



3.20



3.15



Separate quarantine area with controlled access?



□□□



3.21



3.16



Separate, protected sampling area?



□□□



3.22



Separate and safe storage of:

3.17



• returned goods?



□□□



3.23



3.18



• rejected goods?



□□□



3.23



* 1. Fulfilled or available; 2. partially fulfilled; 3. not fulfilled or not available.



© 2004 by CRC Press LLC



14



Handbook of Pharmaceutical Manufacturing Formulations: Over-the-Counter Products



Compliance

1 2 3*



Remarks



EU-Guide



3.19



Separate and safe storage of highly active, toxic or dangerous substances?



□□□



3.24



3.20



Safe storage of narcotics?



□□□



3.24



3.21



Safe storage of printed packaging materials?



□□□



3.25



3.22



Security measurements against theft?



□□□



3.25



3.23



Smoke detectors?



□□□



3.25



3.24



Fire extinguishing system?



□□□



3.25



Operations:

3.25



Reception, sampling and labelling according to written procedures?



□□□



5.2



3.26



Is a sampling plan available?



□□□



suppl. 4



3.27



Cleaning of incoming containers?



□□□



5.3



3.28



Investigation and recording of damaged deliveries?



□□□



5.4



3.29



FIFO principle?



□□□



5.7



3.30



Inventory system?



□□□



5.8



3.31



The location of materials can be detected at all times?



□□□



3.32



Incoming goods: containers and seals intact?



□□□



5.27



3.33



Incoming goods: conformity with bill of delivery?



□□□



5.27



Labelling of incoming containers with:

3.34



• internal name and code?



□□□



5.29



3.35



• allocated batch number?



□□□



5.29



3.36



• quarantine status?



□□□



5.29



3.37



• expiry date or re-analysis date?



□□□



5.29



3.38



Identity test for each incoming container?



□□□



5.29



3.39



Are the sampled containers marked?



□□□



5.30



3.40



Are reference samples taken?



□□□



5.30



3.41



Safe storage of printed packaging materials?



□□□



5.41



3.42



Lot tracing of all packaging materials possible?



□□□



5.42



3.43



Are excessive packaging materials destroyed?



□□□



5.43



Release of starting materials by:



.........



Physical/inventory checks on raw materials, packaging materials and finished goods:

Item:



Stocks: Physical:



Stocks: Inventory:



* 1. Fulfilled or available; 2. partially fulfilled; 3. not fulfilled or not available.



© 2004 by CRC Press LLC



Storage conditions:



Good Manufacturing Practices in Over-the-Counter Drug Product Manufacturing



Compliance

1 2 3*



4



15



Remarks



EU-Guide



DISPENSING/ASSEMBLING

Rooms, general:



4.1



Suitable for the intended use?



□□□



3



4.2



• adequate size?



□□□



3



4.3



• clean?



□□□



3



4.4



Located and designed to exclude external contamination?



□□□



3.1



4.5



Appropriate level of maintenance?



□□□



3.2



4.6



Maintenance works possible without contamination risk?



□□□



3.2



4.7



Appropriate lighting and air conditioning?



□□□



3.3



4.8



Recording of temperature and humidity?



□□□



4.9



Protection against the entry of insects or other animals?



□□□



3.4



4.10



Controlled access for authorised personnel only?



□□□



3.5



Rooms, special requirements:

4.11



Segregated from production and warehouse?



□□□



3.13



4.12



Separate weighing cabins?



□□□



3.13



4.13



Separate AHU for each cabin?



□□□



3.12



.........



3.3



□□□



5.11



Air pressure gradient from weighing cabin → corridor:

4.14



Dust extraction systems available?



Operations:

4.15



Balances regularly calibrated?



□□□



3.41



4.16



Only pharmaceutical raw materials in this area?



□□□



5.17



4.17



Check on remains from previous materials before entering of new materials

into a weighing cabin?



□□□



5.9/5.35



4.18



Only one material in one cabin?



□□□



5.9



4.19



Are dispensed materials correct labelled?



□□□



5.29



4.20



Only released products in the dispensing?



□□□



5.31



4.21



Cleaning SOP’s for the dispensing?



□□□



4.28



4.22



Previously dispensed material recorded on weighing protocol?



□□□



4.8



4.23



Safety measures against mix up’s during assembling (e.g. cage pallets)?



□□□



5.32/5.34



5



SOLIDS MANUFACTURING

Field of activity:

• Granulation







• Compression







• Encapsulation







• Film- and sugar coating







* 1. Fulfilled or available; 2. partially fulfilled; 3. not fulfilled or not available.



© 2004 by CRC Press LLC



16



Handbook of Pharmaceutical Manufacturing Formulations: Over-the-Counter Products



Compliance

1 2 3*

• Visual inspection (Capsules, tablets etc.)







• Premix (Human)







Remarks



EU-Guide



Rooms, general:

5.1



Suitable for the intended use?



□□□



3



5.2



• adequate size?



□□□



3



5.3



• clean?



□□□



3



5.4



Located and designed to exclude external contamination?



□□□



3.1



5.5



Appropriate level of maintenance?



□□□



3.2



5.6



Maintenance works possible without contamination risk?



□□□



3.2



5.7



Appropriate lighting and air conditioning?



□□□



3.3



5.8



Recording of temperature and humidity?



□□□



5.9



Protection against the entry of insects or other animals?



□□□



3.4



5.10



Controlled access for authorised personnel only?



□□□



3.5



Rooms, special requirements:

5.11



Separate manufacturing area for penicillins/cephalosporins or highly

sensitising substances?



□□□



3.6



5.12



Only for processing of pharmaceuticals?



□□□



3.6



5.13



Logical flow of materials?



□□□



3.7



5.14



Walls, floors and ceilings: smooth surface and free of cracks?



□□□



3.8



5.15



Easy cleaning possible?



□□□



3.10



5.16



Adequate drains with traps and grilles?



□□□



3.11



5.17



Appropriate air handling system?



□□□



3.12



Air pressure gradient from working bay → corridor:



.........



Classification according to EC guide?



.........



5.18



Appropriate dust extraction system?



□□□



3.14



5.19



Appropriate lighting?



□□□



3.16



5.20



Separate rest rooms?



□□□



3.30



5.21



Changing rooms designed to avoid contamination?



□□□



3.31



5.22



Toilets segregated from manufacturing areas?



□□□



3.31



Equipment

5.23



Suitable for the intended use?



□□□



3.34



5.24



Well maintained?



□□□



3.34



5.25



Written & validated cleaning procedures?



□□□



3.36



5.26



Maintenance without contamination risk (sep. area)?



□□□



3.35



5.27



Equipment in contact with product: suitable materials quality?



□□□



3.39



5.28



Machinery equipped with measuring and control devices?



□□□



3.40



* 1. Fulfilled or available; 2. partially fulfilled; 3. not fulfilled or not available.



© 2004 by CRC Press LLC



Good Manufacturing Practices in Over-the-Counter Drug Product Manufacturing



Compliance

1 2 3*



17



Remarks



EU-Guide



5.29



Calibration in fixed intervals acc. to written procedures?



□□□



3.41



5.30



Calibration records available?



□□□



3.41



5.31



Contents and flow direction marked on pipes?



□□□



3.42



5.32



Pipes for distilled and demineralized water regularly monitored and

sanitised?



□□□



3.43



5.33



Not functioning equipment in the production area (if yes: clearly marked)?



Y



3.44



N



□□□

5.34



Status of cleanliness indicated?



□□□



5.13



5.35



Previous product indicated?



□□□



5.13



Operations

5.36



Are written and validated procedures for all manufacturing steps available?



□□□



5.2



5.37



Are all manufacturing steps recorded with actual parameters?



□□□



5.2



5.38



Check of each single container of the starting materials (contents, weight,

identity)?



□□□



5.3



5.39



Limits for yields?



□□□



5.8



5.40



Only one batch of one product processed?



□□□



5.9



5.41



Protection against microbial contamination?



□□□



5.10



5.42



Appropriate measures against generation of dust (e.g. closed systems)?



□□□



5.11



Correct labelling of containers, materials, equipment and rooms with:



5.12



5.43



• product name and batch no.



□□□



5.12



5.44



• quarantine status?



□□□



5.12



5.45



Deviations from standard procedures recorded and signed by the supervisor?



□□□



5.14



5.46



Special procedures for the production of antibiotics, hormones etc.?



□□□



5.19



5.47



• Campaign production?



□□□



5.19



5.48



• Special monitoring?



□□□



5.19



5.49



• Validated decontamination procedure?



□□□



5.19



5.50



Double check on weight?



□□□



5.34



5.51



Line clearance before start of production?



□□□



5.35



5.52



Investigation of deviations in yields?



□□□



5.39



5.53



Validated procedures for reworking of rejected batches?



□□□



5.62



5.54



Detailed procedures for the addition of previous batches?



□□□



5.63



5.55



Special release procedure (QA) for those batches?



□□□



5.64



5.56



Use of protective clothing (hair cover, shoes, masks, gloves)?



□□□



2.16



5.57



Clothing regulation for visitors?



□□□



2.11

5.38



IPC

Who performs IPC?

5.58



Are IPC methods approved by QC?



* 1. Fulfilled or available; 2. partially fulfilled; 3. not fulfilled or not available.



© 2004 by CRC Press LLC



.........

□□□



6.18



18



Handbook of Pharmaceutical Manufacturing Formulations: Over-the-Counter Products



Compliance

1 2 3*

Performance of IPCs:



During

Start-up?



Yes



Remarks



EU-Guide



Frequency Automatic

data

recording?



No



Yes



No



Tablets/Kernels

5.59



Individual weights



□□□



........



□□□



5.60



Disintegration



□□□



........



□□□



5.61



Thickness



□□□



........



□□□



5.62



Hardness



□□□



........



□□□



5.63



Friability/Abrasion



□□□



........



□□□



Sugar/Film coated tablets

5.64



Weights



□□□



........



□□□



5.65



Disintegration



□□□



........



□□□



5.66



Residual absolute humidity (IR or . . . . . . . .)



□□□



........



□□□



Capsules

5.67



Individual weights



□□□



........



□□□



5.68



Disintegration



□□□



........



□□□



Validation

5.69



Validation according to fixed procedures?



□□□



5.21



5.70



New procedures released only after validation?



□□□



5.22



Validation of changes of:

5.71



• processes?



□□□



5.23



5.72



• starting materials?



□□□



5.23



5.73



• equipment?



□□□



5.23

5.24



5.74



Revalidation in fixed intervals?



□□□



5.75



Procedures for the retrospective validation of old procedures?



□□□



6



LIQUIDS MANUFACTURING

Operations carried out:

• Dispensing (if different from solid)



□□□



• Syrups and suspensions



□□□



• Drops



□□□



• Ointment manufacture



□□□



• Ointment filling



□□□



• Ampoule solution manufacture



□□□



• Sterile or aseptic ampoule filling



□□□



* 1. Fulfilled or available; 2. partially fulfilled; 3. not fulfilled or not available.



© 2004 by CRC Press LLC



Good Manufacturing Practices in Over-the-Counter Drug Product Manufacturing



Compliance

1 2 3*

• Sterile freeze drying



□□□



• Sterile powder filling



□□□



19



Remarks



EU-Guide



Rooms, general:

6.1



Suitable for the intended use?



□□□



3



6.2



• adequate size?



□□□



3



6.3



• clean?



□□□



3



6.4



Located and designed to exclude external contamination?



□□□



3.1



6.5



Appropriate level of maintenance?



□□□



3.2



6.6



Maintenance works possible without contamination risk?



□□□



3.2



6.7



Appropriate lighting and air conditioning?



□□□



3.3



6.8



Recording of temperature and humidity?



□□□



6.9



Protection against the entry of insects or other animals?



□□□



3.4



6.10



Controlled access for authorised personnel only?



□□□



3.5



Rooms, special requirements:

6.11



Separate manufacturing area for penicillins/cephalosporins or highly

sensitising substances?



□□□



3.6



6.12



Only for processing of pharmaceuticals?



□□□



3.6



6.13



Logical flow of materials?



□□□



3.7



6.14



Walls, floors and ceilings: smooth surface and free of cracks?



□□□



3.8



6.15



Easy cleaning possible?



□□□



3.10



6.16



Adequate drains with traps and grilles?



□□□



3.11



6.17



Appropriate air handling system with filtered air where open products are

exposed to the environment?



□□□



3.12



Air pressure gradient from working bay → corridor:



.........



Classification according to EC guide?



.........



6.18



Appropriate lighting?



□□□



3.16



6.19



Separate rest rooms?



□□□



3.30



6.20



Changing rooms designed to avoid contamination?



□□□



3.31



6.21



Toilets segregated from manufacturing areas?



□□□



3.31



Equipment

6.22



Suitable for the intended use?



□□□



3.34



6.23



Well maintained?



□□□



3.34



6.24



Tanks, containers, pipework and pumps designed for easy cleaning and

sanitation (dead legs!)?



□□□



Suppl. § 2



6.25



Written & validated cleaning procedures?



□□□



3.36



6.26



Maintenance without contamination risk (sep. area)?



□□□



3.35



6.27



Equipment in contact with product: suitable materials quality?



□□□



3.39



* 1. Fulfilled or available; 2. partially fulfilled; 3. not fulfilled or not available.



© 2004 by CRC Press LLC



20



Handbook of Pharmaceutical Manufacturing Formulations: Over-the-Counter Products



Compliance

1 2 3*



Remarks



EU-Guide



6.28



Machinery equipped with measuring and control devices?



□□□



3.40



6.29



Calibration in fixed intervals acc. to written procedures?



□□□



3.41



6.30



Calibration records available?



□□□



3.41



6.31



Contents and flow direction marked on pipes?



□□□



3.42



6.32



Pipes for distilled and demineralized water regularly monitored and

sanitised?



□□□



3.43



6.33



Not functioning equipment in the production area (if yes: clearly marked)?



Y



3.44



N



□□□

6.34



Status of cleanliness indicated?



□□□



5.13



6.35



Previous product indicated?



□□□



5.13



Operations

6.36



Are written and validated procedures for all manufacturing steps available?



□□□



5.2



6.37



Are all manufacturing steps recorded with actual parameters?



□□□



5.2



6.38



Check of each single container of the starting materials (contents, weight,

identity)?



□□□



5.3



6.39



Limits for yields?



□□□



5.8



6.40



Only one batch of one product processed?



□□□



5.9



6.41



Protection against microbial contamination?



□□□



5.10



Correct labelling of containers, materials, equipment and rooms with:



5.12



6.42



• product name and batch no.



□□□



5.12



6.43



• quarantine status?



□□□



5.12



6.44



Deviations from standard procedures recorded and signed by the supervisor?



□□□



5.14



6.45



Special procedures for the production of antibiotics, hormones, etc.?



□□□



5.19



6.46



• Campaign production?



□□□



5.19



6.47



• Special monitoring?



□□□



5.19



6.48



• Validated decontamination procedure?



□□□



5.19



6.49



Double check on weight?



□□□



5.34



6.50



Line clearance before start of production?



□□□



5.35



6.51



Investigation of deviations in yields?



□□□



5.39



6.52



Specification of max. storage time and storage conditions if products are not

immediately filled or packaged?



□□□



Suppl. § 9



6.53



Validated procedures for reworking of rejected batches?



□□□



5.62



6.54



Detailed procedures for the addition of previous batches?



□□□



5.63



6.55



Special release procedure (QA) for those batches?



□□□



5.64



6.56



Use of protective clothing (hair cover, shoes, masks, gloves)?



□□□



2.16



6.57



Clothing regulation for visitors?



□□□



2.11



□□□



Suppl. § 4



Water

6.58



Loop system for purified water?



* 1. Fulfilled or available; 2. partially fulfilled; 3. not fulfilled or not available.



© 2004 by CRC Press LLC



Good Manufacturing Practices in Over-the-Counter Drug Product Manufacturing



Compliance

1 2 3*



21



Remarks



EU-Guide



6.59



Antimicrobial treatment of purified water?



□□□



Suppl. § 4



6.60



Loop system for water for injection?



□□□



Suppl. § 4



Storage temperature of water for injection:



.........



Suppl. § 4



6.61



Loop system constructed to avoid deadlegs?



□□□



Suppl. § 4



6.62



Regular microbiological monitoring?



□□□



Suppl. § 4



6.63



Regular endotoxin control?



□□□



Suppl. § 4

Suppl.



Special requirements for sterile and aseptic products

Rooms and equipment

6.64



Access of staff and materials to clean areas only through air-locks?



□□□



1



6.66



Rooms classified according EC-Guide?



□□□



3



Classification for products to be sterilised:

6.67



• Solution preparation (EC: class C, with special precautions class D):



Class: ..........



5



6.68



• Filling (EC: under LF in class C):



Class: ..........



5



6.69



• Handling of starting materials that can be sterile filtered (EC: class C): Class: ..........



6



6.70



• Handling of starting materials that cannot be sterile filtered

(EC: class A in class B):



Class: ..........



6



6.71



• Handling and filling of bulk (EC: class A in Class B):



Class: ..........



6



Classification for aseptic products:



6.72



All rooms easy to clean disinfect?



□□□



17



6.73



Doors, windows, frames, lighting etc. without edges?



□□□



18



6.74



Suspended ceilings (if yes: sealed?)?



□□□



19



6.75



Traps constructed to avoid microb. contamination?



□□□



21



6.76



Appropriate constructed changing rooms?



□□□



22



6.77



Measures against opening of both doors of air-locks?



□□□



23



6.78



Overpressure gradient from cleanest areas to others?



□□□



24



6.79



AHU validated and regularly revalidated?



□□□



25



6.80



Control instruments for pressure gradient?



□□□



26



6.81



Warning system for errors in air supply?



□□□



26



6.82



Recording of pressure gradients?



□□□



26



6.83



Do conveyor belts leave sterile areas?



□□□



28



6.84



Maintenance works outside from clean areas possible?



□□□



28



6.85



Cleaning and disinfection procedure after maintenance works?



□□□



29



6.86



Regular revalidation of all equipment and systems?



□□□



30



6.87



Water prepared, circulated and stored to exclude microb. contamination?



□□□



31



6.88



Cleaning and disinfection of rooms according to validated SOPs rooms?



□□□



32



• Disinfection methods?

6.89



Microb. monitoring of cleaning and disinfection agents?



* 1. Fulfilled or available; 2. partially fulfilled; 3. not fulfilled or not available.



© 2004 by CRC Press LLC



.........

□□□



33



22



Handbook of Pharmaceutical Manufacturing Formulations: Over-the-Counter Products



Compliance

1 2 3*



Remarks



EU-Guide



6.90



Microb. monitoring programme of production areas?



□□□



35



6.91



Results recorded and considered for the release?



□□□



35



Personnel and Hygiene

6.92



Minimal no. of personnel in clean areas?



□□□



7



6.93



Special and regular training?



□□□



8



6.94



Regular medical examinations?



□□□



10



6.95



Appropriate clean room clothes (material, design)?



□□□



12



6.96



Protective clothes worn correctly?



□□□



12



6.97



Prohibition of cosmetics, jewellery and watches?



□□□



13



6.98



New clean room clothes for each working cycle?



□□□



15



6.99



Appropriate washing and sterilisation of clothes?



□□□



16



□□□



38



Operations

6.100



Validation (media filling) in regular intervals?

Monitoring of water preparation system, frequency:



6.101



• microbiological:



.........



40



6.102



• chemical:



.........



40



6.103



• particles:



.........



40



6.104



• endotoxins:



.........



40



6.105



Microbiological monitoring of starting materials?



□□□



42



6.106



Max. storage times defined for sterilised equipment?



□□□



45



6.107



Max. storage time defined between solution preparation and filtration?



□□□



46



6.108



Material transfer to clean areas through double door autoclaves?



□□□



48



Sterilisation processes

6.109



All processes validated?



□□□



50



6.110



Sterilised and not sterilised materials clearly separated?



□□□



54



Trays and boxes clearly labelled with:

6.111



• Product name and code



□□□



54



6.112



• Batch no.



□□□



54



6.113



• Status: sterilised or not sterilised



□□□



54



Sterilisers:

6.114



• Recording of temp., pressure and time?



□□□



55



6.115



• Coldest point determined?



□□□



55



6.116



• Independent counter check probe?



□□□



55



6.117



• Heat-up time for each product determined?



□□□



56



6.118



• Sterile cooling media?



□□□



57



6.119



• Tightness tests for vacuum autoclaves?



□□□



58



* 1. Fulfilled or available; 2. partially fulfilled; 3. not fulfilled or not available.



© 2004 by CRC Press LLC



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