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 Workshops separate from production areas? 3.32 2.17 Laboratory animal rooms totally segregated
from production rooms?
3.33
3 WAREHOUSE
Rooms, general
3.1 Suitable for the intended use? 3 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 authorized 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 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
Compliance 1 2
3a Remarks EU-Guide
Operations
3.25 Reception, sampling, and labeling 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
Labeling 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 reanalysis 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: Storage conditions:
4 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
Compliance 1 2 3 Remarks EU-Guide
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 authorized 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 Air pressure gradient from weighing cabin→ corridor: 3.3 4.14 Dust extraction systems available? 5.11
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 labeled? 5.29 4.20 Only released products in the dispensing? 5.31 4.21 Cleaning SOPs 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
• Visual inspection (capsules, tablets, etc.)
• Premix (human)
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 authorized personnel only? 3.5
Rooms, special requirements
5.11 Separate manufacturing area for penicillins/cephalosporins or highly sensitizing substances?
Compliance 1 2 3 Remarks EU-Guide
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 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 sanitized?
3.43
5.33 Not functioning equipment in the production area (if yes: clearly marked)?
Y N 3.44
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, and 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 labeling of containers, materials, equipment,
Compliance 1 2 3 Remarks EU-Guide
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,
and gloves)?
2.16
5.57 Clothing regulation for visitors? 2.11
IPC 5.38
Who performs IPC?
5.58 Are IPC methods approved by QC? 6.18 Performance of IPCs: During Frequency Automatic
Start-up? data recording? Yes 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
Compliance 1 2 3 Remarks EU-Guide
5.74 Revalidation in fixed intervals? 5.24 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
• Sterile freeze drying
• Sterile powder filling
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 authorized personnel only? 3.5
Rooms, special requirements
6.11 Separate manufacturing area for penicillins/cephalosporins or highly sensitizing 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!)?
Compliance 1 2 3 Remarks EU-Guide
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
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 sanitized?
3.43
6.33 Not functioning equipment in the production area (if yes: clearly marked)?
Y N
3.44 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, and 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 labeling of containers, materials, equipment, 5.12 and rooms with:
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,
and gloves)?
2.16
Compliance 1 2 3 Remarks EU-Guide