1. Premises Basic Principles of GMP Workshop on
GMP and Quality Assurance of HIV products
Shanghai, China
28 Feb - 4 March 2005
Maija Hietava
M.Sci.Pharm
Quality Assurance and Safety: Medicines, Medicines Policy and Standards, Health Technology and Pharmaceuticals Cluster
Tel: Fax:
World Health Organization
Part One, 12

2. Premises
Objectives
1. To review general requirements

3. Premises
Principle
Premises must be located, designed, constructed, adapted and maintained for the operations:
Minimize risks of errors and cross-contamination
Permit effective cleaning
Permit effective maintenance
Minimize build-up of dirt and dust
Eliminate any adverse effects on quality
Part One, 12.1

4. Premises
Principle
Premises must be located to minimize risks of cross-contamination; e.g. not located next to a malting factory with high airborne levels of yeast
Part One, 12.1, 12.4

5. Premises Location Geography, climate, noise and economic factors
Neighbours
What do they do?
What impact can they have on the business?
Pollution/effluent control
Part One, 12.4

6. Premises Premises should be built to: Facilitate sanitation.
Be maintained and cleaned easily
Services availability
Protection against entry of insects or other animals
Part One, 12.3 – 12.9

7. Premises Ancillary Areas Rest and refreshment rooms
Changing, washing and toilet areas
Maintenance workshops
Animal houses - isolated
Part One –

8. Premises
Design Principles
Process flow
Material flow
People flow

9. Example of Materials and People Flow
Premises
Example of Materials and People Flow
Arrival of goods Entrance for visitors Entrance for Workers Shipment of goods
Material Flow
People Flow
Zone: Clean
Zone: Secondary Packaging
Zone: Controlled

10. Basic Principles of GMP
Premises
Part two
Part One, 12

11. Importance sometimes underestimated!
Premises
Warehouse – I
Importance sometimes underestimated!
Storage areas of sufficient capacity for all the material
Clean, dry and maintained within acceptable temperature limits
Area under cover, protection from heat, dirt, and rain
I will now go through the main areas of the factory and highlight a few key points in each area.
The importance of the warehouse is sometimes under estimated. Incoming goods areas are often the forgotten places at the back of the factory. However, they should be seen as the first point of entry of materials into the factory, and the last point at which the factory still has control of its products before they leave to go to a customer. Warehouses should have sufficient capacity to allow orderly storage of the various categories of materials and products, for example: starting and packaging materials, intermediates, bulk and finished goods, products in quarantine, and released, rejected, returned or recalled goods.
The design must ensure protection against the heat or moisture. It must also provide protection for special deliveries such as tankers. These give rise to special problems. For example, what measures are in place to ensure a clean connection between the tanker and the holding tank? What precautions are taken to ensure that the tanker is using clean transfer pipes before transferring materials into the tank? Is there a static electricity discharge point for safety purposes where necessary?
All the material requirements with regard to temperature and humidity control must be adhered to. This means suitable records have to be maintained and procedures available to describe what to do in the case of failure of cooling equipment or the electricity supply. How long may materials remain exposed to unsatisfactory temperature or humidity conditions? This question must be able to be answered by the responsible staff in the factory. They should have SOPs describing the various storage conditions required and specifying which materials should be stored there. Examples of materials that need special controls are vaccines and gelatin capsules.
Incoming goods containers may be stored outside. They may need to be cleaned before they can be opened for sampling, and before they go into the warehouse. Facilities for this will need to be provided.
These areas must be designed to provide sufficient space to accommodate the deliveries or shipments passing through them. The areas should be operated in accordance with appropriate SOPs.
Part One –

12. Premises Warehouse – II
Areas clearly marked and access limited for quarantine status goods.
QC sampling area with GMP standards
Segregated areas for rejected, recalled and returned materials
Separate areas for highly active, hazardous, narcotic materials – safety issues/national legislation
Printed materials storage – security essential
Part One –12.22

13. Premises Weighing areas Control systems: right product, right quantity
Environmental controls, dust control
Segregation
Smooth, impervious, durable, easy to clean finishes
Cleaning
Documentation
AVOID CROSS-CONTAMINATION
Part One 12.23

14. Manufacturing and Packaging – I
Premises
Manufacturing and Packaging – I
Dedicated and self-contained facilities for:
Highly sensitizing materials (penicillins)
Biological preparations (live microorganisms)
Logical flows of materials and people
Adequacy of working space and orderly and logical positioning of equipment
Interior surfaces smooth/crack-free/easy to clean
In order to minimize the risk of a serious medical hazard due to cross-contamination, dedicated and self-contained facilities must be available for the production of particular pharmaceutical products, such as highly sensitizing materials (e.g., penicillins) or biological preparations (e.g, live microorganisms). The production of certain other products, such as some antibiotics, hormones, cytotoxic substances, highly active pharmaceutical products, and non-pharmaceutical products, should not be conducted in the same facilities. The manufacture of technical poisons, such as pesticides and herbicides, should not normally be allowed in premises used for the manufacture of pharmaceutical products. In exceptional cases, the principle of campaign working in the same facilities can be accepted provided that specific precautions are taken and the necessary validations are made.
Premises should preferably be laid out in such a way as to allow the production to take place in areas connected in a logical order corresponding to the sequence of the operations and to the requisite cleanliness levels.
The adequacy of the working and in-process storage space should permit the orderly and logical positioning of equipment and materials so as to minimize the risk of confusion between different pharmaceutical products or their components, to avoid cross-contamination, and to minimize the risk of omission or wrong application of any of the manufacturing or control steps.
Where starting and primary packaging materials and intermediate or bulk products are exposed to the environment, interior surfaces (walls, floors and ceilings) should be smooth and free from cracks and open joints, should not shed particulate matter, and should permit easy and effective cleaning and, if necessary, disinfection.
Part One – 12.23

15. Premises Other Areas Personnel rest areas/cafeterias/changing rooms
away from operating areas
prevention of cross-contamination
prevention of operators going outside in work clothes
provision of access control
prevention of visitors access to operating areas
Maintenance service areas
separated from production areas whenever possible

16. Premises
Windows should not open to the outside

17. Finish of Floors, Walls and Ceilings
Premises
Finish of Floors, Walls and Ceilings
Difficult but not impossible to get right
Smooth, impervious, hard-wearing, easy to clean
Resistant to operations and materials in use
Windows not opening to the outside
Avoid sliding doors

18. Finish of Floors, Walls and Ceilings
Premises
Not this
Finish of Floors, Walls and Ceilings
Difficult but not impossible to get right, smooth, impervious, hard-wearing, easy to clean; but not bricks, tiles, wood or sliding doors!

19. Finish of Floors, Walls and Ceilings
Premises
Finish of Floors, Walls and Ceilings
Much better

20. Premises Cross-contamination Segregated areas Campaign production
Airlocks and pressure differentials
Treatment of recirculated air
Protective clothing
Effective cleaning procedures
Closed production systems
Residue testing
Status labelling
Part One (a)–(i)

21. Manufacturing and Packaging – I
Premises
Manufacturing and Packaging – I
Pipework and other fittings sited to avoid recesses
Drain design:
equipped to prevent backflow
open channels avoided
Effective air handling to suit product
temperature
humidity
filtration
monitoring
Part One – 12.30

22. Manufacturing and Packaging – II
Premises
Manufacturing and Packaging – II
Specifically designed and laid out to avoid mix-ups and cross-contamination
Changing facilities to provide segregated access
Prevention of cross-contamination
Suitable lighting levels
Part One – 12.32

23. In-Process and QC laboratories
Premises
In-Process and QC laboratories
Located separate from but near manufacturing
prevention of cross-contamination
separate biological , microbiological, radioisotopic areas
Designed for the operations being carried out
suitable storage space
Part One – 12.36