Wednesday, June 28, 2017
Project co-funded by the European Commission in the framework of the 2nd Health Programme
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A.2.2. FACILITIES, EQUIPMENT AND MATERIALS FOR PROCESSING

A.2.2.1. Facilities

A.2.2.1.1. General

1. The facilities of the tissue bank should be, both in organization and size, in accordance to the activities they are used for.  They should be designed in accordance with the general safety requirements of this guide and with the specific requirements for each tissue type.

2. Different areas with specific requirements and maintenance procedures must be defined and, in particular as regards:

a)     The reception area;

b)    Processing areas of tissue or cells;

c)     Packaging and labelling area;

d)    The conservation area and storage (released, quarantine and rejected);

e)     Distribution area;

f)     Laboratory quality control (if applicable);

g)     Archive;

h)    Administrative area.

3. Access to various areas of work is strictly limited to authorized persons.

4. Premises should be situated in an environment which, when considered together with measures to protect the processing, presents minimal risk of causing contamination of materials or tissues/cells.

5. Premises should be carefully maintained, ensuring that repair and maintenance operations do not present any hazard to the quality of tissues/cells.  They should be cleaned and, where applicable, disinfected according to detailed written procedures.

6. Lighting, temperature, humidity and ventilation should be appropriate and such that they do not adversely affect, directly or indirectly, either the tissues / cells during their processing and storage, or the accurate functioning of equipment.

7. Pipework, light fittings, ventilation points and other services should be designed and sited to avoid the creation of recesses which are difficult to clean.  As far as possible, for maintenance purposes, they should be accessible from outside the processing areas.

8. Drains should be of adequate size, and have trapped gullies.  Open channels should be avoided where possible, but if necessary, they should be shallow to facilitate cleaning and disinfection.

9. Premises should be designed and equipped so as to afford maximum protection against the entry of insects or other animals.

10. Steps should be taken in order to prevent the entry of unauthorised people.

11. Processing, storage and quality control areas should not be used as a right of way by personnel who do not work in them.

12. Premises should preferably be laid out in such a way as to allow the processing to take place in areas connected in a logical order corresponding to the sequence of the operations and to the requisite cleanliness levels.  The flow of personnel, tissues and cells, waste materials and consumables should be described.[1]

13. When biological risk exists (viral inactivation, virus removal, processing with live organisms), cross contamination control may require additional precautions with relation to facilities and equipment, such as the use of dedicated facilities and equipment, processing on a campaign basis and the use of closed systems.

A.2.2.1.2. Processing area

1. ‘A tissue establishment must have suitable facilities to carry out the activities for which accreditation / designation / authorisation or licensing is sought.

2. When these activities include processing of tissues and cells while exposed to the environment, this must take place in an environment with specified air quality and cleanliness in order to minimise the risk of contamination, including cross-contamination between donations.  The effectiveness of these measures must be validated and monitored.

3. Unless otherwise specified in following paragraphs, where tissues or cells are exposed to the environment during processing, without a subsequent microbial inactivation process, an air quality with particle counts and microbial colony counts equivalent to those of Grade A as defined in the following paragraphs is required[2].

4. In case of GMP accreditation, the background environment should be Grade B with a subsequent background of grade D.  A risk assessment could be used by the TE to define the background if not working according to GMP (see the provided tool in the hot topics ‘Recovery’).

5. A less stringent environment than specified previously may be acceptable where:

a)    a validated microbial inactivation or validated terminal sterilisation process is applied;

b)    or, where it is demonstrated that exposure in a Grade A environment has a detrimental effect on the required properties of the tissue or cell concerned;

c)     or, where it is demonstrated that the mode and route of application of the tissue or cell to the recipient implies a significantly lower risk of transmitting bacterial or fungal infection to the recipient than with cell and tissue transplantation;

d)    or, where it is not technically possible to carry out the required process in a Grade A environment (for example, due to requirements for specific equipment in the processing area that is not fully compatible with Grade A; [3]

e)     See specific paragraphs on each type of tissue/cells for other requirements

6. In all cases an environment must be specified.  It must be demonstrated and documented that the chosen environment achieves the quality and safety required, at least taking into account the intended purpose, mode of application and immune status of the recipient.  Appropriate garments and equipment for personal protection and hygiene must be provided in each relevant department of the tissue establishment along with written hygiene and gowning instructions.

7. Processing areas should be effectively ventilated, with air control facilities (including temperature and, where necessary, humidity and filtration) appropriate both to the tissues / cells handled, to the operations undertaken within them and to the external environment.

8. If there is recirculation of air into the processing areas, appropriate measures should be taken to control risks of contamination.

9. When the activities for which accreditation / designation / authorisation or licensing is sought involve storage of tissues and cells, the storage conditions necessary to maintain the required tissue and cell properties, including relevant parameters such as temperature, humidity or air quality, must be defined.

10. Critical parameters (e.g. temperature, humidity, air quality) must be controlled, monitored, and recorded to demonstrate compliance with the specified storage conditions.

11. Storage facilities must be provided that clearly separate and distinguish tissues and cells prior to release / in quarantine from those that are released and from those that are rejected, in order to prevent mix-up and cross-contamination between them.  Physically separate areas or storage devices or secured segregation within the device must be allocated in both quarantine and released storage locations for holding certain tissue and cells collected in compliance with special criteria.

12. The tissue establishment must have written policies and procedures for controlled access, cleaning and maintenance, waste disposal and for the re-provision of services in an emergency situation.[4]

A.2.2.1.3. Environmental airborne control

1. Unless any other requirement is indicated in the specific paragraphs for each type of tissues / cells the following requirements should be satisfied:

2. The processing activities should be carried out in clean areas, entry to which should be through airlocks for personnel and/or for equipment and materials.  Clean areas should be maintained to an appropriate cleanliness standard and supplied with air which has passed through filters of an appropriate efficiency.

3. Clean areas are classified according to the required characteristics of the environment.  Each processing operation requires an appropriate environmental cleanliness level in the operational state in order to minimise the risks of particulate or microbial contamination of the tissue/cells or materials being handled.

4. Four grades can be distinguished:

a)    Grade A: Normally such conditions are provided by a laminar air flow work station.  Laminar air flow systems should provide a homogeneous air speed in a range of 0.36 – 0.54 m/s (guidance value) at the working position in open clean room applications.  The maintenance of laminarity should be demonstrated and validated.  A uni-directional air flow and lower velocities may be used in closed isolators and glove boxes;

b)    Grade B: This is the background environment for the grade A zone if tissues or cells are processed according to GMP rules.  The risk assessment tool for defining the air quality can be used to select the background;

c)     Grade C and D: Clean areas for carrying out less critical stages according to documented risk assessment in the processing activities.

5. The maximum permitted airborne particle concentration for each grade is given in the following table.

 

 

Maximum permitted number of particles per m3 equal to or greater than the tabulated size

 

At rest

In operation

Grade

0.5mm

5mm

0.5mm

5mm

A

3520

20

3520

20

B

3520

29

352000

2900

C

352000

2900

3520000

29000

D

3520000

29000

Not defined*

Not defined*

*When the limit of number of particles is not defined, each tissue establishment should do it according to a risk assessment study.

6. The ‘at-rest’ state is the condition where the installation is installed and operating, complete with processing equipment but with no operating personnel present.  The ‘in operation’ state is the condition where the installation is functioning in the defined operating mode with the specified number of personnel working.[5]

7. The ‘at rest’ requirements should be respected in all cases.  The ‘in operation’ requirements are only applicable to sterile operations.

8. For classification purposes in Grade A zones, a minimum sample volume of 1m3 should be taken per sample location.  For classification purposes EN/ISO 14644-1[6] methodology defines both the minimum number of sample locations and the sample size based on the class limit of the largest considered particle size and the method of evaluation of the data collected.

9. Portable particle counters with a short length of sample tubing should be used for classification purposes because of the relatively higher rate of precipitation of particles ≥5.0ìm in remote sampling systems with long lengths of tubing.  Isokinetic sample heads should be used in unidirectional airflow systems.

10. ‘In operation’ classification may be demonstrated during normal operations, simulated operations or during media fills as worst-case simulation is required for this. EN ISO 14644-2 provides information on testing to demonstrate continued compliance with the assigned cleanliness classifications.

11. The rules of particle count cannot be achieved when for example bone is aseptically processed.  Less stringent conditions may then be applied when it is not technically possible to carry out the required process in a Grade A environment with risk assessment or to include in the processing sterilisation or inactivation process.

11. Clean rooms and clean air devices should be routinely monitored in operation, if applicable, and the monitoring locations based on a formal risk analysis study and the results obtained during the classification of rooms and/or clean air devices.

12. For Grade A zones, when ‘in operation’ requirements are applicable, particle monitoring should be undertaken for the full duration of critical processing, including equipment assembly, except where justified by contaminants in the process that would damage the particle counter or present a hazard, e.g. live organisms and radiological hazards.  In such cases, monitoring during routine equipment set-up operations should be undertaken prior to exposure to the risk.  Monitoring during simulated operations should also be performed.  The Grade A zone should be monitored at such a frequency and with suitable sample size so that all interventions, transient events and any system deterioration would be captured and alarms triggered if alert limits are exceeded.  It is accepted that it may not always be possible to demonstrate low levels of ≥5.0 mm particles at the point of fill when filling is in progress, due to the generation of particles or droplets from the tissue/cells itself.

13. It is recommended that a similar system be used for Grade B zones although the sample frequency may be decreased.  The importance of the particle monitoring system should be determined by the effectiveness of the segregation between the adjacent Grade A and B zones.

14. The Grade B zone should be monitored at such a frequency and with suitable sample size that changes in levels of contamination and any system deterioration would be captured and alarms triggered if alert limits are exceeded.

15. Airborne particle monitoring systems may consist of independent particle counters; a network of sequentially accessed sampling points connected by manifold to a single particle counter; or a combination of the two.  The system selected must be appropriate for the particle size considered.  Where remote sampling systems are used, the length of tubing and the ratio of any bends in the tubing must be considered in the context of particle losses in the tubing.

16. The sample sizes taken for monitoring purposes using automated systems will usually be a function of the sampling rate of the system used.  It is not necessary for the sample volume to be the same as that used for formal classification of clean rooms and clean air devices.

17. In Grade A and B zones, the monitoring of the ≥5.0 mm particle concentration count takes on a particular significance as it is an important diagnostic tool for early detection of failure.  The occasional indication of ≥5.0 mm particle counts may be false counts due to electronic noise, stray light, coincidence, etc.  However, consecutive or regular counting of low levels is an indicator of a possible contamination event and should be investigated.  Such events may indicate early failure of the HVAC system, equipment failures or may also be diagnostic of poor practices.

18. The particle limits given in the table for the ‘at rest’ state should be achieved after a short ‘clean up’ period of 15-20 minutes (guidance value) in an unmanned state after completion of operations.

19. The monitoring of Grade C and D areas in operation should be performed in accordance with the principles of quality risk management.  The requirements and alert/action limits will depend on the nature of the operations carried out, but the recommended ‘clean up period’ should be attained.

20. Other characteristics such as temperature and relative humidity depend on the product and nature of the operations carried out.  These parameters should not interfere with the defined cleanliness standard.[7]

A.2.2.1.4. Environmental microbiological control

1. When ‘in operation’ requirements are applicable, microbiological monitoring should be frequent using methods such as settle plates, volumetric air and surface sampling (e.g. swabs and contact plates).  Sampling methods used in operation should not interfere with zone protection.  Results from monitoring should be considered when reviewing batch documentation for finished product release.  Surfaces and personnel should be monitored after critical operations.  Additional microbiological monitoring is also required outside processing operations, e.g. after validation of systems, cleaning and sanitisation.

2. When ‘in operation’ requirements are not applicable, microbiological monitoring should be performed with the aim of ensuring an adequate aseptic grade to initiate any processing activities.  A monitoring program should be established accordingly.

3. The maximum permitted limits for each grade is given in the following table.

 

Recommended limits for microbial contamination (a)

Grade

air sample

cfu/m3

settle plates

(diameter 90 mm)

cfu/4hours (b)

contact plates

(diameter 55 mm)

cfu/plate

glove print

5 fingers

cfu/glove

A

1

1

1

1

B

10

5

5

5

C

100

50

25

-

D

200

100

50

-

Notes

(a) These are average values.

(b) Individual settle plates may be exposed for less than 4 hours.

4. Appropriate alert and action limits should be set for the results of particulate and microbiological monitoring.  If these limits are exceeded operating procedures should prescribe corrective action.[8]

A.2.2.1.5. Sanitation

1. The sanitation of clean areas is particularly important.  They should be cleaned thoroughly in accordance with a written programme.  Where disinfectants are used, more than one type should be employed and rotation-use of disinfectants is recommended.  Monitoring should be undertaken regularly in order to detect the development of resistant strains.

2. Disinfectants and detergents should be monitored for microbial contamination; dilutions should be kept in previously cleaned containers and should only be stored for defined periods unless sterilised.  Disinfectants and detergents used in Grades A and B areas should be sterile prior to use.

3. Fumigation of clean areas may be useful for reducing microbiological contamination in inaccessible places.[9]

4. Maximum permitted microbiological limits for each cleanliness grade after cleaning and sanitation should be specified.

A.2.2.1.6. Isolator technology

1. The utilisation of isolator technology to minimize human interventions in processing areas may result in a significant decrease in the risk of microbiological contamination of aseptically processed tissues/cells from the environment.  There are many possible designs of isolators and transfer devices.  The isolator and the background environment should be designed so that the required air quality for the respective zones can be realised.  Isolators are constructed of various materials more or less prone to puncture and leakage.  Transfer devices may vary from a single door to double door designs to fully sealed systems incorporating sterilisation mechanisms.

2. The transfer of materials into and out of the unit is one of the greatest potential sources of contamination.  In general, the area inside the isolator is the local zone for high risk manipulations, although it is recognised that laminar air flow may not exist in the working zone of all such devices.

3. The air classification required for the background environment depends on the design of the isolator and its application.  It should be controlled and for aseptic processing it should be at least grade D.

4. Isolators should be introduced only after appropriate validation.  Validation should take into account all critical factors of isolator technology, for example the quality of the air inside and outside (background) the isolator, sanitisation of the isolator, the transfer process and isolator integrity.

5. Monitoring should be carried out routinely and should include frequent leak testing of the isolator and glove/sleeve system.[10]

A.2.2.1.7. Ancillary areas

1. The adequacy of the working and in-process storage space should permit the orderly and logical positioning of equipment and materials so as to minimise the risk of confusion between different tissues/cells, to avoid cross-contamination and to minimise the risk of omission or wrong application of any of the processing or control steps.

2. Restrooms, control rooms and refreshment rooms should be separate from other areas.

3. Facilities for changing clothes and for washing and toilet purposes should be easily accessible and appropriate for the number of users.  Toilets should not directly communicate with processing or storage areas.

4. Maintenance workshops should as far as possible be separated from processing areas.

5. Whenever parts and tools are stored in the processing area, they should be kept in rooms or lockers reserved for that use.[11]

A.2.2.2. Equipment

1. Processing equipment should be designed, located and maintained to suit its intended purpose.

2. Repair and maintenance operations should not present any hazard to the quality of the tissues and cells.

3. Processing equipment should be designed so that it can be easily and thoroughly cleaned.  It should be cleaned according to detailed and written procedures and stored only in a clean and dry condition.

4. Washing and cleaning equipment should be chosen and used in order not to be a source of contamination.

5. Equipment should be installed in such a way as to prevent any risk of error or of contamination.

6. Processing equipment should not present any hazard to the tissues and cells.  The parts of the processing equipment that come into contact with the tissues/cells must not be reactive, additive or absorptive to such an extent that it will affect the quality of the tissues/cells and thus present any hazard.

7. Balances and measuring equipment of an appropriate range and precision should be available for processing and control operations.

8. Measuring, weighing, recording and control equipment should be calibrated and checked at defined intervals by appropriate methods.  Adequate records of such tests should be maintained.

9. Fixed pipework should be clearly labelled to indicate the contents and, where applicable, the direction of flow.

10. Distilled, deionized and, where appropriate, other water pipes should be sanitised according to written procedures that detail the action limits for microbiological contamination and the measures to be taken.

11. Defective equipment should, if possible, be removed from processing and quality control areas, or at least be clearly labelled as defective.

12. The services that could impact on the tissues/cells quality (i.e. compressed air, heating, ventilating and air conditioning) should be qualified and scheduled in a maintenance programme. 

13. Calibration and maintenance operations should be carried out according to written procedures and scheduled on an annual basis.

14. Should there be any electronic system in place to manage environmental conditions or any processing quality data, a validation study should be assessed. [12]

 

A.2.2.3. Materials

A.2.2.3.1. General

1. The TE must have the equipment and materials according to the activities to which they are designed and in accordance with the general safety requirements of this Guide and the specific requirement of each tissue type.

2. All equipment and materials affecting the quality and safety of the tissues and cells must be defined and validated.

3. All incoming materials should be checked to ensure that the consignment corresponds to the order.

4. Specifications for starting and primary or printed packaging materials should include, if applicable:

a)    a description of the materials, including:

                        i.     the designated name and the internal code reference;

                       ii.     the reference, if any, to a pharmacopoeia monograph;

                     iii.     the approved suppliers and, if possible, the original producer of the products;

                     iv.     a specimen of printed materials.

b)    directions for sampling and testing or reference to procedures;

c)     qualitative and quantitative requirements with acceptance limits;

d)    storage conditions and precautions;

e)     the maximum period of storage before re-examination.[13]

5. A standardized written procedure (SOP) will regulate the specific media that come into contact with tissues and cells during processing, the addition of therapeutic products to tissues and cells, the choice of those media and products, their characteristics, their source and control and the rules for asepsis and labelling.  A procedure to select the materials must be in place.  Defined specifications and functions of the media; validate the effect of media or other materials on the functional characteristics of the tissues.  New batches must be tested.

6. When using processing media and / or added therapeutic products, their source, lot number and expiration date must be listed in the documentation of the different stages of processing.

A.2.2.3.2. Material requirements

1. The following aspects should be attended to regarding reagents used during the processing of tissues and cells:

a)     Free of viral contamination (certificate should be available);

b)    Free of TSE contamination (certificate should be available);

c)     Produced under GMP conditions when possible;

d)    For human use when possible;

e)     Identity, purity, sterility and quantification of endotoxins should be defined;

f)     Human and animal origin reagents should be substituted when possible;

g)     Antibiotics should be avoided when possible;

h)    Final residues of reagents should be quantified when possible;

i)      Risk assessment of reagent residues should be done.

A.2.2.4. Safety and Environment

1. It should be ensured that the safety of the working environment is according to other safety regulations.

2. Residues of human tissues and cells during their transformation must be destroyed in a specific and traceable way to minimize the risk to the staff involved in transformation and to the environment in accordance with local laws and national regulations in force concerning the disposal of clinical waste.

3. Waste materials and liquids used during processing should be utilised in accordance with local laws and national regulations in force concerning the disposal of medical material waste.



[1] EU Good Manufacturing Practices Guidelines

[2] Commission Directive 2006/86/EC  ( Annex I)

[3] Commission Directive 2006/86/EC (Annex I)

[4] Commission Directive 2006/86/EC (Annex I)

[5] EU Good Manufacturing Practices Guidelines

[6] Cleanrooms and associated controlled environments -- Part 1: Classification of air cleanliness

 

[7] EU Good Manufacturing Practices Guidelines

 

[8] EU Good Manufacturing Practices Guidelines

[9] EU Good Manufacturing Practices Guidelines

[10] EU Good Manufacturing Practices Guidelines

 

[11] EU Good Manufacturing Practices Guidelines

 

[12] EU Good Manufacturing Practices Guidelines

 

[13] EU Good Manufacturing Practices Guidelines

 

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