Tuesday, August 22, 2017
Project co-funded by the European Commission in the framework of the 2nd Health Programme
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A.7.4. VALIDATION

A.7.4.1. General

1. TEs should establish documented evidence that provides a high degree of assurance that a specific process, piece of equipment or environment will consistently produce a product meeting its pre-determined specifications and quality attributes.

2. All critical equipment and technical devices must be identified and validated.[1]

3. All critical processing procedures must be validated and must not render the tissues and cells clinically ineffective or harmful to the recipient’[2].

4. TEs should identify what validation work is needed to prove control of the critical aspects of their particular operations.

5. Significant changes to the facilities, the equipment and the processes, which may affect the quality of the tissues and cells, should be validated.

6. A risk assessment approach should be used to determine the scope and extent of validation.  Such risk assessment should take into account all the equipment (e.g. autoclave, incubator, freeze drier), facilities (e.g. clean rooms, laminar flow module), electronic systems (e.g. clean rooms environmental monitoring system, tissues processing system) and processes (e.g. musculoskeletal processing, skin processing, clean rooms disinfection, tissue transport, analytical methods) which may impact on the quality of processed tissues.

7. The results from the risk assessment study regarding the scope of validation activities within a TE should be covered in a Validation Master Plan.

A.7.4.2. Documentation

1. The Validation Master Plan should consist of at least:

a)   Description of the TE;

b)   List of equipment, facilities, electronic systems and processes that need to be qualified or validated;

c)   State of validation of each element within the scope;

d)   Validation programme;

e)   Validation activities responsibilities;

f)    Procedures related to validation activities;

g)   Criteria for requalification or revalidation;

2. The activities of qualification or validation should be described in a protocol containing at least:

a)   Objective;

b)   Scope;

c)   Responsibilities;

d)   Related documents;

e)   Stages of qualification or validation;

f)    Acceptance criteria.

3. A validation / qualification report should be issued reflecting the results of the activities containing at least:

a)   Objective;

b)   Scope;

c)   Responsibilities;

d)   Related documents;

e)   Deviations from the protocol;

f)    Results;

g)   Conclusions.

 

A.7.4.3. Facility, system and equipment qualification

A.7.4.3.1. Qualification for new facilities, systems and equipment

1. The first element of the validation of new facilities, systems or equipment could be Design qualification (DQ: documented verification that the proposed design of the facilities, equipment, or systems is suitable for the intended purpose).  During DQ the compliance of the design with GTP should be demonstrated and documented.

2. Installation qualification (IQ: documented verification that the equipment or systems, as installed or modified, comply with the approved design, the manufacturer’s recommendations and/or user requirements) should be performed on all critical facilities, systems and equipment.  The IQ protocol should include, but not be limited to:

a)   Verification that all items of equipment / facility fall under the requirements of the purchase order;

b)   Verification of CE-approval (if required for the equipment);

c)   Verification that the location and environmental conditions of the equipment / installation are correct according to the manufacturer's recommendations and internal specifications;

d)   Verification that items are installed in accordance with internal specifications and identified correctly by manufacturer;

e)   Verification of serial numbers of all items/parts;

f)    Verification that all parts of the equipment are free from defects;

g)   Verification that the connection of electricity, water, steam, pressure, vacuum, etc. are functional and that their operating ranges are appropriate for the proper functioning of the installation;

h)   Identification of the action of the items that require calibration.  Check for appropriate calibration certificates and programmme and procedure for periodic calibration;

i)    Checking for instructions for use and cleaning of equipment / manufacturer manual and log book of operations of the unit / installation;

j)    Verification of the existence of instructions for performing preventive maintenance.

3. Operational qualification (OQ: documented verification that the equipment or systems, as installed or modified, perform as intended throughout the anticipated operating ranges) should follow IQ.  The OQ protocol should include, but not be limited to the following:

a)   Tests that have been developed from knowledge of processes, systems and equipment;

b)   Tests to include a condition or a set of conditions encompassing upper and lower operating limits, sometimes referred to as ‘worst case’ conditions;

c)   Identification of critical operating variables, tests performed, alarms, security devices and acceptance criteria;

d)   Verification that the operation of various items of equipment / installation connected to the mains and put into operation is correct.

4. The completion of a successful OQ should allow the finalisation of calibration, operating and cleaning procedures, operator training and preventative maintenance requirements.  It should permit a formal ‘release’ of the facilities, systems and equipment.[3]

5. Performance qualification (PQ: documented verification that the equipment and ancillary systems, as connected together, can perform effectively and reproducibly based on the approved process method and specifications) should follow successful completion of IQ and OQ.  Although PQ is described as a separate activity, it may in some cases be appropriate to perform it in conjunction with OQ, or concurrently with production activities.  The PQ protocol should include, but not be limited to, the following:

a)   Tests, using production materials, qualified substitutes or simulated product, that have been developed from knowledge of the process and the facilities, systems or equipment;

b)   Tests to include a condition or set of conditions encompassing upper and lower operating limits;

c)   Process description or reference to protocol development and / or conditioning to validate;

d)   List of equipment involved;

e)   Critical parameters and operating ranges;

f)    Reference of the procedures involved;

g)   Description of the tests to be performed, or control variables, sample taking, time and reference method sampling and analytical methods;

h)   Acceptance criteria.

A.7.4.3.2. Qualification of established (in-use) facilities, systems and equipment

1. Evidence should be available to support and verify the operating parameters and limits for the critical variables of the operating equipment.

2. The calibration, cleaning, preventative maintenance, operating procedures and operator training procedures and records of the in-use facilities / systems / equipment should be documented.[4]

 

A.7.4.3.3. Qualification of Clean Rooms

Following the steps described in the Facilities, Systems and Equipment Qualification section A.2., the tests to be carried out for the Clean Rooms should include at least:

a)   Air change (renewal) rate per hour within one room: the speed and rate of renewals per hour according to specified will be checked;

b)   Smoke test for air flow within each room;

c)   Absolute filters integrity: the grade of sealing of the filters and the absence of leaks in the filter material will be checked;

d)   Particle counting: the total count of airborne particles (viable or not) will be checked according to specifications;

e)   Temperature / relative humidity: the temperature and relative humidity will be recorded during the test and will be checked according to specifications;

f)    Differential pressure: the pressure differential between the different areas will be checked according to specifications;

g)   Recovery test (normally tested for A and B classified clean rooms): the time required for a clean room to recover the specified classification after an out-of-specifications will be checked;

h)   Laminar flow velocities in laminar flow areas;

i)    HVAC system operations and alarms;

j)    Electricity back-up systems.

 

All these tests should be performed at least in an ‘at rest’ situation.  Additionally, the particle counting test should be performed also in an ‘in operation’ situation.

 

A.7.4.3.4. Qualification of Laminar Flow Hoods

Following the steps described in the Facilities, Systems and Equipment Qualification paragraph A.2, the tests to be carried out for the laminar flow hoods will include at least:

a)   Speed and uniformity of the air: the average speed meets the specified acceptance criteria and that there is uniformity will be checked;

b)   Absolute filters integrity: the grade of sealing of the filters and the absence of leaks in the filter material will be checked;

c)   Particle counting: the total count of airborne particles (viable or not) will be checked according to specifications;

d)   Electronic test: all the operating controls will be checked (light, UV light, fan) and alarms;

e)   Smoke Test (for biological safety cabinets).  The test objective is to study the behaviour of air inside and outside the cabin with the help of a smoke generator.

All these tests should be performed at least in an ‘at rest’ situation.  Additionally, the particle counting test should be performed also in an ‘in operation’ situation.

A.7.4.4. Process validation

1. Facilities, systems and equipment to be used should have been qualified and analytical testing methods should be validated.

2. Processes in use for some time should also be validated.

3. Staff taking part in the validation work should have been appropriately trained.

4. Facilities, systems, equipment and processes should be periodically evaluated to verify that they are still operating in a valid manner.

A.7.4.4.1. Prospective validation 

1. Process validation should normally be completed prior to the distribution of any tissue or cell (prospective validation).

2. Prospective validation should include, but not be limited to the following:

a)    Short description of the process;

b)    Summary of the critical processing steps to be investigated;

c)     List of the equipment/facilities to be used (including measuring / monitoring / recording equipment) together with its calibration status;

d)    Finished product specifications for release;

e)     List of analytical methods, as appropriate;

f)      Proposed in-process controls with acceptance criteria;

g)    Additional testing to be carried out, with acceptance criteria and analytical validation, as appropriate;

h)    Sampling plan;

i)      Methods for recording and evaluating results;

j)      Functions and responsibilities;

k)    Proposed timetable.

3. Using this defined process (including specified components) a series of batches of the final tissues or cells may be produced under routine conditions.

4. The number of process runs carried out and observations made should be sufficient to allow the normal extent of variation and trends to be established and to provide sufficient data for evaluation. It is generally considered acceptable that three consecutive batches/runs within the finally agreed parameters would constitute a validation of the process. 

5. Batches, where applicable, made for process validation should be the same size as the routine scale batches.[5]

A.7.4.4.2. Concurrent validation 

1. In exceptional circumstances it may be acceptable not to complete a validation program before routine production starts and to validate processes during routine production (concurrent validation).  The decision to carry out concurrent validation must be justified, documented and approved by authorised personnel.

2. Documentation requirements for concurrent validation are the same as specified for prospective validation.[6]

A.7.4.4.3. Retrospective validation 

1. Retrospective validation is only acceptable for well-established processes.

2. Retrospective validation will be inappropriate where there have been recent changes in the composition of the tissues or cells, operating procedures or equipment.  Validation of such processes should be based on historical data. The steps involved require the preparation of a specific protocol and the reporting of the results of the data review, leading to a conclusion and a recommendation.

3. The source of data for this validation should include, but not be limited to:

a)    Batch processing and packaging records;

b)    Process control charts;

c)     Maintenance log books;

d)    Records of personnel changes;

e)     Process capability studies;

f)      Finished product data;

g)    Including trend cards;

h)    Storage stability results.

4. Batches selected for retrospective validation should be representative of all batches made during the review period, including any batches that failed to meet specifications, and should be sufficient in number to demonstrate process consistency.

5. Additional testing of retained samples may be needed to obtain the necessary amount or type of data to retrospectively validate the process.

6. For retrospective validation, generally data from ten to thirty consecutive batches should be examined to assess process consistency, but fewer batches may be examined if justified. [7]

A.7.4.5. Cleaning and Disinfection Validation

1. Cleaning and disinfection validation should be performed in order to confirm the effectiveness of a cleaning or disinfection procedure.

2. The rationale for selecting limits of carry over of product residues, cleaning agents and microbial contamination should be logically based on the materials involved. The limits should be achievable and verifiable.

3. Residues of products or cleansing agents should be checked based on risk assessment. Validated analytical methods having sensitivity to detect residues or contaminants should be used. The detection limit for each analytical method should be sufficiently sensitive to detect the established acceptable level of the residue or contaminant.

4. Normally only cleaning or disinfection procedures for product contact surfaces of the equipment need to be validated. Consideration should be given to noncontact parts.

5. The intervals between use and cleaning or disinfection as well as cleaning or disinfection and reuse should be validated.

6. Cleaning or disinfection intervals and methods should be determined.

7. For cleaning and disinfection procedures for products and processes which are similar, it is considered acceptable to select a representative range of similar products and processes. A single validation study utilising a “worst case” approach can be carried out which takes account of the critical issues.

8. Typically three consecutive applications of the cleaning or disinfection procedure should be performed and shown to be successful in order to prove that the method is validated.

9. ‘Test until clean’, is not considered an appropriate alternative to cleaning validation.

10. Products which simulate the physicochemical properties of the substances to be removed may exceptionally be used instead of the substances themselves, where such substances are either toxic or hazardous.[8]

A.7.4.6. Revalidation

1. Revalidation should be performed when there is a change in any equipment, facilities or process, considered significant because it affects the quality of the product / process or have implications for the current European regulations.  These changes should be approved through a change control procedure.

2. When the product quality review confirms that the system or process is consistently producing material meeting its specifications, there is no need for revalidation.



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

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

[3] EU Good Manufacturing Practices Guidelines

[4] EU Good Manufacturing Practices Guidelines

[5] EU Good Manufacturing Practices Guidelines

[6] EU Good Manufacturing Practices Guidelines

[7] EU Good Manufacturing Practices Guidelines

[8] EU Good Manufacturing Practices Guidelines

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