An appropriate validation of the extraction efficiency should be carried out, depending on the stage at which internal standards are introduced and on whether results are reported on product or fat basis.

When applying e. g. the in-house validation model, the performance characteristics are determined in a manner that permits validation for major changes within the same validation procedure.

The methods proposed must reflect the state of the art. The following criteria must be met in order to permit validation of the analytical methods proposed for post-registration control and monitoring purposes:

The determination of a method's reproducibility by the single laboratory studies (in-house validation) concept requires repeated participation in proficiency studies in accordance with ISO guide 43-1 (3) and 43-2 (4).

The pre-defined quality control parameters, e. g. non-specific binding, the relative binding of the control samples, the absorbance value of the blank have to be within the limits obtained during validation of the assay.

d) Tests and acceptance criteria carried out at every critical step, information on the quality and control of intermediates and process validation and/or evaluation studies shall be provided as appropriate.

adjustment of amounts paid in error, which may be achieved by means of deduction beforehand when another validation of the same type is being effected under the chapter, Article and financial year in respect of which the excess payment was made,

adjustment of amounts paid in error, which may be achieved by means of deduction beforehand when another validation of the same type is being effected under the title, chapter, article and financial year in respect of which the excess payment was made.

Hence, the first step of the entire validation procedure shall consider the sample populations that will be analysed in the laboratory in the future in order to select the most important species and those factors which may influence the measurement results.

Accurate measurement and control of the material process rate is essential and must be measured during the validation test in relation to a CCP that can be continuously monitored such as:

When alternative validation procedures are applied, the underlying model and strategy with the respective prerequisites, assumptions and formulae shall be laid down in the validation protocol or at least references shall be given to their availability.

(2) In particular, account should be taken of the concept of the validation of expenditure, as defined in Article 79 of Council Regulation (EC, Euratom) No 1605/2002 of 25 June 2002 on the Financial Regulation applicable to the general budget of the European Communities(5).

As each sample (each factor level combination) has to be spiked with four different concentrations around the level of interest, and one blank sample shall be analysed for each level, 5 x 16 = 80 analyses have to be performed for the entire validation experiment.

If it can be justified that an identification and/or an assay on all the toxicologically relevant constituents is not possible e.g. due to their dilution in the finished medicinal product the quality shall be demonstrated by complete validation of the manufacturing and dilution process.

The competent authority must repeat the validation procedures periodically, when it considers it necessary, and in any case each time any significant alterations are made to the process (for example, modification of the machinery or a change of raw materials).

As a result of advances in analytical chemistry since the adoption of Directive 96/23/EC the concept of routine methods and reference methods has been superseded by criteria approach, in which performance criteria and procedures for the validation of screening and confirmatory methods are established.

The description of the starting material shall include the manufacturing strategy, purification/inactivation procedures with their validation and all in-process control procedures designed to ensure the quality, safety and batch to batch consistency of the finished product.

(4) Some relevant developments have taken place concerning the validation of phthalates migration test methods and the comprehensive risk assessment of these phthalates under Council Regulation (EEC) No 793/93 of 23 March 1993 on the evaluation and control of the risks of existing substances fn.

identification and recommendations on the priority areas for research and action including among others the potential health impacts of electromagnetic pollution sources and including particular attention to the development and validation of alternative methods to animal testing in particular in the field of chemical safety;

The CVMP was thereafter asked by the Commission to provide a scientific evaluation of the existing data including the state of validation of analytical methods for residue control, and to propose, if possible, residue limits for norgestomet for all target tissues including milk and for flugestone acetate for all target tissues except milk.

Addition of 13C-labelled 2,3,7,8-chlorine substituted internal PCDD/F standards (and of 13C-labelled internal dioxin-like PCB standards, if dioxin-like PCBs have to be determined) must be carried out at the very beginning or start of the analytical method e.g. prior to extraction in order to validate the analytical procedure.

(31) The SCTEE, consulted by the Commission. has concluded in its opinion of 28 September 1999 on TNO, LGC and United States CPSC reports on phthalate-migration test validation that none of the phthalate-migration test methods which have been subject to validation attempts is currently suitable for control purposes;

The procedure referred to in Article 8(2) shall apply in respect of the approval, on the basis of compliance with the principles laid down in Article 5, of the preparatory report and of the global implementation plan of each IDA project at the end of the feasibility phase and at the end of the development and validation phase, as well as the approval of any subsequent substantial amendments to that implementation plan.

"Product-or process-oriented" inspections (which may be "pre-marketing" inspections as relevant) focus on the manufacture of one or a series of product(s) or process(es) and include an assessment of the validation of and compliance with specific process or control aspects as described in the marketing authorisation.

Taking into account the response of CVMP and the need for further validation of the analytical methods, and the remaining scientific uncertainty, it is considered nevertheless appropriate to place norgestomet for all tissues and flugestone acetate for all tissues except milk in Annex III of Regulation (EEC) No 2377/90, in accordance with the conditions and the maximum residue limits specified for each of these substances in the Annexes to the present proposal for a Commission Regulation.

an active substance described in the European Pharmacopoeia or in the pharmacopoeia of a Member State when prepared by a method liable to leave impurities not mentioned in the pharmacopoeial monograph and for which the monograph is inappropriate to adequately control its quality, which is manufactured by a person different from the applicant, the latter may arrange for the detailed description of the manufacturing method, quality control during manufacture and process validation to be supplied directly to the competent authorities by the manufacturer of the active substance.

development, testing and validation of user equipment,

Model-independent and model-dependent performance parameters

MODULE V (EC TYPE-VALIDATION BY IN SERVICE EXPERIENCE)

Validation procedure

process validation

The validation procedure should:

Selection of validation agents

Where possible, the validation shall include a certified reference material in the collaborative trial test materials.

Process Validation Scheme for the Medicinal Product

Analytical Methods and Validation Reports

Where possible, the validation shall include a certified reference material in the collaborative trial test materials. A specific method has been validated by collaborative trial and has been shown to meet the requirements of Table 4 (c).

DATA VALIDATION PROCEDURE AND QUALITY CODES

This is an important pre-condition for the success of the validation of the method.

"Validation" means the establishment of documented and objective evidence that the particular requirements for a specific intended use can be consistently fulfilled.

methods of validation and reconciliation of data sources,

Moreover, revalidation shall be applied if key components in the procedure are changed, such as DNA polymerase (different supplier or product) or primers (new lot).

the testing and evaluation or validation of the method for detection;

two more campaigns are currently on-going (Vredepeel, Vienna).

The validation work is expected to be concluded by 2003.

For this diagnosis, within 24 hours after the index PCI procedure, there had to be at least two CK-MB values ≥ 3 x the upper limit of normal; thus, validation by the CEC was not required.

Some relevant developments have taken place concerning the validation of phthalates migration test methods and the comprehensive risk assessment of these phthalates under Council Regulation (EEC) No 793/93 of 23 March 1993 on the evaluation and control of the risks of existing substances(4).

scale-up, implementation and validation of methods in whole food chains;

The first two field validation campaigns (Madrid, Duisburg) have been completed;

internal quality control including specific validation procedures,