GUIA DE VALIDACION

Analytical Method Transfer: Points to Consider

• Method transfer can be via:

o Comparative testing:

 Most commonly used method where resulting data are compared with a set of predetermined acceptance criteria

o Co-validation between two labs:

 The receiving laboratory is involved in method validation but have to identify which validation parameters are to be generated or challenged by the two labs. Usually both labs generate a matrix of data that summarizes the suitability of the testing site, analyst, date of analysis, and instrumentation.

o Complete or partial method validation:

 A repeat of method validation either completely or partially.

o Transfer waiver (omission of formal validation):

 Needs justification as to why method transfer was not needed. For example, lab is already testing the product.

• Required Elements:

o Preapproved Test Plan/SOP:

 Protocol should describe the general transfer process and specific acceptance criteria.

• The document should define the responsibilities and scope of the transferring and receiving labs.

• Selection of materials and samples should be detailed. NOTE: In general, cGMP materials are not used for transfer activities since an OOS investigation could result and complicate clinical utility and/or market use.

• The identity and lot numbers of specific batches should be specified.

• COAs for all reference standards and samples should be provided as well.

• All instrumentation and associated parameters should be noted.

o Description of Test Methods:

 Include records of all methods used during the transfer. Any validation data should be provided to the receiving laboratory.

o Description of Test Requirements:

 The number of lots, replicates, and injections should be summarized. In the case of dissolution testing, the number of individual units should be stipulated too.

o Rationale for Test Requirements:

 Provide a rationale for the parameters chosen and overall impact on success of method transfer. Description should include any system suitability requirements.

o Acceptance Criteria:

 Transfer protocol should include suitable acceptance criteria.

o Documentation of Results:

 Results should be documented in a report that summarizes all the data.

Specifics regarding the MTI transfer:

• It would be helpful to specify what type of method transfer is being used (e.g., comparative, co-validation, etc.).

• If the method transfer is via comparative method, then the transfer protocol should specify the reference lot numbers and samples to be used and attach any body of relevant data (from the Restoragen labs) for those lots – that will be the basis of comparison. COAs should also be provided to MTI where available.

• The MTI protocol details the test method equipment and parameters, but it’s not clear if these are the same as what was used at Restoragen or if this is ‘comparable.’ It might help to note where parameters differ.

• It’s not clear that the MTI method will assess linearity. Although system suitability is assessed via replicate injections with different analysts and possibly differing equipment, it would still be useful to have some linearity data for the potential concentration range of the finished product.

• It’s not clear if the transferred method will also qualify the LOD and LOQ for comparison to the Restoragen method. This could be encompassed under some the dilutions described above.

• I think it might be helpful to specify what parts of the method validation (e.g., per USP) will be assessed in the method transfer. See notes on following page.

GUIDELINE FOR VALIDATION OF ANALYTICAL METHODS

1.0 PURPOSE AND INTRODUCTION:

The purpose of this document is to provide a general guideline for the drafting of analytical method validation protocols for chromatographic methods (HPLC and GC). However, the principles outlined are applicable to any method or assay used for QC testing of bulk API or Final Drug Product. These guidelines are generally consistent with those proposed by the USP, FDA, and ICH.

2.0 REFERENCED DOCUMENTS

2.1. Validation of Compendial Methods, Chapter <1225>, USP 23, p. 1982-4.

2.2 Reviewer Guidance: Validation of Chromatographic Methods, Center for Drug Evaluation and Research, FDA, November 1994.

2.3 International Conference on Harmonization (ICH); Guideline on Validation of Analytical Procedures; Federal Register, Vol. 61, No. 46, March 7, 1996.

3.0 RESPONSIBILITIES AND PRECAUTIONS

3.1 Quality Control personnel are responsible for the drafting of analytical method validation protocols and for providing reference to this document therein.

3.2 Quality Assurance is responsible for ensuring that this procedure has been applied to the drafting analytical method validation protocols appropriately.

4.0 Definitions

4.1 Accuracy (Recovery)

The accuracy of a method is the extent to which the average of a series of repeat measurements made on a product approximates the true value. For the drug product, this is typically carried out by the addition of known amounts of drug substance to the placebo formulation within the linear range of detection of the analyte.

4.2 Precision

Precision is the measure of how close the data values are to each other for a number of measurements under the same analytical conditions. It consists of three components: repeatability (injection repeatability and analysis repeatability), intermediate precision, and reproducibility.

4.2.1. Injection Repeatability

The relative standard deviation of multiple injections of a prepared sample under specified conditions by a single analyst on a single day.

4.2.2 Analysis Repeatability

The relative standard deviation of multiple measurements (preparations) of a sample under specified conditions by a single analyst on a single day.

4.2.3 Intermediate Precision

Intermediate precision (formerly known as ruggedness) is the degree of variation in results obtained by the analysis of the same material under a variety of normal test conditions. This includes variability on multiple days, between analysts, between instruments or any routine change in environmental conditions or component changes. It is expressed as a lack of influence on assay results over a variety of variability.

4.2.4 Reproducibility

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