1. Purpose
The purpose of this guideline is to outline the content and approval process for analytical procedures, and to describe those activities that should be carried out to demonstrate that analytical procedures used in laboratories within R&D and manufacturing operations are suitable for their intended purpose.
2. Scope and Applicability
This guideline applies to qualitative or quantitative analytical procedures that are used to test finished drug product, in-process materials, excipients, raw materials, packaging materials and Active Pharmaceutical Ingredient (API), in support of regulatory registration documents and in cleaning validation.
Technology Transfer and Process Analytical Technology (PAT) are outside the scope of this document.
3. Definitions
3.1 Analytical Procedure
A controlled document that describes in sufficient detail how a specific analysis is performed.
3.2 Analytical Procedure Validation
Confirmation that the performance characteristics of the analytical procedure meet the requirements for the intended application. This is usually established by laboratory studies.
3.3 Analytical Procedure Revalidation
Confirmation that the performance characteristics of the analytical procedure continue to meet the requirements of the intended application, following changes to the specific procedure or the synthetic route/method of manufacture of the test material. This is usually established by laboratory studies.
3.4 Validation Protocol
A validation protocol is written plan or protocol stating how validation, sampling and testing will be conducted, defining roles and responsibilities, and defining acceptance criteria. Analytical procedure validation protocols may be generic or specific and their content will depend on the phase of development or marketing.
4. Responsibilities
Analytical procedures should be developed, validated and approved by the originating laboratory. This may be within Analytical, Microbiology, Device or Packaging, or Quality Control functions.
Analytical procedure validation reports should be written and approved as part of the validation process. Analytical procedure revalidation is the responsibility of the department that will routinely use the revalidated procedure. Quality Assurance will approve any local standard operating procedure that covers analytical method validation.
QA will ensure that analytical procedure(s) and validation exists as required by stage of development, or to satisfy commercial manufacturing requirements, when approving specifications.
5. Guideline
5.1 General Analytical procedures should be available for all stages of development and their content should be appropriate to the phase of development. All analytical procedures, which are used to generate data that could be included in a regulatory submission, must be validated to the degree appropriate for the phase of development before use.
Analytical procedures that are used to test a commercial finished product, raw material or packaging component, must be validated before use.
Analytical procedures in support of other activities, such as validation of cleaning processes, should be validated to the degree appropriate to their intended use.
It is essential to establish that analytical procedures produce data that are sufficiently accurate and precise for their intended purpose. Analytical procedures should be validated/revalidated when:
i) They are initially developed for a specific material and purpose.
(ii) They are used for materials, or purposes that are outside the original scope of the validation studies.
(iii) The materials or relevant manufacturing process has been modified
All departments or sites performing analytical procedure validation, or revalidation should have Standard Operating Procedures (SOPs) describing the process, responsibilities, and documentation requirements. All laboratory work must be conducted to appropriate GMP standards.
5.2 Validation Protocols
The line management in the developing laboratory shall ensure that approved validation protocols, either procedure specific or generic validation SOPs, are in place prior to starting any validation work.
This may take a form of the generic SOP, details listed in a laboratory notebook or equivalent, or a discrete document as considered appropriate to the stage of development. A GMP level, appropriate to the stage of development should be applied on what to validate. In early phases (phase I and II) while knowledge is obtained about the method acceptance criteria can be omitted.
This will then enable appropriate and correct acceptance criteria to be set when full ICH validation is performed during phase III and marketing.
5.3 Pharmacopoeial Procedures
Analytical procedures referenced in a Pharmacopoeial monograph or general chapter do not normally require validation. However prior to use, the suitability of a Pharmacopoeial procedure, including revisions, for dosage forms shall be established by performing a technical suitability review or by performing specific analytical testing on a sample(s) of the material subject to the monograph.
The outcome of the technical review or the results of the testing shall be documented and approved by the line function, including a decision as to the suitability of the procedure for routine use.
5.4 Analytical Procedures
The content of the analytical procedure should summaries the way the analysis is performed. It should describe in sufficient detail the steps necessary to perform each analytical operation.
This may include but is not limited to: the sample, the reference standard and the reagents preparations, use of the apparatus, calibration procedure, and any calculations used to process data. During Phase I and Phase II, procedures may be less detailed compared with Phase III and the marketing phase.
5.5 Analytical Procedure validation
The following characteristics are listed and defined by ICH and would be expected to form part of analytical procedure and/or validation studies (but not necessarily submitted) at the time of submission of the marketing authorization dossier.
(a) Accuracy
(b) Precision
(c) Specificity
(d) Detection Limit
(e) Quantitation Limit
(f) Linearity
(g) Range
(h) System Suitability
(i) Robustness
Analytical procedure validation is usually performed as part of a development programme. Validation information will be included in regulatory submissions, with increasing levels of detail as projects progress through development to the marketing phase.
As a guide each of the validation characteristics listed above should be considered. In the early phases of development, a reduced number of validation characteristics may be assessed according to local procedures.
When a new validated analytical procedure replaces an existing one, appropriate change control should be implemented according to local procedure.
Consideration should be given to a period of ongoing monitoring in order to determine whether the change has resulted in a step change in results. Note that biological testing, for example sterility, endotoxin testing and the microbiological examination of non-sterile products, will be validated in line with Pharmacopoeial requirements.
5.6 Validation reports
An assessment of validation studies demonstrating that the analytical procedure is suitable for its intended purpose shall be documented appropriately. For example as a summary in a laboratory notebook during the early phases of development.
The extent of validation conducted and the report format should follow a GMP level appropriate to the stage of development according to local SOPs.
A suitable validation report (e.g. hard copy, LIMS) should be written during Phase III and prior to technology transfer.