Analytical Method Development and Validation in Pharma: Key Insights

Table of content

Introduction and outcome
Analytical Method Development and Validation
Elements of Analytical Analytical Method Development and Validation?
Quality Attributes of Analytical Method Development and Validation
Difference between Analytical Method Development and Validation
Advantages and Disadvantages of Analytical method development and Validation
Conclusion

Analytical method development and validation play a unique role at each stage of pharmaceutical development in managing quality, safety and efficacy. However, both require knowledge as well as expertise, which is why I decided to share my skill-based knowledge on this topic, In this article, you will learn about analytical method development and validation, their advantages, disadvantages, elements, quality attributes and differences between AMD and AMV with FAQs.

Analytical Method Development and Validation

What is Analytical Method Development?

Analytical method development is the innovative process of optimizing procedures for the analysis of pharmaceutical substances. It falls under the pharmaceutical research and development domain to ensure that pharmaceuticals meet regulatory standards for quality, safety and efficacy.

What is Analytical Method Validation?

Validation is the process of confirming that an analytical method is suitable for its intended purpose and produces reliable, reproducible results under specified conditions outlined in the method. This ensures that the method, once developed, meets specific regulatory requirements and can be used consistently for routine analyses.

Related Topics:

Elements of Analytical Analytical Method Development and Validation?

Elements of Analytical Analytical Method Development

The following are the main elements of the Analytical method development:

Objective: This section deals what is the purpose of the method such as:
- Identification
- Assay
- Related substances
- Content test
- Purity
- Reaction monitoring
Literature report: It is very helpful in selecting the analytical techniques for a new method.
Selection of Analytical techniques: The following techniques are widely used for analytical method development:
- HPLC (high-performance liquid chromatography)
- UPLC (Ultra performance liquid chromatography)
- GC (gas chromatography)
- Spectroscopic techniques such as UV Spectrophotometer and FTIR
- Titration
- TLC (Thin layer chromatography)
- HPTLC (high-performance thin layer chromatography)
- NMR (Nuclear magnetic resonance)
- GC-HS (Gas chromatography with headspace)
- GC-MS (Gas chromatography-mass spectrometry)
- LC-MS (Liquid chromatography-mass spectrometry)
- TGA (Thermal gravimetric analysis)
- XRD (X-ray diffraction)
- ICPMS (Inductively coupled plasma-mass spectrometry)
Optimization of Conditions: It contains procedures for optimising the method.
STP or Standard test procedure: It includes detailed procedures for performing pharmaceutical analysis.
Method development report or method verification report: Parameters like Specificity, Precision, Linearity, DL and QL are performed and the report is prepared to establish reliability of the method

Elements of Analytical Analytical Method Validation

The following are the main elements of the Analytical method development:

Approved Method or Monograph: It is required to prepare an analytical method validation protocol.
Analytical Method validation protocol: It is required to perform an analytical method validation study.
Analytical Method validation report: It contains validation study work.
Method validation parameters: Depending upon the criticality of the method all or some of the following parameters can be performed during method validation:
- Specificity: The specificity parameter is used to establish that there is no interference between an adjacent impurity peak or an impurity peak with the main peak or a blank peak with the main peak or an impurity peak.
- Accuracy and Recovery: The closeness of the measured value to the true value (the reference or accepted standard).
- Precision: The degree of reproducibility of results under normal operating conditions, typically evaluated by assessing repeatability and intermediate precision.
- Linearity: The ability of the method to give results that are directly proportional to the concentration of analyte over a specified range.
- Range: The interval between the upper and lower concentration limits within which the method can provide accurate and precise results.
- RRF or Relative response factor: It is calculated from linearity
- DL or Detection Limit: The smallest amount of analyte that can be reliably detected but not necessarily quantified.
- QL or Quantification Limit: The lowest concentration of analyte that can be reliably quantified with acceptable precision and accuracy.
- Robustness: The method’s capacity to remain unaffected by small variations in operational conditions
- Stability of Solutions: The Stability of Solutions is performed to avoid any failure during analysis in sequence

Related Topic: What is the difference between validation and verification

Quality Attributes of Analytical Method Development and Validation

The following main quality attributes play a vital role in Analytical Method Development and Validation:

Responsibilities
GLP (Good laboratory practice)
GMP (Good manufacturing practice)
SOP (Standard operating procedure)
Data integrity
CAPA (corrective and preventive action)
OOS (out of specification)
OOT (out of trend)
Technology transfer (TT)
Regulatory compliance
Audit management &
QBD (Quality by design) approach

Who are responsible for analytical method development and validation?

The following are the responsibilities of different professionals/ departments:

Analytical Professional/Validation Specialists: They are responsible to perform analytical method development and validation studies
Quality Control (QC) Professional: QC professionals are involved in method validation in reproducibility tests. They are not involved in Analytical method development
Regulatory Affairs Personnel: They coordinate with various regulatory agencies such as FDA, EMA and provide answers to any queries related to AMD or AMV.

What is the role of SOP, GLP, GMP, data integrity, CAPA, OOS, OOT and OOS in analytical method development and validation?

Method development and method validation intrinsically linked to GLP (Good Laboratory Practice), GMP (Good Manufacturing Practice), Data Integrity, SOP, CAPA (Corrective and Preventive Action), OOS (Out of Specification), OOT (Out of Trend) It has happened.

GLP (Good Laboratory Practice): GLP ensures that laboratory processes, including method development, are properly documented, validated, and performed with high standards of quality and integrity. GLP governs analytical research and chemical research activities.
GMP (Good Manufacturing Practice): GMP guidelines require that the methods used in the analysis of pharmaceuticals be thoroughly validated.
Data Integrity: Method development and validation activities must comply with stringent data integrity principles (e.g., ALCOA-Attributable, Legible, Contemporaneous, Original, and Accurate). This ensures that the data generated during these processes is accurate, complete, and traceable.
CAPA (Corrective and Preventive Actions): During method development and validation, any observed issues or deviations must be investigated and addressed using CAPA. If a method does not perform as expected or shows inconsistencies, CAPA procedures are implemented to correct the problem and prevent future occurrences.
OOS (Out of Specification): OOS refers to results that fall outside predefined acceptance criteria. It is only related to validation and not to development.

How are analytical method development and validation helpful in technology transfer?

Analytical method development and validation provide the technical basis to ensure that transferred technology produces consistently high-quality products, complies with regulatory standards, and minimizes the risks associated with transfer between sites or teams.

The analytical method development and validation are helpful in technology transfer in the following ways:

Ensuring Consistency and Reproducibility:
- Method Development: Developing robust analytical methods ensures that the same results can be obtained regardless of where the testing is performed. This is especially important when transferring technology across different sites or between different teams.
- Validation: The validation of these methods demonstrates that they consistently produce accurate results within specified limits, ensuring that the quality of the product is maintained even when produced in new locations or scaled-up processes.
Regulatory Compliance:
- Regulatory agencies (such as the FDA, EMA, etc.) require validated analytical methods for product testing, quality control, and stability studies. Proper validation ensures that the methods comply with these regulations, facilitating smooth technology transfer by reducing the risk of regulatory issues during inspections or audits.
Risk Mitigation:
- Analytical methods provide critical data on the quality attributes of the product, such as purity, assay, degradation products, and impurities. During technology transfer, having validated methods ensures that the new production process or manufacturing site will maintain product quality, thus minimizing the risks of batch failures or product recalls.
Reproducibility Across Different Stages of Production:
- Analytical method development and validation ensure that these methods are capable of maintaining the quality at different production stages
Data Integrity
- Validated analytical methods ensure the integrity of the data generated throughout the technology transfer process.
Training and Knowledge Transfer
- The analytical methods that have been developed and validated are often critical tools for training personnel at the receiving site. By transferring both the method itself and the rationale behind its validation, organizations can ensure that the new team has the necessary knowledge to maintain consistent product quality.

How analytical method development validation are helpful for Drug master file?

The analytical method development and validation plays a vital role in the submission, approval, and ongoing compliance of pharmaceuticals such as:

Ensures Consistency and Quality Control: It controls the quality of the pharmaceuticals such as assay, purity, impurity profile, and stability.
Supports Regulatory Compliance: Regulatory authorities require that all analytical methods used in the testing of pharmaceuticals must be validated according to the approved protocol
Demonstrates the Drug’s Safety and Efficacy: It plays a vital role in maintaining safety and efficacy of the pharmaceuticals.
Enables Stability Testing: Validated stability indicating methods (SIMs) are used to test the stability of pharmaceuticals over time, ensuring that they maintain their efficacy and safety during storage. Stability studies, supported by SIMs, are required for regulatory submissions.
Improves Traceability and Documentation: A well-documented validation process provides a clear, reproducible method for analyzing the drug. This documentation is crucial for the DMF, as it offers regulatory agencies detailed evidence that the product can consistently meet quality standards.
Facilitates Communication with Regulatory Authorities: The inclusion of comprehensive method development and validation data helps in addressing regulatory questions or concerns during the review process, providing a clear understanding of how the drug is tested and ensuring all regulatory requirements are met.

What is role of analytical method development and validation in audit inspection?

Analytical verification plays an important role in audit inspection in pharmaceutical industries. Method validation review is required in almost all audits.

How do Analytical Method Development and Validation fulfil Regulatory Requirements?

Analytical Method Development and Validation plays a vital role in DMF filing and answering the deficiency letter queries.

How is the Quality by Design (QBD) approach helpful in analytical method development and validation?

The QBD approach helps analytical method development and validation by providing scientific rationale in the understanding of critical parameters of the method, reducing variability, and ensuring reliability and compliance. This structured RFT (right first time) approach not only improves the efficiency of method development and validation but also reduces risk.

The QbD approach helps in analytical method development and validation in the following ways:

Understanding the Analytical Target Profile (ATP): It outlines the purpose of the method and the critical parameters that must be controlled to achieve the desired results. This focus helps avoid trial-and-error during method development and guides the optimization of method parameters.
Identification of Critical Quality Attributes (CQAs): In QbD, the Critical Quality Attributes (CQAs) are identified early and ensures that the method delivers reliable and consistent results under various conditions.
Risk Assessment and Control of Variables: It is very helpful in identifying the critical variables which may lead to failure of AMV or AMD.
Design of Experiments (DoE): QbD helps in using design of experiments (DOE) to systematically explore the effect of various factors on method performance. DOE helps in identifying the optimal combination of conditions (e.g., temperature, pH, mobile phase composition) for reliable method development. It is also helpful in finalising the validation protocol and in performing robustness test.
Analytical Method Transfer: QbD helps in Analytical method transfer from the Analytical laboratory to QC (quality control).
Cost-effectiveness: QbD helps in reducing Analytical method development and validation cost
Regulatory Compliance: QbD provides more robust rationale for decisions made during method development, allowing for more streamlined regulatory submissions, approvals, and compliance

Difference between Analytical Method Development and Validation

The following are the main differences between Analytical Method Development and Validation

Elements	AMD	AMV
Definition	AMD is an innovative work and it is performed to establish analytical conditions to perform analysis	AMV is a skill-based work and it is performed to establish the reliability of the developed analytical method
Selection of appropriate techniques	Required (e.g., HPLC, GC, spectrometry)	Not required. Established technique is used
Optimizing conditions	Required(e.g., mobile phase, temperature, detector settings)	Not required.
STP/Monograph	Not needed	Either STP or Monograph is required to perform AMV
Protocol	Not needed	Approved protocol is needed to perform validation
Literature report	Very helpful for AMD	Not needed
Samples	AMD may be performed using pure or impure samples	Representative samples with valid COAs are required to perform AMV
Standards/Impurities	AMD may be performed using individual sample or contaminated /impure sample or standard	Standards/Impurities (as mentioned in the monograph) with valid COAs are required to perform AMV
Validation parameters	Only selected parameters are performed to find out the criticality of the method and avoid any surprise/ failure during complete validation	All parameters (as defined in the validation protocol) are performed to find out the criticality of the method and avoid any surprise/ failure during complete validation
Report	Development report or verification repot or mini-validation report is prepared	Complete validation report is prepared
Approval process	Analytical project coordinator and Analytical head	Analytical/Validation project coordinator, Analytical /Validation head, QC head and QA head
GLP/GMP requirement	Performed under GLP environment	Performed under GLP and GMP environment
Data integrity	Must be maintained	Must be maintained
Guidelines	Not essential	Required
SOP	Not essential	Required
LIR	Not required	Required
QBD	Play a vital role in designing the development experiment	Play a vital role in designing the validation protocol

How helpful are Analytical Method Development and Validation?

Analytical Method Development and Validation are very helpful in:

Ensuring Product Quality, Safety and Efficacy:
- Analytical Method Development: Method must be able to provide specific, accurate, precise and reproducible results
- Validation: Validation ensures that the analytical method is suitable for the intended purpose
Supporting Pharmaceuticals Development
- During Pharmaceutical development, analytical methods are used to characterize, identify and quantify the pharmaceuticals
Regulatory Compliance
- Regulatory agencies such as FDA, and EMA require that pharmaceutical products meet quality standards. Analytical methods must be developed and validated to comply with regulatory guidelines..
- Validation provides documented evidence that the method is reliable. If the method is not validated as per the guidelines then many deficiency letter related questions may arise.
Ensuring Consistency
- Analytical methods ensure consistency in production batches during QC analysis
Controlling Impurities in Pharmaceuticals
- Be it purchasing the ingredients, reaction mix, intermediates and the final API method is used at every stage to monitor the quality
Stability Studies
- Stability indicating method plays a vital role about formation of degradation impurities during stability studies
Batch Release and Quality Control
- In quality control (QC), analytical methods are used to test and release or reject raw materials, in-process samples, and APIs. Hence, the method must be reliable and validated to avoid any failure
Risk Mitigation
- Analytical method validation helps to minimize analytical method risks and ensure the reliability of results.

Advantages and Disadvantages of Analytical method development and Validation

The following are the advantages of the Analytical method development and Validation:

Method reliability
Regulatory Compliance
Consistency in analytical result
Maintaining pharmaceuticals quality
Cost Efficiency
Risk Management
Data Integrity and Traceability
Reproducibility Across Laboratorie

The following are the disadvantages of the Analytical method development and Validation:

Both Analytical method development and Validation takes a lot of time
Needs knowledge as well as expertise
Costly activities

Conclusion

Method development and validation ensures that pharmaceuticals meet required quality standards and are safe for consumer use. I hope this article has helped you understand Analytical method development and Validation. You may also want to check out other articles on my blog, such as:

FAQs

What is the difference between Analytical method development and analytical method validation?

Analytical method development is an innovative task and is done to establish the analytical conditions to perform the analysis whereas AMV is a skill-based task and is done to establish the reliability of the analytical method developed.

References

ICH Q14

Abbreviations

AMD: Analytical method development
AMV: Analytical method validation
CAPA: Corrective and preventive action
OOS: Out of specification
OOT: Out of trend