Analytical Quality by Design (AQbD)

The concept of quality by design (QbD) in pharmaceutical industry has been introduced to enhance robust manufacturing process and to facilitate product quality. Quality is built in the product and process by

design and scientific approach.

As the number of  out-of-trend (OOT) results, out-of-specification (OOS) results are increasing in pharmaceutical industry and the current quality system is unable to address the growing concern,  a strategy to make a robust manufacturing process is felt and a cocept if QbD has emerged.

FDA has implemented the QbD concept first in drug formulation manufacturing processes as the finished drug products are directly consumed by the patients and any variation in the quality will adversaly affect the safety of the patients.

Similar to robust product development, an equally important analytical methods employed to test the quality of product must be robust and capable of producing accurate results. 

The benefits of implementing AQbD are

1.continuous improvement 

flexibility in regulatory filings

2.more robust and rugged methods for quality control labs

3.reduces OOS / OOT investigations  related to method performance 

4.more knowledge and understanding about about the analytical methods

5.avoiding re-validation

Analytical methods developed and used at quality control labs do have many variables that significantly affect the results. Some of the variables are  listed as

1.instrument settings

2.sample characteristics

3.method parameters 

4.choice of calibration models etc. 

To avoid re-validation of methods and to minimise the OOS and OOT results, analytical QbD (AQbD) is introduced during method development stage.

There are basically 6 stages involved in AQbD concept.

1.Analytical target profile 

2.Critical quality attributes 

3.Risk assessment

4.Method operable design region

5.Control strategy

6.Life cycle management

Analytical Target Profile (ATP)

“ATP is a statement that defines the method’s purpose which is used to drive method selection, design, and

development activities.” 

It determines what to measure and where and when to measure it. 

Define ATP and develop measurement requirements based 

on product quality target
product profile and critical quality

attributes.

Critical quality attributes (CQA)

Select appropriate analytical technique for desired measurement

defined in ATP. 

Define method performance criteria.

Accuracy and Precision are common

method performance characteristics for quantification of  impurities.

Risk assessment

Risks associated with method input variables, sample variation,

and environmental conditions shall be assessed.  It is assessed throughout the lifecycle.

Method development includes detailed assessment of the following risks associated with experimental variables such as instrument configuration,  column selection,

injection volume etc.

Assessment of risk associated with methods such as mobile phase variation, pH, column temperature, flow rate etc.shall be assessed for a robust method.

Method operable design region (MODR)

MODR is the operating range for the critical method input variable that produces results which consistently meet the goals set out in the ATP. 

It is based on a science, risk based and multivariate approach to evaluate effects of various factors on method performance. 

DoE ( design of experiments) in AQbD approach includes the following 

screening -  screening of input variables qualitatively 

optimization -  input variables Vs output measures quantitatively

DOE Tools - statistical analysis  is  important to interpret the data generated from input variables vs method responses. 

Different tools available for analysis are full factorial design, Taguchi methods, Plackett-Burman method, Pseudo-Monte Carlo sampling method etc.

surface plots -  data generated by input variables and output responses can be presented by 2D contour plot.

From the contour plots,  method response can be predicted and it can be verified by using actual experimental run.

method validation / verification - methods are validated as per ICH guidelines with robustness parameters one at a time. However method verification can be performed at robust operating ranges derived from MODR experiments.

Control strategy

Control strategy will be made based on various data collected during method development and method verification stages.

However, method controls will be made to ensure relation between method purpose and performance.

Control strategy is critical at every stage of the development and established at raw material testing,  inprocess testing, release testing as well stability testing through well defined analytical methods and appropriate specification controls.

Life cycle management

The analytical method  used in 

quality control department of the manufacturing unit for routine testing over the lifecycle of the product is monitored for its performance over the time to ensure

that the method remains in compliance with the defined ATP criteria. 

The performance of the method in quality control lab is monitored by using day to day  system suitability

analysis and laboratory investigation due to OOS / OOT results arises due to method related deviations and incidents and method related investigations.

 Analytical QbD