In the previous article entitled Critical Process Parameters (CPP) – What’s the Buzz, we had built an understanding regarding Critical Process Parameters and how their identification and selection is based on Critical Quality Attributes (CQAs) among many other factors.

Any manufacturer would like his process to be in a state of complete control, so that the drug product being manufactured shall be accurately, reliably and consistently meeting all the quality parameters. To control the variability in the finished goods, all other sources of variability has to be controlled viz. variability of raw materials by controlling Critical Material Attributes (CMA), variability of processes by controlling Critical Process Parameters (CPP) and variability in finished goods by controlling Critical Quality Attributes (CQA). Sources of variability that can impact product quality should be identified, appropriately understood, and subsequently controlled.

As per ICH Q8 CQA is defined as “a physical, chemical, biological or microbiological property or characteristics that should be within an appropriate limit, range, or distribution to ensure the desired product quality.” CQAs are intrinsic quality characteristics that are required to be met to ensure that the product manufactured are of good quality, and are safe and efficacious for the patient consuming it. CQA are the measurable outcomes of the process and hence, are considered as a fundamental for identification of CPP.

As per the example quoted in our previous article (Critical Process Parameters (CPP) – What’s the Buzz), in a blending process, blend uniformity is a critical quality attribute, means a blend should be uniform to produce a finished good meeting all the specifications. We all know that both the under blending as well as over blending may affect uniformity of blend which is a critical attribute responsible for the quality of the final outcome.

In a drug manufacturing process, there are many quality features that may impact final product characteristics. However, degree of impact of each quality attribute on the final product may vary. It is difficult to evaluate the impact of so many quality attributes on the final product.  Hence, a systematic approach involving principles of Quality Risk Management with an assessment of product for its safety and efficacy on patients is necessary.

Identification of CQA: Identification of CQAs of any product is important so as to study and control the product characteristics which have an impact on the product quality. Potential drug product CQAs derived from the quality target product profile and/or prior knowledge are used to guide the product and process development. Various factors on which identification and selection of CQAs depends are following:

  1. Finished goods specifications: Identification and selection of CQAs depends on the finished goods specifications and other relevant product attributes which may impact product quality. For pharmacopeial products, specification limits are defined, but for novel products or for products with in-house specifications, special consideration should be given to establishing finished goods specifications. It is highly expected that a multidisciplinary team shall systematically evaluate each product quality attribute in terms of the potential impact on safety and efficacy. Previous knowledge and experience may also form the basis of identification of CQA.
  1. Regulatory requirements: Sometimes there are obligatory regulatory and pharmacopeial quality requirements that are required to be evaluated.
  1. Quality Risk Management Approach: During the course of product development a manufacturer may come across many product quality attributes that may impact the final product. But all of them may not be critical and all of them may have different order of criticality. Hence, all the identified quality attributes shall be assessed with the Quality Risk Management Approach to fix the order of criticality or to separate out critical attributes from the non-critical quality attributes. For grading the risks based on the impact, the project team shall have thorough understanding of scientific principles and have prior knowledge and work experience in the relevant field.

Severity of harm (safety and efficacy) may prove to be an important assessment factor for distinguishing CQAs form other quality attributes.

Relevant CQAs can be identified by extensive quality risk management and experimentation that evaluates the degree to which their variation may impact product quality.

Important Considerations:

 

  1. Change in manufacturing process or advancement in technology may lead to change in CQA.
  2. The identified CQAs are dynamic. Based on the manufacturing experience (raw material variability, market complaints, OOS, non-conformance) and data generated, CQA may be added or deleted and specifications may be widened or narrowed down. However, all the proposed changes shall be supported with extensive data and subsequent documentation and shall be approved by the Quality Unit.

References:

  1. FDA Guidance for Industry, Q8, Q9, & Q10 Questions and Answers
  2. ICH Q8(R2) Pharmaceutical Development
  3. ICH Q9 Quality Risk Management
  4. ICH Q10 Pharmaceutical Quality System

Stay tuned for related articles on Critical Material Attributes (CMA), HACCP and many more.