Pharmaceutical manufacturing is an arduous task. With so many regulations, GMP’s, Quality Concerns, newer products, newer diseases, newer challenges coming up every now and then, it is really required that the professionals involved shall be performing the tasks with utmost care and precision. While designing a manufacturing process, a firm come across so many factors related to material, processes, end points, specifications etc. Multiple factors may directly or indirectly impact the finished product.

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. With the advent of Quality by Design (QbD) concept, there has been more emphasis on building the quality into the product. As per the concept of QbD, the quality is built into the product using knowledge of the process. QbD is a systematic process to generate robust processes.

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.

In this article, we shall be focusing on Critical Process Parameters.

As mentioned above, to reduce process variability CPP have to be controlled. Now this statement raises various questions.

What are CPPs? How to identify CPP? If a parameter is not a CPP then can we remove it from recording in Batch Manufacturing Record? Is it acceptable, if a non-critical process parameter does not meet a criterion of a process?

Let’s start answering all the concerns that come to our mind, but foremost is what is a Critical Process Parameter?

Critical Process Parameter: A process parameter or a measured variable whose variability has an impact on one or more Critical Quality Attributes (CQA). Therefore, it should be monitored or controlled within an acceptable range to ensure that the outcome of process meets the desired quality attributes.

For example, 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. Blending is normally done in a blender/ mixer. Blending process can be controlled by two parameters i.e. time and speed (RPM). A blender run for 5 mins at 20 rpm leads to a total of 100 rotations. However, same blender when rotated for 20 min at 20 rpm leads to a total of 400 rotations. Now, we all know both under blending as well as over blending may affect uniformity of blend which is a CQA. Hence, an optimum operating range for both the CPPs i.e. blending time as well as blending speed is required to be established to ascertain the outcome of blending i.e. blend uniformity.

Identification of CPP: Any manufacturing process consists of numerous unit operations. Hence, identification of CPP is a demanding activity. Identification of CPP requires a systematic approach. Scientific rationale and quality risk management (QRM) processes are used to reach a conclusion on what are critical process parameters (CPPs) for a given process. The CPPs are based on the probability of occurrence and detectability and therefore can change as a result of risk management.

Identification of CPP is done at the process design stage. The selection of CPP can be done by following below mentioned steps:

  1. Identification of Critical Quality Attributes: The foremost activity to be done for selection of CPP is to identify CQA. Identification of CQA shall lead to selection of potential CPP. 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 explained above by quoting an example of blending process, blend uniformity is a CQA which helps to identify and select blending time and blender speed as the CPPs.

This is important to understand that CQAs are dependent on finished good specifications. Hence, CPPs are indirectly dependent on finished goods specifications. 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.

  1. Knowledge about the processing equipment and unit operations: A pharma researcher involving in product development shall have thorough knowledge about the unit operation to be carried out and which equipment shall be used to carry out the said unit operation. As we know that the CPP is a measurable parameter that need to be evaluated during the process, hence, the equipment to be used for manufacturing the said product shall have provisions to operate and maintain within the desired parameters. A thorough risk assessment of various parameters of a unit operation may help to select the CPP objectively.
  1. Applying QRM approach to almost anything and everything of materials and unit operations: The firm shall follow the QRM approach to systematically examine all the raw materials, packing materials and unit operations for their impact on CQA. This will help to identify the parameters that have an impact on the product quality characteristics. Risks after identification shall be graded on the basis of the impact of risk. 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.
  1. Design of Experiments (DoE) and other appropriate experimentation: The information and knowledge gained from pharmaceutical development studies and manufacturing experience provide scientific understanding to support the establishment of the design space, specifications, and manufacturing controls. The relationship between the process inputs (material attributes and process parameters) and the critical quality attributes can be described in the design space.

Design of Experiments and various other appropriate tests helps to understand the impact of various process parameters on the product specifications.  Design of Experiments is a structured, organized method for determining the relationship between factors affecting a process and the output of that process.

Analyzing the experimental data helps to determine if a material attribute or process parameter is critical. If variability has an impact, then the same shall be monitored and/or controlled.

  1. Evaluation of CPP: After identification of CPP, the next important and practical issue that arises is the practical application. Ease of use, on-line measurements, ease of evaluation, safety etc. are some of the factors that need to be considered. CPP shall be adjustable to meet the intended target.

If a parameter is not a CPP then can we remove it from recording in Batch Manufacturing Record?

Certainly Not. All the process parameter whether critical or non-critical holds importance of their own. As discussed earlier, there are many factors which decides the criticality of a process parameter. The foremost factor is the QRM approach. During the initial stages of product development when experience with the product behaviour is far less, at that time risk assessments may be are less accurate. The understanding of criticality evolves during development and the product lifecycle. If some adverse event arises during the commercialization and on investigation it was observed to be related to a potential noncritical quality attribute, then one has to revisit the establishment of CPP. Hence, all process parameters are important and shall be recorded diligently.

Is it acceptable, if a non-critical process parameter does not meet a criterion of a process?

Certainly not. All process parameters whether critical or non-critical impacts the outcome of the process in its own unique way. Wherein all the CPPs shall be more critically assessed, non-critical process parameters shall be suitably documented and assessed. All the parameters shall meet the defined acceptance criterion.

 

Important Considerations:

  1. Change in manufacturing process or advancement in technology may lead to change in CPP.
  2. The identified CPPs and their operating ranges are dynamic. Based on the manufacturing experience (raw material variability, market complaints, OOS, non-conformance) and data generated, CPP may be added or deleted and ranges 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.