Process Validation in Tablet Manufacturing: A Regulatory Compliance Case Study, Emphasizing Critical Process Parameters and Critical Quality Attributes

In pharmaceutical manufacturing, documented evidence that a manufacturing process operates within established parameters and consistently produces a product that meets its predetermined specifications has been provided [1]. From a Quality Assurance (QA) perspective, this is not merely a procedural step but a comprehensive, lifecycle-based framework that ensures patient safety and product efficacy.

QA ensures that every step of the process validation, from the initial design to the final verification, is meticulously documented. This documentation serves as a verifiable and defensible record that demonstrates compliance with regulatory requirements. It includes protocols, reports, raw data, and statistical analyses, which provide a high degree of assurance that the process is in a state of control.

The modern quality assurance principle of process validation (PV) moves beyond simple batch testing by taking a holistic view of the entire product lifecycle, starting from the first stages of product development [2]. The QA team was responsible for overseeing and approving the validation activities for all three stages:

Process Design: This initial stage is heavily influenced by the Quality by Design (QbD) principles. The Formulation and Development (F&D) team will develop a new formulation for the dosage form, ensuring that the process is designed with a deep understanding of how material attributes and process parameters affect product quality [3, 4].

Equipment Qualification: The Quality Assurance (QA) team is responsible for verifying that all equipment and facilities are qualified (Installation Qualification), operate as intended (Operational Qualification), and that the process as a whole can consistently produce a quality product (Performance Qualification) [5].

Continued Process Verification: This ongoing commitment to quality. QA establishes a system of routine monitoring and trend analysis to ensure that the process remains in a state of control over time, allowing for the early detection of potential deviations or process drift.

To ensure product quality and regulatory compliance in Nepal, the Nepalese pharmaceutical industry has to align with both national and international standards. QA teams in Nepal are tasked with implementing a quality management system (QMS) that not only adheres to the Department of Drug Administration's (DDA) guidelines but also incorporates internationally recognized standards, such as WHO-recommended Good Manufacturing Practices (WHO-GMP). This dual-compliance approach ensures that locally manufactured products are a standard that is safe for the local population and potentially marketable on a global scale. This proactive stance on quality and compliance is essential for the growth and credibility of the country's pharmaceutical sector [6, 9].

1. MATERIALS AND METHODS

Stages of Process Validation

The process validation lifecycle is a systematic approach to quality assurance that includes three key stages.

1. Process Design

This initial stage involves the development of a robust manufacturing process based on scientific understanding and prior knowledge. It includes:

• Formulation Development: From a Quality Assurance (QA) and Quality by Design (QbD) perspective, formulation development is far more than simply selecting ingredients. It is a scientific and risk-based stage that lays the foundation for a robust and controllable manufacturing process. The goal is to build quality into the product from the very beginning rather than relying on testing at the end to ensure quality [10].
• Process Flow Design: This is a critical and meticulous stage that lays the groundwork for all subsequent validation activities. It involves more than just a list of steps and is a detailed visual and documented representation of the entire manufacturing process. Process flow design serves as the foundation for identifying Critical Process Parameters (CPPs) and establishing control strategies. By outlining the precise sequence of manufacturing steps, it can pinpoint where variations might occur and implement appropriate controls to mitigate risks. This ensures that the process is not only reproducible but also in a state of control, providing a high degree of confidence that the final product will consistently meet its predetermined quality specifications.

Risk Assessment: As guided by the principles of ICH Q9 on Quality Risk Management, it is a crucial and proactive stage in process validation. Its importance lies in the fact that it shifts the focus from a reactive approach to a proactive one. Companies can establish robust control strategies before manufacturing begins by systematically identifying and evaluating potential risks to the product quality. This ensures a higher degree of assurance that the process will consistently produce a quality product, thereby minimizing the need for extensive in-process or final product testing and reducing the likelihood of costly deviations or recalls [10].

2. Equipment Qualification

Equipment qualification is a documented process that proves that equipment is suitable for its intended use, ensuring that it functions correctly and consistently meets regulatory and operational standards [11]. This involves the following four primary elements:

• Design qualification (DQ) is a documented process that ensures that the design of a facility, equipment, or system is suitable for its intended purpose and meets all the necessary regulatory and process requirements before construction begins. It involves a thorough review of design documents against user requirement specification (URS) and a risk assessment, ensuring that potential design flaws are identified and mitigated early to prevent issues during later stages of the validation process, such as Installation Qualification (IQ), Operational Qualification (OQ), and Performance Qualification (PQ).
• Installation Qualification (IQ): In the context of a simple coated tablet, IQ is the documented verification that key equipment and systems are correctly installed in the designated facility. For a coated tablet, this means meticulously checking that the sifters, rapid mixer granulator, binder paste making kettle, multimill, fluidized bed dryer, blender, tablet compression machine, tablet auto coater, primary packaging machine, and air handling units are installed according to the manufacturer's specifications and the approved design drawings. It includes verifying the correct utility connections (e.g., compressed air, electricity, and water), calibrating all instruments, and ensuring that the equipment is properly leveled and secured. A successful IQ confirms that the equipment is ready for operation and is a critical prerequisite for the next stage of validation, Operational Qualification.
• Operational Qualification (OQ): It is the documented verification that all critical equipment, including those for granulation, drying, compression, and coating, can operate within specified limits.

Granulation: OQ involves challenging the granulator by running it at the high and low ends of its specified mixing time and speed to ensure that it produces granules with the desired size and density.

Drying: For a fluidized bed dryer, the OQ verifies that the inlet and outlet air temperatures and airflow rates can be controlled and maintained at set points to achieve a consistent moisture content in the granules.

Compression: OQ for a tablet press involves verifying the machine's ability to maintain consistent compression force and turret speed, ensuring the production of tablets with uniform hardness and weight.

Coating: OQ for a tablet coater would confirm that critical parameters such as pan speed, spray rate, and inlet air temperature are precisely controlled to ensure a uniform and defect-free coating.

In all these stages, the successful completion of OQ provides assurance that the equipment is capable of performing as intended, and is a crucial step before initiating performance qualification.

• Performance Qualification (PQ): PQ is documented evidence that the entire manufacturing process consistently produces a quality product under normal operating conditions. This ensures the reliability and reproducibility of the process from start to finish, as demonstrated across multiple batches.

Sifting: The PQ for sifting verifies that the equipment consistently produces a uniform powder by effectively removing agglomerates and foreign particles without damaging the material.

Granulation: This PQ stage confirms that the granulation method consistently produces granules with the target size, density, and flow properties across multiple runs.

Drying and Milling: The PQ for drying and milling demonstrates that the processes consistently achieve a specified moisture content and uniform particle size distribution, which are both crucial for successful compression.

Blending and Compression: The blending PQ ensures that the final blend is homogeneous, whereas the compression PQ confirms that the tablet press consistently produces tablets that meet all quality specifications, such as weight, hardness, and friability.

Coating: PQ confirms that the coating process consistently applies a smooth, uniform, and defect-free coating that meets all quality attributes, such as appearance and dissolution profile.

Primary Packaging: Finally, the PQ for primary packaging proves that the line consistently seals the tablets into blisters, strips, or bottles, ensuring product integrity and stability throughout its shelf life.

3. Continued Process Verification

Continuous Process Verification (CPV) is an ongoing phase of the Process Validation lifecycle that ensures that the manufacturing process remains consistently in a state of control after initial validation. This is a proactive approach focused on continuous quality improvement.

Key Components of CPV

Routine Monitoring: This involves real-time or periodic collection of data on CPPs and critical quality attributes (CQAs). These data were collected during every production run. For example, in a tablet manufacturing process, this could include monitoring tablet hardness, dissolution rates, and blend uniformity. Data should be systematically collected and recorded for future analysis.

Data Analysis: The collected data were analyzed using statistical tools to identify trends and detect any unwanted variability. Statistical Process Control (SPC) charts are often used to visualize the data and determine if the process is within acceptable limits. This step helps to identify small, gradual drifts in a process before they lead to a significant quality issue.

Corrective and Preventive Actions (CAPA): When the analysis identifies a deviation or negative trend, CAPA is initiated. This involves a root cause investigation to understand why the deviation occurred. Corrective actions are implemented to fix the immediate problem, and preventive actions are implemented to ensure that the issue does not recur. The effectiveness of these actions was then verified through continued monitoring.

4.  CQAs and CPPs

Understanding the relationship between CQAs and CPPs is vital for process validation. Key CQAs for tablets, their associated CPPs, and the validation parameters used to assess them include the following:

• Content Uniformity, a CQA that ensures that each tablet has the correct amount of active ingredient, is directly influenced by several CPPs. The blending time and speed are crucial for achieving a uniform mix, whereas the powder particle size and blend fill volume must be controlled to prevent segregation. To validate this CQA, an Assay Test was performed, with the % Relative Standard Deviation (RSD) being a key validation parameter; a low RSD confirms a consistent dose.
• The Dissolution Rate is a CQA that measures how quickly the drug is released from a tablet, a factor that is significantly affected by various CPPs. The compression force is a primary CPP, as a higher force can create a harder tablet that dissolves slower. Other influencing CPPs include granule porosity, binder concentration, and mixing time. This CQA is validated through Dissolution Testing, where the dissolution profiles  are key validation parameters used to ensure correct drug release.
• Tablet Hardness and Friability are interconnected physical CQAs that measure a tablet's strength and resistance to breaking. These attributes are primarily governed by the compression force applied during the manufacturing process. Other CPPs, such as dwell time and granule moisture content, also play a role. These CQAs were validated using a Hardness Tester and a Friability Tester, with the mean hardness and % friability being key validation parameters, respectively.
• Disintegration Time, a fundamental CQA, measures how quickly a tablet breaks down into smaller particles. This attribute is largely controlled by the compression force, because a harder tablet takes longer to disintegrate. The amount of disintegrant used and the lubricant blending time are also important CPPs. This CQA is validated with a Disintegration Tester, and the validation parameter is simply the time it takes for the tablet to disintegrate within a specified limit.
• Tablet Weight Variation is a CQA crucial for ensuring consistent dosing. This is directly controlled by CPPs such as the feeder speed, fill depth, and turret speed of the tablet press. Consistent granule flow properties are also vital. To validate this CQA, a Weight Check was performed on individual tablets, and the mean weight and standard deviation were the key validation parameters, confirming a consistent tablet weight across the batch.
• Moisture Content is a CQA for both powder blends and finished products that can impact stability and compressibility. It is controlled by CPPs, such as the drying temperature and time during granulation. This CQA is validated using the Loss on Drying (LOD) method, and the validation parameter is the measured moisture content, which must fall within a strict acceptable range.

5.   Regulatory Framework in Nepal

In Nepal, the Department of Drug Administration (DDA) is the primary regulatory body that oversees pharmaceutical manufacturing. The DDA has established guidelines that align with international standards, such as WHO-GMP and ICH, to ensure the quality and safety of pharmaceutical products. Key documents and guidelines include the following:

• Medicine Registration Guidance 2073 [6]: Outlines the requirements for drug registration, including submission of process validation data.
• National Guidelines for Good Practices for Pharmaceutical Quality Control Laboratories, 2075 [7]: Provides guidance on quality management systems for analyzing APIs, excipients, and finished products.
• Updated National GMP Code 2072 [8]: Serves as a key regulatory document ensuring adherence to quality standards.
• Common Working Document for Manufacturing and Marketing License in DDA: This document is the main procedural guide for setting up a new pharmaceutical company or launching a new drug to ensure compliance with national standards.

6.   Case Study: Process Validation of KASFOL 5 Tablets

B. Methodology and Process Control

CPPs and CQAs have been identified and evaluated at various manufacturing stages, including dry mixing, granulation, drying, lubrication, and compression [12–15]. The key parameters monitored included the following:

• Dry Mixing: The rapid mixer granulator (RMG) was operated at 50 RPM, and samples were tested at different time intervals to validate a dry mixing time of 8 min.
• Drying: Granules were dried in a Fluidized Bed Dryer at a temperature of 50°C for three–four hours. The moisture content was measured to ensure that it was within the specified limits, confirming a consistent and reproducible drying process.
• Lubrication: Similar to the dry mixing stage, the lubrication process was validated with the RMG set at 50 RPM to confirm a lubrication time of 5 min.
• Compression: The compression machine was set to an RPM range of 16–20 and a pressure of 3 tons. During this stage, in-process samples were taken at the initial, middle, and final stages to test for weight variation, hardness, thickness, friability, disintegration time, and assay.

7.   RESULT AND DISCUSSION

The results from the three validation batches demonstrated that all critical quality attributes met their predetermined acceptance criteria throughout the manufacturing process.

• Blend and Content Uniformity: Blend and Content Uniformity: The assay results for both the dry mixing and lubrication stages showed a Relative Standard Deviation (RSD) of less than the 5% limit, confirming the homogeneity of the blend (Table 1). All individual assay values were also within the acceptance range of 90%–115% of the label claim (Figures 1–3).
• The moisture content of granules at three different times is shown (Table 2, Figure 4).
• Lubrication assay of all three validation batches at 2, 3 and 5 minutes time point is shown (Table 3, Figures 5–7). At 2 minutes, excellent uniformity (low RSD), but note the wide variation in mean assay values between the top, middle, and bottom layers, especially in FOT-17. This suggests that mixing is not yet complete or perfectly uniform, although the RSD is low. At 3 minutes, RSD remains very good. However, for batch FOT-16, the RSD jumps to 2.962%, which is significantly higher than its 2-minute value. While still passing, this fluctuation suggests the process may not be at its most stable or homogenous point yet. At 5 minutes, RSD is consistently low and stable across all three batches, ranging from 0.861% to 1.783%. Crucially, the assay values between the top, middle, and bottom layers for each batch show less deviation than at the 2-minute mark (e.g., FOT-17's averages are tighter: 107.1%, 103.4%, 106.6%). This stability indicates the blend has reached optimum homogeneity and is unlikely to suffer from over-mixing or segregation from this point.

Thus the assay values are within the acceptance limit of 90%–115%, and a 5 minutes mixing time is suitable for validation in the procedure.

• Tablet Physical Properties: The overall physical and chemical parameters were within the acceptable limits as per pharmacopeial and in-house requirements (Table 4). The compressed tablets from all three batches showed physical properties within the specified limits. Average weight (Figure 8) was between 87.87 mg and 102.15 mg, hardness was NLT 3 kgf, and friability (Figure 9) was NMT 1%. The disintegration time for all batches was well within the NMT 15-minute limit, and all the final tablet assays met acceptance criteria.
• Final Product Testing and Yield: Final product samples taken after primary packaging were confirmed to be within the required specifications for all tested parameters, including dissolution and assay. The overall process yields for the three batches were consistent and reproducible, indicating a controlled manufacturing process.

Process Overview and Critical Parameters: The manufacturing process for KASFOL 5 tablets involves several critical stages. The validation report meticulously monitored and documented the following process parameters.

• Dry Mixing: The mixing of dry ingredients is a critical step to ensure content uniformity.
• Preparation of Binder Paste for Granulation: This process was controlled to ensure proper granule formation.
• Granulation: The duration and speed of wet mixing were monitored to achieve uniform granulation.
• Drying and Sizing: The drying process was controlled to achieve the specified moisture content, while sizing ensured a uniform granule size range.
• Lubrication: This step was validated to ensure mix homogeneity, proper flow, and prevent sticking during compression.

Validation Results and Discussion: The validation protocol established clear acceptance criteria for all CQAs. The results from all three batches demonstrated consistent product quality, meeting the predetermined specifications for critical attributes, such as content uniformity, hardness, and dissolution rate. The successful outcome of this validation confirms that the manufacturing process, as in the Batch Manufacturing Record (BMR) for KASFOL 5 tablets, is robust, reproducible, and capable of consistently producing a product that meets its quality attributes.

The studies provide proof of robustness, as there is stability and reproducibility through a three-batch concurrent validation, which is a key industry practice. The strength of this report lies in its comprehensive evaluation of CQAs and detailed monitoring of CPPs, such as blending speed and compression force. The quantitative data, such as the low RSD for content uniformity, offers strong, verifiable evidence of a consistently homogeneous blend.

However, areas of critical consideration exist. The small batch size of 250,000 tablets raises questions regarding the scalability of the validated process for larger commercial production. The validation can be made more robust by establishing a design space that explores a range of acceptable parameter values instead of just single points. Additionally, the report can be improved by explicitly stating the specific acceptance criteria for each test and by including the actual yield percentages for each batch. Finally, while the report mentioned drying, a deeper critical analysis of all associated variables, such as airflow rate, would provide a more complete picture of process control.

8.   CONCLUSION

Process validation is an essential component of tablet manufacturing, which ensures that products consistently meet quality standards and comply with regulatory requirements. By adhering to national guidelines such as those from the Department of Drug Administration and international standards such as WHO GMP and ICH, the Nepalese pharmaceutical industry can achieve robust and reliable production processes. The case study of folic acid tablet IP exemplifies this framework in practice, highlighting that systematic validation and continuous monitoring are vital for quality assurance and patient safety in the local context. Based on the validation data, the manufacturing process for KASFOL 5 tablets was considered stable, consistent, and reproducible. The results provide a high degree of assurance that the process consistently yields a product that meets the predetermined quality attributes and specifications. The methods employed were validated and can be routinely followed.

REFERENCES

1. Patel B, Bathiya AS, Chauhan NF, Chaudhary AB. A comprehensive review: Concurrent process validation of antihypertensive drug in solid dosage form (tablet). Gradiva Rev J. 2022;8(4):276–83.
2. Jain S, Krishnan NJ, Jayaprakash JW, Pillai RP, Jaganathan JN, Raju BV. Lifecycle approach to process validation and its implementation in the pharmaceutical industry. Int J Pharm Qual Assurance. 2024;15(3):1845–56.
3. Patel R, Kesarpu S, Patel B. Systematic implementation of quality by design (QbD): A perspective from generic pharmaceutical industries. J Pharm Res Int. 2025;37(4):38–56.
4. Tambe K, Bonde S. A review on: Applications of pharmaceutical quality by design in product development. World J Pharm Sci. 2017;5(1):1–80.
5. Jain K, Bharkatiya M. Qualification of equipment: a systematic approach. Int J Pharm Erud. 2018;8(1):7–14.
6. Government of Nepal, Ministry of Health, Department of Drug Administration. Medicine registration guidance. 2016. Available from: https://giwmscdntwo.gov.np/media/pdf_upload/Medicine%20registration%20guidance_s8xkieh.pdf
7. Department of Drug Administration. National guidelines for good practices for pharmaceutical quality control laboratories. 2075 B.S. Available from: https://giwmscdnone.gov.np/media/pdf_upload/202308170641National%20Guidelines%20for%20Good%20Practices%20%20For%20Pharmaceutical%20Quality%20Control%20Laboratories%2C%202075_rztygjg.pdf
8. Department of Drug Administration. Updated national GMP codes. 2072 B.S. Available from: https://giwmscdnone.gov.np/media/pdf_upload/Updated%20National%20GMP%20Codes_v8615tq.pdf
9. U.S. Food and Drug Administration. Guidance for industry: process validation: general principles and practices (revision 1). 2011. Available from: https://www.fda.gov/media/71021/download
10. Yang S, Hu X, Zhu J, Zheng B, Bi W, Wang X, Wu J, Mi Z, Wu Y. Aspects and implementation of pharmaceutical quality by design from conceptual frameworks to industrial applications. Pharmaceutics. 2025;17(5):623.
11. Likhitha B, Bhuvana C, Swathika B, Aroon A. Equipment qualification and maintenance in pharmaceutical manufacturing: strategies for efficiency and compliance. World J Pharm Res. 2024;13(9):298-306. doi:10.20959/wjpr20249-31742.
12. Thapa P, Choi DH, Kim MS, Jeong SH. Effects of granulation process variables on the physical properties of dosage forms by combination of experimental design and principal component analysis. Asian J Pharm Sci. 2017;12(3):253–60. doi:10.1016/j.ajps.2017.03.001.
13. Chauhan R, Dewangan DK, Dwivedi J, Jha AK. Effects of granule particle size and lubricant concentration on tablet hardness containing large concentration of polymers. Braz J Pharm Sci. 2017;53(3):e00149. doi:10.1590/s2175-97902017000300149.
14. Morin G, Briens L. The effect of lubricants on powder flowability for pharmaceutical application. J Pharm Sci. 2013;102(10):3594–602. doi:10.1002/jps.23660.
15. Jakubowska E, Ciepluch N. Blend segregation in tablet manufacturing and its effect on drug content uniformity—a review. Pharmaceutics. 2021;13(11):1909. doi:10.3390/pharmaceutics13111909.

Tables And Figures:

Figure 1. Dry mixing Folic acid assay at 3 minutes.

Figure 2. Dry mixing Folic acid assay at 5 minutes.

Figure 3. Dry mixing Folic acid assay at 8 minutes.

Table 2. Moisture content of granules at three different times.

Figure 4. Moisture content of granules of study batches.