Industrial Process Validation of Tablets: A Review

Abstract

Tablets are used most in health care. They must be manufactured to the best quality. Process validation can assure the tablet products meet the pre-determined quality and can be reproduced consistently within the established limits. This review gives an introduction and general overview on process validation of tablet formulation. It is a requirement for good manufacturing practice and other regulatory requirements.

Keywords: Process validation, Tablets, Validation protocol, Process design

Introduction

Tablets are the most widely used solid dosage form of medicament. It has number of advantages over other dosage forms, such as: simplicity, lowest cost, high convenience, dosage accuracy and stability of drug substance. Tablet as a dosage form comprises a mixture of active substances and excipients, usually in powder form, pressed or compacted into a solid dose. The excipients can include diluents, binders or granulating agents, glidants and lubricants to ensure efficient tabletting; disintegrants to promote tablet break-up in the digestive tract; sweeteners or flavors to enhance taste; and pigments to make the tablets visually attractive. A film coating is often applied to confer specific advances, including protection of the drug from the surrounding, modifying drug release, masking unpleasant taste or odour of the drug, improving product appearance, making it easier to swallow and so on ^[1].

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Process validation is required by the Current Good Manufacturing Practices (cGMP) to consistently produce a desired quality product. In FDA guidance, process validation is defined as the collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality product ^2]. Process validation involves a series of activities taking place over the lifecycle of the product and process. Thus it requires the manufacturer to collect data throughout the whole product lifecycle and evaluate it scientifically and assess if it supports a quality process.

Process validation establishes the flexibility and constraints in the manufacturing process controls in the attainment of desirable attributes in the drug product while preventing undesirable properties ^[3]. Successful process validation contributes significantly to assuring reproducible drug quality in large scale manufacture, and may reduce the dependence on intensive in-process and finished product testing.

To validate the process used in the manufacture of tablets product and for revalidation in case of any change in the manufacturing process or any change in the composition of any ingredient. Traditionally, a minimum of three successive separate successful process batches are required to demonstrate consistency of the reproducibility. The manufacturing process should be controlled and all pre-specified product specifications should be within limits. However, the FDA considers a reduction to three batches as too simple for being able to prove validity of quality product ^[4]. The emphasis for demonstrating validated processes is placed on the manufacturer’s process design and development studies in addition to its demonstration of reproducibility at scale, a goal that has always been expected ^[4].The FDA encourages the use of science and risk-based approaches to determine the number of validation batches.

The FDA guidance describes process validation activities in three stages ^[2]。

1. Process Design: The commercial manufacturing process is defined during this stage based on knowledge gained through development and scale-up activities.
2. Process Qualification: During this stage, the process design is evaluated to determine if the process is capable of reproducible commercial manufacturing.
3. Continued Process Verification: Ongoing assurance is gained during routine production that the process remains in a state of control.

In FDA guidance, it indicates a large change of regulatory requirement from “quality by test” to the current “quality by design” throughout the lifecycle of the product and process. This regulation requires manufacturers to design a process, including operations and controls, which results in a product meeting pre-specified attributes. These encourage the use of sound scientific pharmaceutical development concepts, quality risk management, and quality systems at all stages of the manufacturing process life cycle. Thus we can using not only commercial-scale studies data including process qualification, but also those such as determination of CQAs and identification of process variables from laboratory experiments and pilot scale trials conducted during the process design stage. The goal of stage 1 is to design a process suitable for routine commercial manufacturing that can consistently deliver a product that meets its quality attributes. The number of validation batches for Stage 2 is determined by process knowledge obtained from Stage 1. In Stage 3, it requires a life-cycle approach with continuous verification and adjustment for improvement. When companies do a better and more systematic approach of process development depending on their experience and knowledge, then they will understand their processes and process control better and manufacture a robust product.

REASON FOR PROCESS VALIDATION:

Validation offers assurance that a process is reasonably protected against sources of variability that could affect production output, cause supply problems, and negatively affect public health ^[2]. The possible reasons cause variability may include ^[5]:

1. New product or existing products as per Scale-up and Post-approval Changes.
2. New formulation.
3. Change in formulation.
4. Change in site of manufacturing.
5. Change in batch size.
6. Change in equipment.
7. Change in process existing products significantly.
8. Change in the critical control parameters.
9. Change in vendor of API or critical excipient.
10. Change in specification on input material.
11. Abnormal trends in quality parameters of product through review during Annual Product Review (APR).
12. Trend of Out of Specification (OOS) or Out of Trend (OOT) in consecutive batches ^[6].

TYPES OF PROCESS VALIDATION:

1. Prospective validation is carried out during the development stage by means of a risk analysis of the production process, which is broken down into individual steps: these are then evaluated on the basis of past experience to determine whether they might lead to critical situations.
2. Concurrent validation is carried out during normal production. This method is effective only if the development stage has resulted in a proper understanding of the fundamentals of the process.
3. Retrospective validation involves the examination of past experience of production on the assumption that composition, procedures, and equipment remain unchanged; such experience and the results of in-process and final control tests are then evaluated.
4. Revalidation is needed to ensure that changes in the process and/or in the process environment, whether intentional or unintentional, do not adversely affect process characteristics and product quality.

VALIDATION TEAM:

Multidisciplinary teamwork is required for conducting and monitoring validation studies. Personnel conduct such studies should be qualified by training and experience. The working team would usually include the following staff members to work together to be effectives:

1. Head of quality assurance: Responsible for coordinate the entire validation process and schedule meetings with the team and review validation documents. Preparation of validation protocol, supervising the process, analyzing data and test results and preparing the final report.
2. Head of engineering: Responsible for qualification and calibration of all the processing equipment/instrument/utilities and maintains its efficacy during the manufacture process.
3. Validation manager: Responsible for the review of process validation protocol and execution of process validation. Also responsible for evaluation of results.
4. Production manager: Responsible for verification of process validation protocol and to ensure operation of the production equipment and support systems in order to manufacture the product within its design limits /specifications/ requirements.
5. Head of Quality Control: Responsible for verification of process Validation Protocol, report and co-ordination to ensure operation of the Lab instrument and support systems in execution of the validation process.

Process validation protocol:

A validation protocol showing how validation will be performed, including test parameters, product characteristics, production equipment, and decision points on what constitutes acceptable test results ^[8]. It should include the following items:

1. Purpose
2. Scope
3. Responsibilities of assessment team
4. Acceptance criteria
5. Critical process and product parameters
6. Product details
7. Reference documents for method of manufacturing and testing
8. Reason for validation
9. Bill of raw materials
10. Equipment details
11. Process flow chart
12. Critical process stages to be validated
13. Summary of validation batch
14. Remarks
15. Evaluation of results, conclusion and recommendations

VALIDATION REPORT:

At the end of the Process Validation a Validation report is need to be prepared. The tests results and conclusions of Validation Protocol documented and summarized in a process validation report. The validation report should include the following items:

1. Aim of the validation study
2. Batch No. and Batch size
3. Process summary
4. Verification of critical process controls
5. Conclusion
6. Attachments

Industrial process overview of tablet manufacturing:

Process validation of manufacture tablets involves all the critical parameters challenged in pharmaceutical unit operations like dry mixing, granulation, milling, blending, lubrication, compression, coating, etc. Tablet manufactured process overview is showed in figure 1. A general process steps and product parameters inclusion in the process validation protocol is summarized in table 1. Several process parameters which need to be tested in the manufacture process may have some impact on production of tablets. When understanding of these parameters and their interactions with the respective processes, it will collect rational data for the building of validation evidence and fixing the optimum process parameters. Every processing step is validated for all batches and the results obtained must be present within the acceptance criteria. Throughout manufacturing certain procedures should be validated and monitored by carrying out appropriate in-process controls and finished product tests ^[9]. In-process tests and finish product tests during tablet production see Table 2. The figure 2 and 3 illustrate sampling locations at wet granulation and blending stages. All validation of the manufacturing process and the in-process controls should be documented.

Figure 1 Tablet manufactured process overview

Table 1 Process and Product Parameters Considered During Tablet Dosage Form Manufacture

Table 2 In-process controls and finished product tests

CONCLUSION:

The manufacturing process is released for regular production after careful evaluation of the validation documentation. The efficient process validation is a key element in the development of pharmaceuticals. Both experience and knowledge are important factor for ensuring successful process development and validation. The more you understand the process in the early stages, the less you will need to do to validate it later. A strong mentoring and training program is also attributed much. When the process variables were under control, it reveals that there was no significant variation between batch to batch. In product lifecycle, continued validation will help to ensure the pharmaceutical products with the quality and reproducibility.

References

[1] Pawar Avinash S, Bageshwar Deepak V, Khanvilkar Vineeta V. Advances in Pharmaceutical Coatings. International Journal of ChemTech Research, 2010(2, 1): 733-737.

[2] Guidance for Industry: Process Validation: General Principles and Practices. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), Center for Veterinary Medicine (CVM), January 2011.

[3] Leon Shargel, Isadore Kanfer. Generic Drug Product Development: Solid Oral Dosage Forms [M]. Drugs and the pharmaceutical sciences, 2005(194): 121-123.

[4] Questions and Answers on Current Good Manufacturing Practices, Good Guidance Practices, Level 2 Guidance – Production and Process Controls.

[5] Sharma Ajay, Saini Seema. Process Validation of Solid Dosage Form: A Review. International Journal of Research in Pharmacy and Science, 2013, 3(2): 12-30.

[6] Jignakumari Manubhai Tandel, Zarna R Dedania and KR. Vadalia. Review on Importance of validation IJAPBC. 2012; 1(3).

[7] WHO Expert Committee on Specifications for Pharmaceutical Preparations – WHO Technical Report Series, No. 863 – Thirty-fourth Report.

[8] U.S. Food and Drug Administration. Guideline on General principles of Process Validation. Rockville, MD; May, 1987.

[9] The Third Supplement to the Fourth Edition of The International Pharmacopoeia.