CHEM ENG 4036 | Pharmaceutical Validation | The Concept Of Validation

Introduction

The concept of validation in the pharmaceutical industry has continuously been explored from 1978 in the U.S and even further advanced since 2011 as a result of technological development. The idea of validation has grown over the past decade to incorporate some activities from the quality control of medications using analytical methods to technical applications for clinical trials (Walsh et al., 2013). Therefore, validation is an aspect of quality assurance related to specific criteria. However, there exists a wide range of differences in criteria, and thus no general approach to validation and governing bodies like EC and FDA have designed universal optional procedures.

Validation can, therefore, be defined as providing documented evidence that offers high assurance. It is an integral element of quality assurance. A validated process is that which has been shown to provide a high assurance level that same lots will be generated that is up to expected specifications and thus has been approved officially (Sonawane et al., 2014). According to Boussadi et al. (2011) validation in itself doesn’t enhance processes but approves that the processes have adequately been designed in accordance with established procedures.

Advantages of Validation

Validation of pharmaceutical productions has given insight into the manufacturing processes, minimized the risk of averting difficulties and therefore guarantees the smooth flow of the production process. Parida (2010) observes that processes that undergo constant validation demands minimal support and takes less time. Validation has ensured that batch failures are at minimum and output is maximized. Furthermore, proper validation is reflected in product quality which is likely to expedite pr

Reasons for Validation

APIC (2014) assert that validation makes good business sense because without it would not be viable to utilize equipment which one is ignorant about. Pharmaceutical validation is necessary because the industry invests in costly materials, equipment, and experts. This necessitates the effective use of these resources to ensure the success of the pharmaceutical industry. Additionally, any product failures, rework, recalls, and protests are some of the critical elements that contribute to the production cost. According to Boussadi et al. (2011) validation is inevitable if the total production cost is to be minimized.

Process Validation

Process validation implies developing formal documentation of evidence which outlines the highest level of standard that a given system will endeavor to meet during production and quality of products.

Types of Process Validation

There are four main types of validation namely retrospective, prospective, concurrent validation, and revalidation. Retrospective validation is the development of documented evidence before process implementation so that a system undertakes what it is expected to do according to pre-established protocols. Retrospective validation is usually carried out when the process of a new formula requires validation before the initiation of pharmaceutical production (Wazade, Walde, and Ittadwar, 2012).

Prospective Validation is an approach applicable to processes, facilities and process controls that are in use yet have not undergone a documented process of validation. Prospective validation is carried out before a new product or production process is introduced. The process of validation is accomplished, and the outcomes are sanctioned before any of them is released to the market, thus establishing formal evidence before process implementation that a system is undertaken based on the already established protocols (Sajid, Arayne, and Sultana, 2010).

Concurrent validation is the same as prospective, except that the manufacturing company will release the product to the market during the qualification process at market price. This process comprises monitoring of significant processing procedures and product trials. This approach involves the replication of a validation process or some portion of it. The process is undertaken when a change or substitution takes place in the formulation, equipment or site location (Sajid, Arayne, and Sultana, 2010).

Revalidation comprises of the replication of the original validation or any of its section and entails analytical assessment of the current performance data. Revalidation is significant in the maintenance of approved status of the equipment, plant, production processes and computer systems. This approach can be initiated during the transfer of products between plants and when there is a need for routine monitoring of the outcomes of validation. Furthermore, the method is applicable when there is a substantial variation in batch size. It is also important to note that the scope of revalidation procedures rely on the degree of changes and the impact on the product (Wazade, Walde, and Ittadwar, 2012).

Phases in Process Validation

The activities associated with validation studies can be categorized into three phases:

Phase 1

This is the phase of pre-validation and includes all activities associated with product research and growth, development of pilot batch studies, relocation of technology to business scale batches, and qualification of equipment.

Phase 2

This is the process validation phase that is formulated to validate all recognized parameters of the critical process and to ensure that the set limits are valid and satisfactory. Production can take place in worst settings.

Phase 3

This phase is also called the validation maintenance phase, and it entails a routine assessment of all processes associated documents, in addition to verifying of audit reports, as an assurance of no changes to the process of production and that the outlined protocol has been followed. The validation team comprising of representatives from all primary departments guarantee that no modifications have been undertaken that would likely lead to revalidation and requalification (Ghosh and Dey, 2010). Appropriate design and approval of systems and process controls can develop a high level of trust that all manufactured products will meet the expected standards. The principle of good manufacturing practice (GMP) should be followed during the entire production process and control (Oechslein and Lazar, 2012).

Prior to the commercial distribution of any batch to consumers, the producers are required to ascertain a high level of assurance regarding the manufacturing process in that it will unfailingly produce API’s and drug products that meet the validation standards with regard to identity, quality, cleanliness, and effectiveness. It is expected that the manufacturer obtains the assurance from objective information and data from clinical or experimental studies.

Cleaning Validation

Cleaning validation is documented evidence that it is possible to always and effectively clean a system or equipment. Prabu, and Suriyaprakash (2010) appraise this approach and assert that it is essential because it is the requirement of a customer and guarantees safety and product purity. Cleaning validation creates an assurance in the internal control and the quality of the process. The United States Food and Drug Administration (FDA) inspection guide envisioned to include equipment cleaning anticipates companies to develop documented procedures specifying the cleaning processes in addition to documented general steps on how the cleaning process will undergo validation (Walsh, 2011). It is a requirement by the FDA that a final validation report ratified by the administration and which indicates successful or unsuccessful cleaning process is submitted. Gernaey, Cervera-Padrell, and Woodley (2012) further note that the data should be backed up by a conclusion indicating that the residues have been minimized to the acceptable level. Gernaey, Cervera-Padrell, and Woodley (2012) provided a review of cleaning validation strategy and ascertaining residue limits using sampling methods and indicated that a rise in the utilization of multi-purpose equipment had generated high interest in cleaning validation. Parida (2010) proposed the grouping of products or equipment for testing instead of testing all of them at once.

Formulation of Acceptance Criteria

The cleaning validation should show that the process always eliminates residues of the substance produced before to acceptable levels and that the cleaning process itself does not add the unaccepted levels of remaining materials to the equipment. The predefined parameters should be realistic, attainable and reasonable. In Active Pharmaceutical Ingredient (API) production it is possible for incomplete reactants and undesirable by-products to be present yet have not been recognized chemically. For that reason, it is essential to examine the principal reactants in addition to the by-products (Parida, 2010).

 Firms must show during validation that the cleaning process that is always used for given equipment reduces the risk of contributing to the unacceptable level. The formulated limit ought to be determined on the basis of a standardized scientific formula. The acceptance criteria if possible should be founded on the Acceptable Daily Exposure (ADE) calculations as long as there is the availability of data. The ADE outlines the limit beyond which a patient may regularly be exposed for a lifespan with acceptable hazards associated with severe health impacts. Industrial hygienists and toxicologists are typically involved in the determination of ADE of APIs and intermediates. These persons assess all existing toxicology and experimental data to calculate the limits. The calculation of the limit should also be documented (Parida, 2010).

Under certain circumstances data on toxicology or pharmacology may be restricted, for instance for production materials, chemicals or API’s in the first clinical trials, in such situations, general cleaning limits can be determined or cleaning limits which are a fraction of clinical doses. In the case of equipment cleaning, the acceptance criteria should be established on the basis of physically clean in conditions that are not wet and on an analytical limit. A qualified chemist with expert knowledge regarding the equipment and the clinical processes and the nature of the chemicals used should validate this aspect by assessing the specific situation (Parida, 2010).

Pros of Cleaning Validation

Cleaning validation is of importance to the pharmaceutical industry because it dissolves and visually eliminates the sample and can be used in multiple surfaces of different nature. APIC (2014) report that cleaning validation can be implemented in a wide range of settings because it is widely available and economically viable. Furthermore, the approach can be used in different cleaning agent residues such as in microbial and permits sampling of a specific site.

System Validation

System validation encompasses Computer system validation (CSV) which is defined as the process of guaranteeing that any technology element, whether hardware or software is achieving its objective based on the established controls for a given industry (Patela, Yogib, and Naranga, 2011).

A computer system validation in the pharmaceutical industry is vital to ensure that there is compliance with established procedures and to aid manufacturing companies to maintain the required quality continuously. Therefore, computer system validation examines the effectiveness and efficiency of the system in realizing the objective for which it was developed (Patela, Yogib, and Naranga, 2011).

Process of System Validation

Computer system validation relies on the intricacy of the project and is typically divided into the following stages namely master plan, project plan, installation qualification, operational qualification, and performance qualification (Patela, Yogib, and Naranga, 2011).

1. Master plan

The master plan is significant as it determines whether the conditions meet the user requirements. This phase involves the establishment of teams that will oversee the whole process.

2. Project Plan

This stage defines the standard procedures of operation for each step in the entire process in the validation evaluation program and is a sub-section of the validation plan.

3. Installation Qualification (IQ)

This involves a detailed phase of the installation process and develops checks and balances for all elements such as any new software or hardware installed into the system.

4. Operation Qualification (OQ)

This stage evaluates the precision of the operational functions and the entire security process. Both OQ and IQ are carried out together.

5. Performance qualification (PQ)

This stage checks for specific applications and is mostly focused on maintenance and undertakes performance checks.

Conclusion

Pharmaceutical validation is the most significant and standardized procedures of cGM. Validation in the pharmaceutical industry has evolved over time in its regulation practices with the changing technology. An effective validation programme is that which relies on information and knowledge derived from product and process design. Validation necessitates gathering of formal evidence associated with equipment, process or a farm. Revalidation can be prompted by the implementation of an existing modification of the control system; it can also be as a result of the ordinary, organized replication of the validation process. To meet the current standards of good pharmaceutical practices, organizations should establish a general validation policy which records the steps on how the validation will be undertaken. This will entail the validation of the manufacturing process, cleaning processes, control trials, and electronic systems. Finally, it can be resolved that the objective of validation is to demonstrate that procedures integrated into the design and production of drugs such as production and cleaning are effective and assures drug quality.

References

Active Pharmaceutical Ingredients Committee (APIC), 2014 Guidance on Aspects Of Cleaning Validation In Active Pharmaceutical Ingredient Plants.

Boussadi, A, Bousquet, C, Sabatier, B, Caruba, T, Durieux, P, & Degoulet, P, (2011), A business rules design framework for a pharmaceutical validation and alert system, Methods of information in medicine, 50(01), 36-50.

Gernaey, KV, Cervera-Padrell, AE, and Woodley, JM, 2012, A perspective on PSE in pharmaceutical process development and innovation, Computers & Chemical Engineering, 42, pp.15-29.

Ghosh, A, and Dey, S, 2010, Overview of cleaning validation in pharmaceutical industry, International journal of pharmaceutical quality assurance, 2(2), pp.26-30.

Prabu, SL, and Suriyaprakash, TNK, 2010, Cleaning validation and its importance in pharmaceutical industry, Pharma times, 42(07), pp.21-24.

Sonawane, LV, Poul, BN, Usnale, SV, Waghmare, PV, and Surwase, LH, 2014, Bioanalytical method validation and its pharmaceutical application-A review, Pharm Anal Acta, 5(288), pp.2.

Oechslein, C, and Lazar, MS, 2012, Process Validation from view report of the FDA, Maas & Peither AG–GMP Publishing, LOGFILE No, 3.

Patela, HV, Yogib, RR. and Naranga, E, 2011, A review on computer aided instrument validation, J. Chem, Pharm. Res., 3(2), pp. 134-143.

Parida, RK, 2010, Overview of pharmaceutical validation and process controls in drug development, Pelagia Research Library, 1(1), pp.11-19.

Sajid, SS, Arayne, MS, and Sultana, N, 2010, Validation of cleaning of pharmaceutical manufacturing equipment, illustrated by determination of cephradine residues, Analytical Methods, 2(4), pp.397-401.

Walsh, A, 2011, Cleaning validation for the 21st century: acceptance limits for active pharmaceutical ingredients (APIs): Part I. Pharmaceutical Engineering, 31(4), pp.74-83.

Walsh, A, Mohammad Ovais, MP, Altmann, T, Gr, FC, and Sargent, EV, 2013, Cleaning validation for the 21st century: acceptance limits for cleaning agents, Pharmaceutical Engineering.

Wazade, MB, Walde, SR, and Ittadwar, AM, 2012, An Overview of Pharmaceutical Process Validation And Process Control Variables of Tablets Manufacturing Processes In Industry. International Journal of Pharmaceutical Sciences and Research, 3(9), pp.3007.