A comprehensive validation framework addressing utility parameter validation for application in small and medium enterprises (SMEs):A case study in pharmaceutical industry

Abstract

Purpose: The purpose of this paper is to provide a validation framework to guide future validation practitioners towards completing utility validation projects in small and medium enterprise successfully and in shorter duration compared to current practice. Design/methodology/approach: Literature review was carried out on various existing validation frameworks to analyse the positive and negative elements of the frameworks. The identified positive key elements from this analysis were incorporated to develop a comprehensive validation framework that can be used by future validation practitioners to validate utility system in manufacturing companies. Findings: The case study results proved the capability and effectiveness of the new framework as the validation of the reverse osmosis water system was completed successfully with proper documentation and within shorter period compared to previous validation projects in the case study company. Research limitations/implications: The proposed validation framework is well suited for use in small and medium enterprise companies. Further studies should be carried out to ascertain the effect of the framework. Originality/value: This paper provides a comprehensive validation framework that can guide future validation practitioners towards completing validation projects in small and medium enterprise companies successfully and in shorter period.

Keywords:

• Food and Drug Administration
• Good Manufacturing Practice
• pharmaceutical industry
• reverse osmosis
• small- and medium-sized enterprise
• utility validation
• validation framework

1. Introduction

Quality of products manufactured is the main target of any industry. Achieving this target is the main interest of manufacturing companies, especially pharmaceutical industries which produce health-related products (Nandhakumar et al., 2011). Muddukrishna et al., (2016) emphasized that good personal hygiene is highly required in pharmaceutical companies to avoid any type of contamination which affects the quality of medicinal products, and this will ensure the production of hygienic, safe and top-quality medical products. This is essential since these products are used to treat patients and have direct impact on consumers’ lives. As such, pharmaceutical manufacturing companies which are capable of producing such products of requisite attribute and quality consistently with fast delivery and at the lowest possible cost would always be customers’ choice. In order to achieve this goal, the Food and Drug Administration (FDA) has introduced Good Manufacturing Practice (GMP) to maintain and improve the quality level of pharmaceutical products. GMP covers all the aspects of manufacturing process which ensures products are consistently produced appropriate to the intended use and as required by the marketing authorization. Hence, pharmaceutical companies adopted GMP to ensure that their products are manufactured to specific requirements including strength, quality and purity (Brhlikova et al., 2007). One of the major GMP requirements is that all the manufacturing facilities, utilities and equipment in the pharmaceutical industries must be properly validated before released for production use.

Food and Drug Administration (2008) defined validation as a collection and evaluation of data which establishes scientific evidence that an equipment, utility or facility is capable of consistently delivering quality products. In pharmaceutical view, validation referred as a process of establishing documented evidence that manufacturing facility, utility and equipment must be properly installed, functioned and performed in order to support the manufacturing of high-quality pharmaceutical products. Validation is a process of assurance that the specific equipment or system is able to achieve the predetermined acceptance criteria to confirm the attributes what it purports to do (Rajinder, 2008).

According to Manalo and Brown (1993), inaccuracy of the validity of equipment, utility or any other system may exist if the equipment, utility or any other system is not validated adequately, thus, affecting the quality of the final product. Validation can help pharmaceutical companies save significant maintenance cost as the validated equipment and systems will yield products that are consistent in quality with minimum defects and machine downtime. This results in less maintenance works and rejects. Processes running at marginal level often incur costs because of re-inspection, re-testing, rework and rejection. Validation leads to the optimization of processes and minimizes these expenses (Haider, 2001). The top reason for compulsory requirement of validation in pharmaceutical industries is the safety of the patients, and Pelletier (2005) believes that the safety of the medical products consumed by patients worldwide is ensured by validation. Properly validated system and equipment will perform at optimum level and this will increase the capacity of the system or equipment, which plays a major role in maximizing the production yield. High yield can often become reality by having through comprehensive planning, validation, analysis and specification definition (Eastham, 2012). There are many types of validation activities practiced in pharmaceutical industries such as cleaning validation, method validation, software validation and process validation, which include facility validation, equipment validation and utility validation. Each type of validation comprises four stages of qualification which are design, installation, operational and performance qualification.

Utilities like purified water system must be validated prior to the production use to ensure the purity of the water such as ionic and total organic compound of the water meet the requirements (Khutia et al., 2010). Purified water must be free from any unwanted elements in the physical, chemical and biological characteristics, which may damage the product quality. Similarly, temperature, relative humidity, air change per hour, pressure difference between production rooms and corridor, air borne particle count and microbial test of the HVAC system must be validated to assure all these environmental parameters are within the acceptable limits before the system is released for production. Any deviation in these parameters can certainly affect the product characteristics. For instance, deviation in pressure difference between production rooms and corridor may result in cross-contamination which is considered highly critical in pharmaceutical industries. Likewise, compressed air system validation must ensure that the oil content of the system must be maintained at oil free level. This is highly necessary to avoid product contact with the machine components which use compressed air which may cause oil contamination of product.

Proper validation documentation provides knowledge to others involved in each steps of the lifecycle of a product or process (Singh, 2012). Validation document contains permanent record of the specific validation procedures and related performance. It also verifies that each machine or system does exactly what it is supposed to do.

Pluta (2011) highlights that validation teams in pharmaceutical industries have difficult tasks and face various problems when implementing validation projects. Some validation personnel make common mistakes which often results in the failure of their validation projects which eventually costs their company time, money and effort (Greb, 2008). The major reason for this failure is the common deficiencies found in validation documentation. Based on the research carried out on validation work performed at a FDA regulated company, it was found that 41% of the failures in validation projects were contributed by deficiencies found in validation documentation (Houston, 2009). This scenario is caused by existing validation frameworks in the pharmaceutical world which are not capable and effective enough to assist the users to carry out a complete and successful validation, especially preparing and completing validation documentation properly. Pharmaceutical companies face uphill task to manage projects efficiently without proof of process which are accessible when needed (ABS Group, 2017). Validation documentation is an evidentiary for validation.

However, pharmaceutical industries are facing many issues in producing complete and quality validation documentation. Some of the major hurdles faced by validation practitioners are missing information, unavailability of required documents, no clear guidelines, no standard validation terms and unverifiable test results. According to Houston (2009), records or fundamental information that is missing out from validation documentation is a common problem faced by pharmaceutical companies. Due to the inadequate and unclear description on the requirements in the validation documents, the suppliers often fail to provide the necessary and auditable documents such as material clarification certificates to the validation party. Obtaining necessary documents for validation is often a frustrating exercise (Amer, 2008). Timothy (2011) highlights that one of the main issues which often fail the validation projects is the difficulty to understand guidelines in validation protocols which are not thorough and understandable. Manufacturers are often confused when using different validation terms to refer the same process in validation protocols. For example, the term of “Acceptable Limits” is also mentioned as Acceptance Criteria’ by other manufacturers. In addition, supporting documentation for a manufacturing process tends to be diffuse during validation (Santos, 2016). Test results which are unverifiable make life difficult for validation implementers to verify actual results against the expected results. The word “OK” is written in the results column instead of actual value of the test results. Meanwhile, for small- and medium-sized enterprises (SMEs), proper documentation can seem like an uphill task. This is attributed to the problems faced by SMEs which may have difficulties in understanding and managing the complexity of customs documentation due to their more limited resources (Arteaga-Ortiz & Fernández-Ortiz, 2010). According to Rufaro et al. (2008), SME sector often faces a number of constraints especially in accessing finance, markets, training and technology. The availability of skilled staff or experienced managers remains the most serious problem for a quarter of EU SMEs (European Central Bank, 2019). In 2020–2021, the FDA issued more than 200 warning letters to drug companies which includes 80 citations for procedures not in writing or fully followed and 44 citations for the absence of written procedures (Robert Fenton, 2022). All the problems discussed proved that improper documentation became a major factor causing validation failures. However, a clear and easily understandable validation framework can help the new or existing validation practitioners to complete validation projects smoothly and successfully. This gives rise to the research question: what criteria are necessary to be included in the framework so that the framework can be used to validate the utility system successfully. Therefore, the aim of this research is to develop a framework that addresses utility system validation in small and medium enterprises effectively. This paper introduces the background of validation in section 1, followed by section 2 which presents literature review on existing validation frameworks to identify the positive elements to be integrated into new validation framework. Development process of the new validation framework by integrating identified key elements is explained in section 3. Section 4 elaborates the results of the case study using newly proposed validation framework in a pharmaceutical company in Malaysia. The results, analysis and the advantages of using proposed validation framework are discussed in section 5. The conclusion drawn from the results is presented in section 6.

2. Literature review

Framework can be defined as a structure for driving or providing a foundation toward achieving the goal of the project. Rouse and Putterill (2003) believe that the frameworks have their own strength and functionality which are very useful in providing prescriptive and direction for the users. A framework must be in place or developed first before initiating a validation project. However, Yusof and Aspinwall (2000) came out with few basic design requirements which must be fulfilled in order to build a good framework. It must be simple, systematic and can easily be understood by users. The link between the elements in the framework must be clear and the framework must have the flexibility to be adapted to different contexts.

Analysis was carried out on selected existing validation frameworks which were categorized into phase flow framework and steps flow framework based on their structure. Phase flow frameworks reflect different phases in which validation activities move from one phase to the following phase during the validation. In contrast, step-by-step validation activities throughout the validation process are illustrated by step flow frameworks. Key elements from the reviewed existing frameworks which were found to be potential to contribute to a potential successful validation project were also discussed.

LIMS validation framework (International Society of Pharmaceutical Engineers, 2018) plays a major role in achieving Good Laboratory Practice in regulated industries. This is possible because this step flow framework is capable to eliminate manual, tedious and error prone operations. The framework offers appropriate mix of customer and vendor which helps to achieve the validation target effectively. This framework is very comprehensive since it has risk-based validation plan developed by customer and user requirements specification as well as traceability matrix. Capability of obtaining consistency, reliability, integrity and accuracy of data is the positive element of this framework. However, no protocol preparation before conducting qualification is the main pitfall of this framework which may delay the qualification process.

Sigma validation framework (Six Sigma Inc, 2006) contains a total of 14 validation steps. Some of the positive elements identified from this framework are review, change, user requirement specifications (URS), the protocol preparation and execution of installation qualification (IQ), operational qualification (OQ), performance qualification (PQ), training, document verification and final approval. Review step will maintain the system or equipment from moving out of the validated state. Change control will initiate revalidation when there is a part change or modification on the system. Documentation errors during validation execution can be minimized or eliminated by pre-approval of IQ, OQ and PQ protocol before actual execution. In addition, validation steps will be performed in the best way possible as a result of proper training provided for validation personnel.

Typical 4 Qualification (4Q) validation framework (Smith, 2007) depicts procedures that need to be executed and acceptance criteria that need to be met to perform the qualification. Besides offering positive elements such as user requirement specifications (URS), installation qualification (IQ), operational qualification (OQ) and performance qualification (PQ), this framework practices revalidation process when there is a major repair, modification or the transfer on the system or equipment. Revalidation will ensure the validated status of the system or equipment is maintained and not affected by any modification or transfer activity.

Typical validation framework (Wrigley & Preez, 2005) parallels the engineering and validation activities. The special aspect of this framework is the ability to conduct engineering and validation activities concurrently. For example, installation and operational qualification activities can be executed concurrently with the installation of the equipment or system which can save time and cost of projects. Also, data for design qualification are provided by user requirement specifications which confirms and ensures that all those requirements comply with Good Manufacturing Practice rules.

Process validation framework (Thermo Lab System UK, 2000) provides validation planning and summary reports as key elements which can contribute to the development of new framework. Validation planning defines the overall validation methodology to be used throughout the project and allows the validation personnel to schedule the validation activities accordingly. Summary report will summarize the whole validation activities like validation procedures, results, findings and recommendations. Risk analysis is the major element identified from GAMP4 validation framework (GEA Pharma System India Private Ltd, 2012). It will help the project team to trace all activities from risk detection and avoid unnecessary activities which waste time and money. Meanwhile, Operational and Performance Qualification validation framework (West, 2019) highlighted the combination of execution of Operational and Performance Qualification, which can shorten the validation period as well as save cost by minimizing usage of documents.

GAMP5 (Good Automated Manufacturing Practice 5) was developed by Labman System (2013) to validate vial filling system for the production process. This framework contributes user requirements specification, functional specifications, hard ware and software design specifications. Process validation framework by Khushboo et al. (2014) offers six validation steps which are planning, installation qualification, operational qualification and product qualification to confirm whether the product specifications meet the acceptance criteria, on-going monitoring of product quality and revalidation if any deviation is found in the product specifications.

V Waterfall validation framework (Brook, 1986) which is categorized under phase flow validation framework allows the detection of flaws at initial stage of the system. The communication between phases can be handled in an improvised manner in the process of Sashimi validation framework (Takeuchi & Nonaka, 1986) in which the phases are overlapping in this framework. Therefore, before the completion of one phase, the following phase would already be underway and this can save time and money. Key element of Spiral validation framework (Boehm, 1988) is the high amount of risk analysis in the system. The analysis on the Simple Waterfall validation framework (Boehm, 1988) identified revalidation and validation on each step of the validation process as the main strength of this framework. W validation framework (Herzlich, 1993) is flexible enough to adjust to a situation where an organization has different set of development stages.

VEE validation framework (Forsberg and Mooz, 2005a) is based on project cycle and represents a progressive product development process. User requirements are used to ensure a product or system is built according to its specification. The maintenance of ongoing operation is carried out to ensure the system meets the stated requirements. Forsberg and Mooz (2005) also modified their original VEE framework to produce Architecture VEE validation framework, which implements planning of validation activities. In 2006, Forsberg and Mooz introduced Entity validation framework which emphasizes on direct correlation between activities on the left and right legs of the framework at each elaboration. User requirements, risk investigations, validation planning and preparation are executed in this framework.

The first step in this research was reviewing and analysing previous and existing validation frameworks which were introduced and practiced in validation projects. Frameworks from various sources and background which were divided into step flow and phase flow were selected for this study. The advantages and the pitfalls of those reviewed validation frameworks as well as their simplicity and the complexity were given great consideration in this step. This analysis resulted in the identification of potential elements that can offer major contribution to the development of the new validation framework. Then, the total number of validation phases that need to be deployed in the new framework was determined and followed by employing the identified key elements and new steps as the steps of the new framework. These steps were then grouped in sequential manner according to the functionality of the determined validation phases. Mapping approach was used to map the steps in sequence to provide user a good knowledge on the flow of the validation steps. To help the user complete the steps, input and output information of the steps were given to the framework in order to help the user complete the steps. In the end, the newly developed framework was evaluated and followed by re-structuring of the framework based on the framework design requirements. Finally, a SME company in Malaysia which manufactures pharmaceutical products was selected to apply case study to validate the newly developed validation framework. A newly installed reverse osmosis water system was validated using the new validation framework.

Based on the analysed validation frameworks, it was found that none of the frameworks which are appropriate to validate utilities in pharmaceutical industries. Furthermore, most of the frameworks were found to be too complicated and difficult to understand. Even so, there were few positive elements identified from the literature studies of these frameworks which have the potential to be incorporated into a new utility validation framework. The potential contributing elements are validation planning, user requirement specifications, risk analysis, installation, operational and qualification protocol preparation followed by execution, summary report, periodic review and revalidation. In addition, new key element such as deviation analysis was introduced into this framework to detect root cause of equipment breakdown and propose the following corrective action to overcome the problem. This will provide a clear step-by-step guideline on how to execute a utility validation smoothly and effectively in the small and medium enterprise company. All these key elements were incorporated into the new utility validation framework which was structured based on the four phases which are planning, requirement, qualification and maintenance as shown in Figure 1.

Figure 1. 4 phase validation framework.

3. Framework development

Take in Figure 1

The new framework is named as 4 phase validation (4PV) framework based on the number of phases in the framework. Planning phase is the initial phase of the framework that consists of validation planning, which covers validation team formation (Step 1) and project schedule (Step 2). According to Antoine (2021), the first step of the validation process is for management to form the cross-functional validation team and make sure they have the time and resources to complete the project. Each member in the validation team which comprise of experts from related departments will be assigned respective tasks in order for them to carry out and complete their tasks in validation projects properly. The project schedule is necessary to enable the validation team to execute each step in the validation project according to the schedule and complete within the timeframe allocated. The next phase is requirement phase that focuses on user requirements specification (Step 3) which details the end user’s requirements for the individual aspects of the equipment and system. This will help suppliers to design and supply the utility system according to customer’s requirement. This phase also implement impact assessment (Step 4) which applies Risk Priority Number (RPN) system to evaluate the risk level of the system in order to determine the extent of validation process required. The preparation of qualification protocols (Step 5) for installation, operational and performance qualifications will ensure the availability of the documents before the actual execution. This will ensure the qualification is started immediately after the installation and executed smoothly and this will save qualification time. The following phase is qualification phase where installation qualification (Step 6) of the system will be performed by verifying physical features and design specifications of the system and related documents. This will be followed by operational qualification (Step 7) in which the functionality of the buttons, switches and components of the system will be tested and documented to confirm the system functions as required by customer. To prove the efficiency level of the system, performance qualification (Step 8) will be executed by collecting samples of products of the system and tested if the characteristics of the products meet the requirements. This will confirm the system produce products with expected quality. Validation summary report (Step 9) which summarizes the overall qualification activities such as procedures, acceptance criteria, results, analysis and discussion of the results, completes the qualification phase and also the utility system validation project. Therefore, the system will be released for production use. Periodic review ((Step 10) will be performed periodically on the validated system under maintenance phase where the deviation analysis (Step 11) is carried out to initiate revalidation if the system deviates from its validated status. Else, the system will be continuously monitored periodically according to the maintenance schedule. Between, the cause of the deviations will be rectified and necessary part change or modification on the system will be implemented before revalidation (Step 12). Apart from that, relocation of the system from one area to another in the manufacturing plant or from one plant to another too requires revalidation after the reinstallation of the system which will maintain the validated status of the system. The comparison between elements of existing frameworks and proposed new framework is explained in Table 1.

Table 1. Comparison between elements of existing frameworks and proposed new framework

STEP	ANALYZED EXISTING FRAMEWORKS	4 PHASE VALIDATION FRAMEWORK
Planning	SIGMA (Six Sigma Inc, 2006)No validation planning such as team formation and project schedule available to run the validation project successfully and according to the schedule.	Team Formation: Validation team members played great teamwork by performing their tasks respectively which led to the proper completion of all the validation procedures.
		Project schedule: All the validation steps were completed according to the schedule in Gant chart.
User requirement specifications	Provided physical, functional and characteristics requirements as well as the regulatory requirements of the newly installed reverse osmosis water system and its acceptance criteria to facility engineer for designing purposes and validation engineer for protocol preparation.
Impact assessment	GAMP5 (Labman System, 2013)No risk analysis provided to determine the extent of validation required for the system. Thus, unable to eliminate unnecessary tasks.	Assessed the criticality of the reverse osmosis water system by calculating risk score which determined the validation level (installation, operational and performance qualification) required for the system.
Protocol preparation	Process validation (Khushboo et al., 2014)No earlier validation protocol preparation to accelerate installation, operational and performance qualification process. This may result in qualification protocols with errors and without acceptance criteria and delay validation procedures.	Validation protocols were prepared, checked and approved earlier, thus, available before the commencement of validation procedures.
Installation, operational & performance qualification	Entity (Forsberg & Mooz, 2006b)No specific terms was used to refer installation, operational and performance qualification. Validation and verification were the terms used to refer qualification activities which were very general.	Ensured that the physical characteristics of the reverse osmosis water system were according to the acceptance criteria and the related documents were available.
		Ensured the reverse osmosis water system functioned according to the requirements.
		Ensured the chemical and biological characteristic level of the water produced by reverse osmosis water system were within the acceptable limits.
Validation summary report	Typical 4 Qualification (Smith, 2007)No validation summary report produced to summarize all the validation activities and results to enable the system released for production.	Summarized activities of the whole validation project of reverse osmosis water system and recommended procedures to maintain the system under validated status.
Periodic review & deviation analysis	Architecture VEE (Forsberg & Mooz, 2006b)No maintenance or periodic review was practiced to monitor the system. Therefore, the system may move out of validated status if any deviation occurs. No deviation analysis available to document any deviation in the system which initiate trouble shooting and revalidation.	Periodic review: Physical characteristics and functionality of the reverse osmosis water system were monitored by implementing preventive maintenance and calibration quarter annually. Parameters of water produced by the system were monitored weekly for six months to ensure the system maintained under validated status.
		Deviation analysis: To identify the root cause for the deviation occurred and suggests corrective action required.
Revalidation	Operational and Performance Qualification, West, 2019)No revalidation offered if the system relocated or any deviation in the physical characteristics, functionality or performance level of the system which decide product quality.	To revalidate the system if there is any deviation on the physical conditions, functionality or water parameters of the system which may affect the water quality and also when there is a relocation of the system.

4. Framework validation

A case study method was used to validate the newly formed utility validation framework. To meet the demand of high volume of products, an established local pharmaceutical company based in Ipoh City, Malaysia which manufactures various pharmaceutical products has installed a new reverse osmosis water system in its’ plant. The new utility validation framework was applied to validate this reverse osmosis water system before released for production use in order to meet Good Manufacturing Practice requirement.

A validation team comprising experienced personnel from compliance, quality control, production and facility departments was formed to execute reverse osmosis water system validation. The compliance manager was selected to lead the team which also consists of validation engineer, quality control engineer, facility engineer and senior facility technician. The main duty of compliance manager was to initiate and monitor the whole project as well as verify results and approve protocols and reports. Each other member of the team was assigned respective tasks to be carried out. After having a meeting, the validation team released the validation project schedule in the form of Gant Chart which detailed the time frame for each procedure that need to be performed during validation.

There was a meeting held between the validation teams, production and quality assurance personnel to discuss about the requirements for the purified water to be used in production. As a result, the user requirement specifications report which contains the physical, functional and characteristics requirements as well as the regulatory requirements of the newly installed reverse osmosis water system and its acceptance criteria was released and approved by related department heads.

The criticality of the utility system was assessed by carrying out the impact assessment process in which criticality assessment checklist was filled to calculate the risk score in order to determine the extent of validation required for the new reverse osmosis water system. This was done based on the ideas and views by production and facility personnel regarding the impact level of the reverse osmosis water system on product quality. The reverse osmosis water system has direct impact on product quality and the impact assessment resulted in the risk score of 24. The high score indicated that the water system is critical to water and product quality, thus, required installation, operational and performance qualification.

While waiting for the reverse osmosis water system installation by supplier, the validation engineer prepared the installation, operational and performance qualification protocols based on the details provided by the supplier, catalogue and approved user requirements specification report. The validation engineer also had discussion with production personnel to obtain details on their requirements which must be stated in the qualification protocols which were circulated for approval by head of related departments.

The installation qualification was executed concurrently with reverse osmosis water system installation in which the proper installation and specifications of the components of water system such as cooling tower and ultra violet lighting house were verified according to the pre-prepared installation qualification protocols and the results were documented. Besides, the availability of documents such as standard operation procedure, material clarification certificates, instrument calibration certificates and technical drawings were also verified during installation qualification. A validation document checklist was prepared to ensure all the necessary documents are attached to the final report. Since no deviation was found in the installation qualification, the validation process moved to the next stage which was operational qualification. The facility engineer assisted supplier to carry out installation qualification tests and witnessed by validation engineer.

Operational qualification was carried out by testing the functionality of the switches, buttons, alarm and interlock systems in the reverse osmosis water system. The testing was done by the supplier according to the procedures stated in the operational qualification protocol and witnessed by validation engineer. It was found that storage tank water pump continued functioning even though the overload relay for the component was activated. The supplier rectified the problem immediately and replaced the faulty overload relay for the storage tank water pump with a new one. The replaced component was retested to confirm it functioned according to requirement before the validation process proceeded to the performance qualification. Table 2 illustrates the results of installation and operational qualification carried out on the reverse osmosis water system in the case study company.

Table 2. Reverse osmosis water system qualification test results (Installation & Operational qualification)

Installation Qualification	Meet specification?	Operational Qualification	Meet specification?
Validation related documents (SOP, system & electrical diagrams, manual, material & calibration certificates, pressure leak test report, welding report, maintenance & calibration log books, calibration & preventive maintenance schedule) must be available.	Yes	Each button and switch of the system must function according to the requirements	Yes
Surface of the components and system must be smooth, free from scratches and corrosion	Yes
Material certificate must be available to prove that the product contact parts are made of stainless steel 316 L or 304 grade	Yes	No pressure drop detected during pressure leak test	Yes
Physical specifications of each of the installed components must be according to the specifications in protocol	Yes
Physical specifications of each of the software system must be according to the specifications in protocol	Yes	UV light intensity level of the system must be within the acceptable limits:	Yes
Instruments and gauges must be calibrated and supported with calibration certificates.	Yes
Sufficient safety features, labels and signs must be available to alert the user	Yes	Interlock system of the system (overload relay, UV alarm) must function according to the requirements	Yes
System must be provided with required level of power, municipal water, steam and compressed air supply	Yes
Quantity and specification of spare parts must be verified against the spare parts list	Yes

Performance qualification of the water system covered checking of total organic carbon (TOC), conductivity and microbial level in the water produced by the reverse osmosis water system as well as weekly sanitization of the system which were performed to eliminate any existence of bacteria on the internal surface of piping system. Sanitization was carried out by circulating hot water at 85°C through the piping system for two hours after closing all the user points. Also, during this process, each user point was flushed with the circulating hot water for five minutes to ensure the inner surface of the water outlets was cleaned properly. Once the sanitization process was over, the reverse osmosis system started to supply water to purified water tank again. The hot water supply from the purified water tank was drained out slowly and loop temperature was let to reach approximately 25°C before purified water samples were collected at various selected water user points in the factory. These samples were then sent to microbiology lab for microbial count testing. Similarly, chemical lab tested total organic carbon and conductivity level of the collected water samples. These tests were performed daily for four weeks to confirm the chemical and microbial characteristics of produced water met the acceptance criteria.

Based on the results, the TOC level of the purified water was found to be less than the minimum acceptable limit of 300 parts per billion (ppb). The conductivity level of the water was less than 1.1 microsiemens per centimeter (μS/cm) at 20 °C which was the minimum acceptable limit. Also, the microbial level of the water system which was less than the acceptable limit of 5.66 cubic meter per unit per 10 ml proved that the chemical and microbial characteristics of the water produced by newly installed reverse osmosis water system met the acceptance criteria, thus, suitable to be used for production of pharmaceutical products.

Due to the successful completion of the validation process, the validation engineer released the validation summary report which summarized all the activities performed throughout the whole validation project of the newly installed reverse osmosis water system in the case study company. This includes summary on the reason for validation and validation activities carried out. In addition, it also provided discussion and conclusion on qualification results and suggestions on continuous periodic monitoring that need to be carried out on the reverse osmosis water system so that the system can be maintained under validated status. It was recommended that preventive maintenance for the system and calibration for the measuring devices in the system should be performed quarter annually. Finally, requirements for revalidation process rounded up validation summary report. Table 3 details the results of performance qualification performed on the reverse osmosis water system.

Table 3. Reverse osmosis water system qualification test results (Performance qualification)

Performance Qualification										Meet specification?
Does the water samples collected after sanitization process (by circulating hot water at 85°C through piping system) is chlorine free?										Yes
TOTAL ORGANIC CARBON (TOC) RESULTS (must be < 300 ppb)
DAY	1	2	3	4	5	6	7	8	9	10	11	12	13	14
User Point A	7	21	19	19	22	26	20	23	25	25	18	22	20	21
User Point B	19	21	21	23	19	22	20	18	25	22	21	20	22	24
User Point C	16	18	14	14	17	15	18	14	13	16	14	18	15	14
User Point D	13	11	16	16	17	12	15	19	18	19	21	17	18	18
User Point E	11	14	10	12	10	10	13	15	11	13	14	14	12	10
Does the TOC level meet the acceptable limit?										Yes
CONDUCTIVITY RESULTS (must be < 1.1 μS/cm @ 20 °C)
DAY	1	2	3	4	5	6	7	8	9	10	11	12	13	14
User Point A	0.83	0.87	0.87	0.84	0.82	0.79	0.80	0.80	0.84	0.83	0.83	0.88	0.81	0.82
User Point B	0.80	0.77	0.79	0.82	0.81	0.80	0.80	0.85	0.84	0.88	0.84	0.83	0.81	0.82
User Point C	0.89	0.92	0.87	0.90	0.89	0.92	0.92	0.94	0.91	0.93	0.89	0.95	0.91	0.88
User Point D	0.83	0.79	0.78	0.79	0.80	0.84	0.82	0.82	0.83	0.85	0.81	0.86	0.81	0.84
User Point E	0.76	0.78	0.78	0.81	0.77	0.79	0.80	0.76	0.82	0.83	0.85	0.88	0.87	0.87
Does the conductivity level meet the acceptable limit?										Yes
MICROBIAL CONTENT RESULTS (must be < 200 cfu/10ml)
DAY	1	2	3	4	5	6	7	8	9	10	11	12	13	14
User Point A	0	0	0	1	0	8	0	0	0	0	10	0	1	0
User Point B	0	0	0	0	0	14	0	0	0	0	12	0	0	3
User Point C	0	0	0	0	0	12	0	0	16	0	12	0	0	7
User Point D	0	0	9	0	0	15	0	0	0	0	19	0	5	12
User Point E	0	0	13	0	0	18	7	4	0	0	21	0	0	11
Does the bacteria content level meet the acceptable limit?										Yes

5. Discussion

The case study in which the newly built 4PV framework was used to validate reverse osmosis water system in the case study company proved the effectiveness of the framework in guiding the validation team towards successful completion of the validation project. Table 1 illustrates the advantages offered by 4PV framework compared to existing frameworks. Beside validation steps that were incorporated into the new validation framework, emphasize was also given on improvement of the validation documentation in this project since the significant validation problems highlighted in this study were mainly regarding the issues related to validation documentation. The proposal to form a proper size and combination of a validation team in this case study led to the successful completion of the 4PV framework. Knowledge and experience from the six member team consists of experts from different departments contributed to the success of this validation project. Compliance manager, as the team leader, initiated meetings frequently to discuss about current tasks, findings and related issues and this had motivated the validation team to perform their respective tasks. Apart from preparing qualification protocols before the actual qualification process, validation engineer, as the main person in the team, witnessed each of the validation procedure which was executed by supplier. Production manager provided user requirement specifications which helped facility engineer to design and purchase the required water system from supplier. Facility supervisor helped to monitor the validated status of the system during periodic review as well as collecting water samples to be sent to chemical and micro laboratory for chemical and biological tests respectively. Finally, arrangements to perform chemical and biological tests in respective labs were made by quality control executive. This proved that all the validation team members had fulfilled their responsibility in the best way possible which was a major contribution to the successful completion of this project. Gant chart formed project schedule which was prepared by the validation team depicted the actual workweek that each validation procedure needed to be executed and the time frame that the procedure must be completed. By executing each validation procedure according to this schedule, the validation personnel were able to complete their tasks two weeks earlier than the previous projects. In contrast, existing validation frameworks offer validation planning which is too general and difficult to be understood and practiced by new validation practitioners and this delays the completion of such projects within the timeframe allocated.

Criticality assessment checklist which was used in impact assessment contains clear guidelines on how to evaluate criticality level of the newly installed water system. A formula was used by validation team to calculate the risk score which helped the team to determine the extent of validation required for the system. Risk score of 24 required the qualification of installation, operational and performance. The installation, operational and performance qualification protocols were prepared by the validation engineer before the qualification procedure and this avoided any delay in the validation procedure. In addition, any errors in the protocols were corrected before the validation process commenced, thus, provided the proper and complete validation document. Validation summary report provided the overall summary of reverse osmosis water system validation in the case study company. Executive summary in the report explained about the water system to be validated, reason for the validation and the steps taken to execute validation procedures. This was followed by analysis and discussion of qualification results of the system. The next section concluded the results of the validation project and recommended periodic review to be carried out in order to maintain the system under validated status. Description on requirement for revalidation of the system completed the validation summary report. By using this report which was prepared by validation engineer, a newcomer to this validation world could easily get the main picture of the validation project. Deviation analysis was introduced in 4PV framework but was not used during the six months periodic review of the reverse osmosis water system because no deviation was detected due to the great physical and functional condition of the system. Similarly, the water monitoring during the periodic review showed all the parameters were found to be within the acceptable limits, thus no deviation analysis required. Since there was no deviation in the system, revalidation was not required. However, both deviation analysis and revalidation will be vital if there is any deficiency in the system in future. Table 1 shows the comparison between the drawbacks of existing frameworks and the positive elements of proposed new framework.

The outcome of this case study also showed improvement in the validation documentation system which overcomes documentation drawbacks highlighted in literature review. User requirement specification report was prepared in such a way that it can provide facility engineer and eventually supplier all the necessary details required such as design and functional requirements of the reverse osmosis water system, acceptable limits of chemical and biological parameters of purified water produced and regulatory requirements. This had helped the facility engineer designed the water system according to user and regulatory requirements and paved the way for supplier to install the system accordingly. Furthermore, the validation engineer acquired all the important details from the user requirement report to prepare validation protocols. Therefore, by implementing user requirement specification step, problems such as missing information and no acceptance criteria for test results verification in validation protocols have been minimized.

Likewise, simple language was used in validation protocols to describe validation procedures to enable new validation executers understand the procedures easily and perform the validation steps properly according to protocols. Thus, the smoothness of this project was not affected by the lack of clear guidelines which was identified as one of the major hurdle in completing validation projects successfully. The lack of uniformity in validation terms used in the validation documents was also avoided in this validation project as standard validation terms were used in validation documents. For instance, “Pass” and ‘Fail’ were used to declare test results replacing Yes” and “No”. Similarly, the word “acceptable limits” was replaced with “acceptance criteria” which shows the actual value for test results. In order to justify test results during validation tests, the actual values of main motor specification and main motor speed were recorded in test results column instead of the word “OK” or “YES” which have been in use for many years. This method had made it easier for the validation engineer to verify the results easily. Hence, the unverifiable test results problems were eliminated in this project.

The validation document checklist that was introduced in this project helped the validation engineer gathered all the relevant documents such as technical drawings, material clarification certificates, instrument calibration certificates and training records during validation. Also, the checklist confirmed that all the necessary information were available in the validation documents. Hence, there was no issue regarding important documents or information which were found missing when validation summary report was circulated for approval. Currently, there is no such document in practice in the case study company.

The execution of installation qualification procedure which was performed concurrently with actual installation of the system had also helped validation engineer to complete the tasks ahead of the original schedule. This was made possible because the verification on physical specification of the water system components was done before installation of each component, witnessed by validation engineer.

In the old format of the qualification protocol in the case study company, qualification procedures and test result sheets were displayed by two different pages. However, protocols with new format in which the qualification procedures and the test result sheets were available on the same page were introduced in this case study. The new format eased the protocol approvers to go through the procedure and the test results fast, thus shorten their approval time. Quantity of papers used to produce this new format protocol is less compared to protocols with old format. Therefore, this new format introduction saved the cost of document in this project.

6. Conclusion

Based on the case study results, the 4PV framework was proven to be practical, systematic and efficient. Apart from proving the robustness and validity of the new validation framework, the results of the case studies carried out in the company can also prove the reliability, practicability, efficiency and flexibility of the new framework. It can be concluded that the developed 4PV framework is capable to improve the success rate of any validation project in pharmaceutical industries. On the other hand, the case study also provides a clear and better view of the real application of newly developed 4PV framework in small and medium enterprise pharmaceutical industries. In addition, this framework is also simple and can easily be understood by user which fulfilled the basic requirements for a good framework. By following systematic and comprehensive guidelines provided by the 4PV framework, new validation practitioners can easily perform the validation procedures as well as upgrade their validation knowledge. This is because the framework is capable to transfer the validation knowledge systematically and effectively to new implementers which will save time and cost used by companies to enhance validation knowledge of their validation practitioners.

The new 4 phase validation framework is validated in a small and medium enterprise pharmaceutical company. Thus, the limitation for this framework is only validating utility system in a small and medium enterprise pharmaceutical company. So, in case if this framework is going to be used for validation in a multinational company, it must be fine-tuned according to the requirements in the multinational company.

In future, this framework can be recommended for validation of equipment and other utilities in pharmaceutical industry as well as other departments such as logistics department which are directly related to product manufacturing. This would help future validation implementers to develop a new framework to validate storage areas of raw material and final products. It is a critical requirement that the temperature and relative humidity of storage areas of raw material and final products in pharmaceutical companies must be maintained within the required level to ensure the quality of products. Apart from pharmaceutical industry, future validation executers should take initiative to apply this framework in food industry which is also very critical to customers’ health. By doing this, the flexibility of the framework can be proven. This will pave the way for derivation of a new validation framework which is flexible enough to cover validation in different industries effectively. In order to upgrade current validation protocol approval and data filling method which are carried out manually and may be considered as out of date in future, validation experts should move towards computerizing the documentation system which is faster and more accurate. By using appropriate software system, electronic validation protocols and reports can be approved electronically by related head of departments. This will save time for protocol and reports approval, eliminate the usage of papers for protocols and reports and the documents can easily be retrieved for checking and auditing purposes. In short, the possible computerized validation documentation system will move validation system in pharmaceutical industry to an advanced level in future.

Apart from proving the robustness and validity of the new validation framework, the results of the case studies carried out in the company can also prove the reliability, practicability, efficiency and flexibility of the new framework.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

The authors received no direct funding for this research.