2. Qualification of Equipment – a Risk-Based Approach

Pharma Times - Vol. 44 - No. 11 - November 2012 17

Qualification of Equipment A Risk-Based ApproachS. M. Mudda*Executive Director Technical & Operations, Micro Labs limited, Bangalore & Director of ISPE India Affiliate

Article

*Email Id: [email protected]

Why Qualification?The principle responsibility of a pharmaceutical manufacturer

is to manufacture medicines of the highest quality that are safe and effective.

The quality of the product is achieved through: A well-designed product Qualified facility and equipment Current Good Manufacturing Practices Qualified and trained personnel

While the quality is achieved through all the above factors, it is important to note that selection and qualification of the equipment plays a significant role in ensuring consistency in the quality of the product. Consequently, qualification of equipment has become an essential part of a pharmaceutical manufacturers quality assurance systems and it is no surprise that GMP codes of all the leading regulatory agencies of the world include this activity.

Regulatory Requirements:GMP regulations of all the leading regulatory agencies require

that the equipment used for Manufacturing, Testing or holding and critical systems should be qualified prior to use as described below.

WHO TRS 937, Annex 4, Appendix 6, Qualification of Systems and Equipment. T h e c o n t i n u e d s u i t a b l e

performance of equipment is important to ensure batch-to-batch consistency. Critical equipment should therefore, be qualified.

Cr i t ica l Qual i ty impact ing systems such as Water System, Air Handling System should be qualified.

Q u a l i f i c a t i o n s h o u l d b e completed before process validation is performed. The process of qualification should be logical, systematic process and should start from design phase of the premises, utilities and equipment.

EU Guideline, Annex 15 Qualification and Validation It is a requirement of GMP that manufacturers identify what

validation work is needed to prove control of the critical aspects of their particular operations. Significant changes to the facilities, the equipment and the processes, which may affect the quality of the product, should be validated.

A risk assessment approach should be used to determine the scope and extent of validation.

Evidences should be demonstrated to support the validation and to verify the operating parameters and limits for the critical variables of the operating equipment.

Accordingly, each drug product manufacturer should identify the validation requirements needed to prove control of the critical aspects of the product and process.

In accordance with these regulations, every manufacturer has to qualify equipment used for manufacturing and testing to demonstrate that it serves its intended purpose.

Additionally, the calibration, cleaning, preventative maintenance, operating procedures and operator training procedures and records should be documented.

It is important to note that selection and qualification of the equipment plays a significant role in ensuring consistency in the quality of the product

In the next few paragraphs I intend to give a brief step-wise overview of the qualification process and then focus on the current issues before the industry.

Qualification Process:The journey of equipment qualification starts from the User

Requirement Specifications (URS) which are discussed with the vendor and based on the agreement signed. The URS shall include identified Critical to Quality Attributes and relevant Critical Process Parameters which in general consists of Process/ Product Requirements, Operational Requirements, GMP/GLP Requirements, Safety Requirements, Documentation Requirements, Discussion/Review/Comments etc.

Design qualification: While designing a specific system or equipment the user requirements should be considered. Based on URS, the equipment design is discussed and equipment design qualification is undertaken.

Installation qualification: After the design Qualification, the Factory Acceptance Testing (FAT) is undertaken followed by SAT (Site Acceptance Testing) after approval of the FAT. Once the equipment meets the SAT requirements, the systems and equipment should be correctly installed in accordance with an installation plan and installation qualification protocol. Installation qualification should include identification and verification of all system elements, parts, services, controls, gauges and other components.

Operational qualification: Systems and equipment should operate correctly and their operation should be verified in accordance with an operational qualification protocol. Critical


operating parameters should be identified. Studies on the critical variables should include conditions encompassing upper and lower operating limits and circumstances (also referred to as worst case conditions). Operational qualification should include verification of operation of all system elements, parts, services, controls, gauges and other components.

Training of operators for the systems and equipment should be provided, and training records shall be maintained. Systems and equipment should be released for routine use after completion of operational qualification, provided that all calibration, cleaning, maintenance, training and related tests and results were found to be acceptable.

Performance qualification: Systems and equipment should consistently perform in accordance with design specifications. The performance should be verified in accordance with a performance qualification protocol. The equipment is performing as per its intended use shall be demonstrated at this stage.

Every manufacturer has to qualify equipment used for manufacturing and testing to demonstrate that it serves its intended purpose.

Re-qualification: Re-qualification of systems and equipment should be done in accordance with a defined schedule.

Calibration: The test equipments which are equipped with test instruments and are used for the control, weighing, measuring, monitoring and are critical for assuring the quality of drug substances and drug products should be calibrated according to written procedures and the established schedule.

Preventive Maintenance and Cleaning: There should be a preventive maintenance program for all equipments. Similarly, cleaning of equipments is of utmost importance in the prevention of batch to batch and product to product contamination.

Periodic Review of Validation/ Qualification Status: All the qualified equipments should be periodically evaluated to verify that they are still operating in a valid manner. There should be an annual review and conclusion should be drawn whether equipment stands in validated state or not.

Change Control: Any changes in the equipment which can have impact on the product quality should be addressed through the change control system depending upon the nature of impact of the change on the product quality. The extent of requalification after the change should be justified based on a risk-assessment of the change.

Current Status of GMP Compliance: A review of the deficiencies related to qualification cited by all

major regulatory agencies such as UK MHRA, WHO and US FDA reveals that there is a substantial scope for improvement by the industry on this front. Some of the examples of the deficiencies mentioned below will certainly draw our attention to this fact.

A Major source of GMP deficiencies: Acceptance Criteria: The IQ/OQ for the Drum Hoop Mixer

did not contain sufficient details with regard to the acceptance criteria or how the protocols were enacted. A discrepancy was identified but no explanation or impact was documented.

Measurement Range: The blister packing machine range of temperatures mentioned on the batch documents for forming and sealing had not actually been validated. Furthermore, the speed of the machine had not been specified.

List of Qualified Equipment: There was no list of equipment to aid in assessing the need for periodic evaluation of its validation status.

Validation Protocol: There was no pre-authorized validation protocol for the process.

Validation Report: No report had been written for the validation of the product. There was no conclusion stating that the validation had been successful.

Qualification Protocol: The complexity and criticality of equipment and systems are often not taken into account when designing qualification protocols.

Qualification Protocol: No rationale was documented for the decision not to take all temperature data points into account when averaging the results, and only hourly results were taken and averaged.

Qualification Protocol: No rationale was documented in the qualification protocol for running the dryer under pressurized conditions and for only 6 hours, given that the routine drying processes were performed under full vacuum and for significantly longer periods of time (16 hours).

Issues Before The Industry: Traditional Approach to Qualification:

Historically, the pharmaceutical industry has been using standard equipment for manufacturing and testing of pharmaceuticals as opposed to custom-built equipment that is designed keeping the requirements of the product in mind. We therefore see standard equipment like, Rapid Mixer Granulator, Fluid Bed Dryers, Rotary Compression machines, Automatic capsule fillers of standard make being used in the industry. Over a period of years, addition of new parts for new functionality has been seen in limited processes, either for automated online monitoring of the process or occasionally for controlling the process to ensure that it runs within the pre-determined limits.

Nonetheless, not appreciating the real intent behind the GMP and regulatory expectations related to qualification activity, users are currently spending significant human efforts and financial resources in commissioning and qualification activities. These activities appear to be performed merely for compliance purposes since quite often it involves a mere repetition of verification already performed by the manufacturer.

As stated earlier, since the same standard equipment is employed by different manufacturers for variable formulations of different requirements, the standard bookish approach for qualification makes the whole exercise inefficient since difference in the product and the process require different validation approaches including the level of documentation.

It is therefore, imperative that the qualification study is designed taking into account the critical process parameters, identification of potential failures of the process control parameters leading to a defective product, including these parameters in the Qualification Study and based on the outcome of the study designing appropriate in-process controls for monitoring the quality during manufacturing process.

Absence of this approach obviously has lead to a number of deficiencies that are cited by all the leading global regulatory agencies as stated in the preceding paragraph.


Inadequate URS:URS is the starting point of the qualification process that helps

build an equipment of good design. The experience has shown that inadequately defined URS has been the fundamental weakness in the equipment qualification process.

Very often, the user of the equipment converts the standard technical specification of the supplier into his URS.

Contrary to stating the requirements of design of the equipment clearly based on the product and process needs, very often the user of the equipment converts the standard technical specification of the supplier into his URS.

Such is the lack of knowledge of this important quality impacting activity that the investigations done to identify the cause of a quality complaint of the product rarely point out the lack of good design and good qualification as the root cause thus, allowing the complaints to recur.

Thus, we have a situation of having perfectly qualified equipment that is not able to produce a product of desired quality standards consistently.

Thus, we have a situation of having perfectly qualified equipment that is not able to produce a product of desired quality standards consistently.

Poorly Designed Qualification Protocols:Another commonly seen weakness is the inability to write a

good protocol for qualification of the equipment. Although the protocol approval team is drawn from cross- functional members representing production, Engineering and Quality Assurance, often writing of the protocol is considered as a responsibility of the engineering function alone. This disconnect between the process development, production and QA with the engineering team has lead to serious gaps in the qualification studies leading to inadequate qualification of the equipment and consequently earning critical GMP deficiencies.

In a case of Performance Qualification (PQ) Study of a blender, the number of samples to be drawn, the sampling locations and the acceptance criterion for content uniformity were substantially different in the PQ Protocol from the Process Validation Protocol of the product that was used for qualifying the same equipment. The investigations revealed that both the protocols were written at different times and were signed by different individuals without consulting each other. Worst still, the study was concluded as satisfactory despite differences in parameters stated in the protocols since QA certified the PQ of the equipment without referring to the Process Validation Report and the corresponding Batch Record.

Another weakness is poor facility of language that leads to badly written protocols and equally poorly written reports that clearly indicates that the entire study is carried out without getting into the depth of the subject.

Example - Case Study:An automatic labeling system consisting of three key

components, a labeling head, a conveyor for product transport, and an integrated control system each of which, in turn, having their own sub-components was used for labeling bottles on an integrated bottle packing line. Additionally, an Optical Character Reader was integrated with the machine to ensure the presence of label and also to confirm that the overprinted variable matter is readable and

correct. Bottles with defective labels were in turn rejected by a Rejection System using a pneumatically operated pusher arm that worked at a required pressure level.

The machine was qualified, set for use and was running satisfactorily until a market complaint of bottles with missing print and defective printing came as a surprise.

A detailed root cause investigation was carried out on various aspects such as operations, handling of rejects, operation of the equipment etc. Finally, through a risk assessment carried out, the functioning of the rejection system came into light. It was revealed that defective packs were detected at the detection station but were not rejected by the pusher arm of the rejection system. The probable reason was exceptional pressure drop of the pusher arm that stopped the arm movement which could happen as a result of a power failure or power fluctuations.

Following CAPAs were initiated:

a) UPS back-up to the system.

b) Installation of pressure gauge to measure the pressure required for operating the pusher arm for rejecting the defective bottles.

c) Installation of pressure switch which stops the machine while running, if the pressure of the pusher arm drops.

For implementing the identified CAPAs the operating SOP of the labeling machine and the batch records were revised to include instructions for setting, challenging and monitoring the pusher arm pressure that was adequate for proper functioning of the rejection system.

The case study presented above confirms the points raised in the preceding paras.

It was a case of inadequate URS that did not identify the quality impacting nature of the rejection mechanism and therefore did not capture it as a parameter for qualification in the protocol. Thus, the optimum pressure required for operation of the pusher arm was neither defined nor qualified.

Since the failure of the operation of the pusher arm was not anticipated, no suggestion was made in the URS to provide for a system for dealing with such eventuality that was later implemented as a CAPA in the form of a pressure switch that would stop the equipment should the pressure drop below the required pressure.

Delink between Qualification Report and Batch Record:The outcome of the qualification study should result in defining

the critical process control parameters along with the operating range that can serve as monitoring tool during manufacturing process and will result in consistent delivery of quality product. The inability of capturing these parameters from the qualification report into the batch manufacturing instructions takes away the benefit the extensive qualification study.

It is the responsibility of QA to ensure that the SOPs for Operation of the equipment capture the machine setting parameters, verification of these parameters by challenging them during the machine setting and thereafter including them as in-process controls and in-process challenges in the SOPs and in the Bach Records.

Risk-Based Approach to Qualification:The qualification as practiced today appears to be performed

from a lack of understanding of the GMPs related to equipment suitability leading to huge effort and documentation without


corresponding benefit to the industry. Adoption of risk-based approach will ensure that a balance between the levels of efforts put in the qualification of equipment and benefit to the product quality is achieved. Thus, Risk-based qualification can improve quality and reduce validation efforts.

International Society of Pharmaceutical Engineers (ISPE) is actively engaged in encouraging this approach and has come out with excellent guidelines towards this end.

The ISPE White Paper Risk Based Qualification for the 21st Century published in March 2005 propagates 10 Principles for Risk-Based Qualification that emphasizes focus on critical aspects for qualification while leaving out the others.

ICH Q9, Quality Risk Management (QRM) provides a systematic process for the assessment, control, communication and review of risks to the quality of the drug product across the product life cycle that can be applied to the qualification study. ICH Q9 Annexure-II provides the potential application of QRM.

The guideline expects to determine the scope and extent of qualification studies by applying the risk management principles and tools.

Ten Principles for Risk-Based Qualification

The application of QRM to equipment qualification is explained along side the ICH/QRM model below.

Application of Quality Risk Management for Equipment Qualification

The Key focus in the risk assessment phase is active engagement of the user with the supplier of the equipment that should lead to identification of Critical to Quality components and systems as described below. The supplier can provide a large number of support activities and services during the life cycle of

a product under all the different perspectives offering a significant contribution in the risk management process.

Specification Phase: At the Specification Phase the user can communicate potential risks and the relevant impact to the supplier on Quality of the Product, Safety of the operator & the Business. This phase involves the risk identification and risk analysis.

Design and Manufacture Phase: During Design and Manufacture Phase the Supplier shall identify critical parts and communicate these to users to evaluate the risks and provide additional controls and counter measure wherever necessary and finally accept the system design. This phase involves the evaluation of and control of the risk.

It should be noted that while the technical part of the risk analysis can be performed by the supplier, its a responsibility of the user to evaluate the risks, to provide any required additional controls and finally to accept the residual risks.

The IQ, OQ and PQ activities should be limited to systems and components with Direct Impact on the product quality. All the rest of the system may be simply commissioned and managed according to Good Engineering Practices (GEP). As stated above the identification of critical parts is an outcome of the risk analysis.

The Way Forward: The initiative of Risk-based Qualification was taken forward

by the industry and ISPE under the advise of US FDA. On the publication of the White paper, ISPE worked with pharmaceutical companies and consulting companies to create an American Society of Testing and Measurement (ASTM) standard. The teams goal was to integrate risk-based methodology conforming to the ICH Q8, Pharmaceutical Quality Systems and ICH Q9, Quality Risk Management standards. A new voluntary consensus standard, ASTM E 2500, Standard Guide for the Specification, Design, and Verification of Pharmaceutical and Biopharmaceutical Manufacturing Systems and Equipment was approved in June, 2007.

ASTM E2500 is a Risk-based and Science-based approach to the specification, design, and verification of manufacturing systems and equipment that have the potential to affect product quality and patient safety.

ASTM E2500 is a Risk-based and Science-based approach to the specification, design, and verification of manufacturing systems and equipment that have the potential to affect product quality and patient safety.

The overall objective is to provide manufacturing capability to support defined and controlled processes that can consistently produce product meeting defined quality requirements.

The guiding principle of the ASTM E2500 is to design the equipment by adopting the risk-based approach and manufacture the equipment by following the Quality Systems and Good Engineering Practices (GEP). The guideline strongly recommends, leveraging the information generated during the FAT SAT and commissioning stages to reduce the extent of IQ and OQ activities. In other words the ASTM guideline recommends verification of the data generated during the FAT, SAT and commissioning phase in lieu of IQ and OQ activities and go straight for PQ. The term verification is used to describe both commissioning and qualification.

There is a similarity between GEP and GMP. In both cases, Quality should be achieved by design, and not just tested at the end of the process. Embedding quality into an equipment design is mostly a suppliers responsibility in a cooperative and trustworthy relationship with the user.


ASTM Process Flow:


# Verification as Qualification:

Benefits of ASTM E2500-07 A recent case study on equipment selection, design and

qualification using this approach demonstrated that a substantial amount of time and cost could be saved. The approach encouraged involvement of validation engineers from the URS stage. All functions were involved in performing risk assessment, identifying the individual user requirement, specifying the testing/verification requirements, assessment of the Site Acceptance / Factory Acceptance and application of increased knowledge of the QA.

The application of this approach resulted in reducing a huge amount of time. The time required for vendor documentation was limited to six weeks. The information generated during the FAT/ SAT was leveraged thereby reducing the IQ stage to 10 days from 1-2 months and OQ stage to 3 days from 2- 3 months.

The equipment delivery to qualification and commercial use was completed within a period of less than 3 months.

RISK-BASED APPROACH:The information generated during the FAT/ SAT was leveraged thereby reducing the IQ stage to 10 days from 1-2 months and OQ stage to 3 days from 2- 3 months.

Benefits of Risk-Based Approach

It appears that regulators also will start accepting this approach very soon. In 2006, a new facility to manufacture two new products during facility and equipment qualification used risk assessments, commissioning, and process qualification approach to confirm the equipment was suitable for its intended use. The QA was involved in the risk assessments, approved the overall project quality plan, and conducted post-approval of the process qualification protocols. There was no installation qualification/operational qualification per se performed. The inspectors inquired about this, and observed a much smaller volume of paperwork associated with this phase of the project. The approach used was explained to the inspectors, and the facility passed its inspection.

CONCLUSIONThe risk-based qualification will be immensely beneficial to the

industry since it demonstrably reduces the cost and time required for qualification. It is also good to see that even regulators are willing to encourage this initiative.

However, it has to be understood that the success of this approach is dependent on the equipment manufacturer following his quality system and GEPs. Since the commissioning data is leveraged for qualification the standards for quality of this documentation should be established.

The industry leaders, QA professionals and engineers have to understand this concept and use it judiciously to ensure that the risk assessment is based on good science and supported by Good Engineering Practices.

References1. EU GMP Guideline, Annexure 15

2. Pharmaceutical Inspection Convention /Scheme (PIC/S)

3. WHO TRS 937, Annexure-4

4. ICH Q8 Pharmaceutical Development

5. ICH Q9 Quality Risk Management

6. ISPE White Paper Risk Based Qualification for the 21st Century (2005)

7. ASTM E 2500 (2007), Standard Guide for the Specification, Design, and Verification of Pharmaceutical and Biopharmaceutical Manufacturing Systems.

8. Risk Based Equipment Qualification: A User / Supplier Cooperative Approach, GAMP Italia Equipment Validation Work Group, Pharmaceutical Engineering, Volume 27, No. 3, May- June 2007

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2. Qualification of Equipment – a Risk-Based Approach

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