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Twelve 2-day In-person Interactive GMP and Validation Seminars available in America, Europe and Asia delivered by Dr. Ludwig Huber. 

 

Eight Steps for Cost-effective Laboratory Compliance
Up-to-date overview, hot topics and trends.

Recorded, available at any time  

 

Implementing the New USP Chapter <1224> for Analytical Method Transfer

With SOPs, templates and examples for effective implementation

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How to get the most out of Supplier Support  for Equipment and Computer Validation

Strategies for suppliers to maximize business and for users to minimize validation cost

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FDA Compliant SFC Qualification and Performance Testing

Learn how to select, conduct and document the right tests in the right sequence

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Calibration and Qualification in Analytical Laboratories

With examples from planning to reporting

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Analytical Instrument Qualification According to USP <1058>

With SOPs, Templates and Examples for Easy Implementation

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Qualification and Calibration of Stability Chambers

Learn how to select, conduct and document the right test parameters and conditions

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Validation of Automated Laboratory Systems

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Validation of Software and Computer Systems in Analytical Laboratories

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Understanding the Updated USP Chapters 232/233 for Metal Impurities

With SOPs and Case Studies for Easy Implementation

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Validation of Bioanalytical Methods and Procedures

Conduct and Document for Efficiency and FDA&EMA Compliance

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FDA Compliance for Biopharmaceutical Laboratories

Become familiar with FDA regulations and get tool kits for implementation

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Learning from Recent Warning Letters Related to GMP Laboratory Controls

For Preparation of FDA and International GMP Laboratory Inspections

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Transfer of Analytical Procedures According to the New USP Chapter <1224>

With SOPs, templates and examples for easy implementation

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Learning from Recent Warning Letters Related to Good Laboratory Practices

For Preparation of FDA and International GLP Inspections

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GMP Compliance for Quality Control Laboratories: Step-by-Step

FDA Requirements and Tools for Implementation

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System Suitability Testing for FDA and USP Compliance

With 10+ Best Practices for easy Implementation

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FDA Compliant Use of (Certified) Reference Material

With 10+ Best Practice Guides for Easy Implementation

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Effective HPLC Method Development and Validation

Preparation, conduct and documentation for FDA/EMA Compliance

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FDA/ICH Compliant Development and Validation of Stability Indicating Methods

Sample generation - method development - validation - documentation

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Practical Risk Assessment in Laboratories: Step-by-Step

With Risk Master Plan, SOPs and Case Studies for Easy Implementation

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GMP Compliance for Quality Control Laboratories: Step-by-Step

FDA Requirements and Tools for Implementation

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System Suitability Testing for FDA and USP Compliance

With 10+ Best Practices for easy Implementation

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Validation and Use of Excel® Spreadsheets in Regulated Environments

Comply with FDA Part 11, the PIC/s Good Practice Guide and the EU Annex 11

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FDA Compliant Use of (Certified) Reference Material

With 10+ Best Practice Guides for Easy Implementation

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Stability Testing in Pharmaceutical and API Industry

Learn how to design, conduct and document studies for FDA and ICH

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Validation of Analytical Methods and Procedures

Conduct and Document for Efficiency and FDA, USP/EP and ISO 17025 Compliance

 

How to Efficiently Get ISO 17025 Accreditation

Step-by-step from the idea to cost-effective implementation

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Managing Out of Trend Results in Pharmaceutical Manufacturing and Quality Control

Comply with the FDA and international guidances

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Understanding and Implementing ISO 17025

Requirements, Strategies and Tool Kits for Laboratory Accreditation

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Handling Out-of-Specification Tests Results and Failure Investigations

With case studies to avoid and respond to FDA 483's and warning letters

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FDA Compliant and Efficient HPLC Qualification and Testing

Learn how to select, conduct and document the right tests in the right sequence

 

How to Efficiently Build a GLP Laboratory

Step-by-step from design to cost-effective implementation

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Effective Gap Analysis for ISO 17025

With Practical Tools for Easy Implementation

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Measurement Uncertainty in Chemical Analysis

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Management and Validation of Computers for ISO 17025

Requirements, Recommendations and Tools for Implementation

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Traceability in Chemical Analysis

With strategies and tools for ISO 17025 and FDA Compliance

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Effective Verification of Compendial Methods

Understanding USP and FDA Requirements and get Tools for Implementation

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Auditing Laboratories for FDA and ISO 17025 Compliance

Preparation - conduct - follow up - documentation

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Understanding USP Documents and Reference Standards

General Chapters, General Notices, Monographs, Forum, Reference Standards

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Validation and Part11 Compliance of Chromatographic Data Systems

With 10 Validation Examples: From planning to system retirement

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Residual Solvent Analysis According to USP <467>

Understanding and implementing the revised chapter

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Sampling and Sample Handling in Laboratories

Strategies for  FDA and ISO 17025 Compliance and Tools for Implementation

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Inspection of Pharmaceutical Quality Control Laboratories

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Increasing Productivity with Electronic Laboratory Notebooks

Selection, Implementation and Strategies for Compliance

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Laboratory Equipment Qualification and System Validation

Author: Dr. Ludwig Huber

Frequent speaker and chair person at FDA, ISPE, PDA, USP. IVT, and GAMP conferences and workshops

Here Ludwig Huber (right) in the Q&A Discussion Session on Laboratory Compliance at a ISPE/FDA Beijing University Conference with Nick Buhay, Acting Director in FDA/CDER's Division of Manufacturing and Product Quality

For Dr. Huber's connection with the FDA, click here

Links to specific sections of the tutorial Other information in the tutorial

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2-Day Seminar with Workshops

1. Introduction

The objective of any chemical analytical measurement is to get consistent, reliable and accurate data. Proper functioning and performance of analytical instruments and computer systems plays a major role in achieving this goal. Therefore, analytical instrument qualification (AIQ) and computer system validation (CSV) should be part of any good analytical practice. There is a second aspect to why validation and qualification are important, and this is equally important for those working in a regulated and in an accredited environment. Even though frequently not directly spelled out in regulations and official guidelines, such as Good Laboratory Practice (GLP), Good Clinical Practice (GCP) and Good Manufacturing Practice (GMP), or in quality standards, such as the International Organization for Standardization (ISO) Standard 17025, validation and qualification is usually required. This is confirmed by typical statements such as this one that appears in the U.S. cGMP (current Good Manufacturing Practice) regulations (1): “Equipment shall be routinely calibrated, inspected and checked according to a written program to ensure proper performance” or by the more general requirement “Equipment should be suitable for its intended use”. Although there were lots of discussions about the approach for qualification of analytical instruments in the 90’s and in the early years of this century, this has changed since the USP has published the final version of the chapter <1058> entitled Analytical Instrument Qualification (2).

Following a literature and regulatory overview, this primer will provide information on the entire qualification and validation process from planning, writing specifications as well as vendor qualification to installation, initial and on-going operation.

It covers:

  • Literature overview with milestones on instrument qualification and system validation in laboratories.
  • Overview on regulations and quality standards with impact on analytical instrument qualification.
  • Qualification of equipment hardware, for example, a spectrometer or liquid chromatograph.
  • Validation of analytical computerized systems.
  • Implementing USP chapter <1058>.

Special focus is placed on getting a good understanding of and implementing USP chapter <1058>. After an introduction to the chapter’s approach for instrument qualification, this primer will lead you through individual qualification phases and give recommendations for implementation. The primer will not only help readers understand the instrument qualification process, but also offers templates and examples to easily implement qualification. Because of the nature and size of this primer, all the details of operational qualification and system validation cannot be given. For more details, please refer to reference articles and text books (3-5). Exact procedures and test parameters very much depend on the type of instrument and applications. Details on recommendations and services can be obtained from instrument vendors. Although the primer has recommendations for validation of standard commercial computerized analytical systems without the need for major customization, it does not give details on validation of complex systems, such as Laboratory Information Management Systems (LIMS), or on validation activities during software development but refers to further literature (7-11).

Literature Overview

Due to their importance, equipment qualification issues have been addressed by several organizations. Before 1990 the regulatory focus of instrument and computer validation was primarily on manufacturing equipment, which changed after 1990. In response to industry task forces, regulatory agencies published guidance documents that helped the industry to better understand regulatory requirements. In addition, private authors published reference books with practical recommendations for implementation:

  • The Pharmaceutical Analysis Science Group (UK) developed a position paper on the qualification of analytical equipment (6). This paper was a benchmark because it introduced the 4Q model with design qualification (DQ), installation qualification (IQ), operational qualification (OQ) and performance qualification (PQ) for analytical equipment qualification.
  • The Laboratory of the Government Chemist (LGC) and Eurachem-UK, developed a guidance document with definitions and step-by-step instructions for equipment qualification (3).
  • The United States Food and Drug Administration developed principles of software validation (7).
  • The Good Automated Manufacturing Practices Forum (GAMP) developed guidelines for computer validation in 2001 (8) and in 2008 (9). These guides have been specifically developed for computer systems in general, and because of their importance have also been used for validation of laboratory systems.
  • GAMP also published a Good Practice Guide for Validation of Laboratory Systems (10). It recommends validation activities and procedures for seven different instrument categories.
  • Huber authored two validation reference books for the analytical laboratory (5,   11). The first one covers all validation aspects of an analytical laboratory including equipment, analytical methods, reference compounds and people qualification. The second one covers the validation of computerized and networked systems in analytical laboratories.
  • The Parenteral Drug Association (PDA) developed a technical paper on the validation of laboratory data acquisition system (12).
  • Coombes authored a book on laboratory systems validation testing and practice (4). The term laboratory systems validation (LSV) was used to make a distinction from computer system validation (LSV) and equipment qualification (EQ).
  • Chan and colleagues published the book Analytical Method Validation and Instrument Performance Verification (13). This book has several chapters with practical recommendations for instrument qualification.
  • PIC/S developed a good practice Guide for Using Computers in a GxP Environment (14). This document has been written by inspectors for inspectors as a guide to inspect computerized systems.

All these guidelines and publications follow a couple of principles:

  • Qualification of equipment and validation of computer systems are not one time events. They start with the definition of the product or project and setting user requirement specifications and cover the vendor selection process, installation, initial operation, ongoing use and change control.
  • All publications refer to some kind of life cycle model with a formal change control procedure being an important part of the whole process.

Different models have been suggested for different kinds of instruments. For example, the 4Q model as described by Freeman (6) and Bedson (3) has been recommended for users of commercial instruments without significant customization by the user. The V-model as recommended by GAMP4 (8) is suitable for software development as well as for users of commercial instruments with customization by the user.

A major breakthrough came when USP released its general chapter on analytical instrument qualification (2). The major benefit of the chapter was that it formalized the 4Q model and clarified some issues that have been frequently discussed before, for example, that an instrument’s firmware does not need separate qualification, but should be qualified as part of the instrument hardware.

Terminology: Validation vs. Qualification

An agreement on terminology is of utmost importance for a common understanding of validation and qualification. The author has frequently noted at validation symposia that different speakers used different terms for the same thing and the same terms for different things. Most frequent question arose about the words validation and qualification. USP has recognized this and addressed it in a paragraph on the first page of chapter <1058>. The word qualification relates to instruments that can be individual modules and also systems, for example, a complete HPLC system comprised of a sampling system, a pump, a column compartment and a detector. Checking the baseline noise of a detector and comparing the results with previously defined specifications would be an example for qualification. Qualification is done independently from a specific application or sample. Typically the type of specifications can be found in the vendor’s product specification sheet.

The word validation relates to applications, processes and methods. For example, for method validation we specify the limit of quantitation or limit of detection of our sample compounds. Such specifications can only be verified with a complete system and accessories such as the right chromatographic column, calibration standards and SOPs for running the test.

Unfortunately, validation and qualification are frequently used interchangeably. For example, for software and computer systems the term validation is always used, even though according to the previous definition qualification should be used. Therefore, in the context of software and computer systems, this primer will also use the term validation.

The FDA and other agencies do not really care what users call it, validation or qualification. The inspector’s question will always be: how did you make sure that the data are accurate. As long as there is a good answer, for example through validation of systems and methods, it is of secondary importance how users call it. However, agreement on terminology is of utmost importance within a company, so that everybody has the same understanding of qualification and validation. Therefore, terminology and the exact meaning should be documented in a glossary.

Components of Analytical Data Quality

There were many discussions about the need for instrument qualification in analytical laboratories before the release of USP <1058>, taking into account that there are several other components of data quality, for example, method validation, system suitability testing and the analysis of quality control samples.

USP started the chapter by giving good reasons why instrument qualification is important. Figure 1 illustrates the different components of data quality with analytical instrument qualification as the foundation at the bottom.

 

Figure 1. Components of analytical data quality

Whether you validate methods or systems, verify the suitability of a system for its intended use or analyze quality control samples, you should always qualify the instrument first. It is the basis of all other components. It is the collection of documented evidence to demonstrate that an instrument suitably performs for its intended purpose and that it is properly maintained and calibrated. If the instrument is not well qualified, weeks can be spent to validate an HPLC method without success until a determination is made that the HPLC detector did not meet specifications for linearity or baseline noise.

After you have qualified the instrument, you validate analytical methods on qualified instruments. This should prove that the method works as intended. We do this independently of any specific instrument. If you want to use the method on instruments from different vendors, you also should validate the method on those instruments.

Then you can combine any specific instrument with a specific method and run system-suitability tests. This ensures that the complete system meets the analyst’s expectations under the specific conditions of the tests.

The highest level of testing is the analysis of quality control samples. You analyze standards or samples with known amounts and compare the results with the correct amounts. Again a prerequisite to show that this works is to use qualified instruments and validated methods.

 

2. Regulations and Quality Standards

Qualification of instruments and validation of systems is a requirement of the FDA and equivalent international regulations. No or inadequate qualification can cause regulatory actions, such as shipment stops of drugs and APIs. The rationale behind this is that analytical test results obtained with no or inadequately qualified instruments can be wrong. Because of the importance of compliance, we dedicate this chapter to regulations and quality standards. The purpose of the regulations and standards are listed together with key requirements.

Regulations are quite static and typically don’t change for several years. More dynamic than regulations are inspection and enforcement practices. Information can be found in the FDA’s inspection documents such as warning letters, establishment inspection reports (EIR) and 483 form inspectional observations. Highly important are FDA warning letters. They are sent to companies in case of serious regulatory violations. Companies are expected to respond within 15 days. If there is no response or if the response is inadequate, the FDA will take further actions which may cause delay of new product approvals, import alerts and denials, or product recalls. Since March 2003 warning letters are reviewed by higher-level FDA officials and reflect the FDA’s current thinking. Warning letters are published on the FDA website

The only problem is that there are thousands of them and they mostly relate to marketing and labeling, so it is difficult to find the ones that are of interest to laboratories. Interesting sites exist that only publish warning letters related to GxP issues. For example, http://www.fdawarningletter.com has many quotes related to the qualification of instruments and validation of computer systems.

Good Laboratory Practice Regulations

Good laboratory practice (GLP) regulations deal with the organization, processes and conditions under which preclinical laboratory studies are planned, performed, monitored, recorded and reported. GLP data are intended to promote the quality and validity of study data. GLP regulations were first proposed by the U.S. FDA in November 1976, and final regulations were coded as Part 58 of Chapter 21 of the Code of Federal Regulations in 1979 (15). The Organization for Economic Cooperation and Development (OECD) published the principles of Good Laboratory Practice in the Testing of Chemicals in 1982 (16), which has been since updated (17) and incorporated by OECD member countries. In the meantime most industrial countries and some developing countries have their own GLPs.

All GLP regulations include chapters on equipment design, calibration and maintenance, for example, U.S. GLP regulations, Sections 58.61 and 58.63(15):

  • Automatic, mechanical, or electronic equipment used in the generation, measurement, or assessment of data shall be of appropriate design and adequate capacity to function according to the protocol and shall be suitably located for operation, inspection, cleaning, and maintenance.
  • Equipment used for generation, measurement, or assessment of data shall be adequately tested, calibrated, and/or standardized.
  • Written standard operating procedures shall set forth in sufficient detail the methods, materials, and schedules to be used in routine inspection, cleaning, maintenance, testing, calibration, and/or standardization of equipment and shall specify remedial action to be taken in the event of failure or malfunction of equipment.
  • Written records shall be maintained on all inspection operations.

The GLP principles of the OECD include similar but shorter sections on equipment(17):

  • The apparatus used for the generation of data and for controlling environmental factors relevant to the study should be suitably located and of appropriate design and adequate capacity.
  • Apparatus and materials used in a study should be periodically inspected, cleaned, maintained, and calibrated according to Standard Operating Procedures. Records of procedures should be maintained.

Current Good Manufacturing Practice Regulations

Good Manufacturing Practice (GMP) regulates manufacturing and its associated quality control. GMP regulations have been developed to ensure that medicinal (pharmaceutical) products are consistently produced and controlled according to the quality standards appropriate to their intended use. In the United States, the regulations are called Current Good Manufacturing Practices (CGMP) to account for the fact that the regulations are dynamic rather than static. They are defined in Title 21 of the U.S. Code of Federal Regulations, 21 CFR 210 - Current Good Manufacturing Practice for Drugs, General and 21 CFR 211 - Current Good Manufacturing Practice for Finished Pharmaceuticals(1). Drugs marketed in the United States must first receive FDA approval and must be manufactured in accordance with the U.S. cGMP regulations. Because of this, FDA regulations have set an international regulation benchmark for pharmaceutical manufacturing.

In Europe, local GMP regulations exist in many countries. These are based on the EU directive: Good Manufacturing Practice for Medicinal Products in the European Community (18). This EU GMP is necessary to permit free trade in medicinal products between the member countries. Regulations in the EU allow the marketing of a new drug in the member countries with the acquisition of just a single marketing approval. The intention of the EU GMP is to establish a minimum manufacturing standard for all member countries.

Like GLP, also all CGMP regulations include chapters on equipment design, calibration and maintenance, for example, U.S. CGMP regulation for pharmaceutical drugs, sections 211-140 b and 211-68 (1).

  • Laboratory controls shall include the calibration of instruments, apparatus, gauges, and recording devices at suitable intervals in accordance with an established written program containing specific directions, schedules, limits for accuracy and precision, and provisions for remedial action in the event accuracy and/or precision limits are not met. Instruments, apparatus, gauges, and recording devices not meeting established specifications shall not be used.
  • Automatic, mechanical, or electronic equipment or other types of equipment, including computers, or related systems that will perform a function satisfactorily, may be used in the manufacture, processing, packing, and holding of a drug product. If such equipment is so used, it shall be routinely calibrated, inspected, or checked according to a written program designed to assure proper performance. Written records of those calibration checks and inspections shall be maintained.

International Conference for Harmonization

The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) brings together the regulatory authorities of Europe, Japan and the United States and experts from the pharmaceutical industries in the three regions to discuss scientific and technical aspects of product registration.

The purpose is to make recommendations on ways to achieve greater harmonization in the interpretation and application of technical guidelines and requirements for product registration in order to reduce or obviate the need to duplicate the testing carried out during the research and development of new medicines.

ICH publishes guidelines that are either signed into law by member countries, for example, in Europe or recommended as guidelines by national authorities, e.g., by the US FDA.

Examples for such guidelines are:

  • Testing (Q1A)
  • Validation of Analytical Procedures (Q2)
  • Impurities in New Drug Substances (Q3A) and
  • GMP Guide for Active Pharmaceutical Ingredients (Q7) and
  • Quality Risk Management (Q9)

One of the most important ICH documents is the GMP Guide for Active Pharmaceutical Ingredients (19). Opposite to other official documents, Q7 has very specific requirements for equipment and computer systems in chapters 5.3 and 5.4:

  • Equipment calibrations should be performed using standards traceable to certified standards, if existing.
  • Records of these calibrations should be maintained.
  • The current calibration status of critical equipment should be known and verifiable.
  • Instruments that do not meet calibration criteria should not be used.
  • Deviations from approved standards of calibration on critical instruments should be investigated to determine if these could have had an impact on the quality of the intermediate(s) or API(s) manufactured using this equipment since the last successful calibration.
  • GMP related computerized systems should be validated. The depth and scope of validation depends on the diversity, complexity and criticality of the computerized application.
  • Appropriate installation qualification and operational qualification should demonstrate the suitability of computer hardware and software to perform assigned tasks.

Pharmaceutical Inspection Convention Scheme (PIC/S)

PIC/S' mission is "to lead the international development, implementation and maintenance of harmonized Good Manufacturing Practice (GMP) standards and quality systems of inspectorates in the field of medicinal products".

This is to be achieved by developing and promoting harmonized GMP standards and guidance documents; training competent authorities, in particular inspectors; assessing (and reassessing) inspectorates; and facilitating the co-operation and networking for competent authorities and international organizations. As of October 2008 there are 34 participating authorities in PIC/S and some more have applied for membership, for example the U.S. FDA.

The most relevant PIC/S document related to this primer is the Good Practice Guide: Using Computers in GxP Environments(14). The guidance document is intended to provide a logical explanation of the basic requirements for the implementation, validation and operation of computerized systems. Recommendations are documented in chapters 4.6 and 4.8:

  • Apart from user acceptance testing (OQ) versus the functional specification, the regulated user also has responsibility for the (PQ) performance qualification of the system.
  • The validation documentation should cover all the steps of the lifecycle with appropriate methods for measurement and reporting, (e.g. assessment reports and details of quality and test measures), as required.
  • Regulated users should be able to justify and defend their standards, protocols, acceptance criteria, procedures and records in the light of their own documented risk and complexity assessment.

ISO/IEC 17025

ISO/IEC 17025 is the most relevant ISO Standard for chemical laboratories(20). It specifies the general requirements for the competence to carry out tests and/or calibrations. The standard is widely used as a quality system in environmental, food, chemical and clinical testing laboratories. It is used to assess laboratories that seek accreditation status.

The standard has many requirements related to the subject of this primer. The most important ones can be found in chapter 5.5.

  • Calibration programs shall be established for key quantities or values of the instruments, where these properties have a significant effect on the results.
  • Before being placed into service, equipment (including that used for sampling) shall be calibrated or checked to establish that it meets the laboratory's specification requirements and complies with the relevant standard specifications. It shall be checked and/or calibrated before use.
  • Each item of equipment and its software used for testing and calibration and significant to the result shall, when practicable, be uniquely identified.
  • Equipment that has been subjected to overloading or mishandling, gives suspect results, or has been shown to be defective or outside specified limits, shall be taken out of service.

21 CFR Part 11 – FDA’s Regulation on Electronic Records and Signatures

In 1997 the United States Food and Drug Administration (FDA) issued a regulation that provides criteria for acceptance by the FDA of electronic records, electronic signatures and handwritten signatures21. With this regulation, entitled Rule 21 CFR Part 11, electronic records can be equivalent to paper records and handwritten signatures. The rule applies to all industry segments regulated by the FDA that includes Good Laboratory Practice (GLP), Good Clinical Practice (GCP) and current Good Manufacturing Practice (cGMP).

Part 11 requires computer systems used in FDA regulated environments to be validated. Chapter 10 (a) states:

  • Computer systems should be validated to ensure accuracy, reliability and consistent intended performance.

There is no further instruction on how computer systems should be validated.

Learning from Regulations and Quality Standards

As we have seen in this chapter, all important regulations and ISO 17025 have one or more chapters on equipment and computers. The wording and the level of detail is different. For example, the words calibration and qualification are interchangeably used. Despite different terminology, the message is always the same: instruments and computer systems should be suitable for their intended use.

This means users should:

  • Define the intended use, meaning write specifications.
  • Formally assess the vendor’s quality system.
  • Formally document installation. ICH Q7A calls this installation qualification.
  • Test the instrument in the user’s environment for functional specifications. ICH and PIC/S call this operational qualification.
  • Verify ongoing performance through ongoing preventive maintenance system tests.
  • Keep instruments under change control to ensure that the validated state is ensured after changes.

3. Qualification of Analytical Instruments

Equipment qualification and validation of computerized systems cover the entire life of a product. It starts when somebody has a need for a specific product and ends when the equipment is retired. For computer systems validation ends when all records on the computer system have been migrated and validated for accuracy and completeness on a new one. Because of the length of time and complexity the process has been broken down into shorter phases, so called lifecycle phases. Several lifecycle models have been described for qualification and validation. Most common ones are the V and 4Q model. The V model includes code development and code testing for software, which is important when validation also covers software development. For the purpose of this primer, where we deal with commercially available instruments and systems, we have selected the 4Q model with phases such as design qualification (DQ), installation qualification (IQ), operational qualification (OQ), performance qualification (PQ). The process is illustrated in figure 2.

 

Figure 2. Qualification phases 4Q model

In the DQ phase user requirements are compared with the vendor’s specification. In addition, users conduct an assessment of the vendor. In the installation qualification the selected user’s environment is checked whether it meets the vendor’s environmental specifications. The instrument is installed according to vendor’s recommendations and correct installation is verified and documented. Operational qualification checks if the instrument conforms to the functional specifications, as defined in the DQ phase. Performance qualification verifies that the complete system works for selected applications. Preventive maintenance activities and controlled changes also are part of this phase. All activities are defined in a validation or qualification plan and results are documented in a summary report. Figure 3 illustrates the timeline for the four qualifications.

 

Figure 3. Qualification timeline

 

Qualification Planning

Qualification activities should be described in a master plan. The plan documents a company’s approach for specific activities, for example, how to qualify analytical instruments, how to assess vendors or what to test for commercial computer systems. A master plan serves two purposes: when implemented right, it ensures consistent and efficient implementation of equipment qualifications, and it answers an inspector’s question for a company’s approach for instrument qualification and system validation. A validation master plan is also officially required by Annex 15(22) to the European GMP directive: “All validation activities should be planned. The key elements of a validation program should be clearly defined and documented in a Validation Master Plan (VMP) or equivalent documents”. FDA regulations and guidelines do not specifically require a validation master plan. However, inspectors want to know what the company’s approach towards validation is. The qualification master plan is an ideal tool to communicate this approach both internally and to inspectors. In case there are any questions as to why things have been done or not done, the master plan should provide the answers.

Within an organization a validation master plan can be developed for:

  • the entire company at a corporate level
  • multiple or single sites
  • departments
  • system categories

The master plan is a framework for individual project plans and should be written at the highest level possible. This ensures consistent implementation across an organization.

Equipment and computer validation master plans should include:

  1. Introduction with a scope of the plan, e.g., sites, systems, processes
  2.  Responsibilities, e.g., user departments, QA, IT
  3. Related documents, e.g., risk master plan
  4. Products/processes to be validated and/or qualified
  5. Qualification/validation approach
  6. Risk assessment
  7. Steps for equipment qualification and computer system validation with examples on type and extent of testing
  8. Vendor assessment
  9. Handling existing systems
  10. Change Control procedures and templates
  11.  Instrument obsolescence and removal
  12.  Training plans (system operation, GMP)
  13. Templates and references to SOPs
  14. Glossary

For each individual project a validation project plan should be developed. This plan is derived from the validation master plan.

Figure 4 shows the link between the master plan and project plan. Ideally master plans are developed at a corporate level. Project plans are written in departments specifically for an instrument or system. Depending on the size, structure and geographic distribution there also may be a site or country specific master plan that is derived from the corporate master plan but has been customized according to specific circumstances and requirements of that site.

 

Figure 4. Link between master plan and project plan

The project plan outlines what is to be done in order to get a specific system into compliance. For inspectors it is a first indication of the control a laboratory has over a specific instrument or system and it also gives a first impression of the qualification quality.

For simple equipment qualification a template in table form can be used to outline planned activities. A template example is shown in Figure 5. The left column can be the same for all instruments in the same category, which makes the whole qualification process very efficient.

 

Figure 5. Template for instrument qualification project plan

Design Qualification

“Design qualification (DQ) is the documented collection of activities that define the functional and operational specifications of the instrument and criteria for selection of the vendor, based on the intended purpose of the instrument“ (2).

Design qualification is a shared responsibility between the vendor and the user of an instrument.

The vendor’s responsibilities are to:

  • Design, develop and manufacture instruments in a quality control environment.
  • Develop functional and operational product specifications.
  • Provide information on how software and instruments are validated. during development and supported during the entire life of the products.
  • Allow user audits, if required, and share approaches for development and testing.

The user’s responsibilities are to:

  • Describe the analysis problem and selection of the technique.
  • Describe the intended use of the equipment.
  • Describe the intended environment (including computer environment).
  • Select and document the functional and performance specifications (technical, environmental, safety).
  • Select and assess the vendor.

Specifications

DQ should ensure that instruments have all the necessary functions and performance criteria that will enable them to be successfully implemented for the intended application and to meet business requirements. Errors in DQ can have a tremendous technical and business impact, and therefore a sufficient amount of time and resources should be invested in the DQ phase. For example, setting wrong operational specifications for an HPLC system can substantially increase the workload for OQ testing, and selecting a vendor with insufficient support capability can decrease instrument up-time with a negative business impact.

Figure 6 shows a template that can be used to document design qualification. User requirements for an HPLC system should not only have a section to define chromatographic functions and performance but also for physical requirements, construction and vendor requirements to the vendor. A physical requirement could be that all modules should have the same dimensions to allow stackability for optimal use of the lab’s bench space. An example of a construction requirement are accessibility of the detector lamp and flow cell from the front of the instrument for easy maintenance.

 

Figure 6. Template for design qualification

Figure 7 shows an example of selected functional and performance specifications of an HPLC system. The user defines his/her requirement specifications and compares them with the vendor’s specifications. To set the functional and performance specifications, the vendor’s specification sheets can be used as guidelines. However, it is not recommended to simply copy the vendor’s specifications, because compliance to the functional and performance specifications must be verified later in the process during operational qualification and also when re-qualifying the instrument at a later time. Specifying too many functions and setting the values too stringently will significantly increase the workload for OQ. For example, if a company has a need for an isocratic HPLC system, but plans to purchase a gradient system for future use, only an isocratic system should be formally specified for regulatory purposes. This means, as long as the instrument is not used for gradient runs no gradient test need to be conducted. Later on, when the system is used for gradient analysis, the specifications should be changed through a change control procedure.

 

Figure 7. Selected HPLC specifications for design

 

The specifications should be set so that there is a high likelihood that the instrument conforms to them, not only during initial OQ but also during requalification, for example, a year later. Otherwise users may be expected to initiate an investigation to determine if the non-qualified instrument could have had a negative impact on the quality of the product. For example, these possibilities are expressed in ICH Q7 (19): “Deviations from approved standards of calibration on critical instruments should be investigated to determine if these could have had an impact on the quality of the intermediate(s) or API(s) manufactured using this equipment since the last successful calibration”.

Vendor Assessment

Vendors of analytical instruments should be qualified through a formal process. The objective is to ensure that vendors provide high quality products and can give adequate support. For basic equipment, such as pH-meters or a balance, this can be a single page statement describing why the vendor XY has been selected. Certification for a recognized quality system is sufficient for simple instruments. The formal assessment statement should be supported by the quality systems certificate. Figure 8 shows a template with examples to document vendor assessment criteria for analytical instruments.

 

Figure 8. Selected criteria for vendor assessment

For more complex systems especially for critical computer systems such as chromatographic data systems a more detailed assessment is recommended. Depending on the complexity and criticality of the system this can be a mail audit, 3rd party audit and a direct audit through the user firm.

The purpose of the vendor assessment is to ensure that products are designed, developed and manufactured in a documented quality environment. The assessment should also verify that the vendor provides the right services and can maintain the instrument through phone and on-site support.

Installation Qualification

“Installation qualification (IQ) is the documented collection of activities necessary to establish that an instrument is delivered as designed and specified, is properly installed in the selected environment, and that this environment is suitable for the instrument” (2).

Responsibility for IQ lies with the user but activities should be supported and can be carried out by the vendor. For example, before the instrument arrives, the vendor should provide the user with environmental specifications so that the user can prepare the installation site accordingly.

Tasks performed for IQ include:

  • Prepare the laboratory facility according to vendor environmental specifications.
  • Control and record environmental conditions, if critical. For example, temperature and humidity.
  • Compare equipment received with the purchase order (including, accessories and spare parts).
  • Check equipment for any damage.
  • Verify that the instrument conforms with physical and construction requirements, as specified by the user.
  • Check documentation for completeness (operating manuals, maintenance instructions, standard operating procedures for testing, safety and validation certificates).
  • Install hardware (instrument, fittings and tubing for fluid connections, columns in HPLC and GC, power cables, data flow and instrument control cables).
  • Switch on the instruments and ensure that all modules power up and perform an electronic self-test.
  • List equipment manuals and SOPs.
  • Record firmware revision. Prepare an installation report.
  • Enter instrument data into an inventory data base.
  • Prepare, review and sign formal IQ documentation.

Figure 9 shows a template with selected examples that can be used to document completeness of shipment. Figure 10 shows an example of how to check if construction requirements such as stackability and accessibility of flow cells are met.

Figure 9. Template and examples to document shipment

 

Figure 10. Verification of construction requirement

All instruments should be entered into the IQ protocol and/or into a database. An example of this documentation is shown in figure 11. The IQ documents should be updated whenever there is a change made to any entry in the IQ documents. Examples of changes are a firmware revision and the location of the instrument within a building or site.

 

Figure 11. Equipment documentation for IQ

Testing for Installation Qualification

Installation should verify that the instrument hardware and software are properly installed. It does not verify that the instrument conforms to the functional and performance specification. This is done later in the OQ phase. For individual modules, testing is limited to perform and document the instruments self diagnostics when it is switched on.

For systems comprised of multiple modules, correct connection between the modules should be verified. For a modular analytical system, this can be easily achieved by running a test sample and comparing the output with a reference plot. An example of test specifications and results are shown in figure 12.

 

Figure 12. Verification of correct system installation for IQ

Operational Qualification (OQ)

“Operational qualification (OQ) is the documented collection of activities necessary to demonstrate that an instrument will function according to its operational specification in the selected environment“ (2) Emphasis should be placed on “in the selected environment”. Testing of instrument hardware at the user’s site is required because instrument characteristics can change when shipped from the vendor to the user, for example through mechanical vibration.

The most frequently asked questions related to OQ testing are: what should be tested, which are the acceptance criteria, and who should perform the tests? USP answers all the questions in a single sentence: “Users, or their qualified designees, should perform these tests to verify that the instrument meets manufacturer or user specifications in the user’s environment. Designees could be, for example, vendor representatives.”

If a system is comprised of several modules, it is recommended to perform system tests (holistic testing), rather than performing tests module by module (modular testing). Individual module tests should be performed as part of the diagnosis if the system fails. USP does not give a detailed answer on what exactly should be tested: “The extent of testing that an instrument undergoes depends on its intended applications. Therefore, no specific OQ tests for any instrument or application are offered in this chapter”.

Our recommendation is to look at the vendor’s test procedures as a starting point and to only make adjustments if there is a specific reason. If a laboratory uses the same type of instruments from different vendors, it is more efficient to use the same test procedures for all instruments than to use different ones for different vendor instruments. We also recommend using the same test procedure for a specific instrument throughout the company, independent from the location. This allows comparing instrument performance across the company and facilitates exchange of instruments and analytical methods.

The frequency of OQ depends on the type of instrument, on the stability of the performance characteristics, but also on the specified acceptance criteria. In general, the time intervals should be selected so that the probability is high that all parameters are still within the operational specifications. Otherwise, analytical results obtained with that particular instrument are questionable. Here the importance of proper selection of the procedures and acceptance limits becomes very apparent. For example, if the baseline noise of a UV/Visible detector is set to the lowest possible limit as specified by the vendor, the lamp will have to be changed more frequently than when set at a factor of 5 higher.

Inspectors expect OQ tests to be quantitative. This means that the test protocol should include expected results and actual results. Figure 13 includes an example for recording of test results of a balance. The header includes three control weights and acceptable limits for the weight. The daily protocol records actual weights and the name and signature of the test person.

 

Figure 13. OQ test example

Performance Qualification

“Performance qualification (PQ) is the documented collection of activities necessary to demonstrate that an instrument consistently performs according to the specifications defined by the user, and is appropriate for the intended use.”(2)

Here emphasis is placed on the word ‘consistently’. Important for consistent instrument performance are regular preventive maintenance, making changes to a system in a controlled manner and regular testing. The PQ test frequency is much higher than for OQ. Another difference is that PQ should always be performed under conditions that are similar to routine sample analysis. For a chromatograph system this means using the same column, the same analysis conditions and the same or similar test compounds.

PQ should be performed on a daily basis or whenever the instrument is used. The test frequency depends on the criticality of the tests, on the ruggedness of the instrument and on everything in the system that may contribute to the reliability of analysis results. For a liquid chromatograph, this may be the chromatographic column or a detector’s lamp.

In practice, PQ testing can mean system suitability testing or the analysis of quality control samples. This is supported by USP <1058>: “Some system suitability tests or quality control checks that are performed concurrently with the test samples can be used to demonstrate that an instrument is performing suitably.“ For system suitability testing critical system performance characteristics are measured and compared with documented, preset limits. For example, a well characterized standard can be injected 5 or 6 times and the standard deviation of amounts is then compared with a predefined value. If the limit of detection and/or quantitation is critical, the lamp’s intensity profile or the baseline noise should be tested. For chromatographic equipment SST tests are recommended in USP chapter <621> (23).

For ongoing quality control checks samples with known amounts are interspersed among actual samples at intervals determined by the total number of samples, the stability of the system and the specified precision. The advantage of this procedure is that quantitative system performance is measured more or less concurrently with sample analyses under conditions that are very close to the actual application. Figure 14 shows a template with examples for a PQ test protocol.

Figure 14. Documentation of PQ tests

 

(Preventive) Maintenance and Repair

Analytical instruments should be well maintained to ensure proper ongoing performance. Procedures should be in place for regular preventive maintenance of hardware to detect and fix problems before they can have a negative impact on analytical data. The procedure should describe:

  • The maintenance to be done.
  • When it is to be done.
  • What should be re-qualified after maintenance is done. For example, a PQ test should always be performed after instrument maintenance.
  • How to document maintenance activities.

Instruments should be labeled with the dates of the last and next scheduled maintenance.

Planned maintenance activities should follow a documented instrument maintenance plan. Some vendors offer maintenance contracts with services for preventive maintenance at scheduled time intervals. A set of diagnostic procedures is performed and critical parts are replaced to ensure ongoing reliable system uptime.

Unplanned activities that are necessary in addition to the planned activities should be formally requested by the user of the instrument or by the person who is responsible for the instrument. An example of a request form is shown in figure 15.

 

Figure 15. Request form for unplanned maintenance

The reason for the requested maintenance should be entered as well as a priority. All maintenance activities should be documented in the instrument’s logbook. A template with examples is shown in figure 16.

Figure 16. Maintenance logs

 

Defective instruments should be either removed from the laboratory area or clearly labeled as being defective. Procedures should be available for most common problems such as defective UV detector lamps. Procedures should also include information if and what type of requalification is required. Uncommon problems, for example, if an HPLC pump becomes defect without any obvious reason, should be handled through a special procedure that guides users of instruments through the repair process and reinstallation. In this case the impact of the failure on previously generated data should be evaluated.

Change Control

Analytical instruments and systems go through many changes during their lifetime. New hardware modules may be added to enhance functionality, for example, an automated sampling system replaces a manual one for unattended operation. Vendors may change the firmware to a new revision to remove software errors or application software may be upgraded to be compatible with a new operating system. Or a complete system is moved to a newly designed laboratory. Some changes are also initiated when new technologies are introduced, for example, a standard HPLC pump is replaced by a rapid resolution pump for higher sample throughput.

Any changes to instrument hardware, firmware and software should follow written procedures and be documented. Requests for changes should be submitted by users and authorized by the user’s supervisor or department manager and by QA. Before any change request is approved, business benefits should be compared with the risks a change may bring. USP chapter <1058> states: “Implementing changes may not always benefit users. Users should therefore adopt changes they deem useful or necessary and should also assess the effects of changes to determine what, if any, requalification is required”.

USP also recommends following the same 4Q model for changes as for initial qualifications. This means:

  • Specifications should be updated, for example in case a new automated sampling system replaces a manual one.
  • IQ documents should be updated, if a new firmware revision is installed. Installation documents should also be updated when a system is moved to a new laboratory.
  • OQ documents with new test cases and test protocols should be added if the software is upgraded with new functionality and,
  • PQ tests need to be updated to verify ongoing system suitability of a new rapid resolution HPLC pump.

Before any change is approved and implemented a thorough evaluation should be made if OQ tests should be repeated. Depending on the change, an instrument may need no, partial or full testing of a system.

 

4. Validation of Software and Computer Systems

Validation of software and computer systems follows the same principle as the qualification of instrument hardware. USP <1058> has a short chapter on software validation. Software is divided into three categories

  1.  Firmware integrated as chips into instrument hardware for control through local user interface.
  2.  Software for instrument control, data acquisition, and data processing. An example would be a chromatography data system.
  3.  Standalone software, for example a Laboratory Information Management System (LIMS) package.

Most valuable is the statement about firmware: “Firmware is considered as a component of hardware of the instrument itself. Indeed the qualification of hardware is not possible without operating its firmware. Thus when the hardware is qualified at the user’s site, the integrated firmware is also essentially qualified. No separate on-site qualification of the firmware is needed.” The chapter further recommends recording the firmware version as part of IQ and keeping it under change control.

For software categories two and three the chapter refers to the 4Q activities and recommends the FDA guide on software validation for more detail7.

In general, the effort to validate a computer system is higher than for instrument hardware. Depending on what it is, the costs for software validation and computer system validation can be 50% or more of the costs for the software itself, with an increasing trend. The main reason is that software offers more and more functionality. All software functions with high impact on drug or API quality should be validated. This does not mean correct functionality should always be tested in the user’s laboratory, but as a minimum, all functions should be specified and the need for testing should be evaluated.

This chapter will go into more detail on what is important for validation of software and computer systems. We will follow the same 4Q Lifecycle model as for instrument hardware. The main focus is on relatively small and less complex software and computer systems. As a model we will use a chromatographic data system (CDS) with no or little customization. For more complex systems, for systems with high level of customization and for any software development activities, we refer to literature references with more detail, for example, references 7-12.

Master and Project Planning

Software and computer system validation should be well planned. A computer system validation master plan should not only describe validation approaches but should also have an appendix with a list of all computer systems used in a laboratory. Typically, inspectors ask for a list when inspecting data that have been generated by a computer system. The list should uniquely identify all computer systems. It should include a short description of the system and information on the location, the application and whether the system is used in regulated areas. Inspectors also will ask for the risk category of the system. The risk categories can be, for example, high, medium or low. The categories should have been determined following a documented process and should be justified. Criteria are complexity and impact of the system on (drug) product quality. Most likely the inspector will focus during the inspection on systems that have been classified as high risk.

Figure 17 shows a template with examples on how to document a computer system inventory. The list should also include information on the state of validation. Non-validated systems should have a timeframe for system validation. Now the importance of the risk category becomes obvious: Non-validated systems classified as high risk must not be used for any regulated work.

 

Figure 17. Template for computer system inventory

 

The content items of project plans for computer systems are similar to equipment hardware. However, because of a higher complexity and higher validation effort, the document is longer. For practical reasons table templates will not work well. Longer project plans are written in text form and a hyperlinked table of contents will help to find individual sections. Project plans should have a section on risk assessment. It should describe how risk assessment is planned and documented and what risk levels mean for the extent of validation.

Requirement Specifications

Requirement specifications of software and computer systems should be linked to test cases in some kind of traceability matrix. This can be a table on its own or the link can be built into the requirements table. A template with examples is shown in figure 18. Each specification should have a unique ID code. Criticality of the function can be defined as high, medium or low. Most important questions to ask are: what happens if the function does not work at all or if it produces wrong results? In the next column the test priority is documented. Criticality plays a major role but also the question as to how the user’s environment or the user, for example through a wrong user configuration, can influence correct functioning.

 

Figure 18. Example for requirement specifications of a chromatographic data system

Requirements of a CDS should not only be specified on the ability to run a chromatographic analysis, but also on other requirements that are mainly related to system and data security, and data integrity. Requirements are stated in FDA’s regulation for electronic records and signatures: 21 CFR Part 11 (21) and in Annex 11 to the European GMPs (24). Very important is the electronic audit trail function. Selected specifications for audit trail functionality are shown in figure 19.

 

Figure 19. Selected specifications for electronic audit trail

Vendor Assessment

A thorough vendor assessment is even more important for computer systems than it is for instrument hardware. When instrument hardware arrives in a laboratory it can be physically inspected for any damage and specifications can be fully tested so users can get a good impression of the quality. This is not so easy with software. DVD covers always look very nice but they say nothing about the quality of the product. Also most likely it is impossible for a user to test all functions of a complex commercial computer system. Errors may not even become obvious during initial use, but only later when certain functions are executed together.

During vendor assessment, the user should verify that the software has been designed, developed and validated during and at the end of development. The vendor’s capability and practice to support the user before and during installation and as long as the software is used should also be checked.

Figure 20 lists different assessment methodologies. Costs for the assessment increase from 1 to 5. Vendor audits are most expensive but could make sense when a company plans to purchase complex computer systems for multiple laboratories or sites. The final decision on the methodology should be based on risk assessment. Criteria are vendor risk and product risk.

 

Figure 20. Methodologies for vendor assessment

 

Criteria for product risk are:

  • System complexity
  • Number of systems to be purchased
  • Maturity of the system
  • Influence on other systems
  • Impact on (drug) product quality
  • Impact on business continuity
  • Level of customization

When users purchase software such as CDS they need support from a specific vendor for a lengthy time to ensure retrieval and readability of data for several years. Therefore, the future outlook of a company and the ability to support data is important. The way to make an assessment is to look for how long older data can be supported by the current system. This in combination with the size of the company and the position of the company in the target market are good indications to assess the vendor risk. The selection decision for a specific vendor should be justified and documented.

Installation Qualification

Key points for IQ of computer systems are to verify correct software installation and to document all computer hardware, software and configuration settings as the initial baseline configuration. Recommended steps for installation of computer systems include:

  • Install software on computer following the manufacturer’s recommendations.
  • Verify correct software installation to make sure that all files are correctly installed. Software with MD5 based checksum routines is a good tool for this.
  • Make a back-up of the software.
  • Configure peripherals like printers and instrument modules.
  • Identify and make a list with a description of all hardware, operating system software and application software. Identification of software should include the version number.
  • Make system drawings, where appropriate.
  • For networked systems: check communication with network devices.

As part of the installation process computer systems should be well documented with:

  • Computer hardware, e.g., manufacturer, model.
  • Computer firmware, e.g., revision number.
  • Operating system: vendor, product identifier and version.
  • Application software: vendor, product identifier and version.
  • Hardware peripherals, e.g., printers, CD-ROMs.
  • Network hardware, firmware, software and cables.
  • Documentation, e.g., operating manuals and specifications.

Information should be entered into a data base and should be readily available when contacting vendors to report a problem during operation. Figure 21 shows a template with examples of an installation protocol.

 

Figure 21. Computer system documentation for IQ

 

Operational Qualification

Testing software and computer systems can be a complex task. Extent of testing should be based on a justified and documented risk assessment. The required effort mainly depends on:

  • the criticality of the system for (drug) product quality and data integrity
  • the complexity of the system
  • information on what has been tested by the vendor and the related test environment
  •  the level of customization and configuration.

Most extensive tests are necessary if the system has been developed for a specific user. In this case the user should test all functions. For commercial off-the-shelf systems that come with a validation certificate, only tests should be done of functions that are highly critical for the operation or that can be influenced by the environment. Examples are data acquisition over relatively long distances from analytical instruments at high acquisition rates. Specific user configurations should be documented and tested, for example, correct settings of network IP addresses should be verified through connectivity testing.

When computer systems can control and obtain data from multiple analytical instruments, tests should be conducted with a high number of instruments transmitting data. The example in figure 22 illustrates that, according to specifications, 4 instruments can be controlled. Correct functioning of the system should be verified with all four instruments connected and delivering data at high acquisition rates.

 

Figure 22. Example for high load testing

Test results should be formally documented. Figure 23 shows a template and examples for a test protocol. It consists of three parts. The header describes the test system, test objective and the specification. The step-by-step test procedure, expected results and actual results are documented in the middle. The test protocol also has a column to document evidence of testing. This can be a print out, a screen capture or just handwritten recording of visual observations. The lower part documents the names of the test engineer and reviewer and has s signature section.

Figure 23. Template for testing

 

Performance Qualification

PQ should be designed to challenge a complete system’s performance. For a computerized analytical system this can mean, for example, running system suitability testing, where critical key system performance characteristics are measured and compared with documented, preset limits.

PQ activities for CDS can include:

  • A complete system test to prove that the application works as intended. This can mean running a system suitability test or analyzing a well characterized sample through the system and comparing the results with results previously obtained.
  • Regression testing: reprocessing data files and comparing the results with previous results.
  • Regular removal of temporary files.
  • Regular virus scan.
  • Auditing computer systems.

Most efficient is to use software for automated regression testing. The software runs typical data sets through a series of applications and calculates and stores the final result using processing parameters as defined by the user. During regression testing the data are processed again and results are compared with previously recorded results. Normally these tests don’t take more than five minutes, but give assurance that the key functions of the system work as intended.

Configuration Management and Change Control

The purpose of configuration management is to be aware of the lifetime composition of the system from planning to retirement. The initial or baseline configuration of a system has been documented as part of IQ.

Any changes to specifications, programming codes or the initial set up of computer hardware should follow written change control procedures and be documented. Changes may be initiated because errors have been found in the program or because additional or different software functions or hardware may be desirable. Requests for changes should be submitted by users and authorized by the user’s supervisor or department manager.

Figure 24 shows a form that can be used to request changes. The form should include information on the priority and on business benefits versus costs for additional validation tasks. This information is important to assess if the change has a business advantage and should be approved or rejected.

 

Figure 24.Example for change request form

 

The form should also include information about whether regulatory notification is required and the roll back plan. A roll back plan is like a contingency plan that becomes effective when a change introduces an error, which causes the system to fail. The roll back plan ensures that the system can be brought back to the last working system configuration.

Validation Report

At the end of validation, a summary report should be developed. This should be a mirror of the validation project plan. It should be organized in such a way that it has all the elements and follows the outline of the validation plan. This makes it easy to check if all plan items have been completed successfully. Deviations should be documented, if there are any, together with corrective actions and/or work around solutions. The report should include a statement that the instrument or system is qualified or validated. After the statement and the report have been signed by management, the product can be released for operation.

Typically, the validation plan and the report are the first documents inspectors want to see when they inspect a validation project. If everything is well organized and documented, it may well be that after looking at both documents inspectors get such a good impression about the validation work that they will focus on other inspection areas.

Validation of Existing/Legacy Systems

It frequently happens that existing instruments and systems are not formally validated if they are not used in a regulated environment. Sometimes these systems are called legacy systems. They should be validated if they will be used in a regulated environment, a process called retrospective validation. Inspectors expect the same documented evidence that the system is suitable for its intended use as for new systems.

We recommend following the same 4Q model for validation as for new systems. The main difference is in the DQ phase. Most likely there is not much information from the vendor available and vendors cannot be assessed. There is also no need to develop requirement specifications from scratch. The big advantage of an existing system is that there is a lot of information from past use and the used functions are well known.

The most important task for an existing system is to document the system functions used along with any comments about problems with the functions. The system should be fully documented for IQ, like a new system.

OQ and PQ testing should focus on functions that caused problems in the past. After successful OQ and PQ testing, a summary report should be developed and signed by management. This means the system can be released for use in a regulated environment.

Validation of Spreadsheet Applications

Spreadsheets are widely used in laboratories for data capture, data evaluation and report generation. For example, they can be used to correlate data from a single sample analyzed on different instruments and to obtain long-term statistical information for a single sample type. The processes may be automated, for example, enabling the analytical data to be transferred, evaluated and reported automatically. In all of these programs, analytical data are converted using mathematical formulae.

Today the understanding is that the programs themselves don’t have to be validated by the user, e.g. MS Excel. What should be validated are the custom calculations and program steps written by the laboratory. There should be some documentation on what the application program, written by the user as an add on to the core software, is supposed to do, who defined and entered the formulae and what the formulae are.

Development and validation of spreadsheets should follow a standard operating procedure. Recommended steps are:

  • A user drafts a proposal for a new spreadsheet. The proposal should include a description of the problem that the spreadsheet should solve, how it is handled now and how the spreadsheet can improve efficiency.
  • The system owner writes a project plan.
  • The system owner collects inputs from anticipated users on requirement specifications and writes requirement specifications.
  • The programmer defines and documents required functions. Functions are reviewed by users.
  • The programmer develops design specifications, for example, which formulas are used and the location of input/output cells. For complex spreadsheets and for spreadsheets with VBA scripts, the design specifications are reviewed by peers of the programmer.
  • The programmer develops the worksheet and creates functional tests. The code is reviewed by peers of the programmer (structural testing) for spreadsheets with VBA scripts.
  • The programmer writes a user manual. The system owner develops a test protocol for users.
  • Users load the spreadsheet onto their computer.
  • Users test the spreadsheet and document the results.

5. Implementing USP Chapter <1058>

USP <1058> is the authoritative guide for analytical instrument qualification. Even though as a chapter with a number above 1000, generally, it is not mandated and alternative approaches are possible. Nevertheless, we would recommend implementing it for FDA regulated environments because of several reasons.

  • The chapter is mandated if any USP monographs require using qualified instruments for a specific analysis.
  • FDA inspectors expect instruments to be qualified when used for regulated testing.
  • The applied 4Q qualification model has been very well established since over 10 years and many laboratories are familiar with it.
  • The model is applicable to all types of instruments ranging from simple devices to complex systems.
  • The model is flexible and allows laboratories to define test procedures and acceptance criteria according to the instrument’s intended use.

Because of the importance of the chapter and its advantages we want to dedicate this last primer chapter to recommendations for implementation of USP <1058>.

<1058> Instrument Groups

Analytical laboratories typically include a set of tools ranging from simple nitrogen evaporators to complex automated instruments. Depending on the complexity, the qualification efforts vary. The concept is always the same, but the extent of testing and the required amount of documentation will change. For example, a very simple instrument may only need one or two minutes for physical inspection and making a tick mark in a check list, while more complex systems can easily take several days for full validation.

Because of the large variety of instruments, with different qualification and documentation requirements, it can be very complicated if each type of instrument is handled differently. To simplify the process, USP recommends dividing all instruments into three groups A, B, and C and to define for each group a specific set of qualification tasks.

The standard lists examples for each group but at the same time makes it clear that the categories are not only instrument but also applications specific. Examples for all three groups are shown in figure 25.

 

Figure 25. Instrument groups A, B, and C

 

Group A includes standard equipment with no measurement capability. Examples are nitrogen evaporators, magnetic stirrers, vortex mixers and centrifuges. Group B includes standard equipment and instruments providing measure values, for example, a balance. This group also includes equipment controlling physical parameters, such temperature, pressure or flow. Examples are water baths and ovens. Group C includes instruments and computerized analytical systems. Examples are computerized IR-spectrometers, HPLCs and mass spectrometers.

Allocating Instrument into Instrument Groups

USP recommends dividing analytical instruments into groups, but does not include a matrix with instruments allocated to groups. On the other hand such a matrix is of utmost importance for a company; otherwise discussions will start over and over again about the right allocation whenever an instrument has to be qualified. Our recommendations are:

  1. Develop a list with all analytical instruments and allocate all of them into groups A, B or C.
  2.  Develop a list of procedures for each group that should be available and used when qualifying instruments.
  3.  Develop a list of tasks for each group that should be executed when qualifying instruments.

Within a company the lists, procedures and tasks for groups A, B, and C should be developed at the highest possible level; and preferably there should only be one set available. Having a harmonized approach reduces subjectivity for qualification and it is not only very efficient but also ensures consistency. We would suggest putting examples of instrument categories and applications in an equipment validation master plan. A harmonized approach is also advantageous for external audits or inspections, especially when several laboratories are inspected by the same inspector in the same time frame.

Procedures and Qualification Protocols for Three Groups

The number of procedures required increases from groups A to C. Each company should have a document that specifies which type of procedures should be developed. A template with examples is shown in Figure 26. The point here is not to exactly follow the examples, and this list does not originate from the USP, but it is very important to have a list available within an organization.

 

Figure 26. Recommended procedures for groups A, B and C

The number of documents increases from A to C. An operating instruction and a procedure for reporting problems are enough for group A devices. Group B requires additional procedures for qualification, change control and preventive maintenance and repair. Additional procedures for group C are specific to computer systems, for example, back-up, security, and system administration.

A company should also provide information on which qualification steps should be executed. An example is shown in figure 27. Some recommendations are from the USP chapter. For example it states for group A: “The manufacturers specification of basic functionality is accepted as user requirements. Conformance of group A equipment with user requirements may be verified and documented through visual inspection”. This means a simple checklist can be enough for documentation.

 

Figure 27. Recommended deliverables for groups A, B and C

 

The difference between B and C are mainly in areas of vendor qualification and risk assessment. For B we only document the vendor’s quality system and keep the certificate as a record. For computerized systems in C we should have a vendor assessment program. Risk assessment is also recommended for C. The number of required documents for B and C does not vary much. However, the size of the documents and the format will be different. For example, a qualification plan in B can be documented on a one or two-page template. For C this could be easily a 20 page text document.

Responsibilities, Communication and Training

Implementation of USP <1058> should be communicated to everybody in the organization who is involved in qualification and validation of instruments and systems. People should receive training on the USP chapter, on why the company decided to implement the chapter and what it means for day-to-day operation. The training should be documented and supervisors should follow-up to verify effectiveness.

Vendors should also be informed about implementation of USP and they should be advised to study the chapter and follow-up to fulfill vendor requirements. USP <1058> has a chapter on roles and responsibilities for users, the quality assurance unit and manufacturers.

Users

Users of analytical equipment have the ultimate responsibility for instrument operations and data quality. It is an FDA GMP requirement that analysts must sign the analytical test result and therefore also have the ultimate responsibility to make sure instruments and computer systems are qualified and validated. Users should be adequately trained in the instrument’s use. Training can be provided by anybody who is proven to be competent, for example by vendor representations, 3rd parties and by internal resources.

The fact that users have ultimate responsibilities for instrument qualification does not mean that they have to conduct all qualification activities. For example, IQ and OQ can be delegated to the instrument vendors or to a 3rd party organization. On the other hand PQ should be performed by users because the tests are applications specific and require a good knowledge of the application. Advantage of using vendors for IQ/OQ is that they have all the necessary experience and procedures and even more importantly, they bring along calibrated tools that are required for the qualification. Vendors with worldwide presence typically also offer qualification services around the globe. This is important for companies operating in multinational environments. Whoever is doing the qualification work should be trained and training certificates should be filed with the qualification documents.

Quality Assurance

The role of the Quality Assurance unit is the same as for any other regulated activity. QA personnel are responsible for assuring that the qualification process meets compliance requirements and conforms to internal procedures. QA personnel should also train or advise user groups on regulations and lead or help with the vendor assessment process.

Developers, Manufacturers and Vendors

Developers and manufacturers are responsible for the design of the instrument or software program and for providing specifications to the user. They should validate processes used in development and manufacturing as well as during the entire support period. Manufacturers should allow user audits and share validation processes, test procedures and test results with regulated users. Manufacturers and vendors should also notify all users about hardware and software defects discovered after a product’s release. Furthermore, manufacturers or vendors should provide user training, installation and qualification support and repair services.

References

  1. U.S. FDA, Title 21 of the U.S. Code of Federal Regulations: 21 CFR 211- Current good manufacturing practice for finished pharmaceuticals.
  2.  Unites States Pharmacopeia, Chapter <1058>, Analytical Instrument Qualification, Rockville, USA, 2008
  3.  P.Bedson and M.Sargent, The development and application of guidance on equipment qualification of analytical instruments, Accreditation and Quality Assurance, 1 (6), 265-274, 1996
  4.  P. Coombes, Laboratory Systems Validation Testing and Practice, DHI Publishing, LTD, Raleigh, USA 2002
  5.  L. Huber, Validation and Qualification in Analytical Laboratories, Interpharm, Informa Healthcare, New York, USA, 1998, Second revision 2007
  6.  M. Freeman, M.Leng, D.Morrison and R.P.Munden from the UK Pharmaceutical Analytical Sciences Group (PASG), Position Paper on the qualification of analytical equipment, Pharm. Techn. Europe, 40-46, November 1995
  7.  United States Food and Drug Administration (FDA), General Principal of Software Validation: Final Guidance for Industry and FDA Staff, Rockville, MD, Jan 2002
  8.  GAMP Good Automated Manufacturing Practice, Guide for Validation of Automated Systems, Version 4, 2001
  9.  GAMP Good Automated Manufacturing Practice, A Risk-based Approach for Compliant GxP Computerized Systems, Version 5: 2008
  10.  GAMP Good Practice Guide for Validation of Laboratory Systems, 2005
  11.  L. Huber, Validation of Computerized Analytical and Networked Systems, Interpharm, Englewood, CO, USA, April 2002
  12.  Parenteral Drug Association (PDA), Validation and qualification of computerized laboratory data acquisition systems (LDAS), Technical paper 31, 2000
  13.  C.C.Chan, H. Lam, Y.C.Lee, X.M. Zhang, Analytical Method Validation andInstrument Performance Verification., Wiley Interscience, Hoboken USA, 2004
  14.  Pharmaceutical Inspection Convention Scheme (PIC/S), Good practices for Computerised Systems in Regulated ‘GxP’ Environments, 2003
  15.  U.S. FDA GLP, Good laboratory practice regulations for non-clinical studies, Final rule, U.S. FDA, Rockville, Md., USA, Title 21 CFR, Part 58, 1979
  16.  Organization of Economic Co-operation and Development, Good laboratory practice in the testing of chemicals, final report of the Group of Experts on Good Laboratory Practice, 1982 (out of print).
  17.  Organization of Economic Co-operation and Development, The OECD principles of good laboratory practice, Series on principles of good laboratory practice and compliance monitoring, number 1, GLP consensus document environment monograph No. 45, Paris, 1998
  18.  Commission of the European Communities, The rules governing medicinal products in the European Union, Volume 4, Good manufacturing practices: Medicinal products for human and veterinary use, 2003
  19.  ICH Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients 20 ISO/IEC 17025, General requirements for the competence of testing and calibration laboratories, 2005
  20.  U.S. FDA, Title 21 of the U.S. Code of Federal Regulations: 21 CFR 11 "Electronic Records; Electronic Signatures;
  21.  Qualification and validation, Annex 15 to the EU Guide to Good Manufacturing Practice, 2001
  22.  Qualification and validation, Annex 15 to the EU Guide to Good Manufacturing Practice, 2001
  23. FDA ORA Laboratory Procedure: Volume II - Equipment ORA-LAB.5.5, (link)

The Author Dr. Ludwig Huber Working with the FDA

A good relationship with industry and FDA has always been my highest priority. Most issues between industry and FDA can be resolved by having a good understanding of each others position. Personal visits to FDA's centers in Rockville, panel discussions at public conferences, joint industry/FDA workshops and having FDA and industry guest speakers in the Labcompliance audio seminars helped a lot to get a real good understanding on both positions, and to get an insight on what's coming.

The examples below show interactions with the FDA.

 

Ludwig Huber and Paul Lepore, FDA's 'Father of GLP' during a GLP Workshop in Tokyo.

Paul Lepore told the audience how they should prepare for a GLP inspection and what inspectors will ask.

Ludwig Huber explained how to implement computer validation in GLP environment.
1999
Nick Buhay, Acting Director in FDA/CDER's Division of Manufacturing and Product Quality, and Ludwig Huber in the Q&A Discussion Session on Laboratory Compliance

2006
Ludwig Huber was on conference program's Part 11 panel discussion with FDA's the Joseph Famulare, Acting Director, Office of Compliance, CDER.

2006
Dennis Cantellops (right) , QA manager at the FDA Labs in Puerto Rico, and author of FDA's Excel Bulletins  spoke at Ludwig Huber's Excel audio seminar as guest speaker.
2005 and in 2009
Ludwig Huber has been asked to review FDA's internal SOP and Lab Information Bulletin on Spreadsheet Validation.

FDA acknowledged Ludwig Huber's contribution in the LIB
Thomas S. Savage, Senior Coordinator at FDA's Office of Regulatory Affairs,  told the audience that he took quite a lot of material from Ludwig Huber's Labcompliance website. He also said that he regularly visits this website when he wants to learn about news on FDA inspections.
Ludwig Huber in an joint industry/FDA panel discussion at the IVT Part11 conference in Washington DC:  From right to left: Martin Browning, fEduQuest Inc, Paul Motise, US FDA, Kathryn Davidson. Baxter Healthcare, INC, and Ludwig Huber fAgilent, 1999
Ludwig Huber (middle) with FDA's Paul Motise (second from left) and the speaker panel at an IVT conference in Washington (2002). Other speakers, from right to left: Chris Reid, Rebecca Fuller Heyde, and Jeff Beck
2002


Video Clips with FDA Management are on the Lab Compliance Website

FDA management explained FDA's 21st Century Drug cGMP initiative and the impact on Part 11

Mark B. McClellan, MD., PhD; Commissioner of Food and Drugs, Janet Woodcock, MD. ; CDER Director David Horowitz, Director of CDER's Office of Compliance, Joseph Famulare, Director, Div. of Manufacturing & Product Quality Office of Compliance, CDER/FDA
2003

Ludwig Huber (right) and John Murray, FDA, (left), speaking at the IVT Computer System Validation Conference


2004
George Smith, FDA's national Part11 expert, at a panel discussion with Ludwig Huber during an IVT conference 2005

Smith and Huber discussed and answered questions about computer system validation and e-records.
Ludwig Huber (right) in a panel discussion with FDA inspectors and directors:
 Dr. Robert C. Horan, B Erik Henrikson,Joseph Famulare,  and Nicholas Buhay, Acting Director in FDA/CDERs Division of Manufacturing and Product Quality.

Ludwig Huber (right) with Dr. Robert C. Horan,  FDA, Nicholas Buhay,  and Joseph Famulare, in the joint SINO-SFDA-US FDA cGMP /workshop

  Ludwig Huber has been invited by FDA’s CDER to give a seminar for FDA Quality Professionals

The idea was to share Ludwig’s expertise in the area of laboratory controls, computer validation and integrity of electronic records
  In 2007 Dr. Ludwig Huber has been invited by FDA's Eric Hendrikson to give a post conference tutorial at the annual GMP conference organized by FDA professionals.

Two FDA professionals attended Ludwig's tutorial.  
  Dr. Brenda Uratani, Assistant Country Director US FDA China Offices, and Accociate Prof. Mr. Wang Yamin, Center for Drug Evaluation, SFDA attended Dr. Huber's GMP  compliance workshop at the Bejing University.
Here Dr. Ludwig Huber (left) at lunch with  Dr. Brenda Uratani, , and with Accociate Prof. Mr. Wang Yamin,