Laboratory Equipment Qualification

Article of Kenneth W. Sigvardson,* Joseph A. Manalo,Robert W. Roller, Fatieh Saless, and David Wasserman

The main goal in qualifying laboratory equipment is to ensure the validity of data.The current equipment qualification programs and procedures used within the pharmaceutical industry are based on regulatory requirements, voluntary standards, vendor practices, and industry practices.The result is considerable variation in the way pharmaceutical companies approach the qualification of laboratory equipment and the way they interpret the often vague requirements.The authors summarize the conclusions of the PhRMA Workshop on Acceptable Analytical Practices for the topic “Qualification of Laboratory Equipment.”They describe the areas of  agreement and offer options for areas in which there is variation on what is appropriate

The concept of Acceptable Analytical Practices (AAPs) was developed by the Analytical Research and Development Steering Committee of the Pharmaceutical Research and Manufacturers of America to share information about how the pharmaceutical industry has implemented the CMC and Quality Guidances of the International Conference on Harmonization and worldwide regulatory authorities.AAPs were designed

to provide a process by which one could learn from the experience of experts in pharmaceutical research and development and enhance the understanding of analytical practices that reflect good science

and sound regulatory compliance. The process of discussing and publishing AAPs also is intended to identify and address critical issues in which guidance is lacking, ambiguous, or contradictory.

Initially, the process adopted for the development of the first four AAPs involved a two-and-a-half-day workshop held 19–21 September 2000. The four topics discussed were Laboratory Equipment and Instrument Qualification; Out-of-Specification Results: How to Conduct Laboratory Investigations; Forced Degradation Studies: Issues and Controversies; and Analytical Methods Transfer. This article presents the

first of these presentations. The three remaining topics will be covered in future issues of this magazine. Regulations regarding the qualification of laboratory equipment often are vague and subject to interpretation. The good manufacturing practice requirements state that “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” (1). The good laboratory practice regulations impose similar requirements, stating that “equipment used for the generation, measurement, or assessment of data shall be adequately tested, calibrated, and/or standardized” (2).

Terminology and definitions

In this industry, considerable variation ex-ists in the terminology used in the qualification of equipment. The “Equipment qualification definitions” commonly used terms with their definitions. Throughout this document the term equipment is used to represent both instruments and equipment as they are defined

in the “Equipment qualification definitions”.

General requirements

The equipment qualification program must be defined and documented. The program must contain provisions for the qualification, maintenance, and documentation of failures of all equipment used to collect data for regulatory submissions.This is usually accomplished by using a standard operating procedure (SOP) that describes the overall program. Individual procedures, specific to the equipment used, also must be documented. Specific procedures for equipment qualification can be documented in one of two ways: First, separate SOPs can be written that contain the procedures used for qualifying and maintaining each type of equipment. Alternatively, master SOPs can be used to describe the compliance

requirements for a variety ofequipment, and specific equipment procedures can be created as separate documents similar to test methods. This second approach minimizes the repetition of the compliance requirements in many SOPs, and it provides additional flexibility in documentation practices. In addition to the documentation of the program and its associated procedures, all equipment used to generate reportable

data must be tagged or labeled and have records maintained. The labeling serves as a way to identify equipment that is unqualified or does not meet performance requirements. It prevents the use of such equipment while it is in its normal operating location. Records usually are maintained through some form of log book that documents all critical activities such as failures, maintenance, qualification testing, location, custodian, and so forth.

Qualification life cycle

It is not necessary to formally document any equipment prepurchase activities. These activities normally are referred to as design qualification, or DQ, and they lead to the selection of equipment. Once the equipment arrives, the installation phase begins. The first part of the qualification cycle requiring formal documentation occurs with the installation qualification (IQ). In addition to specific installation activities, a key part of IQ is to enter the equipment into inventory maintained as part of the program by labeling it and creating the equipment log. In some cases, vendors may require that they perform the installation themselves, resulting in shared documentation of IQ activities. The qualification life cycle also includes components commonly referred to as operational qualification (OQ) and performance qualification (PQ). Although no requirement exists to separate qualification components into IQ,OQ, and PQ, these terms often facilitate the qualification activities when complex equipment is involved. The OQ testing ensures that the equipment is capable of meeting performance criteria within the ranges used for all of the testing. The selection of OQ tests is based on good science and the intended use of the equipment. The purpose of such tests is to ensure the validity of the data. Suggestions of specific OQ tests for various equipment types are listed in the sidebar “Examples of operational qualification tests for common analytical equipment.”Depending on the specific use of each type of equipment, the appropriate tests and frequency of testing should be incorporated into the qualification program. Performance qualification involves the testing of the equipment using the specific method or assay to ensure that the method is producing valid data. PQ may consist of method validation testing, system suitability testing, and analysis and trending of control samples. PQ supplements the OQ by adding checks of the specific method used.Again, like OQ, PQ

testing procedures should be based on good science and will depend on the specific method being used. In summary, the procedures used throughout the entire qualification life cycle must be documented, be based on good science, and ensure the integrity of the data generated by the equipment. The procedures and the functions or components qualified also should be based on the intended use of the equipment. Some qualification should be performed on a periodic basis, and this practice should be defined in the written qualification procedures. The regulations and the supporting science offer no distinction between a manufacturing quality control laboratory and an R&D laboratory. The same quality standard applies in each situation.

Equipment maintenance

Some OQ testing should be performed following equipment maintenance. The testing should be limited to the operational functions that are affected by the specific maintenance procedure. This usually involves repeating the OQ tests that evaluate the component that has been repaired or replaced. Components that are subject to wear and require routine replacement are best handled with a preventive maintenance program. The preventive maintenance intervals should be defined, be documented, and be an integral part of the qualification life cycle. Intervals can be defined or adjusted on the basis of the actual equipment qualification or maintenance history. Preventive maintenance is performed mainly for business reasons because it represents the most cost-effective method of maintaining equipment that requires frequent service.

Computers and software used to control laboratory equipment

Current regulations require the validation of computers and software that are used to control laboratory equipment or process data. Systems that acquireprocess, or store data also have additional requirements defined by 21 CFR 11. Although qualification is considered a subset of validation, validation requires additional documentation and change control procedures. Guidance for validation of computers and software for general computer-related systems and data acquisition systems have been described in Parenteral Drug Association technical reports (3,4). These guidance documents offer procedures for the documentation, qualification, and change control aspects of validation. When multiple laboratory computers are maintained with the same configuration of hardware and software, complete validation on a single representative unit can be performed. All other identical configurations would require only the IQ portion of the qualification. All such computers must be maintained in the same system of change control, which requires the appropriate revalidation when any change in configuration is made.

Summary and conclusion

The state of equipment qualification practices in the pharmaceutical industry is evolving and is subject to much variation. Although more extensive guidance exists for computerized systems than for non computerized components of laboratory equipment, the additional validation requirement of the computerized systems present many new challenges. Some commercially available software may not completely meet current requirements. A need exists for greater consistency in the qualification and maintenance practices for common analytical instruments used within the pharmaceutical industry. In today’s environment, there is a tendency to harmonize practices by simply incorporating new procedures into existing programs. In an atmosphere of growing regulatory expectations, this approach is common but not recommended as a means of upgrading qualification programs. The overall program should be evaluated periodically to ensure that current requirements are met and that excessive or inefficient practices are eliminated or changed. Although variations in equipment qualification practices never can be eliminated within the industry, it is recommended that the industry be consistent in meeting core requirements. This article outlines the core requirements that now are widely accepted. It also offers the rationale for making decisions about topics that are not widely accepted and that will continue to evolve in the industry.

References

1. “Laboratory Controls, General Requirements,”

Code of Federal Regulations, Part

211.160, Title 21, Rev. April 2000.

2. “Maintenance and Calibration of Equipment,”

Code of Federal Regulations, Part 58.63,

Title 21, Rev. April 2000.

3. PDA, Validation of Computer-Related Systems,

Technical Report No. 18, PDA J. Sci.

Technol. 49 (1), S1–S17 (1995).

4. PDA, Validation and Qualification of Computerized

Laboratory Data Acquisition Systems,

Technical Report No. 31, PDA J. Sci.

Technol. 53 (4), 1–12 (1999).

5. National Conference of Standards Laboratories,

Establishment and Adjustment of Calibration

Intervals, NCSL RP-1 (1996).

6. J.Agalloco, “Master Planning of Validation,”

PDA Training and Research Institute, April

1998.

7. M. Dorfman and R. Thayer, Standards,

Guidelines, and Examples on Software Requirements

Engineering (IEEE Computer Society

Press,Washington, DC, 1990).

8. P. Bedson, “The Development and Application

of Guidance on Equipment Qualification

of Analytical Instruments,”Accred. Qual.

Assur. 1 (6), 265–274 (1996).

9. P.A. Cloud, “Validating a Laboratory Incubator,”

BioPharm 10 (11), 30–42 (1997).

10. The Rules Governing Medicinal Products in

the European Community,Volume IV (Office

for Official Publications for the European

Communities, Luxembourg, 1992).

11. FDA, “Guidelines on General Principles of

Process Validation,”Rockville,MD,May 1987.

12. Department of Defense,“Definition of Terms

for Testing,Measurement, and Diagnostics,”

MIL-STD-1309D, PAR 3.1.326 (1983).

13. J.K. Taylor, “Standard Reference Materials:

Handbook for SRM Users,” National Technical

Information Services Publication

260–100 (1993).

14. National Conference of Standards Laboratories,

“General Requirements for the Competence

of Testing and Calibration Laboratories,”

ANSI/ISO/IEC 17025 (2000). PT

Definition of Pharmaceutical Terms

Design Qualification (DQ) :

The documented verification that the proposed design of the facilities, systems and equipment is suitable for the intended purpose.

Installation Qualification (IQ) :

The documented verification that the facilities, systems and equipment, as installed or modified, comply with the approved design and the manufacturer’s recommendations.

Operational Qualification (OQ) :

The documented verification that the facilities, systems and equipment, as installed or modified, perform as intended throughout the anticipated operating ranges.

Performance Qualification (PQ) :

The documented verification that the facilities, systems and equipment, as connected together, can perform effectively and reproducibly, based on the approved process method and product specification.

Ref: Qualification and validation, Annex 15 to the EU Guide to Good Manufacturing Practice

Audit checklist for who GMP guideline compliance in pharmaceuticals_Part 5

Equipment/Line/Area Cleaning, Preparation, and Clearance

• Do written procedures detail how equipment is to be checked immediately prior to use for cleanliness, removal of any labels and labeling from prior print operations? Check here YES / NO
• Do written procedures detail any disconnection and reassembly required to verify readiness for use?

Operational Process Validation and Production Change Order Control,

• Have production procedures been validated? (Review selected procedures for validation documentation. Adequate?) Check here YES / NO
• Does the process control address all issues to ensure identity, strength, quality and purity of product? Check here YES / NO
• Does the procedure include formulation that is written to yield not less than 100% of established amount of active ingredients? Check here YES / NO
• Are all weighing and measuring preformed by one qualified person and observed by a second person? Check here YES / NO
• Have records indicated preceding policy been followed by presence of two signatures? Check here YES / NO
• Are actual yields calculated at the conclusion of appropriate phases of the operation and at the end of the process? Check here YES / NO
• Are calculations performed by one person? Is there independent verification by a second person? Check here YES / NO

In-Process Inspection, Sampling, and Laboratory Control

• Are written procedures established to monitor output and validate the performance of manufacturing procedures that may cause variability in characteristics of in-process materials and finished drug products? Check here YES / NO
• Are in-process materials tested at appropriate phases for identity, strength, quality, purity and are they approved or rejected by Quality Control? Check here YES / NO
• Are there laboratory controls including sampling and testing procedures to assure conformance of components, containers, closures, in-process materials, and finished product specifications? Check here YES / NO
• Reprocessing/Disposition of Materials Check here YES / NO
• Do written procedures identify steps for reprocessing batches? Check here YES / NO
• Are quality control review and approval required for any and all reprocessing of material? Check here YES / NO
• Does testing confirm that reprocessed batches conform to established specification? Check here YES / NO
• Does a written procedure outline steps required to reprocess returned drug products (if it can be determined that such products have not been subjected to improper storage conditions?) Check here YES / NO
• Does Quality Control review such reprocessed returned goods and test such material for conformance to specifications before releasing such material for resale?
  Check here YES / NO

Finished Product Control

• Finished Product Verification, Storage, and Handling Check here YES / NO
• Do written procedures indicate how and who verifies that correct containers and packages are used for finished product during the finishing operation? Check here YES / NO
• In addition, do written procedures require that representative sample of units be visually examined upon completion of packaging to verify correct labeling? Check here YES / NO
• Are expiration dates stamped or imprinted on labels? Check here YES / NO
• Are expiration dates related to any storage conditions stated on the label? Check here YES / NO
• Are all finished products held in quarantine until QC has completed its testing and releases product on a batch to batch basis for sale? Check here YES / NO
• Is finished product stored under appropriate conditions of temperature, humidity, light, etc. Check here YES / NO

Finished Product Inspection, Sampling, Testing, and Release for Distribution

• Has the formulation for each product been tested for stability based on a written protocol? (Containers must duplicate those used in final product packaging.) Check here YES / NO
• Are written sampling and testing procedures and acceptance criteria available for each product to ensure conformance to finished product specifications? Check here YES / NO
• Is a quantity of samples equal to at least twice the quantity needed for finished product release testing maintained as a reserve sample? Check here YES / NO
• Are sterility and pyrogen testing performed as required? Check here YES / NO
• Are specific tests for foreign particles or abrasives included for any ophthalmic ointments? Check here YES / NO
• Do controlled release or sustained release products include tests to determine conformance to release time specification? Check here YES / NO

Distribution Controls

• Does a written procedure manage stocks to ensure that oldest approved product is sold first? Check here YES / NO
• Are deviations to the policy above documented? Check here YES / NO
• Does a written procedure identify the steps required if a product recall is necessary? Check here YES / NO
• Is the recall policy current and adequate? Check here YES / NO
  
  

Marketing Controls

• The current regulation does not address marketing controls per se except that all finished products must meet their specifications. Check here YES / NO

Complaint Handling and Customer Satisfaction Program

• Are complaints, whether received in oral or written form, documented in writing and retained in a designated file? Check here YES / NO
• Are complaints reviewed on a timely basis by the Quality Control Unit? Check here YES / NO
• Is the action taken in response to each complaint documented? Check here YES / NO
• Are decisions not to investigate a complaint also documented and the name of the responsible person documented? Check here YES / NO
• Are complaint investigations documented and do they include investigation steps, findings, and follow-up steps, if required? Are dates included for each entry? Check here YES / NO
   

Reference : WHO guideline for GMP/Internet