FDA - GMP820.60/61

The complete Good Manufacturing Practice documentation of the Food & Drug administration is available from the U S Government Printing Office Bookstores. You may contact them directly at (202) 512-1800.

The purpose of section is to ensure that all products, including manufacturing materials used in the manufacture of a finished device, are properly identified as to their current status, for example, whether they are accepted, rejected, or reworked. This requirement is intended to help prevent inadvertent use or release of unacceptable product into manufacturing.

5-1 INTRODUCTION

5-2 MAINTENANCE

5-2 Records

5-2 Equipment Selection

5-3 MANUFACTURING MATERIALS

5-3 Analyze Use

5-3 Control Use

5-3 AUTOMATED PRODUCTION AND QA SYSTEMS

5-4 Software Validation Guidelines

5-4 Employee Responsibility and Training

5-5 Formal Development of Software

5-5 Commercial Software and Equipment

5-6 Validation of Equipment and Processes

5-6 Automated Data Collection and Processing

5-7 Equipment Controls and Audits

5-7 EQUIPMENT CALIBRATION

5-8 CALIBRATION REQUIREMENTS

5-10 Procedures

5-11 Personnel

5-11 Records

5-14 Schedules

5-15 Standards

5-15 EQUIPMENT ENVIRONMENT

5-15 AUDIT OF CALIBRATION SYSTEM

5-16 INTEGRATING MEASUREMENTS INTO THE QA SYSTEM

5-17 EXHIBITS

5-18 P.C. Board Cleaning

5-20 Calibration Procedures for Mechanical Measuring Tools

MAINTENANCE

A manufacturer must determine if the equipment requires maintenance and apply the appropriate parts of the GMP requirements for equipment. The user usually can determine if specific equipment requires maintenance by reviewing the equipment operations and maintenance manuals usually supplied by the equipment manufacturer. If failure to maintain equipment does not appear to adversely affect the device, FDA will not insist that the manufacturer meet the maintenance requirement. Typically, a manufacturer wil l maintain equipment simply because it prolongs equipment life and minimizes the need for major service. If it is necessary to maintain, clean, or adjust equipment, the manufacturer must:

• have a written schedule for performing these activities;
• post the schedule or make it readily available;
• document the activities;
• where adjustment is necessary to maintain proper operation, post the inherent limitations and allowable tolerances of the equipment or make these readily available to personnel responsible for making the adjustments; and
• audit the activities and document the audit.

There is no GMP requirement for a written maintenance procedures, although one is recommended to assure that all aspects of maintenance are covered. An example of an operation and maintenance procedure, "P.C. Board Cleaning," is exhibited at the end of this chapter.

Equipment Selection

MANUFACTURING MATERIALS

Analyze Use

• The adverse material may be measured directly and compared to the process specification.
• If feasible, the component, in-process device or finished device may be tested against its specification. If the item passes, it follows that the residue is not affecting the performance. The test specification must be appropriate for this method of ev aluating residues and may need to include tests for toxicity, pyrogens, etc.

When manufacturing materials such as oils, mold-release compounds, gases, cleaning agents, etc., are used on or in equipment, manufacturers must:

• remove the material or limit it to a safe amount;
• provide written procedures for the use and removal of materials; and document the removal.

AUTOMATED PRODUCTION AND QA SYSTEMS

Medical devices and the manufacturing processes used to produce them vary from the simple to the very complex, thus, the GMP regulation needs to be and is a flexible quality assurance system. This flexibility is valuable as more device manufacturers move to automated production, test/inspection, and record-keeping systems.

One of the basic requirements of the GMP regulation is that formal processing procedures be established, implemented, and controlled as necessary to assure that device design specifications are met [820.100]. Thus, among many other quality assurance elem ents, processing methods and equipment [820.20(a), 820.60] must be selected, and specific operating parameters established and evaluated, in order to establish valid and reliable manufacturing processes. The activities conducted to verify process and equi pment specifications are collectively referred to as process validation.

In addition to this general requirement for all significant processes, the GMP regulation has specific requirements in sections 820.61 and 820.195 for validating and controlling automated equipment used in the manufacture of medical devices.

Software Validation Guidelines

Manufacturers, however, should not rely completely on such documents, but must examine their software needs and develop whatever controls are necessary to assure software is adequate for its intended use [820.20(a)(4)].

Employee Responsibility and Training

A manufacturer probably will experienced problems if employees operating the automated system or inputting data do not have adequate background and/or training. Employees must have adequate knowledge of the system through both on-the-job experience and f ormal training. Those responsible for data input should be able to recognize data errors [820.25]. The GMP regulation requires that adequate checks be designed and implemented to help prevent inaccurate data input [820.20(a)(4), 820.195]. This requirement can be accomplished by the aforementioned training and by software controls. Where practical, software programs should have built-in error controls such as prompts, alpha-only fields, numeric-only fields, length limits, range limits, and sign (+) control to help eliminate mistakes during data entry. These error-control or human-factors requirements, as appropriate, should be part of the specifications for software being developed or purchased.

Formal Development of Software

To validate software, it must be:

• structured, documented and evaluated as it is developed;
• checked to make sure that it meets specifications;
• adequately tested with the assigned hardware systems; and
• operated under varied conditions by the intended operators or
• persons of like training to assure that it will perform consistently and correctly.

The testing of the software with the actual medical device production or testing equipment should exercise all program functions under all expected production conditions. The testing should include the input of normal and abnormal data to test program performance and error handling. The validation must assure to a high degree that the software and associated equipment meet the company specifications. Testing and results should be documented. Any serious deficiencies must be corrected.

Commercial Software and Equipment

When possible, the purchaser also should conduct pre-award audits to verify adequacy of the contractor's quality assurance program. Two key elements that should be checked are the contractor's test plans and system for controlling changes to documentation. Subsequent audits should be conducted as needed to verify that the contractor is complying with the quality assurance plan. The manufacturer who has custom software prepared and validated by a contractor must ensure the software program is running prop erly and producing correct results before using the program to produce medical devices for distribution.

Manufacturers who purchase commercial equipment with incorporated software must still validate the software and associated equipment for the intended applications. If, however, the software has been validated by the developer and proven through use, the purchaser need not test it as comprehensively as new software. For example, automated production and test equipment that is controlled by software can usually be validated through use of a "dummy" device. This "dummy" device should exercise all functions and decisions in normal and worst-case situations that may reasonably be expected during production. In some cases, vendors provide test programs that may be used to assure that the equipment will appropriately and accurately perform all intended function s before it is used for routine production.

Validation of Equipment and Processes

• assuring the adequacy of automated equipment and software;
• verifying that all intended functions will be correctly and
• Breliably performed; and maintaining appropriate records.

The master record [820.3(i)], as explained in chapter 6, is a compilation of records containing the design, formulation, specifications, complete manufacturing procedures, quality assurance requirements, and labeling for a finished device.

All changes to specifications, software programs, and other master record documents must be formally reviewed and approved before implementation [820.100(a) and (b)]. Because changes in one part of software can affect other parts of software, adequate consideration must be given to side-effects of these changes. Such changes are much easier to make and evaluate when the original software is appropriately structured and thoroughly documented.

Automated Data Collection and Processing

The GMP regulation requires [820.181] that device master records be signed by designated individuals, and that changes to master records be signed by individuals designated to authorize such changes. In addition, signatures are required when certain data [820.185(a)(2), 820.185(c)] are recorded in critical device history records. The GMP regulation also requires [820.101] that only designated employees operate equipment used to perform critical operations on critical devices and that the history record c ontain [820.185(b)] the names of these individuals.

The GMP regulation was promulgated when most records were hard copy for which written signatures were appropriate; however, the increased use of computers and related input/output peripherals has affected FDA policy regarding GMP signature requirements. In response to the use of new electronic technology, FDA has issued an advisory opinion stating that magnetically coded badges or other computer-compatible identifiers may be used in lieu of signatures as long as there are adequate controls to prevent ina ccurate data input. If coded badges and the like are not controlled (i.e., not restricted to designated employees), they will not meet the applicable GMP requirements.

Manufacturers may wish to keep appropriate records such as master records and complaint files at central or corporate offices. If the overall data handling system is controlled as stated above, firms may maintain appropriate GMP records at central locati ons if they can transmit these records to the manufacturing establishment by electronic mail (computer plus modem) or other high speed data transfer system.

Equipment Controls and Audits

During their quality assurance system audit [820.20(b)], manufacturers should audit the use and control of their automated production and quality assurance systems. The audit should include software and equipment maintenance procedures and records, and should evaluate the adequacy of security measures, change controls, and other controls necessary to maintain software quality and proper performance of associated equipment. The audit must be documented, important results reviewed with management, and corrective action taken as appropriate.

EQUIPMENT CALIBRATION

Each manufacturer must assure that production equipment and quality assurance measurement equipment (mechanical, electronic, automated, etc.) are:

• suitable for the intended use in manufacture and testing of in-process and finished devices;
• operated by trained employees;
• capable of producing valid results; and
• properly calibrated versus a suitable standard.

In establishing a quality assurance system, manufacturers should determine which measurements are necessary to assure that finished devices meet approved master record specifications, and that the instruments used to make these measurements are included in a calibration program. When measurement equipment that is part of the calibration system is located in the same areas as instruments that are not part of the system, the system equipment should be identified by label, tag, color code, etc., to assure it is the only equipment used in determining compliance of a component, in-process devices, or finished device with specifications.

Equipment used only for monitoring a parameter need not be calibrated but should be identified (e.g., for monitoring). A monitoring function might be to indicate if a voltage or other parameter exists, but the exact value is not important.

CALIBRATION REQUIREMENTS

• large bias + high precision = low accuracy
• zero bias + high precision = high accuracy
• large bias + low precision = low accuracy
• zero bias + low precision = low accuracy

Precision has no unit of measure and only indicates a relative degree of repeatability, i.e., how closely the values within a series of replicate measurements agree with each other. Repeatability is the result of resolution and stability.

Bias is a measure of how closely the mean value in a series of replicate measurements approaches the true value. The mean value is that number attained by dividing the sum of the individual values in a series by the total number of individual values.

Accuracy is the measure of an instrument's capability to approach a true or absolute value. Accuracy is a function of precision and bias. Because different manufacturers have different accuracy requirements, each manufacturer must decide the level of accuracy required for each measurement and provide equipment to achieve that accuracy.

Proper and period calibration will assure that the selected equipment continues to have the desired accuracy. GMP calibration requirements are:

• routine calibration according to written procedures;
• documentation of the calibration of each piece of equipment
• requiring calibration;
• documented validation of the software programs used in automated production or quality assurance equipment;
• specification of accuracy and precision limits;
• training of calibration personnel;
• use of standards traceable to the National Bureau of Standards (NBS), or other recognizable standards; and
• provisions for remedial action to in-process or finished devices.
• Remedial action includes recalibration and evaluation of the impact of out-of-tolerance measurements on the quality of existing in-process or finished devices, and appropriate corrective action.

Information contained in calibration procedures should be adequate to enable qualified personnel to properly perform the calibrations. An example of a calibration procedure for mechanical measuring tools appears at the end of this chapter.

A typical calibration procedure includes:

• purpose and scope;
• frequency of calibration;
• equipment and standards required;
• limits for accuracy and precision;
• preliminary examinations and operations;
• calibration process description;
• remedial action for product; and
• documentation requirements.

The selection and training of competent calibration personnel is an important consideration in establishing an effective metrology program. The GMP regulation requires that, "calibration shall be performed by personnel having the necessary education, training, and experience." Personnel involved in calibration should ideally possess the following qualities:

• technical education and experience in the area of job assignment;
• basic knowledge of metrology and calibration concepts;
• an understanding of basic principles of measurement disciplines,
• data processing steps, and acceptance requirements;
• ability to follow instructions regarding the maintenance and use of measurement equipment and standards;
• knowledge of the overall calibration program; and
• mental attitude which results in safe, careful, and exacting execution of his or her duties.

These decals are examples of the types commonly used to identify the status of measurement instruments and tools. They are available as catalog items or a firm may use its own artwork to purchase decals with specialized wording.

Typical calibration decals have a write-on surface. A tough paper or cloth stock and a pressure sensitive adhesive are used for easy application and removal of the decal. "Due" is the blank for the date when recalibration is due. Measuring equipment that is not calibrated or otherwise unsuitable for use should be placed in a quarantine area or labeled with a "calibration void" decal.

A seal or protective cover for exposed, recessed calibration controls on instruments. The calibration control cannot be adjusted without breaking the seal or removing the instrument case. A decal to be applied to measurement or monitoring instrume nts not intended for use in determining conformance to device master record specifications with respect to testing, manufacturing, environmental control, etc. Calibration information is entered onto cards or forms, one for each piece of equipment, or entered into a computerized data system. Most data systems include the calibration date, by whom calibrated, date recalibration is due, the reason for the calibration, comments, address of the manufacturer and calibration laboratory, equipment specifica tions, serial number, use, etc. An example of a typical card used to record calibration information follows.

	Card # EEEE of # EEEE 
CALIBRATION CARD

	TYPE EEEEEEEEEEEEEEEEEEEEEEEEEEEEEE MANUFACTURER EEEEEEEEEEEEEEEEEEEEEEE
	MODEL	EEEEEEEEEEEEEEEEEEEEEEEEEEEEE	SERIAL NO.	EEEEEEEEEEEEEEEEEEEEEEEEEEEE
	DATE OF PURCHASE	EEEEEEEEEEEEEEEEEE	ASSIGNED TO DEPT.	EEEEEEEEEEEEEEEEEEEEE
	LOCATION	EEEEEEEEEEEEEEEEEEEEEEEEE	CAL. CYCLE	EEEEEEEEEEEEEEEEEEEEEEEEEEE
	USE	q	FREQUENT	q	MODERATE	q	SELDOM	q	NOT USED


	DATE OF	REASON FOR CAL.	DATE NEXT	CAL. INFO. ACCURACY, DEFECTS,
	LAST CAL.	(BROKEN, NORMAL, ROUGH USE)	CAL. DUE	LUBE, CLEAN, ETC.
	TO BE CALIBRATED BY:	NAME	EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE
	COMPANY AND ADDRESS	EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE
	PHONE	EEEEEEEEEEEEEEEEEE	EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE
	FORM #1700-	EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE

A firm should use a suitable method to remind employees that recalibration is due. For small firms, calibration decals on the measuring equipment may be sufficient because recalibration can be tracked by scanning the decals for the recalibration date. Fo r other firms, a computerized system, calibration cycle cards, tickler file, or the like may be used. Calibration cycle cards are maintained in a 12-month (12-section) tickler file. There is one card per item of measuring equipment. The cards in the secti on of the file for the current month are pulled and all of the equipment listed is calibrated. For example, in a 6-month calibration cycle, when an instrument is calibrated in May, the card is moved from the May section to the October section of the file. When the file is checked in October, the cycle card will be there to remind the firm that calibration is due. The process is repeated until an event such as instrument wear-out occurs and the respective cycle card is removed from the file.

Cycle cards are used where a firm has many instruments to be calibrated. It would be rather difficult to keep track of the calibration of a large number of instruments by reviewing calibration record cards or scanning the decal on each instrument. It is easier to use a cycle card file. A cycle card file or equivalent also must be used if the calibration records are filed by type of instrument or manufacturer rather than due date. A typical cycle card follows. The "calibration card number" blank refers to the calibration record card for the same item of equipment.

CALIBRATION CYCLE CARD

	MANUFACTURER:	EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE
	INSTRUMENT:	EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE
	EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE
	MODEL NO.	EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE	SERIAL NO.	EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE
	CALIBRATION INTERVAL:	EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE
	LOCATION OF EQUIPMENT:	EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE
	EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE
	CALIBRATION CARD NO.	EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE

	Form No.

The meaning of traceability to NBS is not always self-evident. Two general methods commonly used to establish and maintain traceability to NBS are:

• NBS calibration of standards or instruments: When this method is used, private standards are physically sent to NBS for calibration and return.
• Standard Reference Materials (SRM's): NBS provides reference materials to be used in a user's calibration program. These SRM's are widely used in the chemical, biological, medical, and environmental fields.
• Information can be obtained from the "Catalog of NBS Standard Reference Materials," NBS Publication 260, 1984-1985 Edition, available free from the National Bureau of Standards, Office of Standard Reference Materials, Chemistry Building, Room B311, Wa shi ngton, D.C. 20234.

EQUIPMENT ENVIRONMENT

AUDIT OF CALIBRATION SYSTEM

Many manufacturers utilize contract calibration laboratories to calibrate their measurement and test equipment. If this is the case, the FDA views the contract laboratory as an extension of the manufacturer's GMP program or quality assurance program. Nor mally, FDA does not inspect contract laboratory facilities, but it would expect the manufacturer to audit the contract lab, if feasible, to verify that proper procedures are being used. If problems occurred due to inadequate calibration, and FDA needed to determine where the problems existed, FDA could visit the contract laboratory. Either the contract laboratory or the manufacturer might be held responsible for inadequate procedures leading to a defective, unsafe device or false data. Generally, the manufacturer of the finished device is responsible for assuring the device is manufactured under an acceptable GMP program.

When a medical device manufacturer utilizes a contract calibration laboratory, FDA expects the manufacturer to have evidence that the equipment was calibrated according to the GMP requirements. The manufacturer can do this by:

• requiring and receiving certification that the equipment was
• calibrated under controlled conditions using traceable standards;
• maintaining an adequate calibration schedule;
• maintaining records of calibration; or
• periodically auditing the contractor to assure appropriate and
• adequate GMP procedures are being followed.

The contractor should have in place the applicable controls called for in the GMP regulation. For example, the contract should have:

• written calibration procedures;
• records of calibration;
• trained calibration personnel; and
• standards traceable to NBS or other independent reproducible standards.

INTEGRATING MEASUREMENTS INTO THE QA SYSTEM

A good quality assurance program must include calibration activities. However, proper calibration will be of little use unless the applications of the measurement equipment are properly developed and qualified during the preproduction development of insp ection test methods and procedures. As stated, effectiveness depends on the participation and influence of QA at the preproduction stage. Calibration of equipment cannot correct poor design of products nor can it compensate for poor applications of equipm ent and techniques. It is the continued use of a completed, integrated quality assurance system that assures that safe and effective devices are produced.

EXHIBITS

P.C. Board Cleaning

Calibration Procedures for Mechanical Measuring Tools