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GUIDELINE ON GENERAL PRINCIPLES OF PROCESS = VALIDATION

MAY, 1987

Prepared by: Center for Drug Evaluation and Research,
Center for = Biologics=20 Evaluation and Research, and
Center for Devices and Radiological=20 Health
Food and Drug Administration

Maintained by: Division of Manufacturing and Product Quality=20 (HFD-320)
Office of Compliance
Center for Drug Evaluation and=20 Research
Food and Drug Administration
5600 Fishers = Lane
Rockville,=20 Maryland 20857

Reprinted February, 1993

The Division of Field Investigations
Office of Regional=20 Operations
Office of Regulatory Affairs
U.S.Food and Drug=20 Administration

PURPOSE=20
SCOPE=20
INTRODUCTION=20
GENERAL=20 CONCEPTS=20
CGMP=20 REGULATIONS FOR FINISHED PHARMACEUTICALS=20
GMP=20 REGULATION FOR MEDICAL DEVICES=20
PRELIMINARY=20 CONSIDERATIONS=20
ELEMENT= S=20 OF PROCESS VALIDATION=20
1. Prospective=20 Validation
  1. Equipment=20 and Process
    
    Equipment=20 : Installation Qualification=20
    Process:=20 Performance Qualification=20
    Product:=20 Performance Qualification
  2. System=20 to Assure Timely Revalidation=20
  3. Documentation=20
2. Retrospective=20 Process Validation
ACCEPTABILITY=20 OF PRODUCT TESTING

Guideline on General Principles of Process = Validation

I. PURPOSE

This guideline outlines general principles that FDA considers to be=20 acceptable elements of process validation for the preparation of human = and=20 animal drug products and medical devices.

II. SCOPE

This guideline is issued under Section 10.90 (21 CFR 10.90) and is = applicable=20 to the manufacture of pharmaceuticals and medical devices. It states = principles=20 and practices of general applicability that are not legal requirements = but are=20 acceptable to the FDA. A person may rely upon this guideline with the = assurance=20 of its acceptability to FDA, or may follow different procedures. When = different=20 procedures are used, a person may, but is not required to, discuss the = matter in=20 advance with FDA to prevent the expenditure of money and effort on = activities=20 that may later be determined to be unacceptable. In short, this = guideline lists=20 principles and practices which are acceptable to the FDA for the process = validation of drug products and medical devices; it does not list the = principles=20 and practices that must, in all instances, be used to comply with = law.

This guideline may be amended from time to time. Interested persons = are=20 invited to submit comments on this document and any subsequent = revisions.=20 Written comments should be submitted to the Dockets Management Branch = (HFA-305),=20 Food and Drug Administration, Room 4-62, 5600 Fishers Lane, Rockville, = Maryland=20 20857. Received comments may be seen in that office between 9 a.m. and 4 = p.m.,=20 Monday through Friday.

III. = INTRODUCTION

Process validation is a requirement of the Current Good Manufacturing = Practices Regulations for Finished Pharmaceuticals, 21 CFR Parts 210 and = 211,=20 and of the Good Manufacturing Practice Regulations for Medical Devices, = 21 CFR=20 Part 820, and therefore, is applicable to the manufacture of = pharmaceuticals and=20 medical devices. Several firms have asked FDA for specific guidance on = what FDA=20 expects firms to do to assure compliance with the requirements for = process=20 validation. This guideline discusses process validation elements and = concepts=20 that are considered by FDA as acceptable parts of a validation = program.The=20 constituents of validation

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presented in this document are not intended to be all-inclusive. FDA=20 recognizes that, because of the great variety of medical products (drug = products=20 and medical devices), processes and manufacturing facilities, it is not = possible=20 to state in one document all of the specific validation elements that = are=20 applicable. Several broad concepts, however, have general applicability = which=20 manufacturers can use successfully as a guide in validating a = manufacturing=20 process. Although the particular requirements of process validation will = vary=20 according to such factors as the nature of the medical product (e.g., = sterile vs=20 non-sterile) and the complexity of the process, the broad concepts = stated in=20 this document have general applicability and provide an acceptable = framework for=20 building a comprehensive approach to process validation.

Definitions

Installation qualification - Establishing confidence that process = equipment=20 and ancillary systems are capable of consistently operating within = established=20 limits and tolerances.

Process performance qualification - Establishing confidence that the = process=20 is effective and reproducible.

Product performance qualification - Establishing confidence through=20 appropriate testing that the finished product produced by a specified = process=20 meets all release requirements for functionality and safety.

Prospective validation - Validation conducted prior to the = distribution of=20 either a new product, or product made under a revised manufacturing = process,=20 where the revisions may affect the product's characteristics.

Retrospective validation - Validation of a process for a product = already in=20 distribution based upon accumulated production, testing and control = data.

Validation - Establishing documented evidence which provides a high = degree of=20 assurance that a specific process will consistently produce a product = meeting=20 its pre-determined specifications and quality attributes.

Validation protocol - A written plan stating how validation will be=20 conducted, including test parameters, product characteristics, = production=20 equipment, and decision points on what constitutes acceptable test = results.

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Worst case - A set of conditions encompassing upper and lower = processing=20 limits and circumstances, including those within standard operating = procedures,=20 which pose the greatest chance of process or product failure when = compared to=20 ideal conditions. Such conditions do not necessarily induce product or = process=20 failure.

IV. GENERAL = CONCEPTS

Assurance of product quality is derived from careful attention to a = number of=20 factors including selection of quality parts and materials, adequate = product and=20 process design, control of the process, and in-process and end-product = testing.=20 Due to the complexity of today's medical products, routine end-product = testing=20 alone often is not sufficient to assure product quality for several = reasons.=20 Some end-product tests have limited sensitivity.(1) In some cases, = destructive=20 testing would be required to show that the manufacturing process was = adequate,=20 and in other situations end-product testing does not reveal all = variations that=20 may occur in the product that may impact on safety and = effectiveness.(2)

The basic principles of quality assurance have as their goal the = production=20 of articles that are fit for their intended use. These principles may be = stated=20 as follows:

(1) quality, safety, and effectiveness must be designed and built = into the=20 product;

(2) quality cannot be inspected or tested into the finished product; = and

(3) each step of the manufacturing process must be controlled to = maximize the=20 probability that the finished product meets all quality and design=20 specifications.

Process validation is a key element in assuring that these quality = assurance=20 goals are met

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It is through careful design and validation of both the process and = process=20 controls that a manufacturer can establish a high degree of confidence = that all=20 manufactured units from successive lots will be acceptable. Successfully = validating a process may reduce the dependence upon intensive in-process = and=20 finished product testing. It should be noted that in most all cases, = end-product=20 testing plays a major role in assuring that quality assurance goals are = met;=20 i.e., validation and end-product testing are not mutually exclusive.

The FDA defines process validation as follows:

Process validation is establishing documented evidence which = provides a=20 high degree of assurance that a specific process will consistently = produce a=20 product meeting its pre-determined specifications and quality=20 characteristics.

It is important that the manufacturer prepare a written validation = protocol=20 which specifies the procedures (and tests) to be conducted and the data = to be=20 collected. The purpose for which data are collected must be clear, the = data must=20 reflect facts and be collected carefully and accurately. The protocol = should=20 specify a sufficient number of replicate process runs to demonstrate=20 reproducibility and provide an accurate measure of variability among = successive=20 runs. The test conditions for these runs should encompass upper and = lower=20 processing limits and circumstances, including those within standard = operating=20 procedures, which pose the greatest chance of process or product failure = compared to ideal conditions; such conditions have become widely known = as "worst=20 case" conditions. (They are sometimes called "most appropriate = challenge"=20 conditions.) Validation documentation should include evidence of the = suitability=20 of materials and the performance and reliability of equipment and = systems.

Key process variables should be monitored and documented. Analysis of = the=20 data collected from monitoring will establish the variability of process = parameters for individual runs and will establish whether or not the = equipment=20 and process controls are adequate to assure that product specifications = are=20 met.

Finished product and in-process test data can be of value in process=20 validation, particularly in those situations where quality attributes = and=20 variabilities can be readily measured. Where finished (or in-process) = testing=20 cannot adequately measure certain attributes, process validation should = be=20 derived primarily from qualification of each system used in production = and from=20 consideration of the interaction of the various systems.

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V. CGMP = REGULATIONS=20 FOR FINISHED PHARMACEUTICALS

Process validation is required, in both general and specific terms, = by the=20 Current Good Manufacturing Practice Regulations for Finished = Pharmaceuticals, 21=20 CFR Parts 210 and 211. Examples of such requirements are listed below = for=20 informational purposes, and are not all-inclusive.

A requirement for process validation is set forth in general terms in = Section=20 211.100 -- Written procedures; deviations -- which states, in = part:

"There shall be written procedures for production and process = control=20 designed to assure that the drug products have the identity, strength, = quality,=20 and purity they purport or are represented to possess."

Several sections of the CGMP regulations state validation = requirements in=20 more specific terms. Excerpts from some of these sections are:

Section 211.110, Sampling and testing of in-process materials and = drug=20 products.

(a) "....control procedures shall be established to monitor the = output and=20 VALIDATE the performance of those manufacturing = processes that=20 may be responsible for causing variability in the characteristics of = in-process=20 material and the drug product." (emphasis added)

Section 211.113, Control of Microbiological = Contamination.

(b) "Appropriate written procedures, designed to prevent = microbiological=20 contamination of drug products purporting to be sterile, shall be = established=20 and followed. Such procedures shall include VALIDATION = of any=20 sterilization process." (emphasis added)

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VI. GMP=20 REGULATION FOR MEDICAL DEVICES

Process validation is required by the medical device GMP Regulations, = 21 CFR=20 Part 820. Section 820.5 requires every finished device manufacturer = to:

"...prepare and implement a quality assurance program that is = appropriate to=20 the specific device manufactured..."

Section 820.3(n) defines quality assurance as:

"...all activities necessary to verify confidence in the quality of = the=20 process used to manufacture a finished device."

When applicable to a specific process, process validation is an = essential=20 element in establishing confidence that a process will consistently = produce a=20 product meeting the designed quality characteristics.

A generally stated requirement for process validation is contained in = section=20 820.100:

"Written manufacturing specifications and processing = procedures=20 shall be established, implemented, and controlled to assure that the = device=20 conforms to its original design or any approved changes in that=20 design."

Validation is an essential element in the establishment and = implementation of=20 a process procedure, as well as in determining what process controls are = required in order to assure conformance to specifications.

Section 820.100(a) (1) states:

"...control measures shall be established to assure that the design = basis for=20 the device, components and packaging is correctly translated into = approved=20 specifications."

Validation is an essential control for assuring that the = specifications for=20 the device and manufacturing process are adequate to produce a device = that will=20 conform to the approved design characteristics

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VII. PRELIMINARY = CONSIDERATIONS

A manufacturer should evaluate all factors that affect product = quality when=20 designing and undertaking a process validation study. These factors may = vary=20 considerably among different products and manufacturing technologies and = could=20 include, for example, component specifications, air and water handling = systems,=20 environmental controls, equipment functions, and process control = operations. No=20 single approach to process validation will be appropriate and complete = in all=20 cases; however, the following quality activities should be undertaken in = most=20 situations.

During the research and development (R& D) phase, the desired = product=20 should be carefully defined in terms of its characteristics, such as = physical,=20 chemical, electrical and performance characteristics.(3) It is important = to=20 translate the product characteristics into specifications as a basis for = description and control of the product.

Documentation of changes made during development provide traceability = which=20 can later be used to pinpoint solutions to future problems.

The product's end use should be a determining factor in the = development of=20 product (and component) characteristics and specifications. All = pertinent=20 aspects of the product which impact on safety and effectiveness should = be=20 considered. These aspects include performance, reliability and = stability.=20 Acceptable ranges or limits should be established for each = characteristic to set=20 up allowable variations.(4) These ranges should be expressed in readily=20 measurable terms.

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The validity of acceptance specifications should be verified through = testing=20 and challenge of the product on a sound scientific basis during the = initial=20 development and production phase.

Once a specification is demonstrated as acceptable it is important = that any=20 changes to the specification be made in accordance with documented = change=20 control procedures.

VIII. = ELEMENTS OF=20 PROCESS VALIDATION

A. Prospective = Validation

Prospective validation includes those considerations that should be = made=20 before an entirely new product is introduced by a firm or when there is = a change=20 in the manufacturing process which may affect the product's = characteristics,=20 such as uniformity and identity. The following are considered as key = elements of=20 prospective validation.

1. = Equipment and=20 Process

The equipment and process(es) should be designed and/or selected so = that=20 product specifications are consistently achieved. This should be done = with the=20 participation of all appropriate groups that are concerned with assuring = a=20 quality product, e.g., engineering design, production operations, and = quality=20 assurance personnel.

a.=20 Equipment : Installation = Qualification

Installation qualification studies establish confidence that the = process=20 equipment and ancillary systems are capable of consistently operating = within=20 established limits and tolerances. After process equipment is designed = or=20 selected, it should be evaluated and tested to verify that it is capable = of=20 operating satisfactorily within the operating limits required by the = process.(5)=20 This phase of validation includes examination of equipment design; = determination=20 of calibration, maintenance, and

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adjustment requirements; and identifying critical equipment features = that=20 could affect the process and product. Information obtained from these = studies=20 should be used to establish written procedures covering equipment = calibration,=20 maintenance, monitoring, and control.

In assessing the suitability of a given piece of equipment, it is = usually=20 insufficient to rely solely upon the representations of the equipment = supplier,=20 or upon experience in producing some other product.(6) Sound theoretical = and=20 practical engineering principles and considerations are a first step in = the=20 assessment.

It is important that equipment qualification simulate actual = production=20 conditions, including those which are "worst case" situations.

Tests and challenges should be repeated a sufficient number of times = to=20 assure reliable and meaningful results. All acceptance criteria must be = met=20 during the test or challenge. If any test or challenge shows that the = equipment=20 does not perform within its specifications, an evaluation should be = performed to=20 identify the cause of the failure. Corrections should be made and = additional=20 test runs performed, as needed, to verify that the equipment performs = within=20 specifications. The observed variability of the equipment between and = within=20 runs can be used as a basis for determining the total number of trials = selected=20 for the subsequent performance qualification studies of the = process.(7)

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Once the equipment configuration and performance characteristics are=20 established and qualified, they should be documented. The installation=20 qualification should include a review of pertinent maintenance = procedures,=20 repair parts lists, and calibration methods for each piece of equipment. = The=20 objective is to assure that all repairs can be performed in such a way = that will=20 not affect the characteristics of material processed after the repair. = In=20 addition, special post-repair cleaning and calibration requirements = should be=20 developed to prevent inadvertent manufacture a of non-conforming = product.=20 Planning during the qualification phase can prevent confusion during = emergency=20 repairs which could lead to use of the wrong replacement part.

b.=20 Process: Performance = Qualification

The purpose of performance qualification is to provide rigorous = testing to=20 demonstrate the effectiveness and reproducibility of the process. In = entering=20 the performance qualification phase of validation, it is understood that = the=20 process specifications have been established and essentially proven = acceptable=20 through laboratory or other trial methods and that the equipment has = been judged=20 acceptable on the basis of suitable installation studies.

Each process should be defined and described with sufficient = specificity so=20 that employees understand what is required. Parts of the process which = may vary=20 so as to affect important product quality should be challenged.(8) In=20 challenging a process to assess its adequacy, it is important that = challenge=20 conditions simulate those that will be encountered during actual = production,=20 including "worst case" conditions. The challenges should be repeated = enough=20 times to assure that the results are meaningful and consistent.

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Each specific manufacturing process should be appropriately qualified = and=20 validated. There is an inherent danger in relying on what are perceived = to be=20 similarities between products, processes, and equipment without = appropriate=20 challenge.(9)

c. Product: Performance=20 Qualification

For purposes of this guideline, product performance qualification = activities=20 apply only to medical devices. These steps should be viewed as = pre-production=20 quality assurance activities.

Before reaching the conclusion that a process has been successfully=20 validated, it is necessary to demonstrate that the specified process has = not=20 adversely affected the finished product. Where possible, product = performance=20 qualification testing should include performance testing under = conditions that=20 simulate actual use. Product performance qualification testing should be = conducted using product manufactured from the same type of production = equipment,=20 methods and procedures that will be used for routine production. = Otherwise, the=20 qualified product may not be representative of production units and = cannot be=20 used as evidence that the manufacturing process will produce a product = that=20 meets the pre-determined specifications and quality attributes.(10)

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After actual production units have successfully passed product = performance=20 qualification, a formal technical review should be conducted and should=20 include:

Comparison of the approved product specifications and the actual = qualified=20 product.=20
Determination of the validity of test methods used to determine = compliance=20 with the approved specifications.=20
Determination of the adequacy of the specification change control = program.=20
2. System=20 to Assure Timely Revalidation

There should be a quality assurance system in place which requires=20 revalidation whenever there are changes in packaging, formulation, = equipment, or=20 processes which could impact on product effectiveness or product=20 characteristics, and whenever there are changes in product = characteristics.=20 Furthermore, when a change is made in raw material supplier, the = manufacturer=20 should consider subtle, potentially adverse differences in the raw = material=20 characteristics. A determination of adverse differences in raw material=20 indicates a need to revalidate the process.

One way of detecting the kind of changes that should initiate = revalidation is=20 the use of tests and methods of analysis which are capable of measuring=20 characteristics which may vary. Such tests and methods usually yield = specific=20 results which go beyond the mere pass/fail basis, thereby detecting = variations=20 within product and process specifications and allowing determination of = whether=20 a process is slipping out of control.

The quality assurance procedures should establish the circumstances = under=20 which revalidation is required. These may be based upon equipment, = process, and=20 product performance observed during the initial validation challenge = studies. It=20 is desirable to designate individuals who have the responsibility to = review=20 product, process, equipment and personnel changes to determine if and = when=20 evalidation is warranted.

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The extent of revalidation will depend upon the nature of the changes = and how=20 they impact upon different aspects of production that had previously = been=20 validated. It may not be necessary to revalidate a process from scratch = merely=20 because a given circumstance has changed. However, it is important to = carefully=20 assess the nature of the change to determine potential ripple effects = and what=20 needs to be considered as part of revalidation.

3.=20 Documentation

It is essential that the validation program is documented and that = the=20 documentation is properly maintained. Approval and release of the = process for=20 use in routine manufacturing should be based upon a review of all the = validation=20 documentation, including data from the equipment qualification, process=20 performance qualification, and product/package testing to ensure = compatibility=20 with the process.

For routine production, it is important to adequately record process = details=20 (e.g., time, temperature, equipment used) and to record any changes = which have=20 occurred. A maintenance log can be useful in performing failure = investigations=20 concerning a specific manufacturing lot. Validation data (along with = specific=20 test data) may also determine expected variance in product or equipment=20 characteristics.

B. Retrospective Process=20 Validation

In some cases a product may have been on the market without = sufficient=20 premarket process validation. In these cases, it may be possible to = validate, in=20 some measure, the adequacy of the process by examination of accumulated = test=20 data on the product and records of the manufacturing procedures = used.

Retrospective validation can also be useful to augment initial = premarket=20 prospective validation for new products or changed processes. In such = cases,=20 preliminary prospective validation should have been sufficient to = warrant=20 product marketing. As additional data is gathered on production lots, = such data=20 can be used to build confidence in the adequacy of the process. = Conversely, such=20 data may indicate a declining confidence in the process and a = commensurate need=20 for corrective changes.

Test data may be useful only if the methods and results are = adequately=20 specific. As with prospective validation, it may be insufficient to = assess the=20 process solely on the basis of lot by lot conformance to specifications = if test=20 results are merely expressed in terms of pass/fail. Specific results, on = the=20 other hand, can be statistically analyzed and a determination can be = made of=20 what variance in data can be expected. It is important to maintain = records which=20 describe the operating characteristics of the process, e.g., time, = temperature,=20 humidity, and equipment settings.(11) Whenever test data are used to = demonstrate=20 conformance to specifications, it is important that the test methodology = be=20 qualified to assure that test results are objective and accurate.

IX. = ACCEPTABILITY OF=20 PRODUCT TESTING

In some cases, a drug product or medical device may be manufactured=20 individually or on a one-time basis. The concept of prospective or = retrospective=20 validation as it relates to those situations may have limited = applicability, and=20 data obtained during the manufacturing and assembly process may be used = in=20 conjunction with product testing to demonstrate that the instant run = yielded a=20 finished product meeting all of its specifications and quality = characteristics.=20 Such evaluation of data and product testing would be expected to be much = more=20 extensive than the usual situation where more reliance would be placed = on=20 prospective validation.

(1) For example, USP XXI states: "No sampling plan for applying = sterility=20 tests to a specified proportion of discrete units selected from a = sterilization=20 load is capable of demonstrating with complete assurance that all of the = untested units are in fact sterile."

(2) As an example, in one instance a visual inspection failed to = detect a=20 defective structural weld which resulted in the failure of an infant = warmer. The=20 defect could only have been detected by using destructive testing or = expensive=20 test equipment.

(3) For example, in the case of a compressed tablet, physical = characteristics=20 would include size, weight, hardness, and freedom from defects, such as = capping=20 and splitting. Chemical characteristics would include quantitative=20 formulation/potency; performance characteristics may include = bioavailability=20 (reflected by disintegration and dissolution). In the case of blood = tubing,=20 physical attributes would include internal and external diameters, = length and=20 color. Chemical characteristics would include raw material formulation.=20 Mechanical properties would include hardness and tensile strength; = performance=20 characteristics would include biocompatibility and durability.

(4) For example, in order to assure that an oral, ophthalmic, or = parenteral=20 solution has an acceptable pH, a specification may be established by = which a lot=20 is released only if it has been shown to have a pH within a narrow = established=20 range. For a device, a specification for the electrical resistance of a=20 pacemaker lead would be established so that the lead would be acceptable = only if=20 the resistance was within a specified range.

(5) Examples of equipment performance characteristics which may be = measured=20 include temperature and pressure of injection molding machines, = uniformity of=20 speed for mixers, temperature, speed and pressure for packaging = machines, and=20 temperature and pressure of sterilization chambers.

(6) The importance of assessing equipment suitability based upon how = it will=20 be used to attain desired product attributes is illustrated in the case = of=20 deionizers used to produce Purified Water, USP. In one case, a firm used = such=20 water to make a topical drug product solution which, in view of its = intended=20 use, should have been free from objectionable microorganisms. However, = the=20 product was found to be contaminated with a pathogenic microorganism. = The=20 apparent cause of the problem was failure to assess the performance of = the=20 deionizer from a microbiological standpoint. It is fairly well = recognized that=20 the deionizers are prone to build-up of microorganisms -- especially if = the flow=20 rates are low and the deionizers are not recharged and sanitized at = suitable=20 intervals. Therefore, these factors should have been considered. In this = case,=20 however, the firm relied upon the representations of the equipment = itself,=20 namely the "recharge" (i.e., conductivity) indicator, to signal the time = for=20 regeneration and cleaning. Considering the desired product = characteristics, the=20 firm should have determined the need for such procedures based upon = pre-use=20 testing, taking into account such factors as the length of time the = equipment=20 could produce deionized water of acceptable quality, flow rate, = temperature, raw=20 water quality, frequency of use, and surface area of deionizing = resins.

(7) For example, the AAMI Guideline for Industrial Ethylene Oxide=20 Sterilization of Medical Devices approved 2 December 1981, states: "The=20 performance qualification should include a minimum of 3 successful, = planned=20 qualification runs, in which all of the acceptance criteria are=20 met.....(5.3.1.2.)

(8) For example, in electroplating the metal case of an implantable=20 pacemaker, the significant process steps to define, describe, and = challenge=20 include establishment and control of current density and temperature = values for=20 assuring adequate composition of electrolyte and for assuring = cleanliness of the=20 metal to be plated. In the production of parenteral solutions by aseptic = filling, the significant aseptic filling process steps to define and = challenge=20 should include the sterilization and depyrogenation of = containers/closures,=20 sterilization of solutions, filling equipment and product contact = surfaces, and=20 the filling and closing of containers.

(9) For example, in the production of a compressed tablet, a firm may = switch=20 from one type of granulation blender to another with the erroneous = assumption=20 that both types have similar performance characteristics, and, = therefore,=20 granulation mixing times and procedures need not be altered. However, if = the=20 blenders are substantially different, use of the new blender with = procedures=20 used for the previous blender may result in a granulation with poor = content=20 uniformity. This, in turn, may lead to tablets having significantly = differing=20 potencies. This situation may be averted if the quality assurance system = detects=20 the equipment change' in the first place, challenges the blender = performance,=20 precipitates a revalidation of the process, and initiates appropriate = changes.=20 In this example, revalidation comprises installation qualification of = the new=20 equipment and performance qualification of the process intended for use = in the=20 new blender.

(10) For example, a manufacturer of heart valves received complaints = that the=20 valve-support structure was fracturing under use. Investigation by the=20 manufacturer revealed that all material and dimensional specifications = had been=20 met but the production machining process created microscopic scratches = on the=20 valve supporting wireform. These scratches caused metal fatigue and = subsequent=20 fracture. Comprehensive fatigue testing of production units under = simulated use=20 conditions could have detected the process deficiency.

In another example, a manufacturer recalled insulin syringes because = of=20 complaints that the needles were clogged. Investigation revealed that = the=20 needles were clogged by silicone oil which was employed as a lubricant = during=20 manufacturing. Investigation further revealed that the method used to = extract=20 the silicone oil was only partially effective. Although visual = inspection of the=20 syringes seemed to support that the cleaning method was effective, = actual use=20 proved otherwise.

(11) For example, sterilizer time and temperature data collected on = recording=20 equipment found to be accurate and precise could establish that process=20 parameters had been reliably delivered to previously processed loads. A=20 retrospective qualification of the equipment could be performed to = demonstrate=20 that the recorded data represented conditions that were uniform = throughout the=20 chamber and that product load configurations, personnel practices, = initial=20 temperature, and other variables had been adequately controlled during = the=20 earlier runs.

Date created: July 1, 1996; last update: July 6, 2005; April 23, = 2008

Page=20 Last Updated: 04/30/2009
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