Medical device regulations for Process validation - Institute of ...

Peer-Reviewed: Medical Devices

Medical Device Regulations for Process Validation: Review of FDA, GHTF, and GAMP Requirements Vladimir Veselov, Helen Roytman, and Lori Alquier

ABSTRACT Process validation is a key part of the quality system for medical device manufacturers. Complying with regulatory requirements is important to obtain premarket approvals and premarket notifications for new and modified medical devices. Simple, but essential, roadmaps assist in making decisions about which processes require validation, how and why to revalidate, when validation is necessary, and what US Food and Drug Administration guidelines to follow during validation. An overview of the overall environmental impact on validation is discussed, along with a process validation map of proper documentation required and FDA guidance to follow for control and monitoring of a quality system. Examples of FDA Warning Letters provide insight into FDA’s remarks and contribute to preventing and overcoming the liabilities encountered therein.

INTRODUCTION Process validation is a key element of the quality system regulation, which supports the main goal of a quality system: to consistently produce products suitable for their intended use (1). Process validation is required by 21 CFR part 820, section 820.75(a), which states, “Where the results of a process cannot be fully verified by subsequent inspection and test, the process shall be validated with a high degree of assurance and approved according to established procedures” (1). The requirement for process validation for the European (EU) market is stated in ISO 13485: 2003, section 7.5.2.1,

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“The organization shall validate any processes for production and service condition where the resulting output cannot be verified by subsequent monitoring or measurement. This includes any processes where deficiencies become apparent only after the product is in use or the service has been delivered” (2). There are additional reasons for process validation: • Customer satisfaction: non-conforming product can lead to lost customers • Customer mandated: provision for securing new business • Product liability: conformance to product specifications must be maintained • Reduced production cost: process validation leads to reduced inspections, testing, scrap and rework; shifts cost from production to prevention • Supports improvements: testing data can be used to support improvements in the process or the development of the next generation of the process • Environment control: control and reduce wastes • Compliance to regulatory requirements: successful submissions, inspection, avoid 483s, warning letters, penalties, etc. (3).

WHAT PROCESSES SHOULD BE VALIDATED? The GHTF process validation guidance outlines the processes that should be validated and states that if the process output is verifiable; and the verification is sufficient and cost effective; then the process doesn’t need to be validated.

ABOUT THE AUTHORS Lori Alquier is director of analytical research & development at Johnson & Johnson. Vladimir Veselov, Ph.D., is a principal scientist at Johnson & Johnson. Helen Roytman is a validation engineer at Johnson & Johnson. Helen can be reached at [email protected].

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Otherwise, the process must be redesigned or validated (4). The Medical Device Quality Systems Manual provides a more detailed explanation for the processes that are required to be validated: • Routine end-product tests have insufficient sensitivity to verify the desired safety and efficacy of the finished devices • Clinical or destructive testing would be required to show that the manufacturing process has produced the desired result or product • Routine end-product tests do not reveal all variations in safety and efficacy that may occur in the finished devices • The process capability is unknown, or it is suspected thattheprocessisbarelycapableofmeetingthedevice specifications (5). Examples of the processes are as follows: • Processes that should be validated • Sterilization processes • Cleanroom ambient conditions • Aseptic-filling processes • Sterile packaging sealing processes • Lyophilization process • Heat treating processes • Plating processes • Plastic injection molding processes • Processes that may be satisfactorily covered by verification • Manual cutting processes • Testing for color, turbidity, total pH for solutions • Visual inspection of printed circuit boards • Manufacturing and testing of wiring harnesses (4).

When to Validate There are two types of validation depending on when the process is validated in relation to product design, transfer to production, and release for distribution: prospective validation and retrospective validation (5). Prospective validation is conducted before a new product is released for distribution or when the process is modified. Retrospective validation is based on historical information that is accumulated during product production, testing, control, and review of customer complaints, and can typically be retrieved from batch records, production log books, lot records, control charts, test and inspection results, customer feedback, field failure reports, service reports, and audit reports. Statistical process control is a valuable tool for generating the type of data needed for retrospective analysis to revalidate a process and show that it continues to operate in a state of control. g x p a n d j v t . co m

PRINCIPLES FOR PROCESS VALIDATION The basic principles for validation are stated as follows in the GHTF guidance: • Establishthattheprocessequipmenthasthecapability of operating within required parameters • Demonstrate that controlling, monitoring, or measuring equipment and instrumentation are capable of operating within the parameters prescribed for this process equipment • Perform replicate cycles (runs) representing the required operational range of the equipment to demonstratethattheprocesseshavebeenoperatedwithin theprescribedparametersfortheprocessandthatthe output or product consistently meets predetermined specifications for quality and function • Monitorthevalidatedprocessduringroutineoperation. As needed, requalify and recertify the equipment (4).

GUIDANCES AND STANDARDS The GHTF guidance provides harmonized requirements for process validation, which conforms to the FDA quality system regulation (QSR), and ISO 13485 (4, 1, 2). Despite the fact that FDA has issued a guidance document for process validation (6), the agency refers to the GHTF guidance in Warning Letters that contain observations for inappropriate process validation. An additional reference is the Medical Device Quality Systems Manual, which provides useful information for understanding the GHTF guidance recommendations (5). Most modern processes are automated and may use electronic records with electronic signatures, which are regulated by 21 CFR Part 11 (7). The current Part 11 guidance refers to General Principals of Software Validation (8) and GAMP 4, which has been revised to GAMP 5 (9). FDA’s Guide to Inspections of Medical Device Manufacturers provides a practical roadmap for internal audits and also helps identify some specific requirements for process validation (10). ICH Q8 and ASTM E2500 standards should be taken into consideration for combination product manufacturing (11, 12). Process development and validation should take into account the ISO 14001 for waste management systems requirements (13). ANSI/ASQ Z1.9, ANSI/ASQ Z1.4, and ANSI/ASQ S2 provide instructions, examples, and tables for sampling plans to assist in defining appropriate sample quantities that should be tested for a typical process validation (14-16). Journal of Validation Technology [SPRING 2012] 83


Figure 1: Process map.

PROCESS MAP

Process Validation Map

A typical process map is presented in Figure 1. The main aspects of the process are: facilities, environment, equipment, utilities, people, and documentation. Each process has inputs and outputs. All aspects should be taken into consideration for process validation. Ignoring one aspect can minimize or eliminate efforts to establish and control other components of the process map. For example, if appropriate security access control is not established, someone can perform actions intentionally or unintentionally that may cause a product non-conformance or product adulteration. Figure 2 demonstrates how quality system regulations control the process from Figure 1. The requirements for process validation specified in section 820.75 (1) are closely integrated with almost all sections of QSR.

Typically, process validation contains the following phases: 1. Process design and development. This phase is completed during design control and documented in the design history file. 2. Validation plan. This step defines the process to be validation, the validation team and responsibilities, validation deliverables, and plan. 3. Requirements and risk analysis. 4. Write and approve protocols. Train protocol executors on the protocols and create a documented training record. 5. Execute protocols and collect data. 6. Analyze data. 7. Prepare, review, and approve reports. 8. Control and monitoring. 9. Process validation review and summary report.

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Figure 2: 21 CFR part 820 controls for process.

The GHTF guidance provides the following checklist to review validation activities: • Form multi-functional team for validation • Plan the approach and define the requirements • Identify and describe the processes • Specify process parameters and desired output • Decide on verification or validation • Create a master validation plan • Select methods and tools for validation • Create validation protocols • Perform installation qualification (IQ), operational qualification (OQ), performance qualification (PQ) and document results • Determine continuous process controls • Control the process continuously (4). This checklist requires several additions. First, the IQ, OQ, and PQ activities refer to the equipment qualification. To validate the process, the equipment should be validated first. If the equipment is automated or computerized, the software has to be validated as well. One of the important QSR requirements, which has to be met in this step, is to establish a schedule for calibration, inspection, and preventive maintenance. Such a schedule can be implemented in software, which would g x p a n d j v t . co m

then need to be validated. Prior to that, the equipment validation can be started and the utilities must be qualified. Second, the test methods must be validated. After that, the process performance qualification protocol can be executed (5). Finally, the process validation activites should be summarized. The Medical Device Quality Systems Manual provides specific information about the details to be covered in the validation plan: • Identification of the process to be validated • Identification of device(s) to be manufactured using this process • Criteria for a successful study • Length and duration of the study • Assumptions (shifts, operators, equipment, components) • Identification of equipment to be used in the process [820.75(b)(2)] • Identification of utilities for the process equipment and quality of the utilities • Identification of operators and required operator qualifications [820.75(b)(2)] • Complete description of the process (may reference the DMR [820.181(b)]) Journal of Validation Technology [SPRING 2012] 85


Figure 3: Process validation documentation.

• Relevant specifications including those for the product, components, manufacturing materials, the environment, etc. (may reference the DMR and quality system files {820.181(a) and (b); 820.186}) • Any special controls or conditions to be placed on preceding processes during the validation • Process parameters to be controlled and monitored, and methods for controlling and monitoring [820.70(a); 820.75(b)(2)] • Product characteristics to be monitored and method for monitoring [820.70(a)(2); 820.75(b)(2); 820.80(c)] • Any subjective criteria used to evaluate the product • Definition of what constitutes nonconformance for both measurable and subjective criteria • Statistical methods for data collection and analysis [820.250] • Consideration of maintenance and repairs [820.72(a)] • Conditions that may indicate that the process should be revalidated [820.75(c)] • Stages of the study where design review is required • Approval(s) of the protocol (5). As we can see from the referenced guidance, there are no unified approaches for process validation, and each company should develop their own procedures and documentation pertaining to process validation. 86 Journal of Validation Technology [SPRING 2012]

PROCESS VALIDATION DOCUMENTATION FDA regulations don’t provide specific requirements for which documents have to be delivered during the validation process. The required documentation should be defined in the procedures for process validation required by 21 CFR part 820.75(b), “Where the results of the process cannot be fully verified by subsequent inspection and test, the process shall be validated with a high degree of assurance and approved according to established procedures” (1). Section 820.75(a) refers to process and equipment validation and states, “The validation activities and results, including the date and signature of the individual(s) approving the validation and where appropriate the major equipment validated, shall be documented” (1). The definition of process validation is defined in section 820.3(z)(1), as follows: “Process validation means establishing by objective evidence that a process consistently produces a result or product meeting its predetermined specifications” (1). However, equipment validation is defined by 820.3(g) and (z), as follows: Equipment. Each manufacturer shall ensure that all equipment used in the manufacturing process meets specified requirements and is appropriately designed, conivthome.com


structed, placed, and installed to facilitate maintenance, adjustment, cleaning, and use. Validation means confirmation by examination and provisionofobjectiveevidencethattheparticularrequirements for a specific intended use can be consistently fulfilled (1). Therefore, equipment validation is one of the most important components of process validation. Unfortunately, the QSR doesn’t define which equipment is considered to be major. It means that companies should have procedures to define which equipment should be validated, and which should not be validated. GAMP 5, system classification can be used for equipment categorization and defining which validation deliverables are required (9). An example of process validation documentation is presented in Figure 3. Software validation and test method validation are two widely separate topics that cannot be covered in this paper.

INSTALLATION QUALIFICATION Installation qualification is establishing by objective evidence that all key aspects of the process equipment and ancillary system installation adhere to the manufacturer’s approved specification and that the recommendations of the supplier of the equipment are suitably considered (4). Important IQ considerations are as follows: • Equipment design features (i.e., materials of construction cleanability) • Installation conditions (i.e., wiring, utilities, functionality) • Calibration, preventative maintenance, cleaning schedules • Safety features • Supplier documentation, prints, drawings and manuals • Software documentation • Spare parts list • Environmental conditions (e.g., cleanroom requirements, temperature, humidity) (5).

OPERATIONAL QUALIFICATION Operational qualification is establishing, by objective evidence, process control limits and action levels that result in product that meets all predetermined requirements (4). OQ considerations include the following: • Process control limits (e.g., time, temperature, pressure, line speed, setup conditions) • Software parameters • Raw material specifications • Process operating procedures g x p a n d j v t . co m

• Material handling requirements • Process change control • Training • Short term stability and capability of the process (latitude studies or control charts) • Potential failure modes, action levels and worst-case conditions (failure mode and effects analysis [FMEA], fault tree analysis) (4). Frank defines OQ as “studies which are designed to challenge the process and process equipment, and establish objective evidence that the process meets predetermined requirements throughout all anticipated operating ranges” (3). The following are examples of OQ elements: • Verification of all systems and subsystem functions • Confirmation of all safety devices and systems • Software qualification • Evaluate impact of key parameters on the process (i.e., DOE, worst-case testing) • Measurement system suitability • Bias or repeatability and reproducibility of measurement systems • Operator training and qualification (3).

PERFORMANCE QUALIFICATION Equipment performance qualification is establishing by objective evidence that the equipment, under anticipated conditions, consistently performs within the specified limits. The equipment PQ shall contain evidence that the equipment is suitable for the process, for which it is used. Process PQ is establishing by objective evidence that the process, under anticipated conditions, consistently produces a product that meets all predetermined requirements (4). The medical device guidance provides definitions for process PQ and product PQ, as follows: • Process performance qualification: establishing documented evidence that the process is effective and reproducible. • Product performance qualification: establishing documented evidence through appropriate testing that the finished product produced by the specified process(es) meets all release requirements for functionality and safety (5). PQ considerations include the following: • Actual product and process parameters and procedures established in OQ • Acceptability of the product • Assurance of process capability as established in OQ (4). Journal of Validation Technology [SPRING 2012] 87


Examples of PQ elements are as follows: • “Verification of released process documentation (e.g., manufacturing procedures, inspection procedures, product specifications, engineering drawings, tool drawings, material specifications, related forms) • Dimensional verification (e.g., first article, layout inspection) • Process stability (x-bar & R charts) • Process capability (Cp, Cpk) • Fault seeding • Product performance evaluation (i.e., impact of the process on follow-on operations, product functionality, material and physical properties) • Cleanliness tests (e.g., extraction tests, ESCA) • Biological tests (e.g., bioburden, cytotoxicity, hemolysis) • Product sterility • Manned and unmanned testing of controlled environments” (3).

PROCESS CONTROL AND MONITORING After the process is validated, it is important to control the validated state of the process. GHTF states, “Trends in the process should be monitored to ensure the process remains within the established parameters. When monitoring data on quality characteristics demonstrates a negative trend, the cause should be investigated, corrective action may be taken and revalidation considered” (4). Process monitoring and control should not be limited to the review of quality charts and data. Possible process variations may be caused by personnel deviations from work instructions; changes in environmental conditions, or equipment failure. GHTF states, “Various changes may occur in raw materials and/or processes which are undetected, or considered at the time to be inconsequential. (An example of this type of process is sterilization.) These changes may cumulatively affect the validation status of the process. Periodic revalidation should be considered for these types of processes” (4). The process map (Figure 1) can be used to evaluate the changes, which can impact the process.

REVALIDATION According to the FDA medical device manual, the process revalidation is necessary in the following cases: • When process changed • When process deviations occur • On a periodic basis. 88 Journal of Validation Technology [SPRING 2012]

In all cases, the process must be reviewed and evaluated; and activities for review, evaluation, and revalidation must be documented (5). To document that the process is not changed and operating in a state of control, day-to-day in process control data and finished product testing data should be analyzed for conformance with specifications and for variability.

WARNING LETTERS FDA Warning Letters are published on the FDA website (www.fda.gov). These letters contain valuable information about issues related to process validation. Table I contains examples of Warning Letters related to observations pertaining to process validation activities.

STATISTICAL TECHNIQUES AND SAMPLE SIZE The QSR doesn’t provide specific requirements for statistical techniques and sampling plans. However, FDA requires that the rationale for the statistical techniques and sampling plans should be documented, as follows: Sec. 820.250 Statistical techniques][1] (a) Where appropriate, each manufacturer shall establish and maintain procedures for identifying valid statistical techniques required for establishing, controlling, and verifyingtheacceptabilityofprocesscapabilityandproduct characteristics. (b) Sampling plans, when used, shall be written and based on a valid statistical rationale. Each manufacturer shall establish and maintain procedures to ensure that sampling methods are adequate for their intended use and to ensure that when changes occur the sampling plans are reviewed. These activities shall be documented (1). Standards for acceptance sampling (14, 15, 16) and publication (17) refer to acceptance sampling for lots. The GHTF guidance provides an explanation of how these techniques can be used for process validation: “Acceptance sampling plans are commonly used in manufacturing to decide whether to accept (release) or to reject (hold) lots of product. However, they can also be used during validation to accept (pass) or to reject (fail) the process. Following the acceptance by a sampling plan, one can make a confidence statement such as: “With 95% confidence, the defect rate is below 1% defective” (4). The final decision on how many samples to test cannot be made until process test results are available. The following approach can be used: 1. Using preliminary assumptions about the process, define the number of samples 2. Execute the sample plan ivthome.com


Table I: FDA Warning Letters. Date

Company

Link

Observation

September 18, 2009

Advanced Medical Optics Uppsala Ab

http://www. fda.gov/ICECI/ EnforcementActions/ WarningLetters/ ucm193872.htm

Failure to adequately ensure that when the results of a process cannot be fully verified by subsequent inspection and test that the process shall be validated with a high degree of assurance and approved according to established procedure, as required by 21 C.F.R. 820.75(a). For example, your firm failed to perform and document equipment-cleaning validation for the production of Healon D ophthalmic viscoelastic devices.

April 11, 2008

VIBE Technologies, LLC

http://www.fda.gov/ foi/warning_letters/ s6745c.htm

5. Failure to establish and maintain procedures to ensure that equipment is routinely calibrated, inspected, checked, and maintained, as required by 21 CFR 820.72(a).

April 26, 2007

Medical Wire & Equipment Co (Bath), Ltd. Potley Road Corsham, Wiltshire, England SN13 9RT

http://www.fda.gov/ foi/warning_letters/ s6345c.htm

4. Failure to ensure all inspection, measuring, and test equipment, is suitable for its intended purposes and is capable of producing valid results as required by 21 CFR 820.72(a); and failure to document equipment identification, calibration date, the individual performing the calibration, and the next calibration date as required by 21 CFR 820.72(b)(2). For example, there is no documented calibration history for the [redacted] which is used to test the conductivity of the process water.

June 1, 2006

Visionary Contact Lens, Inc. 2940 E. Miraloma Ave. Anaheim, CA 92806

http://www.ortsedu. com/warning1.pdf

9. You have not completely established procedures to ensure that equipment is routinely calibrated. Specifically, the daily check of manufacturing equipment is not described or referenced [21 CFR 820.72(a)].

September 28, 2007

Healthway Home Products, Inc. 4941 N. Jefferson St. Pulaski, New York 13142-4102

http://www.fda.gov/ foi/warning_letters/ s6543c.pdf

8. Failure to establish and maintain procedures to ensure that inspection, measuring and test equipment is routinely calibrated, inspected, checked and maintained, as required by 21 CFR 820.72(a). For example, written procedures have not been established for acceptance testing equipment (i.e. digital high voltage meter and particle counter) utilized on Air Cleaners prior to distribution to assure the testing equipment are routinely calibrated and properly maintained.

December 2, 2005

Restorative Products, Inc. 13560 Wright Cir Tampa, FL 33626

http://www. casewatch.org/ fdawarning/ prod/2005/ restorative.shtml

Your firm failed to establish and maintain procedures to ensure that equipment is routinely calibrated, inspected, checked, and maintained as required by 21 CFR 820.72(a). In particular, your firm did not establish and maintain procedures for calibrating temperature and speed controls on wave soldering equipment and an oven. (FDA 483, Item #7). Your firm failed to establish and maintain procedures to control environmental conditions that could reasonably be expected to have an adverse effect on product quality as required by 21 CFR 820.70(c). Your firm’s soldering work instructions require that sensitive components and circuit boards, when not being worked on, must be enclosed in shielding bags or boxes. The investigator observed a minimum of 10 antistatic bags containing sensitive components and p.c. boards in open bags in the storage area (FDA 483, Item #8).

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3. Estimate the confidence level and evaluate the sample plan. In most cases, if the p-value (the probability to accept null hypothesis, i.e. reject the process) is less then 5% at 95% confidence level, then the sampling plan is adequate 4. Correct the sample plan and repeat the testing if needed. The following are considerations that need to be taken into account: • Evaluate the measuring system. Is your testing method and equipment adequate for the purpose of testing? • Sampling procedure. Different lots, different raw materials lot, different equipment, different locations? • Random sampling. Random testing may be something along the lines of testing the 5th sample in every 9th row. • Check the distribution. Most statistical test methods are valid for the normal distribution only. Perform the normality test, if applicable. The following spreadsheet analysis tools can be used: Tables (14, 15), Microsoft Excel, Minitab, SAS. Frank provides another practical consideration for sample size determination: The sample size for each test should be established in the test plan, and should be based on the criticality of the process. Sample size is normally based on the level of confidence desiredtoensureacertainportionofthepopulationiswithin the sample range. This may be calculated by the Wilks equation: npn-1 – (n-1)pn = 1 - alpha where: n = sample size p=proportionofpopulationcontainedwithinthesample range alpha = confidence level Typically, a sample size of 30 is adequate for most testing, which covers 90% of the population with 80% confidence. Occasionally, a sample size as low as 3 may be used in development activities, where 50% of the population is covered with 50% confidence (3). To provide a practical recommendation for the sample size calculation, definitions for the main terms need to be provided: • Null Hypothesis—the probability that the statistical result is false. For example, when a process is changed, we need to prove that the changes don’t impact process outputs. In case of a non-parametric output, where the output is a variable, the appropriate tool to provide 90 Journal of Validation Technology [SPRING 2012]

statistical evidence that the process outputs have not changed is the analysis of means. In this case, two sample sets need to be collected—outputs from the original process and outputs from the modified process. The null hypothesis is that there is no difference in means between the two sample sets. • Statistical Power—the probability to reject the null hypothesis when the null hypothesis is true. The more samples that are collected, the greater the value of the power. Usually, the power depends on the criticality of the process, and the value can be 0.8 or 0.9. • Confidence level—the level of confidence in the statistical results. The confidence level usually is selected at 0.95 or 0.99 for critical parameters. If the standard deviation of the process is not know, then an assumption of its value can be made based on the results of process monitoring and development activities. After process data are collected, this assumption can be tested. Another assumption that has to be made is the acceptable difference in means that indicates that the process has not changed. That assumption can be based on the specification limits, or accuracy of the test method. Usually, 5-10% of the specification can be considered as a reasonable difference. Suppose in our case the allowable difference is two standard deviations. Figure 4 was calculated with Minitab, version 15. Alpha is selected 0.05, which means that the confidence level is 0.95. The result shows that the sample size of 7 can be selected for the planned study. Also, the sample size depends on power and allowable difference in means.

CONCLUSION Process validation is one of the key components of a quality system. The main constituents of the process are environment, buildings, equipment, personnel, and documentation. The existing guidances and standards cover different aspects of process validation, which requires one to take into consideration multiple sources for establishing a specific process validation methodology for each company. FDA, as a government organization, strives to maintain the public safety by providing guidances and regulations to follow in order to produce safe products in qualified facilities. Individual companies establish validation processes to conform to FDA’s guidelines. Public complaints and FDA inspections of manufacturing and research facilities allow the government to control quality operations and development activities in the pharmaceutical industry. Failure to follow FDA guidances and regulations may lead to observations and possible consent decrees, which are aimed at outlining corrective action procedures for companies to return to a compliant good manufacturing practice environment. ivthome.com


Figure 4: Sample size calculation.

REFERENCES 1. FDA, Quality System Regulation, Title 21 Part 820 of the Code of Federal Regulations (www.accessdata.fda.gov/scripts/ cdrh/cfdocs/cfcfr/CFRSearch.cfm? CFRPart=820, Apr 2003). 2. ISO, ISO 13485:2003 Medical devices, Quality management Systems http://www.iso.org/iso/catalogue_ detail?csnumber=36786. 3. Doug Frank, “Process Validation for a Regulated Environment,” presentation http://www.scribd.com/doc/36833841/ Process-Validation-Presentation-Final-Version 4. GHTF SG3/N99-10 Quality Management Systems—Process Validation Guidance, Jan. 2004. 5. FDA, Medical Device Quality Systems Manual: A Small Entity Compliance Guide (http://www.fda.gov/MedicalDevices/ DeviceRegulationandGuidance/PostmarketRequirements/ QualitySystemsRegulations/MedicalDeviceQualitySystemsManual/default.htm, Dec 1996). 6. FDA, Guidance for Industry: Process Validation: General Principles and Practices (http://www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/Guidances/ UCM070336.pdf, January 2011). 7. FDA, Guidance for Industry Part 11, Electronic Records; Electronic Signatures—Scope and Application (http://www.fda. gov/RegulatoryInformation/Guidances/ucm125067.htm. g x p a n d j v t . co m

8. FDA, General Principles of Software Validation; Final Guidance for Industry and FDA Staff (http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm085281.htm, Jan 2002). 9. ISPE, GAMP 5 Good Automated Manufacturing Practices. 10. FDA, Guide to Inspections of Medical Device Manufacturers (http://www.fda.gov/ICECI/Inspections/InspectionGuides/ ucm074899.htm, Dec 1997). 11. ICH, Q8 Pharmaceutical Development, August 2009. 12. ASTM, E2500–07 Standard Guide for Specification, Design, and Verification of Pharmaceutical and Biopharmaceutical Manufacturing Systems and Equipment. 13. ISO, 14001:2004 Environmental Management Systems. 14. ANSI/ASQ Z1.9-2003 Sampling Procedures and Tables for Inspection by Variables for Percent Nonconforming. 15. ANSI/ASQ Z1.4 Sampling Procedures and Tables for Inspection by Attributes. 16. ANSI/ASQ S2-1995 Introduction to Attribute Sampling. 17. Dr. Wayne A. Taylor, Guide to Acceptance Sampling, Taylor Enterprises, Inc., Lake Villa, Illinois, 1992. JVT

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