Project 1 - Device Master File

Device Master File

Introduction

Device master record (DMR) is the term used in the Quality System (QS) regulation for all of the routine documentation required to manufacture devices that will consistently meet company requirements. Section 820.3(j) of the QS regulation defines device master record as a compilation of records containing the procedures and specifications for a finished device. The detailed requirements for device master records are contained in section 820.181, as well as throughout the regulation. The definition for design output in 820.3(g) gives the basis and/or origin of the device master record for all Class II and III devices as follows:

Design output means the results of a design effort at each design phase and at the end of the total design effort. The finished design output is the basis for the device master record. The total finished design output consists of the device, its packaging and labeling, and the device master record.

For some devices, many of the design output documents are the same as the device master record documents. Other device output information is used to create a DMR drawing such as for a test or an inspection procedure. Figure 6.1 shows the close relationship between design output and the device master record.

Section 820.181, Device Master Record, lists some typical documents in a DMR as follows:

The DMR for each type of device shall include, or refer to the location of, the following information:

(a) Device specifications including appropriate drawings, composition, formulation, component specifications, and software specifications;

(b) Production process specifications including the appropriate equipment specifications, production methods, production procedures, and production environment specifications;

(c) Quality assurance procedures and specifications including acceptance criteria and the quality assurance equipment to be used;

(d) Packaging and labeling specifications, including methods and processes used; and

(e) Installation, maintenance, and servicing procedures and methods.

The definition for Design Output 820.3(g) and requirements for Design Output 820.30(d) do not apply to most Class I devices. Therefore, the requirements for the DMR for most Class I devices are in 820.181 Device Master Record. Of course, a manufacturer of Class I devices may use the design output sections of the GMP as guidance.

However, almost all sections of the QS regulation have requirements related to the device master record. The device master record contains specifications for the device, accessories, labeling, and packaging, and contains a full description of how to procure the components and manufacture the device including specifications for facilities, environment, and production equipment. In addition to the device specifications, a device master record contains documents that cover typical manufacturing activities such as:

• procurement,
• assembly,
• labeling,
• test and inspection,
• packaging, and
• where applicable, sterilization.

Note that the listed activities and records or documents are required to produce any product ‑‑ medical, industrial, or consumer. There is nothing special about device master records except the name. Also, note that in common usage, the term "device master record" refers to the total record or any of its individual records. Therefore, the term is singular for the total record, singular for a single document, and plural for a group of single documents. The term also may refer to an original record or a copy of a record.

Device master records should be technically correct, contain and/or reflect the approved device and process designs, be under change control, contain the release or other control date, contain an approval signature, and be directed toward the intended user. These requirements are in the QS regulation because the device master record is the "beginning and end" of a product ‑‑ errors in the device master record will have a serious impact on the state‑of‑control of the manufacturing operation and may have a serious impact on the safety and performance of the device. The device master record should be accurate and complete because the essence of the QS regulation is a quality system based on designing a device to meet user needs, documenting the design and production procedures in the device master record and then producing a finished device that meets the device master record requirements. Thus, the device master record shall accurately reflect the device intended to be produced by a manufacturer.

Document For Intended Employees

The content, style, language, graphics, etc., of device master records should be directed toward the needs of the intended employees and, if the record is a specification or text for labeling, it should be directed toward users. A failure to consider the intended user leads to confusion and means that the company has not achieved the state‑of‑control intended by the QS regulation. Therefore, applicable records should be directed toward the needs of procurement, processing, and test/inspection personnel, rather than the needs of drafting, technical services, or product development departments. Likewise, installation instructions should be directed to installers. Labeling is often prepared by the same employees that draft device master records; and, these employees should also be aware that labeling shall meet the needs of the user as directed by 21 CFR 809.10, 801.6 and 820.30. In any manufacturing activity such as assembly, labeling, processing, testing, etc., achieving and maintaining a state‑of‑control is enhanced by appropriate personnel knowing:

• what task is to be done,
• how to do the task,
• who is to do the task,
• what task is being done, and
• what task was done and/or the results of the activity.

In order for employees to perform a job correctly, they should know exactly what is to be done and exactly how to do the work. Section 820.181 requires that what is done be documented in the device master record. The device master record also contains test and inspection procedures and data forms that are used to help determine and record what was done.

Documents that instruct people how to fabricate, assemble, mix, label, test, inspect, etc., or how to operate equipment should:

• be directed toward the needs of the employees who will be using them and not directed toward the drafts-person or designer;
• match the tools and equipment to be used;
• be correct, complete, and current; and
• depend on part numbers and basic drawings to transfer information rather than almost photographic type drawings.

If a component is changed, the representations on pictorial/photographic type drawings are no longer correct and may be very confusing to employees, particularly new employees. The how‑to‑manufacture instructions should be adequate for use by the intended employees and correct for the intended operation. In the medium‑to‑large company, the instructions tend to be extensive technical (engineering) drawings and written procedures. In any company, particularly small manufacturers, the work instructions may take several forms as discussed below.

• Engineering drawings may be used if employees are trained to read and use them. Some of the how‑to information comes from employee training rather than from drawings.
• Assembly drawings may contain parts list and quality acceptance criteria. A separate quality acceptance test and/or inspection procedure is not always necessary. An example of an engineering drawing for assembling a handle is exhibited at the end of this chapter. This drawing also includes some of the quality acceptance criteria for evaluating the handle in Notes 1 and 2. The parts list for the handle is on the page after the assembly drawing. Some manufacturers that manufacture simple devices use large sheets of paper for assembly drawings and include the parts list on it. The combination drawing results in instant availability of the parts list and reduces the number of drawings to be controlled. An example of an engineering drawing for assembling a cable and the associated parts list follows the handle assembly drawings.
• Exploded‑view drawings are used when employees cannot read plan‑view engineering drawings. Exploded‑view drawings tend to be more "how to" than plan‑view drawings. Exploded‑­view drawings are expensive to draft ‑‑ in some cases it may cost less to teach employees how to read and use ordinary plan‑view drawings.
• Step‑by‑step written procedures may be used to detail how to perform specific tasks with check‑off blanks to show that each specific task was performed. This type of procedure is commonly used for critical operations and where there is little or no visual indication of what has been done, such as for cleaning operations and for mixing chemicals.

Documentation may be supported by production aids such as labeled photographs, video tapes, slide shows, sample assemblies, or sample finished devices. All of these perform device master record functions and should be identified, and be current, correct, and approved for the intended operation. The most commonly used aids are models or samples. There are two conditions that should be satisfied in order to use these aids. First, a written specification for the sample shall be contained in the device master record. This specification, of course, may be the same as the specification for the assembly or finished device to be manufactured. This specification shall be subject to a formal change‑control procedure. Even though a model is available, the specification is needed for present and future product development, and for production control purposes. Second, the sample should:

• adequately reflect the device master record specification;
• be identified as an approved acceptable representative sample, which means it shall meet the company required workmanship standards; the sample need not be a working model if the nonworking condition is not misleading to employees being guided by the sample; and
• when appropriate, contain or be tagged with a drawing number, revision level, and control number (lot, serial, batch).

A card or tag as shown in the exhibits or an equivalent card may be used to identify and help control the use of samples of assemblies or finished devices. Such tags are usually covered by a clear plastic pouch and attached to the model or sample.

Samples and other aids such as photographs are subject to normal wear and tear in a production environment. Therefore, such aids should be adequately protected by a suitable means such as being located in a protected area, or covered by a protective pouch or container. Production aids should be periodically audited to make sure they continue to be suitable for the intended use. Section 820.100 contains requirements for corrective action. Corrective action may involve the use of samples, changes to the samples, or changes in the control of the samples.

Adequate Information

Although a manufacturer tries to document for the intended employees, there is a need to audit periodically to see how well the goal is being met. There are various means of determining if information in the device master record, production tools, and other production elements are adequate for a given operation and associated employees. These include analyzing the:

• assistance required by new employees;
• assistance required when a new device is introduced into production;­
• confusion and hesitation;
• information exchanged among employees;
• "homemade" documentation drafted by the line employees;
• rework;
• products produced (productivity);
• complaints from departments that subsequently process the device; and
• customer complaints.

If any of these factors persist and are out of line with industry norms or with the previous production experience, then the manufacturer should take corrective action. Management shall review the quality system as directed by 820.20 and, thus, be aware of device quality problems or quality system problems such as listed above. The corrective action may include changes in supervision or documentation, adding new documentation, modifying the design, using different tools, modifying the environment, etc.

Preparation and Signatures

A separate device master record is required for each type or family of devices. Also, a separate device master record may be needed for accessories to devices when these are distributed separately for health care purposes. Such accessories are considered to be finished devices. In practice, if the device and accessories are made by the same manufacturer, the device master record for the accessory may be incorporated into the device master record for the primary device.Within a family of devices, variations in the family may be handled by dash number extensions on drawing and procedure numbers. Usually, a top assembly or other major drawing contains a table/list of the devices in the family and lists the variable parameters for each member of the family.

Section 820.40 of the QS regulation requires that an individual(s) be designated to: review, date, and approve all documents required by the QS regulation including the device master record and authorize changes. An individual(s) with the necessary technical training and experience shall be designated to prepare and control device master records. In addition to requiring approval signatures on device master records, the QS regulation requires individual identification for a few other activities. For convenience, these activities along with the section numbers that require them are listed in Table 1.

Table 1: GMP ACTIVITIES REQUIRING INDIVIDUAL IDENTIFICATION

820.30(b)	Approval of Design Plans
820.30(c)	Approval of Design Input
820.30(d)	Approval of Design Output
820.30(e)	Results of Design Review
820.30(f)	Results of Design Verification
820.30(g)	Results of Design Validation
820.40	Approval of in Device Master Record or Changes
820.70(g)	Equipment Maintenance and Inspection Activities Performed
820.72(b)	Calibration Performed
820.75(a)	Approval of Process Validation
820.75(1)(2)	Performance of Validated Process
820.80(d)	Release of Finished Devices
820.80(e)	Acceptance of Activities Conducted
820.90(b)	Authorization to Use Non-Conforming Product
820.120(b)	Labeling Inspection
820.180(c)	Audit Certification
820.198(b)	Decisions Not to Investigate Complaints

The list is self‑explanatory except for audit certification. When a manufacturer certifies in writing to FDA that quality system audits have been performed, the certification letter is signed by management having responsibility for the matters audited. Also note that the records in 820.70, 820.72, 820.80, 820.90(b), 820.120(b) and 820.160 are not part of the device master record but, instead, are part of the device history record (DHR). Records in 820.198(b) are part of the complaint files. If a record that requires a signature is maintained on a computer, it is best if the designated individual(s) maintains an up‑to‑date signed printout of the record. Where it is impracticable to maintain current printouts, computer‑compatible identifiers may be used in lieu of signatures as long as there are adequate controls to prevent improper use, proper employee identification, inaccurate data input, or other inappropriate activity. If identifiers such as coded badges and equipment keys are not controlled (i.e., not restricted to designated employees), then these will not meet applicable GMP “signature” requirements.

Location of Records

Device master records shall be stored at the manufacturing establishment or at other locations (820.180) that are reasonably accessible to company employees responsible for the manufacturing activities and accessible to FDA investigators. Appropriate records may be maintained in computer data banks if the records are protected, change controlled, and readily accessible for use by responsible employees at all relevant facilities. It is acceptable for a manufacturer to maintain records on microfilm and discard the original hard copies. Microfiche and/or microfilm reductions may be used in lieu of original record retention if the following conditions are met.

• All reductions shall be readily available for review and copying by FDA investigators and designated company personnel at any reasonable time.
• All necessary equipment shall be provided for viewing and copying the records.
• Reproductions shall be true and accurate copies of the original record.I

If the reproduction process results in a copy that does not reveal changes or additions to the original record, the original should be retained. In this situation, the reproduced copy and any image shown on a viewing screen should note any alteration from the original and indicate that the original record is available.

By maintaining the device master record, complaints and other records required by the QS regulation at the manufacturing establishment or other reasonably accessible location, responsible officials of a company can exercise control and accountability over the entire design, manufacturing, and postmarketing activities and, thereby, maximize the probability that the finished device conforms to its design specifications. This GMP requirement helps assure that responsible officials at the manufacturing establishment have ready access to those documents essential for producing devices and for conducting self‑inspections, complaint investigations, failure analyses, audits, and corrective action.

The device master record is a single source document or file. Portions of this file may be kept in various locations. A device master record may exist as:

• one or more files or volumes of the actual records containing the information required by the QS regulation;
• a reference list of such documents and their location; or
• any combination of actual documents and/or reference lists.

These documents shall contain the latest DMR revisions, be signed, and be dated to show they have been checked for adequacy and approved for use (820.30, 820.40 and 820.181). The QS regulation allows use of reference lists as a means to reduce the duplication of records, particularly duplication of general documents such as standard operating procedures (SOP's). General SOP’s (not directly related to a product or process) however should be made a part of the quality system record (QSR) (820.186). Use of a reference list also allows filing of device master record documents at several convenient locations. If the device master record contains a list of documentation, the actual documents shall be available for employee use and FDA inspection at the manufacturing site or other reasonably accessible locations. As noted above, this is a key and important GMP requirement. Typical locations of various device master records are shown in Table 2.

When performing an inspection of a company, FDA investigators shall have access to actual records for review and copying during reasonable business hours. FDA investigators review these records to determine if a manufacturer is complying with the QS regulation and with the Food, Drug, and Cosmetic Act. Records deemed confidential by a manufacturer should be marked to aid FDA in determining whether or not specific information may be disclosed under the Freedom of Information Act. However, routinely stamping every document as “Confidential” defeats the purpose of requesting extra care be taken to protect a specific document or set of documents.

Table 2: LOCATION OF DEVICE MASTER RECORDS

TYPE OF DMR ELEMENT	ORIGINALS	Typical Locations of Documents WORKING COPIES
Reference list(s)	Engr. master file
Component acceptance procedures	SOP master file	Receiving department
Device Input specifications (final version)	Engr. master file	Marketing or Engineering
Manufacturing procedures	Engr. or Manuf. Engr. master file	Manufacturing
Test specifications	Engr. master file	Engr. or Manuf. Engr.
Test procedures	Engr. or Manuf. Engr. master file	Manuf., QA, QC or Final Test
Inspection procedures	Manuf., QC, or SOP master file	Manufacturing or QC
Label drawings	Engr. master file	Engr., QA, or Manuf.
Label artwork	Artwork master file	Engr., Procurement
Label control procedures	Manuf., QC, or SOP master file	Manufacturing
Specific cleaning procedures	SOP master file	Manufacturing
General cleaning procedures	QSR master file
System audit procedures	QSR master file
Employee training procedures	QSR master file

SOP = Standard Operating Procedure

QSR = Quality System Record

QA = Quality Assurance

QC = Quality Control

Record Retention

The QS regulation in section 820.180(b) requires that all records pertaining to a device shall be retained for a period of time equivalent to the design and expected life of the device, but in no case less than two years from the date of release for commercial distribution by the manufacturer. Manufacturers of long‑life products should make prudent decisions as to how long to keep records. For example, there may be no value in keeping records for long‑life devices such as stretchers, surgical tools, containers, etc., forever if the probability is low that any post‑distribution remedial activity will occur. For devices that require repair or capital equipment devices that probably will be updated, appropriate records should be retained to support these. Device master record requirements apply to devices modified in the field by the manufacturer's representatives after the devices are commercially distributed. Modification of a device is manufacturing and the QS regulation covers all manufacturing of devices where the result is placed into commercial distribution. In any case, a manufacturer should be prepared to provide a rationale for its decision to discontinue record-keeping.

DEVICE MASTER RECORD CONTENTS

As discussed above, the device master record shows and/or tells employees how to perform specific functions related to the production of a device. The QS regulation does not dictate how this information is to be arranged or filed in the device master record and quality system record except that it shall be readily accessible. Because each device master record and quality system record contain many documents, an index of each is usually needed.

Device Specification

There may be many specifications in the device master record. One of these is the device specification. A device or product specification is a specific document in the device master record that briefly describes and gives all important details of the external characteristics of a device. The product specification may also contain some internal characteristics of the device that are important to the manufacturer and/or the users. The finished device specification is derived from the design input specifications in 820.30. For some devices, many of the external characteristics such as temperature tolerance are related to the environment in which the devices will function properly. For some in vitro products, the package insert is used by some manufacturers as the product specification for marketing purposes.

Generally a product specification will contain the device's:

• product trade and common name(s);
• intended use(s);
• performance characteristics and theory of operation;
• regulatory classification;
• physical characteristics;
• environmental limitations and product stability;
• important components and formula (if applicable); and
• user safety characteristics.

Table 3 contains a list of characteristics that often appear in product specifications; however, note that not all of the listed items will appear in the product specification for a given device.

In addition to defining and describing a device, a product specification is a communication tool which, if used in a timely manner, can help achieve some important results. First, it helps assure that everyone is talking about the same device and working toward the same objectives with respect to safety, effectiveness, human factors, configuration, labeling, packaging, processing, finished device acceptance, etc. Ultimately, the device specification or a condensed version of it should be used in catalogs, or other product documentation, to aid communication between salespersons and customers. If the marketing department uses the product specifications when preparing advertisements and catalog sheets, public relations with users will be enhanced because the marketing documents are based on proven scientific safety and performance claims for the actual device. The user has an opportunity to read the technical specifications of the item actually being offered for sale.

Thus the use of device product specifications will result in:

• improved communication between employees on a departmental and interdepartmental basis;
• less confusion and increased morale;
• an improved state‑of‑control;
• a higher probability of meeting cost, time, safety, effectiveness, and regulatory compliance objectives; and
• product literature that correctly describes the device for the prospective customer.

A sample product specification for a portable defibrillator is in the exhibits at the end of this chapter. This specification is long and detailed because it is a combined product and test specification, and because it is for a complex device.

Specific Documents

Specific documents are drawings, procedures, labels, data forms, etc., for a specific product or family of products. Product specific documents are almost always part of the device master record. The originals of specific documents are usually located in files in engineering or technical service departments. In most manufacturers, specific documents contain no general information; however, they often refer to general documents. (A list of specific and general documents is exhibited later in this chapter.) The number of specific documents for a given product line may range from about 10 to several hundred. If large numbers of documents are needed, an index is usually needed to help locate them, particularly for personnel that do not work in the drafting department or in technical services.

Records for In Vitro Diagnostic Products

The main differences between device master records for chemical‑based in vitro products and for electromechanical products, such as instruments and artificial kidneys, is terminology and the relatively extensive use of written processing procedures and status reports for in vitro diagnostic products rather than a few assembly drawings and test/inspection reports. For example, device master records for chemical‑based devices would contain a manufacturing section dealing with areas such as solution preparation and filling, whereas manufacturing sections for electromechanical products would cover operations such as assembly. Status records for weighing, mixing, filling, etc., are used for general control of in vitro products. Status reports are also used because it is often difficult to determine the status of in‑process in vitro products by looking at them ‑‑ the opposite is usually true for most hardware devices. Records for in vitro devices also shall contain control data that allows components and kits to be traced [809.10(a)(9), etc.].

Table 3: ITEMS THAT MAY APPEAR IN A DEVICE SPECIFICATION

1. Name of Product

a. Trade name

b. Trademark

c. Generic name

d. Chemical name

e. Official name

f. Common name

2. Performance Characteristics

a. Description/Intended use

b. Accessories

c. Functional parameters

d. Limitations

e. Contraindications

f. Input/Output requirements

g. Human interface

h. Others

3. Classification

a. Regulatory

b. Commercial

c. Functional

d. Others

4. Physical Characteristics

a. Weight

b. Size

c. Color

d. Form/Shape

e. Consistency

f. Packaging

g. Power requirements

h. Others

5. Environmental Limitations

a. Operating temperature range

b. Storage temperature range

c. Vibration and shock range

d. Voltage range

e. Humidity range

f. Moisture protection

g. Pressure, altitude limits

h. Electromagnetic interference

i. Electrical transients

j. Shelf life/Other

6. Important Components

a. Active ingredients

b. Major subsystems

c. Diagnostic kit materials

d. Accessories

e. Labeling

f. Service labeling

g. Components/items supplied by user

h. Software

i. Periodic Warranty/Other

7. User Safety and Performance Considerations

a. Chemical

b. Electrical

c. Thermal

d. Mechanical sharp, moving parts

e. Personnel training

f. Periodic testing

g. Maintenance

h. Other

QUALITY SYSTEM RECORD DOCUMENTS

Quality system record (QSR) (820.186) or general documents are used for many activities that are essential to operating a manufacturing establishment ‑‑ these are not specific to any given product even if the company produces only one product. Thus, the quality system record includes general documents such as standard operating procedures (SOP's) and standard quality assurance procedures (QAP's). If the company added another product line, the basic content of these documents would undergo none or only minor changes.

In a typical manufacturing operation, general QSR, SOP, and QAP documents may include the following:

• Employee training procedures

• Supplier assessment policy

• General design control procedures

• Component inspection procedures

• Workmanship standards

• Design review policy/procedure

• Label review policy/procedure

• Cleaning procedures

• Insecticide use‑removal procedures

• Air conditioning/heating procedures

• Tool kit policy

• Safety procedures

• Sterile water system maintenance

• Calibration policy

• Complaint handling procedure

• Recall procedure

• Procurement procedures

• Returned goods policies

• Drawing numbering system

• Change control procedure

• Service policy

• Deviation review policy/procedure

The above list is not all inclusive. Medium‑to‑large companies tend to have many of these general documents to guide management in maintaining consistent operations. A very small company may have only the most essential and appropriate of these documents such as procedures for design controls, drawing numbering system, change control, employee training, use of hazardous materials, etc. The original copy of each general procedure is filed in the department specified by management as having responsibility for maintaining that procedure, or it is filed in an automated system with access by the designated departments. The working copies of the above procedures are usually located in SOP manuals and QA manuals. The procedures are usually numbered and arranged in a logical order by topic. The QS regulation does not require manufacturers to keep quality system record documents in SOP or QA manuals; however, the experience of many industries has demonstrated that such manuals are worthwhile if they are kept current and contain only the real working procedures.

WRITTEN PROCEDURES

Many sections of the QS regulation require written procedures for instructions in performing various quality system, design product acceptance, QA, and manufacturing tasks. Certain devices such as in vitro products, because of the nature of the manufacturing operations, tend to have a relatively large number of written procedures.

Written procedures are used for quality system audits, product development, manufacturing, post‑marketing activities, etc., to:

• improve communication and guidance;
• assure consistent and complete performance of assigned tasks; and
• promote management of operations.

In large manufacturing facilities involving many operations and people of various skill levels, many written procedures are usually necessary. In a small manufacturer, communication lines are usually short, few people are involved, and management is readily available to provide guidance, so that the need for written procedures is usually less than for a larger manufacturer. A manufacturer, particularly a small manufacturer, may conclude that GMP requirements for written procedures are not applicable for a particular operation. Although the number of written procedures may vary, all manufacturers are required to maintain a device master record (820.181) for each type or family of devices they produce.

Often training and work experience alone or combined with drawings, photographs, and models are valid substitutes for written procedures. For example, machinists are typically skilled personnel who fabricate components and finished devices using dimensional drawings for guidance instead of written procedures. The company and FDA investigator will evaluate each situation based on the training and knowledge of the operators and the control needed to meet device specifications. Typically, a written procedure is not necessary when:

• the activity is very simple;
• the activity is relatively simple and models are used as production aids;
• straightforward quantitative rather than qualitative standards determine acceptability; and
• the operation is performed by personnel highly skilled relative to the task being performed.

Written procedures and associated history or status records, however, are often needed for activities where there is no change, such as color, texture, or form, to indicate that the activity has been performed correctly. Manufacturers should determine that they meet all GMP requirements and, if necessary, exceed them in order to produce finished devices that meet device master record specifications because FDA insists that manufacturers meet their quality claims [FD&C Act, section 501(c)]. Achieving this required state‑of‑control may require fewer or more written procedures than specifically required by the QS regulation. FDA does not insist that a manufacturer generate records that do not contribute to assuring conformance to specifications.

Developing Procedures

Developing written procedures is relatively labor intensive and time consuming, which may lead to use of "back‑of‑the‑envelope" notes instead of formal procedures. Likewise, changing these procedures is time consuming, which may lead to delays or forgetting to make the changes. Drafting or changing written procedures is also prone to errors. Therefore, manufacturers are encouraged to use computers and low‑cost printers as word processors to aid in writing and changing procedures. With the use of computers, these tasks become easier thereby increasing the probability that they will be performed correctly and when needed. Computers can also be used for generating and maintaining device master record indices and complaint files, and performing a host of other GMP related activities.

There is a method for developing procedures that will result in short, clear procedures that help solve real problems. The first two steps are:

• identify the problems to be solved; and
• decide if new or modified procedures are needed to help solve or reduce the problems.

Events that point to a problem are excessive rework, employee confusion, customer complaints, recalls, etc. These "pointers," however, may not be the real problem. The real problem may be inadequate design, components, equipment, maintenance, operational techniques, documentation, environment, etc. The real problem should be identified before it can be solved. A written procedure may or may not be needed to help solve the problem.

The real problem can be identified by careful analysis of:

• the "pointers" noted above,
• device design,
• process design,
• process flow and employee work habits (operational analysis),
• test and inspection data, and
• any other activity related to the quality of the device.

Operational analysis is aided by flow-charting which is a step‑by‑step chart of the minute details of the operation. Thus, a flow chart is much more detailed than a QA audit report and is very helpful in determining what is actually happening in a particular manufacturing operation. This knowledge may lead to a solution of manufacturing and quality problems. From a company quality system, interface, and personnel management viewpoint, the problem, the reason for flow‑charting the given activity, etc., should be discussed with affected personnel. Their input should be requested with respect to identifying and solving the real problem. By using the information presented by the flowchart and the experience gained while producing the chart, the QA auditor is better able to:

• analyze the particular operation with respect to process requirements;
• determine what needs to be added, modified, or deleted to solve any problems or improve performance; and
• if needed, write or modify a procedure to cover the new way of performing the activity.

Content of Procedures

Written procedures are widely used and industry experience has shown that these should contain the following items:

• company identification and a procedure title;
• an identification or control number with a revision level code;
• an approval signature, and date the procedure becomes effective;
• the number of pages (e.g., sheet 1 of 4) in the procedure or another means to indicate that the employee has the complete document; and
• step-by-step instructions for performing the required activities

The effective date may be the same as the approval date. Also, the effective date may appear on a separate document such as an engineering change order (ECO) form. The main body of the procedure should cover, as appropriate:

• subject, scope, and objectives;
• who is assigned to perform the task;
• what activity or task is to be performed;
• when and where the task is to be performed; and,
• how to perform the task including what tools, materials, etc., to use.

Particularly for the new employee, it is important for the procedure to state the reason for performing a function and the reason it is to be performed in a certain way. Background information such as this helps the employee to understand an assignment and remember how to perform it. For example, when working on static sensitive integrated circuits that are easily damaged by electrostatic potentials, unskilled employees need to understand why they have to be grounded, work on grounded mats and, especially, why they are not allowed to wear certain fabrics while at work. Likewise, employees working in environmentally controlled, clean manufacturing areas need to be told about invisible microbes and particulates, and that humans are the major source of these unwelcome contaminates. If so informed, employees are more likely to follow the operational procedures for working in controlled areas.

The task description in each procedure should cover appropriate details such as:

• the expected and actual results from performing the tasks, such as what data to collect and how to analyze, file, and report it;
• what to do with the component, in‑process device, or finished device if such is involved; and
• any related activities that need to be performed in order for the overall operation to remain in a state‑of‑control or for the device to meet the company device master record specifications.

If the procedure being developed, for example, covers change control, the procedure should also cover related activities such as changes to labeling. Consider a change to a device where an analog meter is replaced with a digital meter ‑‑ obviously the instruction manual (labeling) and service manual also need to be modified. Otherwise the finished device:

• may not meet company labeling policies;
• is misbranded because it does not meet the labeling requirements of the FD&C Act; and,
• is adulterated because the change does not meet the change control requirements of the QS regulation.

After the procedure is drafted, if appropriate, it should be reviewed with the affected personnel before it is approved and implemented. During the initial implementation, the use of the procedure should be monitored. Then, based on actual experience in using the procedure, if necessary, it should be modified to more exactly meet the need of the operation or process.

CHANGE CONTROL

The QS regulation in section 820.181 by reference to 820.40 requires that any changes to the device master record be authorized by the signature of a designated individual(s). Change control requirements also appear throughout the QS regulation. The control of changes to devices, processes, and the associated device master records is one of the most important elements of a quality assurance system. The requirements for a successful change control system are so extensive that the entire next chapter of this manual is devoted to changes and associated procedures.

EXHIBITS

Reprinted on the next pages are typical documents (records) that appear in device master records. Manufacturers may use these as guides in developing their device master records.

Documents That May Appear in a Device Master Record

The first exhibit is a list of documents that might appear in device master records. Each device master record would contain only those documents that are applicable for a specific device. Some of the listed documents are general rather than product specific. General documents are usually called standard operating procedures (SOP's) and, if necessary, are referenced in the device master record rather than actually being included. The general documents are usually part of the quality system record (QSR).

Device Master Record Index

This exhibit is a policy/procedure for drafting a device master record index. An index is also known as a document plan, table of contents, etc. An example of a device master record index follows immediately after the policy/procedure. Note that this particular policy/procedure contains definitions. It is important that procedures contain definitions, in a case like a complex device master record index where employees may not be familiar with the terminology.

Product Specification for a Portable Defibrillator

Finished device or product specifications are the backbone of any device master record. The one illustrated as the third exhibit is for a complicated piece of equipment and is, therefore, extensive. For long documents it is recommended that a table of contents be incorporated as was done in this specification. Appendix A and B of this specification are not exhibited.

Zener Diode Specification

This specification for a non‑complicated part contains the necessary information to describe the item in sufficient detail for the correct part to be procured per the 820.50 Purchasing Controls.

Label Example

A sample label is exhibited. Labels and labeling are components and their specifications, art work, etc., are part of the device master record. As for any component, labeling shall be specified (document­ed). The resulting device master record document shall be reviewed, approved, change controlled, and stored such that it may be readily accessed. Such records are used to meet requirements such as those in 820.50, 820.80(b), 820.80(d), 820.120(b), 820.120(e), etc.

Handle Assembly and Parts List

This exhibit is an engineering drawing and parts list for a handle assembly. Engineering drawings, parts lists, or formulations are a vital part of many device master records. In this case, the engineering drawing not only details how this assembly is to be made, but there is also important information in the notes on the drawing. If properly trained and with sufficient experience, employees are able to use this drawing as the instructions for assembly of this handle. A written assembly procedure is not necessary.

Cable Assembly and Parts List

This exhibit is similar to the handle assembly mentioned above. The type of drawing used and information on a drawing can aid a manufacturer in reducing paperwork needed to manufacture a specific product.

Device Master Record Index for Amylase

This document is a device master record index for an in‑vitro diagnostic product. Proprietary information in this index is replaced by X's. The company that prepared this index uses purchase specifications and raw material specifications. Some manufacturers, particularly small companies, specify and purchase standard, routine items such as bottles and caps by using catalog numbers. Component specification drawings are not always used for routine items such as standard bottles.

Product Description

This exhibit is a product description for an in vitro diagnostic product. The standard operating procedures, quality control procedures, manufacturing flow sheets, and notes mentioned in this product description are not reprinted herein.

Amylase Diluent Solution

This exhibit is the procedure for making a batch of amylase solution. In this procedure, note that for each step the company requires the initials or signature of the person actually performing the operation and of the individual who checked that person’s performance of the operation.

Filling Record ‑ Liquid, Non Freeze Dried

This is an exhibit of a filling record used for liquid products to document the steps in a filling operation. The completed filling record becomes a part of the device history record (DHR) for the batch being filled.

Finished Product Release Form

This form is used to record that the device history record is complete for a lot of product, the product meets specifications, and the lot may be approved for release.

Production Sample Card

This exhibit shows both sides of a card or tag used to identify and help control the use of manufacturing aids such as samples of assemblies or finished devices. The use of a sample identification card is described in the main text of this chapter.

Shop Order Traveler

The last exhibit is two job travelers or job followers. These cards, forms, tags, etc., are used to identify a batch or sub‑batch of in‑process assemblies as they are passed from one department to another. Where needed, travelers are used to reduce mixups and confusion and, in general increase the state‑of‑control of an overall manufacturing operation. Travelers help meet the general requirements of 820.60, Identification, and the specific requirements of 820.86, Acceptance Status.

DOCUMENTS THAT MAY APPEAR IN A DEVICE MASTER RECORD

Device Master Record Index

The device master record Index is a table of contents which is used for convenience. It may be known as a:

• Device Master Record Index
• Documentation or Device Master Record Unit;
• Documentation Plan;
• Product Tree;
• Documentation Index;
• Product Structure; or
• Bill of Materials (if it also lists the device master record documents).

Manufacturing Information

List of components

• List of ingredients (including grade or type)

• Bill of materials (i.e., component list usually arranged by subassembly or other sub‑product level or by process steps)

• Formula

Procurement documentation

• Specifications

• Drawings

• Certificate of compliance requirements

• Supplier Assessment procedures

Device documentation

• Fabrication drawings

• Surface finish procedures
• Subassembly drawings
• Wiring and piping diagrams
• Assembly procedures
• Assembly drawings
• Reference documentation
• Wiring and piping schematics
• Test specifications
• Sub‑batch procedures
• Blending or mixing procedures
• Solution procedures
• Final formulation procedures
• Software packages

Precautions and special notations

• Apparel

• Cleaning

• Storage conditions
• Filling, mixing conditions
• Hazards and safety precautions

Equipment, lines, and procedures

• Process lines

• Assembly lines
• Vessels
• Mixers, tools
• Molds
• Machine maintenance procedures
• Calibration procedures
• Setup procedures
• Operating procedures
• Process flow charts

Sterilization procedures

• Procedures for ethylene oxide, radiation, filtration, steam, etc.

• Cycle parameter specifications

• Diagrams for loading products in the chamber

• Handling and flow procedures

Production control documentation

• Inspection procedures

• Test procedures

• Blank job travelers

• Blank inspection/test forms

• Instrument chartsReporting forms

• Approved deviations

Labeling

• Label drawings

• Labeling drawings

• Label/labeling review procedures and forms

• Production control procedures and history record forms

• Instruction manualsService manuals

• Customer software

• Customer feedback forms

Packaging

• Package drawings (usually includes labeling information)

• Closure drawings

• Filling and/or packaging procedures

• Packing procedures

• Special shipment procedures

Storage requirements

• Temperature

• Humidity

• Shelf‑life

Inspection procedures

• Incoming

• In‑process
• Finished devices
• Process control charts
• Blank data reporting forms

Test procedures

• Incoming

• In‑process

• Pretest conditioning

• Finished device

• Process control charts

• Blank device history record forms

• Automated test programs and/or software

Device Description
The Device master file should include the following device descriptive information:

a) The intended use of the Diagnostics kits. This may include:

1) what is detected
2) its function (for example screening, monitoring, diagnostic or aid to diagnosis, staging or aid to staging of disease);
3) the specific disorder, condition or risk factor of interest that it is
intended to detect, define or differentiate;
4) whether it is automated or not;
5) whether it is qualitative or quantitative;
6) the type of specimen(s) required (eg. serum, plasma, whole blood, tissue biopsy, urine);
7) testing population;

b) the intended user (lay person or professional);
c) a general description of the principle of the assay method
d) the Class of the device and the applicable classification rule according to any one of the countries Viz. USA, Canada, Japan, Australia and European
e) a description of the components (e.g. reagents, assay controls and calibrators) and where appropriate, a description of the reactive ingredients of relevant components (such as antibodies, antigens, nucleic acid primers) and where applicable:
f) a description of the specimen collection and transport materials provided with the Diagnostics kits or descriptions of specifications recommended for use;
g) for instruments of automated assays : a description of the appropriate assay characteristics or dedicated assays;
h) for automated assays: a description of the appropriate instrumentation characteristics or dedicated instrumentation;
i) a description of any software to be used with the Diagnostics kits;
j) a description or complete list of the various configurations/variants of the Diagnostics kits that will be made available;
k) a description of the accessories, other Diagnostics kits and other products that are not Diagnostics kits, which are intended to be used in combination with the Diagnostics kits.

Essential Principles (EP) Checklist

The Device master file should include an EP checklist that identifies:

a) the Essential Principles of Safety and Performance;
b) whether each Essential Principle applies to the IVD medical device and if not, why not;
c) the method used to demonstrate conformity with each Essential Principle that applies; and
d) the reference to the actual technical documentation that offers evidence of conformity with each method used.

The method used to demonstrate conformity may include one or more of the
following:

a) conformity with recognized or other standards;
b) conformity with a commonly accepted industry test method (reference method);
c) conformity with appropriate in-house test methods that have been validated and verified;
d) comparison to an IVD medical device already available on the market.

The EP checklist should include a cross-reference to the location of such evidence both within the full technical documentation held by the manufacturer and within the Device master file (when such documentation is
specifically required for inclusion in the Summary Technical Documentation as outlined in this guidance).

Risk Analysis and Control Summary

a) The Device master file should contain a summary of the risks identified during the risk analysis process and a description of how these risks have been controlled to an acceptable level. Preferably, this risk analysis should be based on recognised standards and be part of the manufacturer‟s risk management plan.
b) The summary should address possible hazards for the IVD medical device such as the risk from false positive or false negative results, indirect risks which may result from IVD medical device-associated hazards, such as instability, which could lead to erroneous results, or from user-related hazards, such as reagents containing infectious agents.
c) The results of the risk analysis should provide a conclusion with evidence that remaining risks are acceptable when compared to the benefits.

Device Design

The Device master file should contain information to allow a reviewer to obtain a general understanding of the design applied to the IVD medical device. It should include a description of the critical ingredients of an assay such as antibodies, antigens, enzymes and nucleic acid primers provided or recommended for use with the IVD medical device. This section is not intended to take the place of the more detailed information required for a QMS audit or other conformity assessment activity. If design takes place at multiple sites, a controlling site must be identified.

Manufacturing Processes

The Device master file should contain information to allow a reviewer to obtain a general understanding of the manufacturing processes. It is not intended to take the place of the more detailed information required for a
QMS audit or other conformity assessment activity. The information may take the form of a process flow chart showing, for example, an overview of production including the technologies used, assembly, any in-process and final product testing, and packaging of the finished IVD medical device.

Manufacturing Sites

The Device master file should identify the sites where these activities are performed (this does not include the sites of all suppliers of raw materials but only the sites that are involved in critical manufacturing activities). If QMS certificates, or the equivalent, exist for these sites, they may be annexed to the Device master file.

Product Validation and Verification

The information provided in the product validation and verification section of the Device master file will vary in the level of detail as determined by the class of the device. As a general rule, the Device master file should summarise the results of validation and verification studies undertaken to demonstrate conformity of the IVD medical device with the Essential Principles that apply to it. Where appropriate, such information might come from literature.

For the purpose of the Device master file document, summary and detailed information are defined as:

1. Summary Information: A summary should provide enough to assess the validity of that information
by the Regulatory authorities. This summary should contain a brief description of:

a) the study protocol,
b) the study results,
c) the study conclusion.

This summary may include:

a) Where a recognized standard exists, a declaration/certificate of conformity to a recognized standard can be provided with a summary of the data if no acceptance criteria are specified in the standard;
b) In the absence of a recognized standard, a declaration/certificate of conformity to a published standard that has not been recognized might be provided if it is supported by a rationale for its use, and summary of the data, and a conclusion, if no acceptance criteria are specified in the standard;
c) In the absence of a recognized standard and non-recognized published standards, a professional guideline, industry method, or in-house standard may be referred to in the summarized information. However, it should be supported by a rationale for its use, a description of the method used, a summary of the data in
sufficient detail and a conclusion to allow assessment of its adequacy;
d) A review of relevant published literature regarding the device/analyte (measurand) or substantially similar IVD medical devices.

2. Detailed Information

Detailed information should include:

a) the complete study protocol,
b) the method of data analysis,
c) the complete study report,
d) the study conclusion.

For detailed information, when a recognized standard exists that contains the protocol and the method of data analysis, this information can be substituted by a declaration/certificate of conformity to the recognized standard along with a summary of the data and conclusions.

Analytical Studies

The statements and descriptions in the following sections refer to all IVD medical devices. It must be noted however that there are applicability differences between instrumentation and reagent-based assays, and that
the assays themselves may be quantitative, semi-quantitative or qualitative in nature. There may be limited applicability of some of the following subsections for qualitative or semi-quantitative assays. Where possible, comments regarding instrumentation or qualitative assays appear in the subsections.

Specimen type

This section should describe the different specimen types that can be used. This should include their stability and storage conditions. Stability includes storage and where applicable transport conditions. Storage includes
elements such as duration, temperature limits and freeze/thaw cycles. This section should include summary information for each matrix and anticoagulant when applicable, including a description of the measurement
procedure for comparison or determination of measurement accuracy. This includes information such as specimen type tested, number of samples, sample range (using spiked samples as appropriate) or target concentrations tested, calculations and statistical methods, results and conclusions.

Accuracy of measurement

This section should describe both trueness and precision studies. While measurement trueness, affected by systematic error, is normally expressed in terms of bias, measurement precision, affected by random
error, is naturally expressed in terms of standard deviation. Accuracy is affected by a combination of systematic and random effects that contribute as individual components of the total error of measurement.

Reproducibility

This section should include reproducibility estimates and information about the studies used to estimate, as appropriate, variability between days, runs, sites, lots, operators and instruments. Such variability is also known as “Intermediate Precision”. Reproducibility data is obtained for instrumentation in conjunction with an appropriate assay.

Such studies should include the use of samples that represent the full range of expected analyte (measurand) that can be measured by the test as claimed by the manufacturer.

If a recognized standard is used, a declaration/certificate of conformity to the recognized standard along with a summary of the data and conclusions.

Analytical sensitivity

This section should include information about the study design and results. It should provide a description of specimen type and preparation including matrix, analyte (measurand) levels, and how levels were established. The number of replicates tested at each concentration should also be provided as well as a description of the calculation used to determine assay sensitivity.
For example:
a) Number of standard deviations above the mean value of the sample without analyte (measurand), commonly referred to as limit of blank (LoB).
b) Lowest concentration distinguishable from zero, based on measurements of samples containing analyte (measurand), commonly referred to as limit of detection (LoD).
c) Lowest concentration at which precision and/or trueness are within specified criteria, commonly referred to as limit of quantitation (LoQ).
Typically for a Class C and D IVD medical devices, detailed information would be provided.

Analytical specificity

This section should describe interference and cross reactivity studies to determine the analytical specificity, defined as the ability of a measurement procedure to detect or measure only the analyte (measurand) to be detected, in the presence of other substances/agents in the sample. Provide information on the evaluation of potentially interfering and cross reacting substances/agents on the assay. Information should be provided on
the substance/agent type and concentration tested, sample type, analyte (measurand) test concentration, and results. Interferents and cross reacting substances/agents, which vary greatly depending on the assay type and design, could derive from exogenous or endogenous sources such as:

a) substances used for patient treatment (e.g. therapeutic drugs, anticoagulants, etc.);
b) substances ingested by the patient (e.g. over the counter medications, alcohol, vitamins, foods, etc.);
c) substances added during sample preparation (e.g. preservatives, stabilizers);
d) substances encountered in specific specimens types (e.g. haemoglobin, lipids, bilirubin, proteins);
e) analytes of similar structure (e.g. precursors, metabolites) or medical conditions unrelated to the test condition including specimens negative for the assay but positive for a condition that may mimic the test
condition (e.g. for a hepatitis A assay: test specimens negative for hepatitis A virus, but positive for hepatitis B virus).

Typically, interference studies involve adding the potential interferent to the sample and determining any bias of the test parameter relative to the control sample to which no interferent has been added.

Metrological traceability of calibrator and control material values

Where applicable, summarize the information about metrological traceability of values assigned to calibrators and trueness control materials. Include, for example, methods and acceptance criteria for the metrological traceability to reference materials and/or reference measurement procedures and a description of value assignment and validation. Precision control materials, used when establishing the reproducibility of a
measurement procedure do not require the assessment of metrological traceability to a reference material or a reference method.

Measuring range of the assay

This section should include a summary of studies which define the measuring range (linear and non-linear measuring systems) including the limit of detection and describe information on how these were established.
This summary should include a description of specimen type, number of samples, number of replicates, and preparation including information on matrix, analyte (measurand) levels and how levels were established. If
applicable, add a description of high dose hook effect and the data supporting the mitigation (e.g. dilution) steps.

Definition of Assay Cut-off

This section should provide a summary of analytical data with a description of the study design including methods for determining the assay cut-off, including:

a) the population(s) studied (demographics / selection / inclusion and exclusion criteria / number of individuals included);
b) method or mode of characterization of specimens; and
c) statistical methods e.g. Receiver Operator Characteristic (ROC) to generate results and if applicable, define gray-zone/equivocal zone.

Stability (excluding specimen stability)

This section should describe claimed shelf life, in use stability and shipping studies

Claimed Shelf life

This section should provide information on stability testing studies to support the claimed shelf life. Testing should be performed on at least three different lots manufactured under conditions that are essentially equivalent to routine production conditions (these lots do not need to be consecutive lots). Accelerated studies or extrapolated data from real time data are acceptable for initial shelf life claim but need to be followed up with real time stability studies. Such detailed information should describe:

a) the study report (including the protocol, number of lots, acceptance criteria and testing intervals)
b) when accelerated studies have been performed in anticipation of the real time studies, the method used for accelerated studies
c) conclusions and claimed shelf life

Shelf life can be derived from the lot with the longest real time stability data as long as accelerated or extrapolated data from all three lots are comparable.

In use stability

This section should provide information on in use stability studies for one lot reflecting actual routine use of the device (real or simulated). This may include open vial stability and/or, for automated instruments, on board stability.

In the case of automated instrumentation if calibration stability is claimed, supporting data should be included.
Such detailed information should describe:

a) the study report (including the protocol, acceptance criteria and
testing intervals)
b) conclusions and claimed in use stability

Shipping stability

This section should provide information on shipping stability studies for one lot to evaluate the tolerance of products to the anticipated shipping conditions. Shipping studies can be done under real and/or simulated conditions and should include variable shipping conditions such as extreme heat and/or cold.
Such information should describe:

a) the study report (including the protocol, acceptance criteria)
b) method used for simulated conditions
c) conclusion and recommended shipping conditions

Clinical Evidence

The Device master file should contain the Clinical Evidence Evaluation report that demonstrates conformity of the IVD medical device to the Essential Principles that apply to it.

Labelling

The Device master file should typically contain a complete set of labeling associated with the IVD medical device as described in Rule 96 of Drugs and Cosmetics Rules on labelling should include the following:

a) Labels on the IVD medical device (immediate and outer container)
b) Instructions for use
c) The label should bear name of the product, batch/Lot number, date of expiry or use before date, storage
conditions, name and address of the actual and Legal manufacturer(if any), and Name and address of Importer, Import license number, etc.

Post Marketing Surveillance Data (Vigilance Reporting)

The dossier should contain the Post Marketing Surveillance/ Vigilance Reporting procedures and Data collected by the manufacturer encompassing the details of the complaints received and corrective and Preventive actions taken for the same

1. All the test reports submitted as a part of the dossier should be signed and dated by the responsible person.
2. Batch Release Certificates and Certificate of Analysis of finished product for minimum 3 batches should be submitted.
3. All certificates submitted must be with in the validity period.
4. Any information which is not relevant for the subject kits may be stated as „Not Applicable‟ in the relevant Sections/Columns of the above format, and reasons for non-applicability should be provided.
5. The above information should be submitted in bounded form (like spiral binding or hard binding).

Source:

https://www.fda.gov/medical-devices/premarket-approval-pma/master-files

https://elsmar.com/pdf_files/Device%20Master%20Records.doc

pathwise.com/wp-content/uploads/White-Paper-Device-Master-Records-and-Medical-Device-Files-How-Do-They-Compare.pdf

https://cdsco.gov.in/opencms/export/sites/CDSCO_WEB/Pdf-documents/IVD/Checklist/Revised-pre-screening-Checklist_MD_IVD2.pdf

https://www.fdanews.com/ext/resources/files/01/01-14-IndiaIVDreg.pdf

https://morulaa.com/medical-device-registration-in-india/things-to-remember-while-preparing-your-regulatory-dossier/

https://cdsco.gov.in/opencms/export/sites/CDSCO_WEB/Pdf-documents/medical-device/Essentialprinciples.pdf