11

LABELING
displayed in proximity to the article or shipped to the user before or after shipment of the device. The distinction between labeling and advertising, while both draw attention to the article to be sold, is often nebulous or superficial. Both are forms of publicity and are used for an identical purpose. An appellate court described the relationship between the two as follows: Most, if not all, labeling is advertising. The term labeling is defined in the Act [section 201(m)] as including all printed matter accompanying any article. Congress did not, and we cannot, exclude from this definition printed matter which constitutes advertising. Section 502(f)(1) and (2) of the FD&C Act requires that device labeling bear adequate directions for use, operating and servicing instructions, and either adequate warnings against uses dangerous to health, or information necessary for the protection of users. All devices require directions for use unless specifically exempted by regulation. Conditions for exemption from this requirement are in 21 CFR 801, Subpart D. Misbranding Section 502 of the FD&C Act contains the misbranding provisions for drugs and devices. It states a device is misbranded under a number of different circumstances, including: Its labeling is false or misleading. Its packaging does not bear a label containing the name and place of business of the manufacturer, packer, or distributor, and an accurate statement of the quantity of contents. Words, statements, or other required information are not prominent on the labeling or are not stated clearly. It is intended for human use, and the label fails to bear the name and quantity or proportion of any narcotic or habit-forming substance contained in the product, and fails to display the statement, Warning: may be habit forming.

LABELING REGULATIONS Medical devices in commercial distribution in the U.S. shall be properly labeled according to laws and regulations enforced by the Food and Drug Administration (FDA). Specific labeling requirements for medical devices are contained in: The Federal Food, Drug, and Cosmetic (FD&C) Act; The Fair Packaging and Labeling Act; The Radiation Control for Health and Safety Act; Title 21 of the U.S. Code of Federal Regulations, Part 801 for general devices, and Part 809 for in vitro diagnostic products; Title 21 of the U.S. Code of Federal Regulations, Part 812.5 for investigational devices; Title 21 of the U.S. Code of Federal Regulations, Part 820 for design and manufacturing controls for labeling; and Title 21 of the U.S. Code of Federal Regulations, Part 1010 - Performance standards for electronic products. Also see Parts 1020 and 1040.

Section 201(k) of the FD&C Act defines the term label as a display of written, printed, or graphic matter upon the immediate container of any article . . . . Under Section 201(l) of the FD and C Act, the term immediate container does not include a package liner. Any word, statement, or other information appearing on the immediate container should also appear on the outside container or wrapper, if any, of the retail package or be easily legible through the outside container or wrapper. The label is not required to appear on the shipping carton. Section 201(m) of the FD&C Act defines the term labeling as all labels and other written, printed, or graphic matter: (1) on the device or any of its containers or wrappers, or (2) accompanying the device. The term applies any time while the article is in interstate commerce, or being held for sale after shipment or delivery in interstate commerce. The term accompanied is interpreted liberally. It extends to posters, tags, pamphlets, circulars, booklets, direction sheets, fillers, etc., that may be Section Eleven; Page 1 of 21

Its label does not contain adequate directions for use. These include warnings against use in certain pathological conditions; against use by children where its use may be dangerous to health; and against unsafe dosage, methods, duration of administration or application unless exempt as unnecessary to protect the public health. It is dangerous to health when used in the dosage or manner, or with the frequency or duration prescribed, recommended, or suggested in the labeling. It does not comply with the color additive provisions listed under Section 706 of the FD&C Act.

and indirection. It might be caused by failure to inform the consumer of facts that are relevant to those statements actually made. In other words, the label that remains silent as to certain consequences may be as deceptive as the label that contains extravagant claims. Examples of misleading labeling include: ambiguity; half-truths; trade puffery; expressions of opinion or subjective statements; and failure to reveal material facts, consequences that may result from use, or the existence of difference of opinion. In the past, labeling found by the agency to be objectionable has featured such practices as: deceptive pictorial matter; misleading testimonials; misleading lists of parts or components; and brand or trade names instead of established names (see Sections 201(h), 502(e)(2), and 508 of the FD&C Act). Examples of false representations are: incorrect, inadequate or incomplete identification; unsubstantiated claims of therapeutic value; inaccuracies concerning condition, state, treatment, size, shape, or style; substitution of parts or material; subjective or unsubstantiated quality or performance claims; and, use of the prefix U.S. or other similar indication suggesting government or agency approval or endorsement of the product.

The Medical Device Amendments expanded the authority of the FD&C Act over misbranded medical devices. These amendments contain further circumstances under which a device is misbranded: The devices established name (if it has one), name in an official compendium, or including common or usual name, is not printed prominently in type at least half as large as used for any proprietary name. The device is subject to a performance standard and it does not bear the labeling requirements prescribed in that standard. There is a failure or refusal to comply with any requirement prescribed under Section 518 on notification and other remedies; failure to furnish material or information requested by or under Section 518; or failure to furnish any materials or information requested by or under Section 519 on records and reports. The device is commercially distributed without FDA concurrence on a 510(k) premarket notification submission.

Adequate Directions for Use Title 21, CFR Part 801.5, defines adequate directions for use as directions under which the layman can use a device safely and for the purpose for which it is intended. See Part 801.4 for a definition of intended use. Among other reasons, directions for use may be inadequate because there is partial or total omission or incorrect specification of one or more of the following items: Statement of all conditions, purposes, or uses for which the device is intended. This includes conditions, purposes, or uses for which it is prescribed, recommended, or suggested in its oral, written, printed, or graphic advertising. This statement also includes conditions, purposes, or uses for which the

False or Misleading Labeling Section 502(a) states that a drug or device is misbranded if its labeling proves false or misleading in any particular. It is not a necessary condition that the labeling should be flatly and blatantly false for the FDA to take action. The word misleading in the FD&C Act means that labeling is deceptive if it creates or leads to a false impression in the mind of a reader. A false impression may result not only from a false or deceptive statement, but may be instilled in the mind of the purchaser by ambiguity Section Eleven; Page 2 of 21

drug or device is commonly used. These statements should not refer to conditions, uses, or purposes for which the drug or device can be used safely only under the supervision of a practitioner licensed by law; those conditions, uses, and purposes may only be referred to in advertisements directed to a licensed practitioner. Quantity of dose including usual quantities for each intended use and usual quantities for persons of different ages and physical conditions. Frequency of administration or application. Duration of administration or application. Time of administration or application in relation to meals, onset of symptoms, or other time factors. Preparation for use, adjustment of temperature, or other manipulation or process.

in which he or she practices to use or order the use of the device; and the method for its application or use.

Labeling on or within the package from which the device is to be dispensed shall also bear information for use under which practitioners licensed by law to administer the device can use the device safely and for the purposes for which it is advertised or represented. This labeling information includes indications, effects, dosages, routes, methods, frequency, and duration. Safety labeling includes relevant information on hazards, contraindications, side effects, and precautions. When a device is capable of producing serious injury, even when used by a person thoroughly familiar with its operation, the directions for use shall provide detailed information. FDA has specific regulations on the labeling of intrauterine contraceptive devices, 21 CFR 801.427, and for diagnostic x-ray devices, 21 CFR 1020.30(h). In addition, FDA has issued general guidances for labeling certain devices, i.e., transcutaneous electrical nerve stimulators and electronic muscle simulators. Where appropriate, directions for use should be supplemented with adequate warnings against the use of the drug or device under certain conditions. Any caution statement, similar to the direction statement, may appear in the labeling of the product; it is not necessary that it be printed on the label. In each instance, the responsibility for the adequacy of the warning statement appearing on the labeling rests with the manufacturer or distributor. For some devices, there are national consensus standards that specify that certain caution statements be on the device. There is no list of prescription devices in the CFR. Sterile Devices Special attention should be given to the labeling of sterile devices. For example, sterility may be needed only for a portion of certain devices and this condition should clearly be identified in the labeling. Devices that are not sterile in their entirety should be labeled to properly inform users what is actually intended to be sterile in the package. For example, a possible limiting statement might be:

Prescription Devices Labeling exemptions for prescription devices are in 21 CFR Part 801.109. These are devices which because of a potential for harmful effect, potential for misuse, or the collateral measures necessary to use, are not safe except under the supervision of a practitioner licensed by law. Hence adequate directions for use cannot be prepared for these devices. They are exempt from Section 502(f)(1) of the FD&C Act provided that all conditions specified in the labeling regulation are met. These conditions state that the device shall be in the possession of a person, or his or her agents, or employees regularly and lawfully engaged in the manufacture, transportation, storage, or wholesale distribution of prescription devices; or in the possession of a practitioner such as a physician, dentist, or veterinarian licensed by law to use or order the use of these devices. These devices can be sold only to, on the prescription of, or by order of such practitioner for use in the course of their professional practice. The label of the prescription device, other than surgical instruments, is required to bear: the statement Caution: Federal law restricts this device to sale by or on the order of a _____, the blank to be filled with the word physician, dentist, veterinarian, or with the descriptive designation of any other practitioner licensed by the law of the State

Section Eleven; Page 3 of 21

Caution: Only the fluid path of this set is sterile and nonpyrogenic. Do not use in a sterile or aseptic area without proper precautions. The label of multi-device kits or packages containing a combination of sterile and nonsterile products will be considered to be false or misleading if it implies that all contents are sterile. Some devices are intended to be sterilized by the user before use. In this situation, the labeling should provide adequate information about a suitable method of sterilization and any precautions or safeguards to be followed. For example, the labeling should describe any: special cleaning methods required; changes in the physical characteristics of the device that may result from reprocessing which affect its safety, effectiveness, or performance; and limit on the number of times resterilization and reuse can be done without affecting the safety or effectiveness of the device.

Shelf life dating solely for package integrity and sterility is not usually required for general medical devices. There may be a need for expiration dating when a particular component of a device, such as a battery or diagnostic reagent, has a finite useful life. Labeling for in vitro diagnostic devices [809.10 (a) and (b)] requires an expiration date or some other means by which users may be assured of quality at the time of use. This requirement applies to both sterile and nonsterile in vitro diagnostic devices. Although not required by regulation, most manufacturers of complex devices and sterile devices voluntarily use lot or serial numbers for production control and, if the need arises, to expedite failure investigations, repairs, modifications, or recalls. Lot, batch, or other control numbers are required for: implantable and life sustaining devices [820.65, Traceability]; some products subject to radiological health standards [1002.30(b)(1), Records to be maintained by manufacturers]; and in vitro diagnostic devices [809.10(a)(9), Labeling for in vitro diagnostic products].

In the case of single-use sterile devices, many manufacturers include labeling to advise against resterilization and reuse. Some devices are not designed or constructed to be recleaned, and may not be capable of withstanding the necessary recleaning and resterilization procedures. Where reuse is common practice, manufacturers are encouraged to provide the information described in the above list. The need for users to have instructions on how to open a sterile device package to avoid contamination of the device also needs to be evaluated. When necessary, such instructions should be included in the labeling. If a manufacturer modifies a device, the manufacturer should also review the labeling to ensure that it reflects current revisions and specifications. Thus, change control forms should contain a check off box for labeling and packaging. Some manufacturers identify labeling with a drawing number plus a revision code or date as an aid in identifying current labeling. The package insert or other labeling for in vitro diagnostic products is required to contain the revision date [21 CFR 809.10(b)(15)].

DESIGN OF LABELING Various sections of the Quality System (QS) regulation have an impact on labeling including: section 820.30, Design controls; section 820.80, Receiving, in-process, and finished device acceptance; and section 820.70(f), Production and Process controls, which requires buildings to be of suitable design and have sufficient space for packaging and labeling operations. Section 820.120 deals with specific requirements for device labeling. These sections apply controls to the labeling content to meet the needs of the user and patient, as well as to meet the labeling specifications contained in the device master record. Applying the regulations to the physical design applications of labeling assures legibility under normal conditions of use over the expected life of the device. It also helps assure the proper inspection, handling, storage, and distribution of labeling. The requirements in 820.30(c), Design input, address the intended use of the device, and the needs of the user and patient.

Section Eleven; Page 4 of 21

Labeling includes equipment labels, control labels, package labels, directions for use, maintenance manuals, etc. The displays on CRTs and other electronic message panels are considered labeling if instructions, prompts, cautions, or parameter identification information are given. Adequate labeling for a medical device requires proper design and procurement of the labels and labeling. Design includes generating the content of labels and labeling and making sure the content meets FDA requirements as well as the needs of the customer. To achieve these goals a number of concepts must be kept in mind such as: writing to the reader, referring to the actual device in labeling, obvious identification of the controls used, etc. Design controls for label integrity are discussed later. There are some basic guidances, rules, and practices that can be used to immediately improve writing. The following paragraphs will discuss them, with emphasis on how they can be used to make labeling clear and comprehensible. As an essential aid, writers are encouraged to obtain a copy of 40,000 Words published by Websters New World Dictionary or a similarly titled book by any of the reference-book publishing companies. Most of these reference books have about four pages of punctuation rules. Using these pages of rules can immediately improve not only the style and clarity but also the accuracy of your writing. Writers are also encouraged to obtain and use a standard college-level text on technical writing. Write to the Reader The most serious problem is that writers tend to write to themselves. Their material is clear to them so they mistakenly think it is as clear to others. For example, the sensitivity control on an instrument is called gain control on page one of the instruction manual, amplitude control on page two, and level control in the next section. Further, the photograph in the introduction shows the same

control with a call-out identification note labeled Signal Adjust. No wonder readers get confused! Yet the author of the example knew what he was trying to write about and, most certainly, he was writing to himself. When writing labeling, especially for an over-thecounter (OTC) device, the author must know the reading level of the target audience. If data on reading levels is not available, this may necessitate reader interviews to establish a reading level for the target audience. If the device is designed for home use, a useful guide is Write It Right available through DSMA. Refer to Actual Device One simple way to reduce control identity confusion as described above, reduce other types of labeling errors, and increase clarity is for authors to keep a labeled instrument, kit, or photograph(s) nearby and refer to it as they write. It is easier to write the truth when you know the truth. Make sure the terminology and descriptions in the labeling match that on the actual device. It is best to always use the same title for each given item or control throughout the manual, insert, label, and advertisement. Likewise, the same title should be used in charts, figures, or screen displays such as cathode-ray tubes, LCD panels, etc. Remember to write to your intended readers, write with a labeled device or photographs in sight, and use consistent titles. Obvious Identification of Controls Because the title of controls or other items in screen displays and other labeling should be exactly the same as in the labels on equipment, reagents, accessories, etc., authors may need to develop and use an appropriate correlation technique for corresponding titles in instruction manuals, package inserts, etc. One common and simple technique is to use all capitals for the titles of controls in labeling. For example:

OFF =

ON

+----+ +----+

+---+ +---+

Section Eleven; Page 5 of 21

POWER SWITCH

PRESS FOR HEAT

READY LAMP

Section Eleven; Page 6 of 21

The associated text, for example, might state: Flip the POWER SWITCH to ON. In about three seconds, the READY LAMP will illuminate. Now press the HEAT button to switch the heater on. With this correlation technique, the words on and off are capitalized in the labeling only when they actually appear on the instrument control panel. Note that ON is capitalized in POWER switch to ON as the actual switch has POWER, ON, and OFF printed by it. In contrast, note that on is not capitalized in the statement to switch the heater on as it is not a label of a control on the device. Also, be careful to use a simple correlation system that is readily apparent to the intended audience. Dont Distract Reader Readers are very busy trying to learn how to use a new device. They should not be annoyed by any unnecessary distractions such as: changes in format, unusual typeface, incorrect page numbers, and incorrect figure numbers.

changed, titles are more noticeable by writers and typists than are page numbers. The use of correct figure numbers is easy just check them. Short and to the Point It is important to use sentence structure that will convey the intended message with a minimum of misinterpretation or need to reread. Tests have been conducted to determine the ability of readers to follow instructions in a sentence based on the number of activities to be performed. The average persons ability to follow instructions decreases rapidly when a sentence contains more than two facts. (Keep in mind your own experiences in reading instructions.) Therefore, sentences in labeling need to be short and to the point. Avoid long strings of adjectives and be specific. Try to be as specific as possible with your instructions. For example, ambient or room temperature generally should not be used. Instead specify the desired or necessary range of operating conditions. In many cases a list of activities to be performed is better than burying the facts in long sentences. A numbered list is better if the user may have to repeat any part of the procedure. If it takes lots of words to get to the point, the reader will probably miss the point! Short, choppy sentences are acceptable in instruction manuals and other labeling. You are not trying to entertain readers with beautiful, flowing prose rather, you want to catch their attention with key facts so they correctly perform the specified instructions. Thus, use short sentences, get to the point, be specific, and keep graphics and pictures near the corresponding text. Gobbledygook Another way to be more specific and shorten sentences is to avoid gobbledygook. The following terms were collected from actual instruction manuals: ORIGINAL PREFERRED EQUIVALENT When And Perform Reaches May Ensure

For a person trying to read in a hurry, a font such as script can be a major distraction; therefore, it is best not to use script, italics, or any other unusual or hard-to-read typefaces. Remember, you have decided to write for the benefit of the intended audience. Forget about your personal preferences and use only the most common fonts. Also, select a type size that is readable at the intended distance. For example, labeling displayed on the screen of a wall-mounted heart monitor should be readable from several feet away. Also, use a consistent format throughout the document. Check the format and section titles against information on the content page. In some cases, such as for in vitro diagnostic products, the arrangement of information in the labeling may be dictated by a regulation. Page numbers should not be referenced in instruction or service manuals. It is too easy for the actual page numbers to be changed during the original writing or when the manual is updated. It is much better to refer to paragraph titles or numbers as these are less likely to change; and, if Section Eleven; Page 7 of 21

At the time of In conjunction with Carried out in Comes up to Will also serve as a chance to Will be sure that will

Care should be used so as not to Causes power to be applied to Due to the fact that Take the form of

Be careful Switches power to Because Be

caution statements. When standard terminology exists in a consensus standard, creating new caution statements is not advisable. Confusion is less likely to occur when one stays with the commonly understood terminology. Select Words Wisely When large print is needed for reading at a distance or to attract attention to signs, caution labels, and screen prompts, words generally should be short in order to fit the available space. This rule also applies to the wording on control labels. This situation places a burden on the writer to select terms that convey the desired message. Consider the following wording from two actual highway signs: PLANT TRAFFIC ENTERING HIGHWAY NO FISHING OFF BRIDGE

In most cases, the equivalent term in the list can replace the original term. Of the terms listed, the combination most often used is makes provision for. Simply eliminating makes provision for and be provided for from labeling will result in an immediate improvement for readers. Introduce Each Item Always introduce each control, indicator, device, or subject before it is discussed in the text. The introductions should be brief and may be very brief. Keep in mind the items will be described in more detail later. Abbreviations and new or uncommon terms should be defined. The introductions and definitions prevent readers from going into mental shock, breaking their train of thought, and asking: What is this? By then readers have probably forgotten the last two or three facts read. Also, readers may wonder about any cliff-hanging item when they resume reading. This disturbance may detract readers from fully assimilating the next instructions being read. To avoid distractions and confusion, a writer of labeling should always: introduce each item, and define new or uncommon terms.

Have you ever been run over by a pachysandra? If you cant fish off the bridge, does that mean you are allowed to fish only on or from the bridge? Better choices for the intended messages are: Traffic entering highway and No fishing from bridge. Test Labeling Finally, always have someone not familiar with the product operate it exactly according to the draft instructions, labels, screen displays, etc. You should not do any coaching because coaching destroys the validity of the trial. By coaching you transfer your memory to the user. Therefore, no coaching this is the acid test good luck! During the trials, note any significant problems and make appropriate corrections to the instructions, prompts, or other labeling. Label Integrity

With respect to definitions, a writer should never give a new meaning to an existing common term in the language. To avoid this disservice, coin a special term or code number such as Class Q, Code 1, or Level 2. Accentuate Key Terms Whenever it is stated in instructions that something shall be done, then shall should be set in bold type, or otherwise delineated. Likewise, boxing, bold type, etc should emphasize caution and warning statements. Underlining should not be used as it makes the descending part of a letter hard to read and appears to be top lining on some printers. Refer to any regulations or standards for a specific product and use the recommended or required Section Eleven; Page 8 of 21

All labels shall be designed and applied to devices and containers so that the labels will remain in place and legible during the customary conditions of distribution, storage, and use [820.120(a)]. Likewise, other labeling such as user instructions should remain legible during customary storage and use. For example, labeling printed by machines onto plastic in vitro diagnostic media plates is often smeared and thus is inadequate [FD&C 502(f)]. The

manufacturers of such devices should assure that the print is legible and will remain legible until used. Many magazines use wet ink that smears when touched by sweaty or oily fingers. Obviously, this type of ink will not meet the design requirements for package inserts, instruction manuals, and the like. Labels may be mounted by adhesives, screws, rivets, drive screws, etc., or printed or etched onto panels and/or onto controls. The labels should be located so that they will be seen but not be abraded during use. (Many of us have seen the unbelievable cases where safety labels on ladders and riding lawnmowers were placed in the foot rest areas. Of course, they were worn off after a few uses!) Approval Policy and Procedure The review of labeling from the design stage through to the finished device should be documented like the review of other significant components. This includes the labeling development, any changes, and final approval. Documentation should be included in the design history file of the procedures used, signature of the responsible person, and date. Because several activities are performed and controlled during the development and use of labeling, Table 11.1, Drafting and Approval of Labeling and Final Approval of Labeling, Advertising, Etc. are presented as guidances. This table contains a typical sequence of events required to develop and control labeling. Other controls are discussed below. Before release for use, labeling should be reviewed and approved by product development, service, marketing, quality assurance, and other appropriate managers (820.30). Manufacturers need to have a policy/procedure that covers the drafting, review, and approval of labeling. Approval forms are generally used in conjunction with such a policy/procedure. A sample approval form and procedure are presented at the end of this chapter. Other procedures

and forms such as Change Control are referenced in this procedure. Note that this procedure also covers other elements such as a correct device master record, correct transfer of labels into production, lot control, change control, etc. Samples of various procedures appear at the end of chapters throughout this manual. Design Transfer Specifications are required in the device master record for the content and physical design parameters of labels. (see Chapter 8). Labeling specifications include the engineering drawing and/or artwork for each label, appropriate inspection or control procedures, and appropriate procedures for attaching the labels. All procedures, drawings and artwork should have the name of the preparer, an approval signature, and a date. The approval signature, date, etc., may be on the backside of artwork or on a label approval form. Further, artwork may contain only an identification code or title if the content of the artwork is duplicated on approved engineering drawings, adequately identified, or cross-referenced with respect to the label approval form. That is, a manufacturer should be able to identify isolated artwork. Hardcopy labels, package inserts, and similar labeling are also specified and purchased as components (see Chapter 8). For correct purchase and use of labeling, specifications are usually stated on engineering drawings and/or purchase specifications. Thus, artwork or copy alone will not fulfill the device master record and purchasing control requirements for labeling except for the most simplistic labeling such as brief errata sheets. The engineering drawings or purchase specifications should specify, as appropriate, the label substrate, dimensions, ink, finish, mounting method, etc., so that the purchased label will remain attached and legible during the customary conditions of processing, storage, handling, distribution, and use.

Section Eleven; Page 9 of 21

PHASE 1. Design

SECTION 820.30, 820.120 & 820.130

CONTROL ACTIVITY Meets needs of user and intended use. Text review. Quality of mounting such as rivets, adhesives, etc. Quality of ink, anodize, etc. Content per 21 CFR 801 and 809 company claims and standards. Simulated or actual processing such as sterilization, shipping tests, label affixing, etc. Saline, alcohol, and coffee spill tests? Establish and maintain approval procedures. Approve, date and change control label drawings. A key label shall contain the control number of the finished device either on or accompanying device. Proofread before release to inventory stock. Record signature of proofreader and date. Store labels to prevent mix-ups. Restrict access to authorized persons. Separate multiple operations to prevent mix-ups. Before beginning labeling operations, designee to inspect area and remove extraneous devices and labels. Examine for identity and, where appropriate, expiration date and control number. Record date and person examining labels. Copy of primary identification label shall be in the device history record. Inspect finished device per written procedure. Designee shall check all acceptance records and test results and see that requirements are met and records are present and complete.

2. Verification/ Validation 3. Changes 4. Documentation 5. Procurement 6. Storage 7. Separate operations 8. Area inspection 9. Issuance

820.120, 820.75 & 820.30 820.30 & 820.75 820.30, 820.181 & 820.120(e) 820.120(b) 820.180 820.120(c) & (d) 820.120(d) 820.120(d) 820.120(b), 820.120(e) & 820.65 820.184(e) 820.80(d), 820.86 & 820.80(e)

10. File Sample 11. Inspection

Front panels, other instrument panels, meters, fuses, pushbuttons, and the like often are either labels or contain labels and thus should, as appropriate, meet device master record and control requirements. Component specifications, assembly drawings, and test/inspection procedures are appropriate controls to prevent mix-up of meters, push buttons, and other labeled instrument controls. Whether a manufacturer considers a software driven display to be labeling or data makes little difference under the QS regulation because, either way, the finished device labeling or data should meet the device master record specifications. When manufacturers develop and validate software, they should also review any electronic displays to see that the labeling meets all applicable requirements, such as adherence to specifications in the device master record, correct parameter identification, agreement with the

instruction manual, and, of course, correct display of performance data. Production Controls When reviewing or auditing labeling operations, it is wise to keep in mind that the GMP requirements are flexible. The degree of labeling control needed to satisfy the QS regulation varies considerably for different devices and operations. In order to avoid wasting money and increasing the cost of health care, manufacturers need to give considerable and prudent thought to the appropriate level of control needed for their operations as allowed by 820.5. Information and guidances presented in this manual should aid manufacturers in making these decisions. The level of control needed should be reconsidered when products are changed. Likewise, the controls needed, and the success of

Section Eleven; Page 10 of 21

the existing control program, should be reviewed during quality system audits (see Chapter 17). Medical device manufacturers should incorporate in their quality system several elements that relate to labeling in order to meet the GMP requirements. The quality system should be adequate to assure that labeling reflects user needs, meets the device master record requirements with respect to legibility, adhesion, etc., and assure that labeling operations are controlled so that the correct labeling is always issued and used. Receipt and Inspection Upon receipt, all packaging and labeling materials, including preprinted containers, inserts, and preprinted packaging materials, should be examined and, if deemed necessary by the company, tested to assure conformance with specifications as discussed in Chapter 10, Purchasing and Acceptance Activities. Also, samples of labels, including labeled panels, meters, etc., shall be proofread by a designated individual(s). After being accepted by a responsible individual, these components may be placed into inventory or into production. These inspections shall be recorded in the device history record as required by 820.80(e) and 820.120(b) to show that inspection and proofreading were performed. The inspection record for device labeling should be kept simple. Area Separation and Inspection All labeling and packaging operations should be separated to the degree necessary [820.120(d)] to assure there are no mixups between similar products or labels. Separation may be either a physical or spatial separation or by performing the labeling and packaging at different times for different devices. Separation is not required when mixups are impossible, such as the case of labeled front panels that only fit the intended family of devices. The likelihood of a labeling mix-up determines how stringent production area controls should be. For example, label control need not be stringent if only one product or dissimilar products and labeling that are unlikely to create confusion are processed. Before beginning any packaging and labeling operation in which mixups could occur, the production area and equipment for the operation should be Section Eleven; Page 11 of 21

thoroughly examined to ensure that any devices and labeling materials remaining from previous operations have been removed. It is important to make certain that the surrounding area, tables, packaging lines, printing machines, and other equipment are cleared of labels and other materials used in the previous operation. Unused labeling that contains pre-coded serial numbers, manufacturing dates, expiration dates, control numbers, etc., should be destroyed and not returned to the label storage area. The GMP requirements do not include reconciliation of the number of labels used with the number issued, although, this control is recommended for some devices, such as when different sizes of the same product are being packaged or otherwise labeled. STORAGE Where feasible, labels for similar devices should be designed with different shapes and colors to reduce the probability of mixups. Thereafter, all printed packaging and labeling materials, including preprinted containers, inserts, and preprinted packaging materials shall be stored in an area and manner suitable to prevent mixups [820.120(c)]. For example, if labels from one container are accidentally dropped, they should be stored so they will not fall into another container of similar labels. Labeling should be identified and segregated to the degree necessary to prevent mixing of similar labeling. Access to labeling should be limited to authorized personnel. Storage control should be appropriate for the number and kind of devices. For example a manufacturer that has only one product with one label does not need an elaborately controlled storage area. Similarly, a manufacturer with only a few types of devices having dissimilar labeling would not normally require stringent control. One case that requires dedicated attention to storage and control is prelabeled sterile but not-yet-sterilized devices. Manufacturers should make absolutely certain that mixups cannot occur. Also, they should make certain that all samples used for market promotion are sterile or labeled with a manifest caution statement, because a packaged and labeled market-promotion sample might be used by the recipient. One approach is to sell sterile samples at zero

cost so that such samples are subjected to all of the company product release and distribution controls. Quality awareness training is required by section 820.25. Marketing personnel should be informed of labeling control requirements and the consequences of a violation. Label Check and Record In summary labeling should be carefully examined to assure that the contents of the labeling comply with the labeling specifications in the device master record. This examination should include any control numbers or expiration dates used on the labels. A record of this check, including the date and name of the person performing the examination, should be made in the device history record. If expiration dates are used, they should reflect the time limitations within which the device is fit for its intended use when stored and used per its labeling. The manufacturer should have stability test data establishing how long the device will remain fit for use to support expiration dates. If label mixups cannot occur for example, a manufacturer makes only one device or uses only one label and there are no control numbers or expiration dates, the original inspection when the labeling was placed into inventory is an adequate check for compliance with the device master record specifications. A second check need not be performed because it serves no purpose (820.5). If, however, there is any possibility that incorrect labeling can be used, a second check should be made when the labeling is issued for application, packaging, or shipping. Control Numbers Devices intended for surgical implant, and devices intended to support or sustain life and whose failure to perform properly can be expected to result in significant injury, shall contain a control number, serial number, letters, etc., for traceability (820.65). Procedures for establishing and maintaining control numbers shall be documented in the DHR. This means a control number for the finished device, and not the label itself. Although this control number may be on a label, most labeling also contains another number, such as a drawing number, for control of labeling configuration and procurement. Section Eleven; Page 12 of 21

The control number for traceability need not be on every label on the device; however, the control number should appear on the primary label that goes to the ultimate user. The label on a shipping carton does not meet this requirement because bulk items may go to a central distribution point in the user-facility and the shipping carton will most likely be disregarded. Access Restriction Access to labeling should be restricted to authorized personnel. Labeling also should be stored in an adequately segregated area to minimize the chance of mixups. Segregation is recommended because it increases the control over the label storage area with no significant increase in cost. CHANGES Labeling is a component of the device and part of the device design output; therefore, all changes to labeling should be made under a formal change control system. Design changes shall meet 820.30(i); and other changes are made according to 820.40. Any changes to labeling should be formally reviewed and authorized before implementation. That is, follow the guidance in this chapter as if new labeling is under development. When making changes to primary aspects of a device and to primary documentation, the review group should determine if any secondary items such as labels or instructions are affected and also need changing. There should be a check-off block on change-order forms, or any other change control mechanism, for recording that the effect of the primary change on labeling was considered and appropriate action was taken. The failure of a change control system to alert employees of basic requirements is considered to be a serious deficiency in a quality system.

SHIPPING FOR PROCESSING Devices that are prelabeled sterile, but are not yet sterilized, require be controlled at the manufacturer and during shipment for further processing. Likewise, devices that have been sterilized and shipped to the manufacturers warehouse or other controlled distribution point before final release should be properly labeled. The pallets, or designated unit, should be marked to indicate the status of the device, such as non-sterile, sterilized: awaiting test results, or an equivalent statement (820.86). The company should be able to show that it has control of the devices until final release and, could have them destroyed or returned for reprocessing if necessary. Unless so qualified, a distributors warehouse or facility is not considered a controlled distribution point. The QS regulation states that each manufacturer shall establish and maintain procedures to ensure that mixups, damage, deterioration, contamination, or other adverse effects to product do not occur during handling (820.140). The storage regulation at 820.150 states, (a) Each manufacturer shall establish and maintain procedures for the control of storage areas and stock rooms for product to prevent mixups, damage, deterioration, contamination, or other adverse effects pending use or distribution and to ensure that no obsolete, rejected, or deteriorated product is used or distributed. When the quality of product deteriorates over time, it shall be stored in a manner to facilitate proper stock rotation, and its condition shall be assessed as appropriate. (b) Each manufacturer shall establish and maintain procedures that describe the methods for authorizing receipt from and dispatch to storage areas and stock rooms. Manufacturers of sterile devices commonly label devices as sterile at one establishment and ship them to another facility or a contract sterilizer for sterilization. Shipments of nonsterile devices labeled as sterile are clearly misbranded and adulterated, and if diverted into consumer channels, could create a potential health hazard. FDA recognizes that this longstanding practice is an economic necessity for many manufacturers. Therefore, to meet the needs of these manufacturers in a way that will also assure the protection of the public health, FDA added

Part 801.150(e) to the Code of Federal Regulations (CFR). It is reprinted below. (e) As it is a common industry practice to manufacture and/or assemble, package, and fully label a device as sterile at one establishment and then ship such device in interstate commerce to another establishment or to a contract sterilizer for sterilization, the Food and Drug Administration will initiate no regulatory action against the device as misbranded or adulterated when the nonsterile device is labeled sterile, provided all the following conditions are met: (1) There is in effect a written agreement which: (i) Contains the names and post office addresses of the firms involved and is signed by the person authorizing such shipment and the operator or person in charge of the establishment receiving the devices for sterilization, (ii) Provides instructions for maintaining proper records or otherwise accounting for the number of units in each shipment to insure that the number of units shipped is the same as the number received and sterilized, (iii) Acknowledges that the device is nonsterile and is being shipped for further processing, and (iv) States in detail the sterilization process, the gaseous mixture or other media, the equipment, and the testing method or quality controls to be used by the contract sterilizer to assure that the device will be brought into full compliance with the Federal Food, Drug and Cosmetic Act. (2) Each pallet, carton, or other designated unit is conspicuously marked to show its nonsterile nature when it is introduced into and is moving in interstate commerce, and while it is being held prior to sterilization. Following sterilization, and until such time as it is established that the device is sterile and can be released from quarantine, each pallet, carton, or other designated unit is conspicuously marked to show that it has not been released from quarantine, e.g., sterilized -awaiting test results or an equivalent designation.

Section Eleven; Page 13 of 21

OVER-LABELING Over-labeling by placing a new label over an old label is discouraged by FDA but is acceptable as long as the new label and its use meet GMP requirements [(820.30, 820.120, 820.90(b)(2)] for user needs, attachment, legibility, reprocessing, and change control. Over-labeling is also discouraged in some foreign countries. EXHIBITS Exhibits that cover labeling design and labeling control are presented on the following pages. These exhibits show how some GMP requirements for label control may be met. These procedures and forms may need to be modified to meet the needs of a specific operation. Drafting and Approval of Labeling This drafting and approval procedure is used to establish a uniform system for controlling the content of labeling and for approving labeling. This procedure is adaptable for use by any size manufacturer. The approval form that follows may be used with this procedure. Approval Form for Labeling, Advertising, Literature, etc. This form is intended for use by a medium to large manufacturer, however, the checklist style can be adapted even to a small manufacturer. The areas of concern are listed under the group that is responsible for that concern. Thus, every department has input into the acceptability of the labeling.

Administration Set Label This example of a label for an administration set begins with a complete description of the device inside the package. The directions for use section is arranged so that each point in the directions for use is numbered and only one point is made for each step. The various points in the directions are short and to the point. Where emphasis is needed, as in the case of air bubbles, the information is bolded for further emphasis. Labeling Control Record This blank copy of a labeling control record shows what a sample form looks like. At the bottom of the form, there is space to attach the actual labeling used so that a comparison of the actual labeling used versus that required can be made during product release review. Device History Record: OB/GYN (Plate) The history record exhibited here is limited to the filling operation for a media product. The form has space to print the same label as printed on the plates during the filling operation for label control and release review. This technique eliminates human copying errors. User/Reader Comments Feedback is an important element in any QA system. Whenever manuals or instructions form part of the labeling for a product, it is wise to solicit review from persons not familiar with the use of the product. These people can be employees of the manufacturer or, as in this exhibit, actual users of the product. The information received will reflect the problems encountered by persons trying to follow the instructions without any preconceived knowledge of the actual operation of the product.

Section Eleven; Page 14 of 21

Procedure Policy Title: DRAFTING AND APPROVAL OF LABELING SOP#:_______ Prepared by: App: Date:__________________ Prep. Date: Rev: Date: ECN History: 1.0 PURPOSE To establish a uniform procedure for controlling the content of labels and labeling and obtaining approval within our company. To assure compliance with GMP requirements and with company policy directives. 2.0 SCOPE Applies to all devices including those used for market research or clinical investigations. Advertising material is excluded from this SOP. It is covered by our SOP #____, "Advertising Material Control and Approval." 3.0 REFERENCE DOCUMENTS 3.1 Food and Drug Administration LABELING, GMP, etc. requirements in 21 CFR Parts 800-1299. 3.2 SOP #_____, Advertising Material Control and Approval 3.3 SOP #_____, Change Control System 4.0 FORMS 4.1 Form SOP #_____, Labeling Development and Verification Checklist 4.2 Form SOP #_____, Labeling Approval Form 4.3 Form SOP #_____, Engineering Change Order Form 5.0 DEFINITIONS 5.1 Labeling is all labels and other written, printed or graphic matter accompanying or attached to the device or its contain er. 6.0 PROCEDURE 6.1 Preparation and Approval The Labeling Development and Verification Checklist should be used as guidance for all activities because the fin ished labeling must be evaluated versus this checklist. 6.1.1 An operating department such as Engineering, Marketing, Manufacturing, or Quality Assurance determines the need for a label or labeling. Marketing, as appropriate, will conduct and document literature searches and perform designinput market research to determine any special needs of the users. Design input, regulatory, safety, and other ap propriate information shall be used to create a labeling specification. 6.1.2 The Engineering Department prepares a manuscript complete with illustrations or prepares a drawing(s) of the label showing the wording, label use, and/or location. The label may be on a front panel drawing or oth er engineering drawing. 6.1.3 When final prototypes and/or pilot production models are available, the labeling shall be verified and the results recorded on the Labeling Development and Verification checklist. If needed, the appropriate department shall take appropriate corrective action. The completed checklist shall be filed with the device design verification records. 6.1.4 Before final approval, labeling will be discussed at appropriate design review meetings. The minimum attendees are the originator, Engineering, and QA. 6.1.5 The Engineering Services Department then prepares form SOP #_____, Labeling Approval Form, and circulates it to the originating department, Training and Education, Marketing, and Quality Assurance for approval. (See the following sample approval form.) 6.1.6 Engineering Services will coordinate and file all labeling verification checklists, notes, approvals and approval forms in the design history file. 6.1.7 When approval is received from all parties, the label or manuscript is assigned a drawing number and is released and added to the product structure (DMR Index) following the Change Control System (SOP #_____) procedure. 6.2 Implementation and Control 6.2.1 When labels or labeling are produced, Quality Control must proofread the material and verify that it is correct by first article inspection and so indicate by signing an appropriate document. 6.2.2 All labels and labeling will be reviewed by QA for lot control requirements. Each origi nal document will be marked by Engineering Services to indicate the level of control required. At least one label on each device intended for surgical implant into the body or to support or sustain life must have a lot, serial, or other control number. See 820.65, Traceability. 7.0 EXPERIMENTAL DEVICES 7.1 Labels and labeling for experimental or investigational devices are required. 7.2 The documentation need not be as complete as for production labels and labeling; but, it must be adequate to allow procurement of the labels or labeling and adequate for the intended use. If appropriate, such labeling must meet 21 CFR 812.5. Section Eleven; Page 15 of 21

8.0 CHANGES 8.1 Any changes to released labels or labeling are accomplished according to SOP #_____, "Change Control System". 9.0 SCHEDULES (Design QA requirements are presented below. There are also related production requirements.) 9.1 Drafts must be generated according to a schedule that allows a normal approval procedure. While urgent copy approval is occasionally necessary, it should not become standard operating procedure. 9.2 All labels must be approved according to the routine engineering schedule for components. 9.3 Labeling must be approved before or when the device is released for full-scale production. HOWEVER, any pilot units placed in commercial distribution must be labeled with approved pilot or final labeling. 9.4 The design review for any pilot lots and the design review of initial full-scale production lots shall include a design review of labeling. 9.5 The design review records for labeling shall be identified for easy recall. These records shall be a part of the design history file.

Section Eleven; Page 16 of 21

FINAL APPROVAL OF LABELING, ADVERTISING, Etc. Return to Approval Coordinator after each signature or after checking any "no" box. Title Doc. No. Dwg. No.__________ Intended use/distribution Project Leader Approval Coordinator Yes No [] [] [] [] [] [] [] [] [] [] [] [] [] [] [] [] [] [] N/Applicable [] [] [] [] [] [] [] [] [] ENGINEERING Tech. specs., installation data, & part numbers correct. Procedural information is accurate and complete. Standards imposed by CSA, UL, IEC, etc. are met. Illustrations are technically accurate. Equipment protection cautions included where necessary. Procedures verified on final prototype or prod. model. Changes requested in draft have been made or negotiated. Procedures are safe and effective. Final draft has been proofread. Project Engineer: []Approved []Approved with noted changes Engineering Services Mgr.: []Approved []Approved with noted changes SERVICE Maintenance information is written for intended user. Lists part numbers needed for maintenance and repairs. Service Manager: []Approved []Approved with noted changes

Date: __/__/__ []Not approved Date: __/__/__ []Not approved

Yes No [] [] [] []

N/A [] []

Date: __/__/__ []Not approved

Yes [] []

No [] []

N/A [] []

TRAINING AND EDUCATION Document is adequate for training purposes. Document agrees with experience of training specialists, if experienced with this or similar products. Training Manager: Date: __/__/__ []Approved []Approved with noted changes []Not approved MARKETING Material is effective and complete for intended use. Material meets the needs of the international market. Material is professional and projects the company image. All claims supported by verification data. Project Manager: []Approved []Approved with noted changes Director Marketing: []Approved []Approved with noted changes QUALITY ASSURANCE Hazards situations are highlighted with adequate warnings. All FDA labeling and GMP requirements, are met. Quality Engineer: []Approved []Approved with noted changes Approval Coordinator signature Approved

Yes No [] [] [] [] [] [] [] []

N/A [] [] [] []

Date: __/__/__ []Not approved Date: __/__/__ []Not approved

Yes No [] [] [] []

N/A [] []

Date: __/__/__ []Not approved Date: / / Date: / /

Form #

Section Eleven; Page 17 of 21

MAJOR MEDICAL, INC. ADMINISTRATION SET

Catalog Number 1403 With macro non-vented drip chamber, 80-inch length and "Y" site. INSTRUCTIONS FOR USE 1. Prepare solution container. 2. Close side clamp and open device. 3. Remove protector cap from drip chamber piercing spike. 4. Aseptically insert spike through set port of solution containers. 5. Squeeze and release drip chamber until solution half fills the drip chamber. 6. Open slide clamp and allow the tubing to fill with solution, thus eliminating all air bubbles. DO NOT ALLOW AIR TO BE TRAPPED IN SET. 7. Close slide clamp. 8. Make venipuncture with I.V. device of choice. 9. Open slide clamp. 10. Regulate rate of infusion with device. Micro Set: 60 drops delivers about 1 ml; Macro Set: 15 drops delivers about 1 ml. 11. To stop flow without disturbing valve adjustment, use slide clamp. PRECAUTIONS: Supplementary medication may be injected with 20 or 22 gauge needle into injection site. If fluid path is interrupted, take special care to ensure fluid path has not been contaminated. Do not use to administer blood, blood products, suspensions, emulsions or any medication not totally soluble in the solution being administered. These medications may be administered through the distal Y-injection site with slide clamp closed. Puncturing drip chamber or tubing can cause air contamination and leaking. FOR SINGLE USE ONLY CAUTION: Puncturing tubing can cause air embolism. NONPYROGENIC STERILE: Unless Package has been opened or damaged. CAUTION: U.S.A. Federal law restricts this device to sale by or on the order of a physician. STORE AT ROOM TEMPERATURE Sterilized by E.T.O. Date of Sterilization: Lot No. Manufactured for: Major Medical, Inc. Debbiville, Maryland 20906 Printed in U.S.A.

Section Eleven; Page 18 of 21

LABEL CONTROL RECORD

1. Labeling area was inspected and no labels from previous operations were present. Initials: 2. Just before starting the labeling operation, labels were examined for correct: [ ] Identity Name: 3. REAGENT INFORMATION Description Catalog Number Stability Lot Number Reagent Expiration Date Initials 4. [ ] Labels were correctly applied. 5. [ ] Unused labels with filled-in expiration date were destroyed. 6. [ ] Remaining labels, if any, were returned to proper storage area. 7. Place sample(s) of labels here: 8. Inspector Comments: 9. [ ] Place completed form in the device history record for this lot. Form No. LC-11-21 Rev. A Approved Date Completion date Date Recorded [ ] Expiration date on label [ ] Control number Date: 3.1. CONTAINER INFORMATION Size Type Quantity Other

Section Eleven; Page 19 of 21

DEVICE HISTORY RECORD I. INITIATION DEVICE NAME: DEVICE LOT NO.: INITIATED BY: II. FILLING OPERATIONS A. CONTAINER: B. LABELING LABEL PREPARED BY: LABEL APPROVED BY: .......................... . . . Paste Label Here . or . Run This Sheet Through . Labeling Machine .......................... MFG: LOT NO. OB/GYN THEORETICAL YIELD: EXPIRATION: DATE INITIATED: 2500

. . . .

C. MEDIA SECTION 1 2 3 4 5 MEDIA Levine EMB BiGGY Mannitol Salt Agar TSA w/5% Human Blood Mod. Thayer Martin BATCH NO. TEMP. DEPTH OF RANGE FILL (mm) 41-52 C 41-52 C 41-52 C 44-52 C 44-52 C 3.5 - 4 3.5 - 4 3.5 - 4 3 - 3.5 2.5 - 3.5

FILLING ROOM PERSONNEL: DATE DEVICES FILLED:

Section Eleven; Page 20 of 21

User's Name: Employer: City: Zip: Country:

Position: Department: State: Date: Form Number: MKT-139 Rev. 1

Section Eleven; Page 21 of 21