Project 1 - Device Master File

Master Files for Devices (MAFs) are MFs that may be used to provide confidential, detailed information [about facilities, manufacturing processes (e.g., sterilization), packaging materials, and contract packaging, as well as nonclinical and clinical study data] associated with Premarket Approval Applications (PMAs), Investigational Device Exemption Applications (IDEs), Premarket Notifications (510(ks)), or other device submissions. As with other MFs, the person holding the MAF (MAF holder) may authorize one or more sponsors or applicants to rely on information contained in the MAF to support a submission to FDA without having to disclose that information to the sponsors or applicants.

A premarket approval application (PMA) or an investigational device exemption application (IDE) usually contains data and other information that the applicant has developed and regards as trade secret or confidential commercial financial information. Often the applicant needs to use another party's product (e.g., ingredient, subassembly, or accessory) or facility in the manufacture of the device. In order that a sound scientific evaluation may be made of the PMA, IDE, or other device submission, the review of data and other information related to the other party's product, facility, or manufacturing procedures is required. The other party, while willing to allow FDA's confidential review of this information, may not want the IDE, premarket notification [510(k)], or PMA applicant to have direct access to the information. To help preserve the trade secrets of the ancillary medical device industry and at the same time facilitate the sound scientific evaluation of medical devices, FDA established the device master file system. In addition, a master file may be considered when several applications may be submitted for different products which may use a common material or process, etc., such as the same sterilization method.

The following are commonly used terms relating to MAFs for devices and the documents referring to them:

• An "MAF holder" is an organization or person filing an MAF.
• An "applicant" is an organization or person filing a PMA.
• A "sponsor" is an organization or person filing an IDE.
• An "agent or representative for an MAF holder" is a person or organization authorized to represent the MAF holder before FDA concerning the contents of the MAF.

As of May 2021, the medical devices market is estimated to be at US$ 12 billion in India. India is the 4th largest Asian medical devices market after Japan, China, and South Korea, and among the top 20 medical devices markets globally.

Between 2020-25, diagnostic imaging market is likely to expand at a CAGR of 13.5%.

India has a 75-80% import dependency on medical devices. Export of medical devices from India stood at US$ 2.53 billion in FY21, and are expected to rise to US$ 10 billion by 2025.

To increase export of medical devices in the country, the Ministry of Health and Family Welfare (MOHFW) and Central Drugs Standard Control Organisation (CDSCO) implemented the following initiatives:

• Re-examination and implementation of Schedule MIII (a draft guidance on good manufacturing practices and facility requirements)
• System for export labelling
• Clinical evaluation and adverse reporting clarification
• State licencing authority to extend free sales certificate validity from 2 years to 5 years to allow exports
• Create a list of manufacturers with export licencing for easy access to regulatory authorities worldwide.

The Medical Devices Virtual Expo 2021 showcased Indian products and enabled direct interaction between Indian suppliers and buyers/importers from participating countries; 300 foreign buyers from the healthcare sector participated in this event.

Some major investments and developments in medical devices are as follows:

• FDI inflow in the medical and surgical appliances sector stood at US$ 2.41 billion between April 2000-March 2022.
• In July 2022, Godrej Appliances launched the new InsuliCool product range – Godrej InsuliCool and Godrej InsuliCool+, which are innovative cooling solutions especially designed for insulin storage, in order to address the challenge faced by diabetic patients with respect to insulin storage at recommended temperatures.
• In July 2022, the Rajiv Gandhi Cancer Institute and Research Center (RGCI) in New Delhi received its first-ever Made-in-India Surgical Robotic System, the SSI-Mantra, which was developed by med-tech startup SS Innovations.
• In July 2022, Ultrahuman announced its latest wearable: the Ultrahuman Ring, which can track users’ metabolism, measure movement, sleep and other body dynamics in real-time.
• Medtronic has launched a Surgical Robot Experience Center (SREC) in Gurugram, Haryana, the first of its kind in South Asia. The SREC will be focused on the education and training of surgeons in robot-assisted surgery.
• Indian Institute of Technology (IIT) Delhi has developed a national centre for medical technology development in an effort to help medical device startups produce their goods in a facility that has received ISO certification and secure the necessary certifications.
• In November 2021, Cipla launched ‘Spirofy’, India's first pneumotach based portable, wireless spirometer.
• In November 2021, Serene Envirotech Pvt. Ltd., a Mumbai-based start-up, launched a portable molecular hydrogen generating machine ‘udazH’ for personal use. The molecular hydrogen inhaler comes with a dual-use technology that lets two users simultaneuosly use the machine.
• In October 2021, Innovation Imaging Technologies Pvt. Ltd. (IITPL) established a ‘state-of-the-art’ facility in Bengaluru to manufacture 240 catheterisation laboratories in the next 12 months. Through this initiative, the company aims to strengthen the infrastructure to treat cardio-vascular diseases in the country.
• In October 2021, the HMD achieved a milestone by supplying 500 million 0.5 ml AD syringes to the government to accelerate the vaccination drive and contribute to India’s Atmanirbhar mission. The company further plans to achieve annual capacity of 3.5 billion syringes by March 2022.
• In September 2021, Medtronic India Private Limited collaborated with Stasis Health Private Limited to boost patient monitoring in India.
• In September 2021, Siemens Healthineers announced that molecular testing kits will be manufactured in its Vadodara unit in Gujarat.
• In September 2021, Siemens Healthineers extended its collaboration with SyntheticMR with a new licence agreement for distribution of the company’s (SyntheticMR) products.

The Government of India has commenced various initiatives to strengthen the medical devices sector, with emphasis on research and development (R&D) and 100% FDI for medical devices to boost the market.

• In the Union Budget 2022-23, Rs. 86,200 crore (US$ 11.3 billion) was allocated as a budget for the pharmaceutical and healthcare sector.
• In October 2021, the government announced plan to draft a new drugs, cosmetics and medical devices bill to increase the acceptability of Indian medical devices in the global market.
• In October 2021, the government announced that 13 companies have been approved under the PLI scheme for medical devices, which is expected to boost domestic manufacturing in the country.
• In September 2021, the government sanctioned a proposal worth Rs. 5,000 crore (US$ 674.36 million) to build a medical devices park in Himachal Pradesh’s industrial township, Nalagarh, in the Solan district.
• In September 2021, the government approved a medical devices park in Oragadam (Tamil Nadu) that is expected to attract an estimated investment of Rs. 3,500 crore (US$ 472.05 million) and offer direct and indirect employment to ~10,000 people.
• In July 2021, the government announced that they would build a medical park in Uttar Pradesh, which is expected to generate an estimated Rs. 500 crore (US$ 67.13 million) business in the state.
• In June 2021, the Quality Council of India (QCI) and the Association of Indian Manufacturers of Medical Devices (AiMeD) launched the Indian Certification of Medical Devices (ICMED) 13485 Plus scheme to undertake verification of the quality, safety and efficacy of medical devices
• To boost domestic manufacturing of medical devices and attract huge investments in India, the department of pharmaceuticals launched a PLI scheme for domestic manufacturing of medical devices, with a total outlay of funds worth Rs. 3,420 crore (US$ 468.78 million) for the period FY21-28.
• In March 2021, the PLI Scheme for pharmaceuticals worth Rs. 15,000 crores (US$ 1.96 billion) was launched. This scheme aims to enhance India’s manufacturing capabilities by increasing investment and production in the pharmaceutical and medical devices sectors and contribute to the availability of a wider range of affordable medicines for consumers.
• On March 25, 2021, the Department of Pharmaceuticals released a revised notice on the Public Procurement Order (PPO), incorporating 19 medical devices in the revised guidelines of the PPO, which is expected to improve domestic medical devices manufacturing (and strengthen ‘Make in India’) and reduce import bills by ~Rs. 4,000 crore (US$ 538.62 million).
• In April 2021, in order to expedite the clearance of medical devices such as nebulisers, oxygen concentrators and oxygen cannisters, the government made it easier to import critical medical devices by easing the requirements for clearance under the Legal Metrology Act (Packaging Rules 2011).

A device master file contains all of the information and specifications needed to produce a medical device from start to finish, including instructions for all manufacturing processes, drawings, documented specifications and labeling and packaging requirements.

The FDA regulations for DMR appear in 21 CFR Part 820.181, under subpart M which deals with record-keeping requirements for medical device companies. The device master record contains all of the information needed to produce the medical device from beginning to end. While the device history record makes reference to specific lots, units, or batches of product, the DMF contains specifications for producing an individual device. You can think of it as the comprehensive instruction manual for building your device, starting with the design and ending with distribution.

What Are The DMF Requirements Set By The FDA?

When the FDA audits your medical device company, you will be expected to produce a DMR that complies with 21 CFR Part 820.181. Here's the full text of that part for reference:

Each manufacturer shall maintain device master files. Each manufacturer shall ensure that each DMF is prepared and approved in accordance with 820.40. The DMF 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 main purpose of the device master record is to centralize a record of the production process in a way that distinguishes it from the design process. A product development engineer might design a silicone part for a medical device, draw the design, and include it in the design outputs portion of the design history file, but the DMR would also include specific instructions for manufacturing the part, including what mold to use when casting the silicone, equipment specifications and production methods, and anything else required to produce the part according to the design.

Risk analysis related to design & manufacturing processes:

Generally speaking, within the medical device industry, risk analysis consists of recognizing and addressing any factor that might hinder the ability to get your product to market. If you are in the midst of developing a medical device without doing an appropriate risk analysis, chances are high the product has a flaw. Even if you’re able to address it early on, it will still take longer than if you had conducted risk analysis from the very start.

Connected risk analysis gives you a holistic view of risks and their potential impact. In the medical device industry, having this level of visibility isn’t optional.

There are four specific actions required for connected risk analysis: identify possible threats, estimate the likely impacts and the likelihood these threats will happen, and consider risk management options.

Identify Possible Threats: Compile data from throughout the organization, and use this information to develop a list of possible threats. Assess each item on the list, and determine whether or not they apply to your device.

Estimate the Likelilhood and Impact: Calculate the likelihood and impact of each possible threat. It’s important to consider their impact to your organization, the device, the environment, and end users.

Consider Risk Management Options: You can choose to manage risk in four separate ways: avoiding the risk, sharing the risk, accepting the risk and controlling the risk. Ideally, you want to avoid the risk, and with connected risk analysis you can put risk and compliance measures in place early in the product lifecycle.

Risk Assessment Process:

There are four integral steps in the risk assessment process. They are hazard identification, dose-response assessment, exposure assessment, and risk characterization.

Hazard identification: Hazard identification is the process that involves the determination of any adverse health condition upon exposure to an agent (e.g. chemicals). Birth defects, cancer, decreased fertility, and thyroid dysfunction are just few of the cited effects of one’s exposure to toxicants. Hazards may be identified using one of the following methods:

• Epidemiological investigation, a study of the frequency and distribution of diseases within human population. It has the advantage of knowing and measuring the risk hazards that have direct effects on human.
• Toxicological studies. It is a method of measuring health hazards affecting living organism. It is usually conducted in a controlled environment like the laboratory. Animals are used for conducting the test.
• Ecological studies. This is a method of determining hazards based on the ecological studies of wildlife. It is believed that potential endocrine disrupters that have adverse affect on animals may be potentially harmful to human as well.

Dose-response assessment: “All substances are poisons: there is none which is not a poison. The right dose differentiates a poison and a remedy. The characterization of dose-response relationship involves determination of the amount of agent that will not cause an effect. This is the determination of the upper limit, which is also called as the “allowable limit”. The response to the agent varies depending on the level of exposure, duration of contact or the agent’s level of toxicity.

Exposure assessment. This is the estimation of the quantifiable dose of human exposure to an existing agent. Estimation includes that of the duration, frequency, and intensity of exposure. One’s exposure to different toxicants may come from the different sources in the environment, which may be synthetic or natural occurring. Synthetic sources of endocrine toxicants can be categorized as voluntary or involuntary exposure. The former includes exposure to commercial products like pesticides, cosmetics or medications. The latter may come from contamination in water, air or contact in the contaminated soil. Routes of exposure in the human body differ according to the chemical properties and human biology. Routes of exposure can be dermal (skin-absorbed), respiratory (inhaled), and gastrointestinal (ingested). Chemical toxicants that are insoluble in water like PCB’s can be skin absorbed while chemicals that are volatile can be inhaled. Once contaminants enter the body, they travel to organs and tissues through bloodstream. The measure of exposure to chemical contaminants in the body is done through blood sampling.

Risk characterization. The final step of the risk assessment process includes the evaluations and results of the previous three steps. Risk characterization measures the overall risk of the agent towards human exposure. The allowable limit is then compared to the estimated limit of adverse health effects that determines the agent’s safety. Risk estimation is assessed in direct proportion for both levels of hazard and exposure. The presence of both assessments constitutes an end result that determines the amount of risk involved. If a hazard exists and the risk is known to be low, then it is an acceptable risk. In the context of the total risk assessment, the uncertainty of the hazard level is a pre-defined approach for a more extensive analysis on the amount of hazard involved in the compound. The four risk assessment steps discussed are vital to the overall assessment of the medical device’s exposure to risk. Thus, it is important to take into consideration the accuracy of the test data and results that will determine the device’s acceptable safety level for market release.

One of the most nebulous aspects of compliance for a medical device manufacturer is knowing whether a process should be verified or validated to ensure its conformity to regulatory requirements. High-level answers to medical manufacturers' process verification vs. process validation questions can be found in the Quality System Regulation (QSR) requirements outlined in 21 CFR Part 820, which is enforced by the U.S. Food and Drug Administration (FDA). However, many device makers have expressed concerns that the QSR does not specifically define the activities that require process validation and those that require process verification.

Knowing the appropriate verification vs. validation choice depends on whether you want to know the answer to the question, “Are we building the right thing?” or the question, “Are we building the thing right?”. Here's the distinction between the objectives of each:

• Purpose of process validation: Building the right thing.
• Purpose of process verification: Building the thing right.

Process verification is generally approached from a systemic level while manufacturing process validation is applicable to the product's users. In that regard, a device maker's process verification should be concerned with confirming that specifications are correctly implemented by the system. Process validation activities, on the other hand, should be aimed at meeting the needs and expectations of users/customers.

Process verification isn't testing to confirm that a process or medical device product actually works. It's confirming that the specifications have met predetermined parameters. Manufacturing process validation comes in to play when parameters can't be measured, which occurs frequently in medtech manufacturing (more on that later).

Process verification is used throughout the life cycle of a medical device, from design development to upscaling production. However, since the QSR stipulates that objective evidence must exist as proof that specs have been met, process verification is contingent upon quantifiable metrics that serve as key performance indicators (KPIs). In short, if KPIs are measurable, the process can be verified.

Still, few processes are measurable with 100% accuracy, even with the most stringent controls. That's why the “fully verified” clause in the QSR is a sticking point for many medical device manufacturers. It's also the reason why process validation is always prudent whenever it's a cost-effective option.

The QSR has never explicitly defined what it means for a process to be fully verified. However, the chief of the postmarket and consumer branch of the FDA's Center for Devices and Radiological Health (CDRH), Joseph Tartal, clarified its meaning and context in a recent FDA Industry Basics Workshop Series.

Tartal explained that verifiability is reliant on objective evidence and defined a fully verified process as one that is “able to confirm with high confidence all of the key quality attributes.”

“By objective evidence, we mean supporting the existence or truthfulness of it,” he said. “Objective evidence may be an observation, a measurement or a test.”

However, when objective evidence cannot be measured in a process, it cannot be fully verified and QSR guidelines call for a validation approach. The guidelines for a medical device validation approach are set forth in Section 75(a) of Part 820 which says, “Where the results of a process cannot be fully verified by subsequent inspection and test, the processes shall be validated with a high degree of assurance and approved according to established procedures.”

Process validation substantiates that intended performance yields consistent results. Yet, as noted above, many processes' outputs can't be quantified. And inspection and testing are insufficient in some cases. Therefore, in many instances, meeting the FDA's vague “high degree of assurance” expectation for medical device process validation is an attempt to make the unmeasurable measurable in some manner. Such is the case when problems in medical devices are undetectable until they're actually in use (e.g., it is impossible to precisely know the longevity of a knee replacement component until after it has been surgically implanted in a patient and the device is actively in use). In other situations, validation may not be possible without a cost-prohibitive deconstruction of the device.

The FDA does not offer guidance regarding processes that specifically require validation, other than four processes identified in the preamble of the QSR (sterilization, injection molding, aseptic processing, and welding). The agency instead has historically pointed to the Global Harmonization Task Force (GHTF) Process Validation Guidance as the best advice on meeting medical device validation expectations.

The GHTF guidance identifies two fundamental questions that medical device manufacturers should ask to determine if process validation is required:

• Is the process output verifiable?
• Is verification sufficient and cost effective?

If the answer to both is no, the GHTF guidelines recommend that the process should be validated, or that the process and/or product potentially needs to be redesigned.

A medical device manufacturer's decision to validate a process up front is the most cost-effective measure in many scenarios. Manufacturing process validation enhances control over factors like variations, which typically results in benefits like optimized operations, increased yields, and reduced scrap. Taking into account these types of measurable impacts that tie directly to the bottom line, the relative cost of validating a wide variety of processes may outweigh, or in many cases even reduce, the cost of inspection.

Expected life of a device means the time that a device is expected to remain functional after it is placed into use. Certain implanted devices have specified “end of life” (EOL) dates. Other devices are not labeled as to their respective EOL, but are expected to remain operational through activities such as maintenance, repairs, or upgrades, for an estimated period of time.

The potential benefit from the use of a medical device ranges from relieving minor irritations to correcting life threatening conditions. If the device design and manufacturing processes are done adequately, there is a high probability that the device will perform as desired at the time it is manufactured.

However, there are many naturally occurring factors that can affect how long after manufacturing the device will maintain the ability to fully perform the intended function.

An expiration date is the termination of shelf life, after which a percentage of the commodity, e.g., medical devices, may no longer function as intended. To determine if a particular device requires a shelf life and assign an expiration date, there are a number of different parameters that must be considered.

The device must be analyzed to determine if it is susceptible to degradation that would lead to functional failure and the level of risk that the failure would present. For some devices, e.g., tongue depressors, it is not reasonable to assign a shelf life because of the small likelihood of time-dependant product degradation and the lack of serious consequences if it did fail to perform as designed. For certain devices susceptible to degradation that are intended to treat life-threatening conditions, e.g., pacemakers, the failure rate should approach zero within the labeled shelf life.

“Shelf life” is the maximum time a device will remain functional from the date of manufacture until it is used in patient care.

Medical device manufacturers must incorporate in their quality assurance (QA) program several elements that relate to labeling in order to meet the Good Manufacturing Practice (GMP) requirements of the Quality System regulation. The QA program must be adequate to ensure that labeling meets the GMP device master record requirements with respect to legibility, adhesion, etc., and ensure that labeling operations are controlled so that correct labeling is always issued and used.

Labeling includes equipment labels, control labels, package labels, directions for use, maintenance manuals, etc. The displays on CRT's and other electronic message panels are considered labeling if instructions, prompts, cautions, and parameter identification information are given.

Various sections of the QS regulation have an impact on labeling: Section 21 CFR 820.80(b) requires the inspection and testing of incoming materials including labeling; and 21 CFR 820.70(f) requires buildings to be of suitable design and have sufficient space for packaging and labeling operations. 21 CFR 820.120 deals with specific requirements for the control of labeling. It applies to the application of labeling to ensure legibility under normal conditions of use over the expected life of the device; and also applies to inspection, handling, storage, and distribution of labeling. FDA considers a device to be adulterated if these requirements are not met. These requirements do not apply to the adequacy of labeling content, except to make sure the content meets labeling specifications contained in the device master record. However, failure to comply with GMP requirements, such as proofreading and change control, could result in labeling content errors. In such cases, the device is misbranded and adulterated.

Specifications are required in the design history file (DHF) 21 CFR 820.30 for the content and physical design parameters of labels. Labeling specifications are: 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 must 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 or adequately identified (cross-referenced) with respect to the label approval form.

Hard copy labels, package inserts, and similar labeling are specified and purchased as components. 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 requirements for labeling except for the most simplistic labeling such as brief errata sheets.

The engineering drawings or purchase specifications and mounting procedure must 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.

Front panels, other instrument panels, meters, fuses, pushbuttons, and the like often are labels or contain labels and must, as appropriate, meet device master record and control requirements. Component specifications, assembly drawings, and test/inspection procedures may be appropriate controls to prevent mixup of meters, pushbuttons, and other labeled instrument controls. Controls to prevent mixups are generally not needed for front and other instrument panels.

Whether a firm considers a software driven display to be labeling or data makes little difference under the Quality System regulation, because either way, the finished device labeling or data must meet the device master record specifications. When firms develop and validate software, they should also review these 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.

When reviewing or auditing labeling operations, it is wise to keep in mind that the Quality System regulation contains flexible requirements and thus allows flexibility in a quality assurance program. The degree of labeling control needed to satisfy the Quality System 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. Information and guidelines presented in this chapter should aid manufacturers in making these decisions. The level of control needed should be reconsidered when products are added or changed. Likewise, the controls needed and success of the existing control program must be reviewed during QA system audits.

Specific Requirements for Labeling

Label Integrity: All labels must 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. 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 sometimes smeared and thus is inadequate [FD&C 502(f)]. The manufacturers of such devices must assure that the print is legible and will remain legible until used.

Receipt and inspection: Upon receipt, all packaging and labeling materials, including preprinted containers, inserts, and preprinted packaging materials must be examined and, acceptance activities performed to assure conformance with specifications. Also, samples of labels must 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 acceptance activities must be recorded in the device history record as required by 21 CFR 820.80(e) and 21 CFR 820.120 to show that inspection and proofreading were performed. The acceptance record for device labeling should be kept simple.

Area Separation and Inspection: All labeling and packaging operations should be separated to the degree necessary to make certain 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 labels from panels that fit the intended family or instruments (devices).

The likelihood of a labeling mixup determines how stringent production area controls should be. For example, label control need not be stringent if only dissimilar products and labeling are processed. Before beginning any packaging and labeling operation in which mixup could occur, the production area and equipment for the operation must be thoroughly examined to make certain 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 date, expiration date, control number, etc., should be destroyed and not returned to the label storage area. The Quality System regulation does not require reconciliation of the number of labels used versus 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: All printed packaging and labeling materials, including preprinted containers, inserts and preprinted packaging materials, must be stored in an area and manner suitable to prevent mixups (21 CFR 820.120). 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 firm that manufacturers only one product with one label does not need an elaborately controlled storage area. Similarly, a firm 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. Firms must make certain that mixups cannot occur. Also make certain that all such samples, if used for market promotion, are sterile or stamped with a manifest caution statement because a package and labeled market-promotion sample might be used by the recipient.

Label Check and Record: When issued for use, labeling must be carefully examined to make certain the contents of the labeling comply with the labeling specifications in the device master record for the specific device being produced. This examination must include any control numbers or expiration dates used on the labels. A record of this issuance check, including the date and name of the person performing the examination, must be made in the device history record.

If used, expiration dates must reflect the time after final packaging during which the device is fit for its intended use when stored and used per its labeling. The manufacturer should have stability test data which establishes the interval that the device remains fit for use.

If label mixups cannot occur--for example, a firm 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.

Changes: Labeling is part of the device master record; therefore, all changes to labeling must be made under a formal change control system similar to that required for specifications [21 CFR 820.30(i)]. Any changes to labeling must be formally reviewed and authorized before implementation.

When making changes to primary aspects of a device and to primary documentation, the review group must 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 for recording that the effect of the primary change on labeling was considered and appropriate action was taken.

Relabeling and 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 for attachment, legibility, reprocessing, and change control. (Over-labeling is also discouraged in some foreign countries.)

Control Number: Devices intended for surgical implant into the body or to support or sustain life and whose failure to perform when properly used in accordance with instructions for use provided in the labeling can be reasonably expected to result in a significant injury to the user require a control number on each unit, lot, or batch of finished devices and where appropriate components for traceability [21 CFR 820.65]. This means a control number for the finished device, and not the label itself. Most labeling, however, also contains another number, such as a drawing number, for control of labeling configuration and procurement.

The control number for traceability need not be on every label on the device; however, the control number must appear on the unit label that goes to the ultimate user. The label on a shipping carton for bulk items does not meet this requirement because bulk items may go to central distribution point in the user-facility and the shipping carton would most likely be discarded. In order to meet this traceability requirement, a label that would most likely reach the nurse or other user station must have the control number.

Sterile Device Labeling: Special attention should be given to the labeling of sterile devices. Devices that are not sterile in their entirety (for example, sterility may be needed only for the lumen of certain devices) must be labeled to properly inform users what is actually intended to be "sterile" in the package. For example, a possible limiting statement might be:

"Caution: Only the fluid path of the set is sterile and non pyrogenic. Do not use in a sterile or aseptic area without proper precautions."

Some devices are intended to be sterilized by the user before use. In this situation, the labeling should provide adequate information as to at least one 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.

In the case of single-use sterile devices, some manufacturers include labeling to advise against resterilization and reuse. Some devices are simply 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 label of multi-device kits or packages containing a combination of sterile and nonsterile products must not state or imply that all contents are sterile.

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, and when necessary, such instructions should be included in the labeling.

When a manufacturer modifies a device, the manufacturer must also review the labeling to make certain that it reflects current revisions and specifications. 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)].

Shelf-life dating solely for package integrity and sterility is not usually required by FDA 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 [21 CFR 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 always 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:

• certain devices [21 CFR 820.65];
• some products subject to radiological health standards; and
• in vitro diagnostic devices [21 CFR 809.10(a)(9)].

Adequate labeling for a medical device requires proper design and procurement of the labels and labeling. Design includes labeling content that meets the requirement of the QS regulation 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.

Contract Sterilization

Finished devices that are terminally sterilized by a firm other than the manufacturer pose a unique labeling problem. A common industry practice is to send the finished device in its final packaging to a contractor for sterilization. The final packaging is labeled as sterile even though the goods are unsterile during shipment from the manufacturer to the contractor. Specific restrictions apply in this instance, and a written agreement between the parties must be in effect [21 CFR 801.150(e)]. The requirements for the labeling of in process sterile goods in transit to the contract sterilizer are addressed in detail by 21 CFR 801.150, and covered under Other Labeling Exemptions. Care must be taken in this situation to eliminate the possibility of an unsterilized product being mistaken for a sterilized product. A firm should seriously consider the use of "visual indicator" labeling to distinguish between product before and after sterilization, e.g., the use of indicator tape with bands that develop color upon exposure to steam or ethylene oxide, or stick-on "dots" which change color upon exposure to radiation. Bear in mind that visual indicators will provide confidence that the product has been exposed to a sterilant and not that the product is sterile. A firm should also consider the use of dosimeters, i.e., a product that undergoes an irreversible change in physical or chemical properties that is proportional to the amount of exposure to a sterilant. Some contract sterilizers affix labeling to a contractor's product in the form of a sterilization number stamped upon the device container, or outer shipping containers. Firms who use the contract sterilizer's lot number as assurance that their devices have undergone sterilization should determine, via an audit of the facility if possible, that sterilization lot numbers are applied after, not before, being subject to sterilization.

Regulations on distribution are contained in 21 CFR 801, Subparts A and E; and Quality Systems Regulation 21 CFR 820.160. Devices that have been sterilized, held, or shipped to the manufacturer's warehouse or other controlled distribution point before final release must be properly labeled. The pallets, or designated unit, must be marked to indicate the status of the device such as "sterilized: awaiting test results," or an equivalent statement. The company must be able to show that it has control of the devices until final release and, if necessary, could have them destroyed or returned for reprocessing. For this reason, a distributor's warehouse or facility is not considered a controlled distribution point.

PMS is a collection of processes and activities used to monitor the performance of a medical device. These activities are designed to generate information regarding use of the device to expediently identify device design and/or usage problems and accurately characterize the real-world device behaviour and clinical outcomes. The need for PMS arises immediately upon commercialization of the device.

Ensuring adequate medical input into the risk management process during product development will help manufacturers characterize possible product safety issues. The risk profile of the device evolves from these efforts and can be used to effectively develop the PMS strategy for the device. It is important to note that the requirements for PMS should be directly proportional to the risk associated with the device based on its intended use.

In developing a robust PMS process, manufacturers should consider whether or not the product or technology is new to the manufacturer and/or the marketplace. Where a manufacturer has a long history of development and marketing of similar device types, they are likely to have a clear understanding of the patient population and the reasonably foreseeable risk associated with the device. Available data regarding state-of-the-art market experience for similar products and technology may be adequate for low-risk devices with a long history of clinical use. For those manufacturers pursuing the literature route to support clinical evaluation requirements,2,6 these data types often give the manufacturer knowledge of the patient population, co-morbidities and the effect of different patient demographics for the use of the device. Literature of high quality (e.g. randomized control trials, meta-analysis) will give manufacturers quantified clinical data regarding the safety profile of these device types.

In the case of new technology, manufacturers often have a limited understanding of the patient population and the complexities of the disease state, which may affect the performance of the device. This limited knowledge may result in under or over representation of risks in the pre-market assessment of the device design and its interaction with the patient/user. Manufacturers introducing technology new to the organization should respond accordingly with an increased monitoring program to ensure early detection of problems not foreseen in development. Also of concern is the extent of available scientific knowledge for new devices. In the case of novel or new treatments, knowledge of long-term effects may be limited. Post-market clinical follow-up (PMCF) may be warranted to ensure adequate characterization of the real-world clinical use of the device.

PMS could be ‘reactive’ – responding after an event; of which there are many types ranging from complaints to those involving serious injury or in an extreme case where a serious injury or death has occurred known as ‘Vigilance’. These activities can be considered ‘passive’ as they are largely data collection activities. On the other hand, PMS could be ‘proactive’ – endeavours meant to anticipate and curtail events before they occur; there are many types such as user surveys, manufacturer-sponsored clinical registry studies, PMCF studies. In ‘proactive’ PMS activities, information is actively sought to gain insight and data into the real-world performance of the device.

Pre-market data is often a major determinant for the development and placement of medical devices. Unfortunately, pre-market data is based on design, and test-model assumptions that may not accurately represent real-life situations. In addition, pre-market data typically reflect ‘short term’ periods of observation or use, and may not reflect potential incidents or adverse information that would arise over longer periods of time i.e. during the post-market phase. Given these considerations, a properly implemented vigilance system, which involves the cooperation of users, manufacturers, competent authorities, and others could effectively facilitate the detection of previously unknown adverse product information and prevent future recurrence of incidents that might have otherwise led to death or serious deterioration in health.