Project 1 - Device Master File

• They 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.

• 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.

• Re-examination and implementation of Schedule MIII (a draft guidance on good manufacturing practices and facility requirements)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.

• 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.

• 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).

• 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.

• 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.

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

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

• It 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.

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).

• 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.

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

• 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.

• The Periodic Safety Update Report or PSUR is not a new term, at least to the pharmaceutical community. The industry has been operating with regulations related to PSUR for some time. But for the medical device and IVD community, it’s a new requirement that stems from EU Regulations MDR 2017/745 (article 86) and IVDR 2017/746 (article 82).
• A PSUR is basically a report summarizing critical actions and conclusions derived from post-market surveillance data of a medical or in vitro diagnostic device. All associated preventive and corrective actions should be documented throughout the lifetime of the device, even if the product is no longer on the market.
• The introduction of the PSUR under the MDR and IVDR requires a more consistent, standardized, and systematic review of all Post Market Surveillance (PMS) data by medical and IVD device manufacturers.
• The PSUR is meant to summarize the results and conclusions of the analysis of the post-market surveillance data that has been gathered, resulting from the activities detailed in either the Post-Market Surveillance Plan (PMSP). In addition, any rationale and description of any preventive and corrective actions taken for safety reasons should be included.

• The purpose of a PSUR is for manufacturers to demonstrate with objective evidence that they have designed and deployed a Post-Market Surveillance system which uses data to drive action within their Quality Management System and ensure the continued safety, performance, and efficacy of their devices. It’s intended for moderate and high-risk devices (MD Class IIa, IIb, III: IVD Class C and D) and provides a detailed summary of results and conclusions derived from the PMS data.
• Post Market Surveillance Report (PMSR) and Periodic Safety Update Report (PSUR) compose critical documentation of Post Market Surveillance (PMS) of a Medical Device and an In-Vitro Diagnostic Device (IVD). Medical Device and IVD manufacturers with an intent to market the products in the European Union (EU) shall comply with Medical Device Regulation (EU MDR) 2017/745 and In-Vitro Diagnostic Regulation (EU IVDR) 2017/746. Post Market Surveillance, commonly called as PMS, is one such compliance requirement applicable for manufacturers of all device classes and is covered under Articles 83-86 of MDR and Articles 78 – 81 of IVDR. The information, frequency, and submission requirements for PMSR and PSUR vary based on the device class.
• The manufacturers of Low-risk Class I Medical Devices and Class A, B In-Vitro Diagnostics (IVDs) should maintain a Post Marketing Surveillance Report (PMSR). The PMSR need not be submitted to any authority for CE Certification of the device. This report should be compiled, updated periodically, and shall be readily available for submission to the competent authority upon request.
• The manufacturers of moderate and high-risk Class IIa, IIb, III Medical Devices and Class C, D In-Vitro Diagnostics (IVDs) should submit Periodic Safety Update Report (PSUR). PSUR must be submitted to Competent Authority or Notified Body as a part of technical documentation. The PSUR document is evaluated as part of Conformity Assessment.
• The PMSR shall contain summary of results and conclusions derived from analysis of PMS data collected as per the PMS plan. It should also describe the Preventive and Corrective actions taken. The PSUR, on the other hand, shall summarize the results and conclusions derived from the analysis of Vigilance, PMS, and PMCF data collected as per the PMS Plan. It should also describe the Preventive and Corrective actions taken.

The PSUR shall include -

• the conclusions of the benefit-risk determination
• the main findings of the Medical Device Post-Market Clinical Follow-up (PMCF) or IVD’s Post-Market Performance Follow-up (PMPF)
• the volume of sales of the device and an estimated evaluation of the size and other characteristics of the population using the device, and, where applicable, the usage frequency of the device