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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 14  |  Issue : 2  |  Page : 79-83

Quality and regulation standards for positron emission tomography equipment and bone marrow cell separator as medical devices in India


1 Amity Institute of Pharmacy, Amity University Uttar Pradesh, Noida, Uttar Pradesh, India
2 Centre for Advanced Formulation Technology, Delhi Pharmaceutical Science and Research University, Government of NCT of Delhi, New Delhi, India

Date of Submission28-Nov-2021
Date of Decision19-Apr-2022
Date of Acceptance20-May-2022
Date of Web Publication20-Jul-2022

Correspondence Address:
Ramanpreet Walia
Amity Institute of Pharmacy, Amity University Uttar Pradesh, Sector 125, Noida - 201 303, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ajprhc.ajprhc_11_21

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  Abstract 


Introduction: Indian medical devices regulations have drastic changes since 2018. Few amendments have been incorporated in 2020. However, certain devices which are still not regulated and there are no quality checkpoints available for scrutiny from Central Drug Standard Control Organization, Delhi. This manuscript aims to provide quality checklist for two medical devices, positron emission tomography equipment, and bone marrow cell separator which are neither categorized nor regulated by the central drug standard control organization, Delhi. Methods: The quality checklist for the selected medical devices has been prepared by the survey based evaluation and quality tests have been identified by various methods available in the literature for checking risks associated with medical devices. Results and Discussion: Following quality checklist steps such as designing of primary checklist, quality assurance parameter evaluation for pet medication fabricating plant and equipment qualification criteria was identified with cross referencing and literature search. Conclusion: the new regulations would increase the accountability of the manufacturers and the importers to provide an assurance of safety to the customer. It needs to be incentivized by giving preference in public healthcare procurement instead of seeking USFDA and CE approvals. For the import of medical devices, the application should be reviewed based on risk analysis as suggested for these two devices. Further, local manufacturing of medical devices should be encouraged in India for reduced the cost of the medical devices.

Keywords: Bone marrow cell separator, medical devices, positron emission tomography, quality standards


How to cite this article:
Pandey N, Jain GK, Thakkar AR, Walia R. Quality and regulation standards for positron emission tomography equipment and bone marrow cell separator as medical devices in India. Asian J Pharm Res Health Care 2022;14:79-83

How to cite this URL:
Pandey N, Jain GK, Thakkar AR, Walia R. Quality and regulation standards for positron emission tomography equipment and bone marrow cell separator as medical devices in India. Asian J Pharm Res Health Care [serial online] 2022 [cited 2022 Sep 27];14:79-83. Available from: http://www.ajprhc.com/text.asp?2022/14/2/79/351524




  Introduction Top


The medical devices scenario is changing in India and is expected to reach USD 50 Billion by 2025. It is among the top 20 markets for medical devices worldwide and fourth-largest market in Asia.[1] The Government of India has regulated/notified thirty-seven categories of devices as drugs, dated 11/02/2020. As per the notification, with effect from 01/04/2020, the medical devices with subsequent descriptions would be synchronized as “Drug” under the Drug and Cosmetics Act and Medical Device Regulation 2017. It was recommended by National Health Policy, 2017 to regularize medical devices.[1] Furthermore, establish an authoritarian body for medical devices in enjoin to monitor quality matching with international standards. In India, regulatory approval to “low-risk” devices (Class A and B) are under the purview of the State Licensing Authority and for “high-risk” devices (Class C and D) are regulated by the DCGI, the Central Licensing Authority in India.[1] As per the Drugs and Cosmetics Act 1940 and rules, medical devices are defined as devices such as apparatuses, instruments, appliances, implants, materials or other articles, whether used primarily or in combination, including software or accessories, designed by its manufacturer for humans and animals which does not achieve the primary intended action in or on human body or animal, by any immunological, metabolic means and pharmacological action, but which may assist in intended function by such means for one or more specific purposes of:[2] (i) Diagnosing diseases, mode of avoidance, monitoring and treatment or alleviation of any diseases/disorders (ii) Diagnosis and treatment, palliative treatment or assistance for, any disability or injury. (iii) Examination, variation, or replacement of the anatomic or of the physiological procedure. (iv) Supporting and sustaining life. (v) Disinfection of devices and Conception Control.

Further, it has been notified that from October 1, 2021, all currently unfettered medical devices should be registered by manufacturers or importers.[3] However, those medical devices, previously notified for regulation or regulated were exempted from the registration requirement. It is categorized under Class A (low-risk) and Class B (medium-risk) have to gain license before 11/08/2022, applied to all manufacturers, distributors, importers, retailers, and whole sellers. Further devices under Class C (medium-high risk) and Class D (high-risk) have to gain license before 11/08/2023 [as described in [Figure 1]].
Figure 1: Regulations for Medical Devices

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To obtain a list of medical equipment, manufacturers and importers must be accredited in accordance with ISO-13485 (Medical Devices, Quality Management Systems, Requirements for Control Objectives). It aimed to cover all medical equipment. Therefore, medical devices sold in India are regulated by Medical Devices Regulations 2017 which was amended in April 2020. Medical equipment that has not been notified by February 11, 2002 (excluding 37 categories), will be included under the new definition of medical equipment and will be called “Newly Notified Medical Devices.”[3]

The Medical Device (Amendment) Rules, 2020 (“MDR Amendment”) is the preamble of a new section for registration of recently Notified Medical Devices and is an exclusion of 37 categories of previously notified devices from the necessity of registration.[4] Apart from those medical devices listed under 37 categories, there is no quality checkpoint or regulations for Positron Emission Tomography (PET) Equipment and Bone Marrow Cell Separator by CDSCO, India. Thus, in the present manuscript, quality standards and regulatory requirements for the PET Equipment and Bone Marrow Cell Separator have been evaluated and a required checklist for the quality test have been suggested.


  Methods Top


In the present study, the survey-based checklist for two equipment has been studied and designed to maintain the overall quality.

Positron emission tomography equipment

PET is an advance method for the radiographic investigation to determine malignancies, gastrointestinal diseases, etc., that uses radiotracers to visualize and measure changes in metabolic processes, as well as other body functions including blood flow, local changes, composition, and absorption processes.[4] Various tracers are utilized for different imaging purposes. Like, 18F-FDG is typically used to distinguish malignant growth, NaF-F18 is utilized for identifying bone development, and oxygen-15 is used to gauge bloodstream. PET is an imaging procedure, a clinical scintillography method utilized in atomic medication. The radiopharmaceutical radioisotope attached to the drug is inserted into the body as a trace. Gamma beams are generated and separated by gamma cameras to form a three-dimensional image, aligned with these lines where the X-beam image is captured. PET scanners can joint with computed tomography (CT) scanners and then be acknowledged as PET-CT scanners. PET scan images can be resized using a CT scan performed with a single scanner during the same session. Section 121 ©[1] (A) of the Food and Drug Administration Modernization Act of 1997 engaged FDA to recognized CGMP necessities for PET drugs. Concurrently with the issuance of guidance, FDA is established this requirement in 21 CFR part 212. Various steps for Quality checklist are:[5]

  • Step 1-Designing of Primary checklist:
  • Step 2-Quality Assurance parameter evaluation
  • Step 3-Equipment qualification
  • Step 4-Evaluation.


Bone marrow cell separator

The bone marrow separator is a standard lab device that will be used to separate target cells from bone and blood-based cells. Bone marrow samples can be gained by aspiration and trephine biopsy. The cell separator is used primarily to collect blood platelets or thrombocytes. Although red blood cells primarily carry oxygen and other blood cells to protect them from infection, thrombocytes play a vital role in blood clotting. Peoples with less thrombocyte suffer from an incapability of the body fluid to coagulate appropriately. Bone marrow cell separator requires mandatory registration via CDSCO from April 1, 2021.[6]


  Results and Discussion Top


Quality check parameters for positron emission tomography equipment

Step 1 – Designing of Primary checklist

PET drugs designed to deliver twin photon positron emission tomographic pictures.[7] The radionuclide is usually formed by a particle accelerator (like cyclotron) and has a short half-life. As definite in 212.1 of the protocols, a PET drug comprises PET drug merchandise. Patients are usually given a PET medication product within a few minutes to a few hours of it being prepared. PET medicine products have specific storage, shipping, and handling difficulties due to the radionuclide's short half-life and the method of manufacture. Quality assurance work is required by Section 212.20 in the PET pharmaceutical industry. The following activities are described as legal process activities:[8]

  1. Monitor production to verify that PET medicines have well-specified identities, strengths, quality, and purity
  2. Examine components, containers, closures, in-process materials, and packaging and accept or reject them
  3. Approve or reject any proposed changes, as well as specifications, methods, processes, and procedures
  4. Examine production records to see whether any errors occurred. Determine the need for an inquiry and take necessary corrective action if errors have occurred or standards have not been met
  5. The Quality Assurance Function's role and responsibilities execution and oversight tasks make up the majority of the quality assurance job in a PET medicine manufacturing facility.


Step 2-Quality assurance parameter evaluation

The following functions should be included in the execution of quality assurance functions:

  • Before using a range of inputs, check, and evaluate them to make sure they meet the specifications
  • Before approving the final release or rejection of bulk PET drugs, collection records, and laboratory control records are checked for accuracy, completeness, and compliance with prescribed specifications
  • Ensuring that any deviations from normal operating procedures are properly documented and forgivable


We recommend that quality assurance activities be overseen by the following:

  • Consent for specifications and procedures required
  • Ensuring that staff are properly equipped
  • Ensure that the identification, efficacy, quality, and purity of PET medicines are well defined
  • Make sure all errors are checked properly. If an investigation is found to be necessary, record the investigation and take corrective measures to prevent errors from occurring
  • Periodic inspections are conducted to ensure that the prescribed procedures and procedures are followed.


Criteria for pet medication fabricating plant

A PET medication fabricating plant should have enough offices to guarantee the efficient treatment of materials and gear, the evasion of misunderstandings, and the aversion of defilement of hardware or item by substances, workforce, or natural conditions.[9] Methodologies are being set up to guarantee that this does not occur. Guarantee that PET medications have sufficiently characterized personality, strength, quality, and virtue. Guarantee that all errors are evaluated. At the point when not really set in stone that an examination is fitting, record the examination and take remedial action (s) to forestall the repeat of the any errors which occur. Periodic inspections are conducted to monitor compliance with established processes and procedures.

  1. A PET medication fabricating plant should have enough offices to guarantee the methodical treatment of materials and hardware, the evasion of mistakes, and the aversion of tainting of gear or item by substances, staff, or ecological conditions
  2. The execution of strategies to guarantee that all hardware that could sensibly be worked to adversely affect the personality, strength, quality, or virtue of a PET medication, or give incorrect or invalid test outcomes when inappropriately utilized or kept up with, is spotless, reasonable for its planned purposes, appropriately introduced, kept up with, and able to do reliably creating legitimate outcomes is perfect, appropriate for its expected purposes, appropriately introduced, kept up with, and fit for delivering substantial outcomes
  3. Exercises completed as per these rules
  4. Documentation of exercises completed in consistence with indicated guidelines is required
  5. Surfaces that come into contact with parts, in-process materials, or medication items should not be responsive, added substance, or absorptive to keep up with the nature of the PET drug.


As per USP chapter 1015 Automatic Radiochemical Synthesis Apparatus.[10]

The automated equipment

Applies to synthesis conducted by general-purpose robots and by special purpose apparatus. Both are automated devices used to assemble radiochemicals. The precise way to control the synthesis device varies. Both hard-core connecting devices and control software fall under the common name, and there is a spectrum ranging from conventional hand-held devices to semi-automated devices to fully automated devices.

Mutual fundamentals of automated synthesis equipment

Use of chemical materials to affect radiochemical combinations, control of parameters such as interval, temperature, pressure, capacity, and order is required. These parameters can be monitored and prevented from falling within certain limits.

Equipment qualifications

The aim of quality assurance is to aid confirm that the succeeding radiopharmaceutical meets standards of Pharmacopeia. Although the practice of good medical device production (21 CFR 820) may not work, it may be helpful in developing a quality assurance system. It involves the written measurement and control of all the relevant parameters controlled by the synthesis apparatus.

Routine quality control testing

A standard automated quality control test means periodic testing of all parameters initially approved during quality assurance. Depending on the severity and stability of the parameter setting, testing may be as frequent as the day. This performance appraisal process should be supplemented with a standard end product test. For example, variations in oil bath temperature may be acceptable if radiochemical (final product) can be shown to meet all related testing criteria.

Reagent audit trail

The materials and reagents used for the combination of radiopharmaceuticals must comply with the specifications and standardized tests. Procedures for the testing, storage, and use of these items should be established. In this context, the reagent is defined as any chemical used in the process, leading to the final radiochemical production, while the materials used are described as auxiliary substances (cylinders, glass containers, vessels, etc.). For example, in some procedures compressed nitrogen is used to transfer liquid reagents. In this case, both nitrogen and tubing must meet the required requirements.

Documentation of apparatus parameters

Significant variables to be identified, monitored, and documented. These factors include physical, chemical, electrical, and functional properties. Method to diagnose, test, and record computer and hardware-software is extremely important for microprocessors-and computer-controlled devices.[11] This program should include regular checks of the computer hardware. In addition, the software program code should be periodically checked to determine whether it has not been modified and that it continues with the result that the final product meets all specified specifications. In-process feedback is one of the ways to ensure that integration is under control. Changes to the software code must include a valid authorization process, and changes must be recorded. Each type of radiochemical synthesis device requires a set of specific procedures to test and monitor the reliability and reproduction of the various sub-systems that make up the integration system. It is important that the rating of each component is verified in accordance with the established repair timetable. The estimate or monitoring be made under actual consolidation conditions. Delivery times, reagent volumes, temperatures, gas pressures, and flow rates need to be measured and shown to be stable and reproducible within the set limits. Delivery of reagents and solvents requires periodic measurement. Other elements should be measured in general include the radiation detection system and sensory monitoring system and system.

Step 4: Evaluation

The PET scanner is designed to provide a detailed metabolic image of the human body. With a unique combination of positron output, enhanced images, and image processing, this scanner provides tomographic images with high resolution. A PET scanner can capture almost any organ that can enter a machine, doctors often use it as a standard image supplement to detect, stage, and control breast, brain, colon, and cancer.[12] It is very compact, portable, and easy to use with 3-D tomographic images and a stable procedure for patients (50% less pressure than mammography) and less time-consuming.

Quality check parameters for bone marrow cell separator

Bone marrow cell separator quality checks can be determined by the method published by Guttridge et al.[13] the samples can be obtained by aspiration and Trephine biopsy. In the manuscript, the authors provided detailed studies on factors affecting volume reduction and reduction of red bone marrow cells in the COBE Spectra cell separator proceeding to embedding of hematopoietic stem cells. The authors explained that the transit time between the collection and recycling center should be reduced once it has been obtained from the processing center laboratory. Furthermore, after collection, the cells should be refrigerated overnight for better cell recovery.[13],[14]


  Conclusion Top


The new regulations increase the accountability of the manufacturers and the importers also provide an assurance of safety to the customer. It needs to be motivated by a choice of public health care options instead of seeking USFDA and CE approval. For the import of medical devices, the application should be reviewed on the basis of risk analysis as suggested for these two devices. Further, local manufacturing of Medical Devices should be encouraged in India for reduced the cost of medical devices. Now a day, NPPA is also capping the price of medical devices. Due to which most of the MNC companies like ABBOTT have withdrawn their medical devices from the Indian market. Substantial amendments and streamlined processes will motivate manufacturer to have a manufacturing of devices in India. CDSCO, New Delhi, is continuously working in that direction and also, these suggested quality checks would help in assuring the quality of medical devices such as PET and bone marrow cell separators. The Bone marrow cell seperator requires mandatory registration in India w.e.f 1 April 2021, the registration is under Class B of Medical Devices.

Acknowledgments

The authors are thankful to Amity University Uttar Pradesh and CDSCO, New Delhi for providing basic infrastructure to carry out the present study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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2.
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3.
Drug Controller General of India, Directorate General of Health Services, FDA Bhawan; Classification of Newly Notified Medical Devices. Available from: https://cdsco.gov.in/opencms/opencms/en/Medical-Device-Diagnostics/Medical-Device-Diagnostics/. [Last accessed on 2020 Dec 17].  Back to cited text no. 3
    
4.
Health Ministry Notifies Medical Devices Rules 2017. Press Information Bureau, Government of India; 2017. Available from: https://cdsco.gov.in/opencms/export/sites/CDSCO_WEB/Pdf-documents/medical-device/digosfaq19.pdf. [Last accessed on 2018 Aug 28].  Back to cited text no. 4
    
5.
European Commission. Guidelines for the Classification of Medical Devices; 2001. Available from: https://tinyurl.com/y7ccb9bl. [Last accessed on 2019 Jul 18].  Back to cited text no. 5
    
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Baspinar O, Irdem A, Kilinc M. Off-label use of Amplatzer devices in congenital heart disorders during childhood. Acta Cardiol 2013;68:31-35.  Back to cited text no. 6
    
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Medicines and Healthcare Products Regulatory Agency. Guidance: Off Label Use of a Medical Device; 18 December, 2014b. Available from: https://tinyurl.com/y8p28fh8. [Last accessed on 2018 Jul 12].  Back to cited text no. 7
    
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Medicines and Healthcare Products Regulatory Agency. Medical Devices: Conformity Assessment and the CE Mark; 2016. Available from: https://tinyurl.com/yadzgv8j. [Last accessed on 2018 Jul 12].  Back to cited text no. 8
    
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European Commission. Council Directive 93/42/EEC; 14 June, 1993. Available from: https://tinyurl.com/haq6prc. [Last accessed on 2018 Jul 12].  Back to cited text no. 11
    
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Lennard N, Coutinho M, Campbell B. The surgeon and medical devices: Adverse incident reporting and off-label use. Ann R Coll Surg Engl 2013;95:309-10.  Back to cited text no. 12
    
13.
Guttridge M, Sidders C, Booth-Davey E, Pamphilon D, WattS M. Factors affecting volume reduction and red blood cell depletion of bone marrow on the COBE Spectra cell separator before haematopoietic stem cell transplantation. Bone Marrow Transplant 2006;38:175-81.  Back to cited text no. 13
    
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Cochrane Database System Rev. 2010:CD007798. https://doi.org/10.1002/14651858.cd007798.pub2.  Back to cited text no. 14
    


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