ivd inspections technical update 2018 · • iso 14971:2007 (2012) medical devices-application of...

IVD Inspections

Technical Update 2018

Dr Dragana Milic

Medical devices inspections

1 Copenhagen, Denmark 24-28 September 2018


• Harmonisation - internal and external

(PQ Medicines/Vaccines/Vector Control and MDSAP)

• Transparency (clarify rules and requirements)

• Are we hitting the mark, what can we do better together?

Objectives


• Requirements of mature national regulatory authorities

including: USA FDA, Australian TGA, Health Canada,

Japanese PMDA, Brazilian ANVISA

– These are MDSAP Authorities

– (Medical Devices Single Audit Program)

Observers

– WHO - Diagnostic Prequalification Program

– European Union (a decision about full participation?)

MDSAP


Recognized Auditing Organisations conduct audits of a

medical device manufacturers that satisfy the QMS

requirements of 5 Regulatory Authorities. WHO requirements

about to be added.

– ‘Single Audit Program’

Initiated in 2012 by the International Medical Device

Regulators Forum - IMDRF - ex GHTF

Pilot ended 2016, transition until end 2018

MDSAP

Assess and recognize

Make regulatory decisions – Market Authorisation

Audit and certify

Share audit report and certificate

Auditing

Organisations

Medical

Device

Manufacturers

Regulatory

Authorities CONCEPT

5


• PQDx_014 Information for Manufacturers on the Inspection of

Manufacturing Site(s)

• ISO 13485:2003 and 2016 Medical Devices-Quality

management systems – Requirements for regulatory purposes

• ISO 14971:2007 (2012) Medical devices-Application of risk

management to medical devices

• IMDRF and GHTF Documents

Reference and Guidance documents


Assessment Types


Full Assessment

Dossier review Site inspection Laboratory evaluation

Dossier incomplete

PREQUALIFICATION DECISION

Dossier complete

Dossier screening

Priority product

Yes

No

Maintenance of PQ Status


Abridged procedure

Site inspection Laboratory evaluation

Priority product

Yes

No

Maintenance of PQ Status

PREQUALIFICATION DECISION

Review on-site

dossier aspects


Inspection Process

Stage 1

Plan

Stage 2

Inspection

2 rounds CAP

Ready for

Inspection

Compliant

(<7 level 4 NC)

(Seek techn.

assistance)

Recommendation for

PQ

No

Yes

Yes

No

Dossier Screening

Dossier Review

List of

questions

Compliant?

2 rounds CAP

Yes

No

No

No

Terminate

Yes

Terminate


Element Required documents

Quality

Management

System

Quality manual including staff organogram

List of current quality management procedures (SOP)

Standard operating procedures for:

Complaint handling and vigilance

Control of nonconforming goods/processes

Change control/change notifications (product and

processes)

Risk management

Supplier evaluation and control, verification of purchased

product

Design and development

Audit report of the most recent full regulatory inspection/audit

and all subsequent surveillance inspections/audits

Any valid quality management system certificate(s) (e.g. ISO

13485)

Name and contact details of the responsible person at the site

of manufacture regarding the inspection

Required information – Full and Abridged

Inspection



Product Labelling (instructions for use (IFU),

component and box labels

Photographs of kit, box including contents, kit components

Accessories (including photographs)

Copy of current product regulatory approval certificate(s)

Summary of changes initiated or applied to the product

subsequent to the above regulatory approvals


Inspection



Manufacturing

Full address, including latitude and longitude of the

manufacturing facility(s)

Site floor plan

Manufacturing flowchart including in-process control points

List of critical raw materials ( including details of the

supplier of each material)

List of outsourced processes with direct product impact

(e.g. outsourced manufacturing of components (conjugated

antibodies, strips, reagents…), outsourced laboratory testing,

packaging, printing, etc.) including details of the supplier for

each process


Inspection

– WHO is taking into account the outcomes of MDSAP

inspections.

– WHO is reviewing MDSAP reports and where they include

the evidence of manufacturer‘s compliance with relevant

requirements a WHO inspection may be:

• Waved

• Shortened

• Undertaken as planned

– Exceptions - for couse inspection; or requested during

screening or dossier assessment process.

25/09/2018 14

On site inspections and MDSAP

WHO is worknig with MDSAP, AOs and manufacturers

– Content of the MDSAP report to enable utilisation in lieu of

WHO inspection:

• Includes relevant requirements of ISO 13485

• Includes eidence of compliance with WHO specific

requirements

• Evidence of implemenetation of TSS, TGS, standrads

• Product specification requirements

25/09/2018 15

International Alignment – WHO‘s activities

– Content of the report continued:

• Risk management (appropriate for intended use)

• Design inputs/outputs including TSS

• Performance requirements,

• Design validation: Usability in resource limited settings

Clinical data, performance data

Stability

Labeling, IFU

QC requirements

• Feedback provisions

• Other

25/09/2018 16

International alignment

Prerequisite for an onsite inspection



• Fully implemented quality management system (design &

development, manufacturing including quality control, storage,

distribution)

• Meets ISO 13485:2003 requirements with the transition to 2016

version still often delayed ( external reasons seem preveiling)

• Product design,

• Validation of processes

• Products undergoing prequalification must be in routine

manufacturing

• Sufficient capacity to ensure reliable delivery

• Quality control processes follow risk principles, performance tested

according to claims in instruction for use

• Storage conditions, temperature and humidity, validated for

intermediates, components and kit, real time data required

Quality Management System


• Risk management to meet ISO 14971:2007 (2012)

• Throughout product lifecycle

• Risk management for product realisation

(design, manufacturing, storage,

transportation), user and patient

• Risk management file

• Risk management plan

• Risk analysis

• Risk evaluation and control

• Residual risk acceptable?

Risk management


• Product stable to meet challenging conditions (hot, wet,

dry, dusty)

• Stability ensured by design

• Stabilty ensured through teh control of critical

processes

• Transportation studies (simulate "worst" conditions)

• Long term stability at limiting conditions

• In-use stability studies (open kit, strip, vial)

• Data to support all claims available on-site

• Consistency of product labelling (component, kit and

shipping box)

Product Stability


• Transfer from R&D to production completed

• Evaluated and approved suppliers (think of services!)

• Validated processes (acceptance ranges determined, in-process controls established)

• Standardized batch sizes

• Established non-conformance management and "out-of-specification" processes

• Batch manufacturing records established (include all manufacturing information, full traceability of material and equipment)

• Trained personnel (requirements determined, training plan, records)

Routine Manufacturing


Abridged Inspection


Abridged Inspection

• Aim:

• To avoid duplication

• Reduce time

• Reduce cost

• When:

• If a stringently assessed regulatory version is submitted for

prequalification

• If a non-stringently assessed (rest of the world) regulatory

version of the product is submitted for prequalification

assessment but a stringently assessed regulatory version

also exists (no difference between the two versions)


Stringently Assessed

• Approved by a GHTF/IMDRF founding member regulatory authority and assessed at a level comparable to that required by WHO

• Competent Authorities from the Member States of the European Union

• Directive 98/79/EC on in vitro diagnostic medical devices

• Associated Notified Bodies

MDSAP authorities

• US FDA

• Health Canada

• Japanese Ministry of Health, Labour and Welfare

• Australian TGA

• Brazilian ANVISA


PQ Stage

Full assessment

Abridged assessment

Dossier review Yes No

Site inspection Full Inspection Abridged inspection (information

package requested)

Laboratory evaluation Yes Yes

Full and Abridged Inspections


• Less time spent on site

• Fewer inspectors (usually one inspector and one technical

expert)

Objectives of Abridged Inspections


• Inspection team determined

• Communication with manufacturer (suitable inspection dates,

required documentation)

• Manufacturer to agree on the inspection team (Brief CVs

provided)

• Inspection plan provided one to two week prior to the

inspection

Inspection planning


• Opening meeting, debriefings, full transparency

• Open exchange of information between WHO and

Manufacturer throughout the entire process

• Inspection of the full site to review the manufacturing process

• Manufacturing of the WHO/or a similar product is

required

• Access to all requested documents and records

• Sampling process with risk based emphasis

• Review and confirmation of raw data related to the dossier

submission including all validations, stability studies and

performance data

The onsite Inspection


• Follows MDSAP model

• Utilises MDSAP report format and Ninconformities Grading and

Exchange (NGE) form.

The onsite Inspection

Ris

k M

anagem

ent

Purc

hasin

g

30

Management

Device Marketing

Authorisation and

Facility

Registration

MD Adverse

Events and

Advisory Notice

Reporting

Device Marketing

Authorisation and

Facility

Registration

Measurement,

Analysis and

Improvement

Design and

Development

Production and

Service

Controls

MDSAP

Audit

Sequence

of ISO

13485

and

Regulatory

Processes

• Design and Development

• Priority criteria for selection of design files for review:

• Complaints of known problem with a particular device,

• Product risk

• Recent design changes particularly design changes

made to correct quality/design problems

• Reviewing complaints and NCs enables this selection

31

MDSAP Model, its application by WHO and

how/why it makes sense?

• Production and Service Controls

• Priority criteria for selection of production processes for

review:

• Corrective and preventive action indicators of process

problems…

• Production processes for higher risk products…

• Processes with direct impact on devices quality….

32



• Production and Service Controls continued:

• Purchasing: criteria for selection of suppliers:

• Indications of problems with supplied products or

processes from audit of the Measurement, analysis and

Improvement process……

33




• Closing meeting to discuss any findings

• A list of findings is left onsite for the manufacturer to begin CAPA preparation whenever possible.

• A report is issued within 30 days of the site inspection unless otherwise informed. (Of note MDSAP reports are required to be issued by AOs within 90 days).

• WHO challenge - aligning MDSAP reporting format with WHO’s reporting timelines.

• Grading of nonconformities is automated and independently reviewed before the final report is released.

End of Inspection


• Based on the GHTF Model

GHTF/SG3/N19:2012

‘Quality management system – Medical devices – Nonconformity

Grading System for Regulatory Purposes and Information

Exchange’.

Grading nonconformities - Levels 1 to 5.

Grading of nonconformities

Nonconformity grading

•GHTF N19 - Nonconformity Grading System for Regulatory Purposes

•NCs are assigned a grade, 1 – 5

•Calculated in two steps

– Grading Matrix

– Escalation Rules

No Documented Process, +1

Release of nonconforming medical device, +1

3 4

1 2

Occurrence

Imp

act

First Repeat

Indirect

Cl 4

.1 –

6.3

Direct

Cl 6

.4 –

8.5

.3

36


• Required to be submitted within 30 days of receipt of report

• Root cause analysis

• Correction

• Corrective action

• Timeline and responsible person/department

• Evaluation of the effective implementation of the

corrective action

• Two rounds of CAPA are allowed

Corrective action plan


14

33

11

25

16

59

16

50

0

10

20

30

40

50

60

70

Number of Inspection Number of products reviewed

2015

2016

2017

2018

Inspection statistics


Next presentation:

Inspection findings

What worries us (and you)

Expectations

Where to find information


• Contact us by email

[email protected]

• Sign up for our mailing list

By emailing [email protected]

• Check our website

http://www.who.int/diagnostics_lab

oratory/evaluations/en/

mailto:[email protected]