GMP inspection reliance from a PIC/S perspective

Boon Meow HoePIC/S Immediate Past Chairman cum Member of PIC/S Executive Bureau (2020 – 2021)

Contents

1. Some terminologies used

2. PIC/S Inspection Reliance Journey

3. NASEM 2020 published : “Regulating medicines in a globalized

world: The need for increased reliance among regulators

4. PIC/S GMP Inspection Reliance Guidance Document & Framework?

5. PIC/S GMP Inspection Reliance Statistics

6. Challenges

Reliance

Harmonization

Convergence

Work

sharing

Confidence

building

Recognition

Information

exchange

TrustTreaty

Alignment

Some terminologies used

Source: Adapted from a figure created by Dr. Petra Doerr

Recognition

Reliance

Work sharing

Confidence building

Information Sharing

Trust

TrustReliance

and Recognition

Although the Working Group on PIC/S Inspection Reliance was only established in

2020, inspection reliance has a long history in PIC/S.

In the context of increased foreign inspections, PIC/S has taken a number of

measures over the past few years to reduce duplicate foreign inspections such as

➢ through the maintenance of a list of planned foreign inspections (since 2012);

➢ through the adoption of various procedures such as the PIC/S procedure for team

inspections (PI 031-1), in force since 1 September 2009; and

➢ through the “Procedure to inform Foreign Regulatory Agencies of Foreign

Inspections to be conducted in their Jurisdiction” (PI 039-1), which entered into

force on 1 November 2015.

PIC/S Inspection Reliance Journey

➢ In 2015 a survey on “same scope inspections” was carried out amongst all PIC/S

PAs to understand how Members deal with “same scope inspections”

➢ In 2017, the Committee accepted an offer from International Coalition of Medicines

Regulatory Authorities (ICMRA) to take over the ICMRA GMP project and to adapt

the ICMRA draft Guidance on Inspection Reliance for PIC/S purpose.

The PIC/S Guidance on Inspection Reliance (PI 048-1) was adopted

by the Committee in April 2018 with an entry into force on 1 June 2018.

➢ In 2019, PAs were invited to collect statistics on desk-top assessments.

The purpose of these statistics is to document the efforts made by PIC/S PAs to rely

on existing inspection reports rather than duplicate foreign GMP inspections.

PIC/S Inspection Reliance Journey (Continue…)

➢ The 2019 statistics also revealed a marked difference between PAs, which are

EU/EEA Competent Authorities and which only rely on EU/EEA or MRA GMP

certificates, and PAs, which are not Members of the EU/EEA and which rely on

MRA GMP certificates and, more generally, on PIC/S inspection reports.

➢ In order to identify barriers that prevent PAs to rely on already existing inspection

reports, the Committee, based on a proposal by the SCSD, established a Working

Group on Inspection Reliance on 6 October 2020 (PS/INF 60/2020). The Working

Group, led by Stephen Farrell (Australia / TGA), comprises 7 Members from 6 PAs.

PIC/S Inspection Reliance Journey (Continue…)

https://doi.org.10.17226/25594

National Academies of Sciences,

Engineering and Medicines (NASEM)

• Formal and informal recognition and

reliance arrangements are highly effective

tools

• Help regulatory authorities to address

public health challenges from increasing

complexity of medicines and globalised

supply chains

• Regulation through such arrangements

can now be considered as 21st century

“best regulatory practice”

Inspection Reliance

Inspection RelianceNASEM 2020

Regulating medicines in a globalised world: The need for

increased reliance among regulators

Regulatory systems could be reviewed with an eye to

effectiveness i.e. doing the right thing

and

efficiency i.e. doing the thing right

➢ Leveraging the work of other trusted authorities is essential

Benefits

10

At the request of ICMRA:

GMP

INSPECTION

RELIANCE

PIC/S GUIDANCE ON GMP inspection

reliance

Adopted by PIC/S on 1 June 2018

PURPOSE & SCOPE

Conclusion: Aligned

The aim of the ICMRA guidance is to help “Inspectorates to prioritise resources for GMP inspections. It outlines a process for remote assessment of GMPcompliance of overseas facilities to identify instances where an acceptable level of GMP compliance can be confirmed and assured from the activities of anotherregulatory authority or authorities without the need for an onsite inspection.”

The aim of the ICMRA guidance is compatible with Chapter X of the PIC Scheme on the Sharing of Information, in particular paragraph 33:

“The aim of sharing information in PIC/S is to facilitate the risk management made by each Participating Authority on whether to carry out or not an inspection. It gives Participating Authorities the possibility to share in confidence any information e.g. on whether medicinal products have been produced in accordance with the GMP requirements applied in PIC/S or whether such products are due for inspection.”

ICMRA guidance is voluntary

Conclusion: Aligned

The ICMRA document provides non-binding “high level guidance” to facilitate the assessment

process and does not supersede country / regional guidance, procedures or legislation where

they exist.

This is in line with the PIC Scheme, which provides that:❖ “In line with the PIC/S Guidance on GMP Inspection Reliance, the sharing of information in PIC/S

shall be fully voluntary” (paragraph 32).

❖ “Information shared in PIC/S is not binding for the Participating Authority which has requested it.

Each Participating Authority shall remain competent on how to use the shared information.

There is no obligation to accept the conclusions from another Participating Authority in PIC/S.” (paragraph 34)

❖ “The sharing of information in PIC/S shall be subject to legal requirements such as laws, decrees, and treaties

– including regional integration treaties (e.g. EU or ASEAN) and Mutual Recognition Agreements.

It shall not affect the exchange of GMP certificates under such treaties and agreements.” (paragraph 35)

“r”= reliance

“MrA” is not an official term. It is a self-created term

”MrA” = Mutual reliance Arrangement

International Coalition of Medicines Regulatory Authorities

ICMRA’s GMP reliance Framework / Tool

Hosting CARequesting CA

GMP Certificate? (Min.)✓Hosting CA✓Central depository (e.g.

EudraGMP)

Inspection report (Min.)

Additional information:latest inspection by the hostingCA. E.g. dates , scope,

outcome, report, CAPA plan, and next inspection date (if known).

Postinspectioninformationfromhosting CA

Information relating toinspections by other CA

Assessment of site compliance

Gathering

information

Site Master File(SMF)

Risk assessmentE.g. changes

Additional

Information: From other sources:

E.g. warning letters, rapid alerts and recalls.

Obtained from the manufacturer and verified with the hosting CA if necessary

•

• AIM: to gain assurance that GMP compliance has been established and

that there is no other new evidence that would warrant an on-site

inspection by the requesting authority

• The assessment outcome should be recorded

• The outcome of the assessment should be communicated to the

manufacturing site and the local authority

Assessment and Outcome

Triggers for Requiring an On-Site Inspection

•

•

Triggers

for an

on-site inspection

Failure of the site to supply the requestedinformation

There is no inspection history for thesite

Information about the products inspected at the siteis not supplied

The GMP evidence does not coverproducts or processes requested

Another inspectorate hasnot approved the manufacturing facility, or dosage forms

Additional

considerations:➢ Translation may be needed

➢ Need to protect the confidentiality

of information shared

➢ Questions to the hosting CA

should be specific and once off if

possible. i.e. kept to a minimum

for the purpose to verify

information provided by the

manufacturing site with the

hosting CA to ensure its

authenticity.

Monitoring and review

PIC/S Inspection Reliance

Summary statistics of the number of inspections waived by PIC/S PA in 2019:

• 19 out of 54 Agencies (53 PA + Brazil / ANVISA) provided statistics (35 PAs had either no statistics available or “0”)

• Around 7,400 inspections were waived of which 5,400 (PIC/S), 1,800 (MRA) and 200 (MOU & others).

• Some PAs do not distinguish between PIC/S and MRA. As a result, MRA figures are underestimated.

Statistics under PIC/S Guidance on Inspection Reliance (PI 048-1) in 2019:

Total number of foreign GMP inspections

waived

7,413

of which due to reliance on GMP

inspection reports / certificates from:

PIC/S PAs* 5,423

MRA Partners* 1,801

MoU Partners 96

Others 93

Have you carried out joint inspections

with another PIC/S PA (e.g. under the

International API Inspection

Programme)?

YES: 5

If yes, how many? 27

PIC/S Inspection Reliance

19 Agencies having responded to survey come from:

2

17

EEA NON-EEA

PIC/S Inspection Reliance

35 PAs with no figures available or “0” come from:

29

6

EEA NON-EEA

PIC/S Inspection Reliance

Challenges - MrA

The need to respect sovereignty –

National (or supranational) legislations does not allow a CA to waive an

overseas on-site GMP inspection.

“Lack of political will…”

Challenges -- MrA

Political

Will

• Leadership direction to rely on

and trust others

Legislation• Sovereignty & national provisions to be

respected

Practice

• Learn from others &

implement

• Monitoring

Political will is needed

Challenges and possible way to fix it:

Conclusions

• International inspection cooperation has been an increasing area of focus

• PIC/S plays an important role in bringing about regulatory convergence through harmonization of requirements, training and exchange of information between participating authorities

• The PIC/S Reliance Framework and PIA offer standardized multilateral

structures that facilitate better use of inspection resources

• As with any significant change, continued leadership is required to fully

implement the inspection reliance frameworks

Acknowledgement and thanks to:

PIC/S Secretariat, Geneva

Susan Laska, US/FDA, Chair of PIC/S Sub-Committee on Strategic Development

National Academies of Sciences, Engineering, and Medicines. 2020Dr. Petra Doerr