GMP Clearance

Stephen Farrell Director (A/g), GMP Clearance SectionDarika Sowana Assistant Director, GMP Clearance Section

Overview• Where we are now, future direction and focus• GMP agreements and the PIC/S guide• Answers to Industry’s most frequently asked questions• GMP Clearance for listed, over-the-counter and prescription medicines

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Where we are now, future direction and focus

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Background - January 2016• GMP Clearance team of 7 within the

licensing and certification section:– 4 in application receipt– 3 in assessment

• Mutual Recognition Agreement (MRA) backlog

• Compliance Verification (CV) backlog

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Background - January 2016• Sterile CV’s performed by Inspectors• GMP Clearance mailbox backlog• Extensions backlog• Transfers and name changes backlog• Outdated guidance• Poor system processing and data capture• Poor quality applications

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Progress – 2016 to 2017

Initially Targeted

MRA, extension and email backlogs

Improved internal

monitoring and

reporting capabilities

Re-designed the

application e-form

Re-wrote the GMP

Clearance guidance and

introduced CAAT

Streamlined receipt and assessment processes

Recruitment

Training

Measure

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Progress – 2018 to 2019

Reduction of the CV back-

log

Introduced TGA vs

industry time

Several guidance updates

Published new target timeframes

Recruitment

Training

Measure

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November 2019• We are now a GMP Clearance Section of

20 staff ‒ 5 in application receipt‒ 15 in assessment

• No backlogs across the section• Accurately capturing TGA vs Industry time• Improved data analytics to ensure no

return to backlog7

November 2019• Published processing times‒ MRA – 30 working days‒ Non Sterile API – 60 working days‒ Sterile API – 75 working days‒ Non Sterile finished product – 90 working days‒ Sterile finished product – 120 working days

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Our impact

7%

93%

Overseas Manufacturers

On-site Inspections

GMP Clearance

68%

32%

MRA vs CV

MRA

CV

44%56%

API vs Product

API

Product

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MRA or equivalent breakdown

3.30%

92.03%

3.71%

0.96%

0.00% 10.00% 20.00% 30.00% 40.00% 50.00% 60.00% 70.00% 80.00% 90.00% 100.00%

CANADA

EUROPE

NEW ZEALAND

SINGAPORE

MRA Pathway

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Compliance verification breakdown

44.79% 27.41% 9.94% 4.36%

1.89%

1.76%

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CV pathway

India US China Japan Israel

Taiwan Korea - Republic of Mexico Slovenia Argentina

Romania Turkey Croatia Bulgaria Macau - SAR of China

Thailand Brazil United Arab Emirates United Kingdom Malaysia

Oman South Africa Serbia - Republic of Bangladesh Chile

Hong Kong - SAR of China Indonesia Italy Jordan Canada

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GMP clearance metrics

649 606 584 572 548 559 530 561 525 494 504 494 512 520 518 487 482 492 452 432

85136 172 169 166

221182 156 159

196 209170 168 176

139 146189 161 152

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0

100

200

300

400

500

600

700CVs total MRAs total

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CV applications by type

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CV incoming vs outgoing

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CV applications (474) - status breakdown

1 Nov 201915

MRAs not issued

16

CVs not issued

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Future direction and focus• Expect a period of stability • Continue to select complete over incomplete applications• Further education and engagement with industry• Focus will be on internal processes and improvements• Continue to evolve our data analytic capabilities • Only action true priority requests i.e. for reported medicine

shortages• Increased involvement in the Indo-Pacific Regulatory

Strengthening Program

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Future direction and focus• Increased focus on 2 key areas of

assessment:– Release For Supply– GMP agreements

• These areas are the biggest source of deficiencies for finished product GMP Clearances

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Future direction and focusWhy focus on Release for Supply and GMP agreements?

– Australia has no Qualified Person (QP) system – We do not license our sponsors or regulate Good

Distribution Practice (GDP)– Proposed update to Annex 16 (Certification by the

Authorised Person and Batch Release)

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GMP agreements and the PIC/S guide

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Manufacturer outsourced activities• Cleaning• Training• Waste management• Outsourced engineering for

facilities and equipment• Contract hire services• Suppliers of materials and

components

• Regulatory affairs consultants• Outsourced vendor auditing• Expert consultation• Certification• Calibration• Testing and analysis• Contract manufacture

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MAH Outsourced

Activities

Finished Product

MNF

Testing Laboratory

Alternative Finished Product

MNF

Alternative Testing

Laboratory

MAH Outsourced

Activities

Finished Product

MNF

Testing Laboratory

Alternative Finished Product

MNF

SteriliserSecondary packaging

MNF

API/Drug Substance

MNF

Release for Supply (AP)

OR

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PIC/S Chapter 7

Clause (updated text in red) Requirements for GMP Clearance

7.1 There should be a written contract covering the outsourced activities, the products or operations to which they are related, and any technical arrangements made in connection with it.

All outsourced activities need to be covered by a contract

7.3 Where the Marketing Authorisation holder and the manufacturer are not the same, appropriate arrangements should be in place, taking into account the principles described in this chapter.

Generally, contracts must be in place between the sponsor and manufacturer

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PIC/S Chapter 7Clause (updated text in red) Requirements for GMP Clearance

The Contract Giver7.4 The Pharmaceutical Quality System of the Contract Giver should include the control and review of any outsourced activities. The Contract Giver is ultimately responsible to ensure processes are in place to assure the control of outsourced activities. These processes should incorporate quality risk management principles….

How is the Contract Acceptor reviewed/controlled?

MAH should demonstrate the suitability/legality of the contract acceptor.

7.4.1 Prior to outsourcing activities, the Contract Giver is responsible for assessing the legality, suitability and the competence of the Contract Acceptor to carry out successfully the outsourced activities. The Contract Giver is also responsible for ensuring by means of the contract that the principles and guidelines of GMP as interpreted in this Guide are followed.

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PIC/S Chapter 7

Clause (updated text in red) Requirements for GMP Clearance

7.4.3 The Contract Giver should monitor and review the performance of the Contract Acceptor and the identification and implementation of any needed improvement.

Need processes for monitoring of outsourced activity

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PIC/S Chapter 7Clause (updated text in red) Requirements for GMP Clearance

7.7 The Contract Acceptor should ensure that all products, materials and knowledge delivered are suitable for their intended purpose.

Evidence of appropriate knowledge transfer

7.8 The Contract Acceptor should not subcontract to a third party any of the work entrusted under the contract without the Contract Giver’s prior evaluation and approval of the arrangements. Arrangements made between the Contract Acceptor and any third party should ensure that information and knowledge, including those from assessments of the suitability of the third party, are made available in the same way as between the original Contract Giver and Contract Acceptor.

Evidence of appropriate knowledge transfer

MAH must be made aware of subcontracting as well as issues with subcontractors

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PIC/S Chapter 7Clause (updated text in red) Requirements for GMP Clearance

7.11 A contract should be drawn up between the Contract Giver and the Contract Acceptor which specifies their respective responsibilities and communication processes relating to the outsourced activities. Technical aspects of the contract should be drawn up by competent persons suitably knowledgeable in related outsourced activities and Good Manufacturing Practice. All arrangements for outsourced activities must be in accordance with regulations in force and the Marketing Authorisation for the product concerned and agreed by both parties.

Modification to existing agreements may be required

Review and assess the suitability of your existing agreements

Emphasis may need to be on the communication processes to ensure these are clear and unambiguous

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PIC/S Chapter 7Clause (updated text in red) Requirements for GMP

Clearance

7.12 The contract should describe clearly who undertakes each step of the outsourced activity, e.g. knowledge management, technology transfer, supply chain, subcontracting, quality and purchasing of materials, testing and releasing materials, undertaking production and quality controls (including in-process controls, sampling and analysis).

Some modification to existing agreements required

MAH access to documents required

Supply chain integrity

7.13 All records related to the outsourced activities, e.g. manufacturing, analytical and distribution records, and reference samples, should be kept by, or be available to, the Contract Giver. Any records relevant to assessing the quality of a product in the event of complaints or a suspected defect orto investigating in the case of a suspected falsified product must be accessible and specified in the relevant procedures of the Contract Giver.

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Chapter 1 pharmaceutical quality systemProduct Quality Reviews (PQR) Requirements for GMP Clearance

1.11 The manufacturer and, where different, Marketing Authorisation holder should evaluate the results of the review and an assessment made as to whether corrective and preventive action or any revalidation should be undertaken, under the Pharmaceutical Quality System. There should be management procedures for the ongoing management and review of these actions and the effectiveness of these procedures verified during self-inspection. Quality reviews may be grouped by product type, e.g. solid dosage forms, liquid dosage forms, sterile products, etc. where scientifically justified.

MAH to review the annualPQR and ensure a mechanism is in place for any potential required actions

One of these reviews is regarding Market Authorisation variations (1.10 vi) submitted, granted or refused

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Chapter 1 pharmaceutical quality systemPQR Continued Requirements for GMP Clearance

Where the Marketing Authorisation holder is not the manufacturer, there should be a technical agreement in place between the various parties that defines their respective responsibilities in producing the product quality review. The Authorised Person responsible for final batch certification together with the Marketing Authorisation holder should ensure that the quality review is performed in a timely manner and is accurate.

Contracts should cover the MAH input into and subsequent review of the PQR

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Industry’s most frequently asked questions

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Communication and educational materials• Since January 2019, we have implemented

a range of communication, educational materials and activities to provide support for industry

• Continuing efforts to seek feedback to inform our stakeholder engagement and regulatory activities

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GMP Clearance Guidance

V 18.3

Clearance ApplicationAssistance Tool (CAAT)

GMP Application

Decision Tree

Educational Materials and

Communications

News UpdateWebinars

GMP Clearance Application

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General feedback mechanisms• TGA Industry Working Group on GMP

(TIWGG) industry association members• GMP Clearance Inbox• Additional Research Initiative - GMP

Clearance Industry Survey (Aug-Sep 2019)

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GMP clearance industry survey• 196 completed the survey in full• 62.4 % - mostly satisfied with the current

communication• 96% refer to GMP Clearance guidance

when submitting application• 58% - aware of the Clearance Application

Assistance Tool (CAAT)

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General GMP clearance process

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I want to import a dietary supplement from the US, what information do I need to provide and can I access the MRA pathway?

• MRA Pathway not available for manufacturing sites in USA• US FDA does not regulate dietary supplements the same way as Australia• US FDA applies dietary supplement GMP standards which is not the same as the US FDA drug

GMP standard • For a dietary supplement manufacturer in USA, it is most likely that a TGA on-site inspection will be

required

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How does TGA determine the period of GMP clearance validity? What is the maximum expiry the TGA provides?

• The validity is typically 3 years plus 6 months• The 6 months additional validity is essentially an automatic extension• In some cases, validity may be reduced because:

– condition placed by the regulator – compliance issues– determined during an assessment of the evidence

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If TGA has conducted an on-site audit, does TGA issue a GMP clearance to the sponsor or does the sponsor have to apply for a GMP clearance post TGA inspection?• TGA overseas on-site inspection = TGA Certification (CE) application• GMP Clearance issued after the inspection is successfully closed out.• GMP Clearance automatically issued to sponsors who contribute towards the

inspection cost

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If my application is marked to ‘with manufacturer’ what does this mean? Shouldn’t I have received a ‘request for information’?

• The status ‘With Manufacturer’ indicates a stop clock is applied• Reasons:

‒ Outstanding fee payment‒ Missing or incorrect evidence i.e. incomplete application‒ Deficiencies identified during assessment

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I am experiencing issues in validating my clearance for a product listing / variation? The validation message says my clearance is not licensed for the selected dosage form, what should I do?• Confirm the relevant regulatory area - dosage form and/or manufacturing steps for your

listing application. • Then submit either a clearance application or a variation to include correct scope

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GMP clearance extension

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My clearance has expired for 6 months. Unfortunately my predecessor did not apply for extension at the time prior to their departure from the organisation. Can I please get an extension on the clearance?• Extension requests can be submitted up to 30 days after the expiry date

of their GMP clearance• Expired GMP clearances (i.e. > 30 days) may be reinstated at your

request • The fee to reinstate a GMP Clearance is $1,180

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How to deal with timing issues when GMP clearance is due to expire and a competent authority has not yet inspected the site, or has inspected the site but the report/certificate is not yet available?

• MRA - submit an extension request (TBS portal) - stating the reason

• CV - if no acceptable evidence, then the alternative option is a TGA on-site inspection

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What is the impact of Brexit on my GMP Clearances?• Due to Brexit, the MHRA has recently issued a number of

GMP Certificates from a desktop assessment (DTA) for UK manufacturing sites

• MHRA DTA GMP Certificate is accepted for extension requests

• MHRA DTA GMP Certificate is not sufficient evidence for a full renewal of a clearance

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GMP clearance evidence

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Besides poor quality documents what other common reasons are GMP clearances not issued?

• Inequivalent GMP standards used• Inadequate or no responses received as requested during assessment• Insufficient detail in the inspection reports • Expired evidence • Lack of clarity in GMP Agreements and supply chains

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GMP Clearance for Complementary, Over-the-counter and Prescription Medicines

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Product registration or listing on the ARTG• GMP Clearance is not just a pre-requisite to register or list a

medicine. Maintaining the on-going validity is required• Product regulators determine what steps of manufacture get

recorded• Increasing use of automated lodgement systems which have pre-

set validation rules• GMP is applicable to all medicines therefore the selectable

dosage forms or manufacturing steps is extensive• Refer to existing product relevant guidance to avoid having to

submit variations to correct errors

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Complementary medicines• GMP Clearance is required prior to submitting your listing application • Generally not required to be provided for Active Pharmaceutical Ingredients• There are 6 manufacturing steps generally applicable for complementary medicines:

– Manufacture of dosage form– Packaging and labelling– Secondary packaging– Testing chemical and physical– Testing microbial– Release for Supply

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Complementary medicines• Use the listed and assessed listed guidance

when submitting GMP Clearance applications• Contains a list of the correct dosage forms that

will validate • https://www.tga.gov.au/sites/default/files/listed-

assessed-listed-medicines-application-submission-user-guide.pdf

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Over-the-counter medicines• GMP Clearance is required prior to submitting your registration application • It is generally not required to be provided for APIs however its required for

intermediate product (e.g. API mix or premix)• There are 8 manufacturing steps generally applicable for OTC medicines:

‒ API active premix (where applicable)‒ Manufacture of Dosage form‒ Packaging and Labelling‒ Secondary packaging‒ Testing chemical and physical ‒ Testing microbial ‒ Release for Supply‒ Sterilisation (Where applicable) 56

Prescription medicines• The requirements for GMP Clearance can differ depending on

whether the prescription medicines is:‒ Chemically derived‒ Biological medicine

• Generally, GMP Clearance is required for both API/drug substance manufacture and Finished product manufacture

• We are finalising an update to the ‘Evidence of GMP Compliance for Prescription Medicines’ guidance

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Prescription medicines – API/drug substance• Chemically derived:

‒ Active Material Manufacture including manufacture of the crude, synthesis and purification of the API

• Biological Medicines:‒ Working cell bank (WCB) manufacture, storage and

maintenance‒ Active Material Manufacture‒ Any test performed on the drug substance used for

Release for Supply that is not repeated on the finished product

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Prescription medicines – finished product• Manufacture of dosage form (including manufacture of intermediates)• Manufacture of diluent• Primary Packaging and labelling• Secondary packaging (including assembly of kits and composite packs)• Sterilisation• Chemical and Physical Testing• Microbiological Testing (including endotoxin and sterility)• Biological Testing• Release for Supply

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Visit the GMP clearance tableDrop by and have a chat with Rheannon, Jodie and Karman from the GMP Clearance section who can provide guidance on:• Any questions you have about GMP Clearance in general• Any questions you have about your specific GMP Clearance

application

Don’t forget to grab a copy of our handy GMP Clearance QR code reference page for easy access to all our guidance and information!

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