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Webinar recording: GMP Clearance applications - common pitfalls

25 March 2020

Disclaimer

This recording is provided on the TGA's website solely for the purpose of indicating or suggesting what TGA representatives spoke about to the various conferences and seminars to which it relates. The papers are not legislative in nature and should not be taken to be statements of any law or policy in any way.

The Australian Government Department of Health (of which the TGA is a part) advises that (a) the recording should not be relied upon in any way as representing a comprehensive description of regulatory requirements, and (b) cannot guarantee, and assumes no legal liability or responsibility for, the accuracy, currency or completeness of the information contained in the recording.

Recording of online webinar

  • Presented by: Karman Leung
  • Webinar date: 6 December 2019
  • Webinar summary: Overview of process and evidence submitted for the GMP clearance application process, commonly identified issues and ways to improve application quality. The presentation provides information on the common deifiencies identified at both receipting and assessment stage, including how to reduce common errors which may result in unnecessary delays or ineffective applications.

Transcript

Good morning, my name is Karman Leung and I am a GMP assessor from the GMP clearance section of the Manufacturing Quality Branch and have been with the branch since February 2017.

Today's webinar is the last of the series of 3 for this year, the first webinar providing an overview of the GMP clearance current framework and future directions, the second on how to submit an effective GMP clearance application and today's webinar will cover the common deficiencies identified with GMP clearance applications.

There will be quite a lot of information to go through so I will not be going through details of all deficiencies in this webinar today. This presentation however will be uploaded onto the TGA website shortly after the completion of the webinar.

Slide 3 So the GMP clearance program is to ensure overseas manufacturers comply with the principles of GMP, that is, to meet the Pharmaceutical Inspection Co-operation Scheme, also known as the PIC/s guide, for the products being supplied to Australia. Currently there are 2 desktop assessment pathways to obtain a GMP clearance – the Mutual Recognition Agreement pathway, also known as the MRA pathway and the Compliance Verification pathway (also known as the CV pathway).

MRA pathway can be used if the manufacturing site is located within the borders of an MRA country and has been inspected by that country's regulatory authority. Since April 2017, the current target processing time for an MRA application is 30 TGA working days.

If the manufacturer you are seeking GMP clearance for does not meet the criteria for the MRA pathway, you may utilise the CV pathway as long as it has been inspected by a regulatory authority that has an agreement or arrangement with TGA.

In January 2019, a stop clock process was introduced throughout the entire application to ensure applicants who provide complete applications are not disadvantaged. The stop clock will be applied if your application has been identified as either waiting on payment, incomplete or waiting on evidence. Furthermore, from 1st July 2019, we implemented target processing times based on the type of CV application shown here in this table and can also be found in the GMP clearance guidance. Sponsors are expected to plan their regulatory activities in line with these timelines.

Slide 4 Let's start with applications submitted via the MRA pathway. With the increase number of submissions and to ensure applicants who provide the correct information are not disadvantaged, we implemented a decision in March 2016 where in certain instances (outlined on this slide) we do not seek further clarification from the sponsor and a determination is made to not issue the application.

Slide 5 And since the implementation, we are still receiving a number of applications where incorrect evidence is provided, with roughly 270 out of the 367 applications submitted either investigational, veterinary certificates or marketing authorisation licences and the remaining not issued applications sponsors have provided either expired certificates, evidence is for another site or it does not support your scope.

Slide 6 So What can you do to make sure you are submitting the correct evidence? Make sure the GMP certificate is for human medicinal products and not for human investigational or veterinary products. And if you are submitting a GLP certificate, make sure it is accredited to the ISO standard 17025 – General requirements for the competence of testing and calibration laboratories).

Slide 7 One of the major factors contributing to a delay in processing MRA applications is not providing an API declaration upfront. If the drug substance is not specifically mentioned in the GMP certificate, a declaration is required to provide assurance from the manufacturer that the API in your application is manufactured in the same facility and buildings as those inspected and referenced in the GMP certificate.

For example, if the scope of your application is for the manufacture of a pegfilgrastim and the GMP certificate only mentions biological medicinal products, you will need to provide a manufacturer's declaration for this drug substance at the time of submission to avoid any delay.

Slide 8 Let's move on to the next desktop assessment pathway – the CV pathway. I will be going through common pitfalls during both the receipting and assessment stage.

A snapshot of submissions at receipting stage was captured in October this year to identify the number of applications waiting on payment and ones that were incomplete. And at least 48% have not paid the relevant fees (such as the CV or liaison fee). During application submission, ensure the relevant sections have been completed. For example, shown here, if your application is for CV assessment, make sure you select "Yes" to the question, "Is this a compliance verification assessment?" in the TGA Business Services portal. For more information, please refer to our second webinar published on the TGA website or refer to the GMP clearance guidance.

Slide 9 During the receipting stage, we also identified 66% of applications submitted were incomplete.

To clarify, applications are identified as incomplete when we have not received all the evidence required. Applicants will not be contacted regarding evidence requirements during the receipting stage and will experience significant delay. A stop clock will be applied to incomplete applications and the status on your application will be visible to you as "with manufacturer" in the TBS portal. It is very important for you to understand the type of application you are submitting and evidence requirements to ensure your application is not placed in the incomplete queue.

A common example is when the list of products has not been uploaded in the required section of the TBS portal as the sponsor knows this can be found within the annexes of the GMP agreement, however this was never made aware to us. So at receipting stage it would appear the list of products was not submitted and the application will then be categorised as incomplete. For this specific example, it is highly recommended for you to provide clarification upfront to ensure your application is not placed in the incomplete queue.

Another common deficiency is when manufacturers provide evidence directly to TGA and there are times when they do not end up providing any evidence or they did not submit the correct information. We understand due to confidentiality issues the Australian sponsor will have no visibility on this, however it is highly recommended to have that dialogue with your manufacturer to confirm whether the evidence provided directly to TGA is current, relevant and contains sufficient information specific to your product.

Slide 10 Now, let's move onto applications at assessment stage. In September 2017 we implemented a process improvement whereby during assessment stage if the assessor identified deficiencies or further clarification is required, the assessor will send you one request with a specified due date for the sponsor to provide a complete response to address the deficiencies raised. If the response is not provided by the due date, or the response fails to address all the deficiencies, this may result in the application not being issued. And to date we have identified roughly 41% of applications at assessment stage have been flagged as waiting on evidence.

A major factor contributing to a delay during assessment is when we get several documents as a response from the sponsor. There are instances where we do get up to say 20 additional documents but no explanation on how it addresses the deficiencies. It is recommended that you provide an explanation on how the extra documents addresses the issues and reference the specific sections to avoid any delay or confusion that may negatively impact the outcome of your application.

Now for the remainder of this webinar I will be going through each piece of evidence and common pitfalls we have come across and tips on how you can submit the right kind of evidence.

Slide 11 Let's begin with the GMP certificate. One of the common deficiencies we come across is when the GMP certificate may look like it covered the scope of your application however the corresponding inspection report in fact may not have covered it at all. For example, if tablets and capsules were included in the GMP certificate and the inspection report only contained sufficient information on the manufacturing operations of tablets then based on this we may not be able to include capsules in the scope of your application.

So what can you do? It is highly recommended to understand the level of detail the inspection report covered your scope as opposed to what is in the GMP certificate.

Slide 12 The inspection report needs to provide sufficient commentary on the manufacturing operations, facilities, utilities and processes relevant to your product. We find when the inspection didn't cover specific buildings, systems and processes applicable to the scope of your application, there is no justification from the sponsor on how that inspection relates to your products. To give you an example, if your product is manufactured in building B but the inspection report only covered manufacturing operations and utilities in Building A. There is no information on how this inspection relates to the facility and manufacturing operations that are relevant to your product.

So what can you do? It is highly recommended to talk to your manufacturer before you submit your application to have a good understanding on what was covered in the inspection report, the level of detail your product was covered, where your products are manufactured, and how the scope of the inspection relates to your products. If your product is not covered in the report, again, provide justification upfront on how and why the inspection report can be used as evidence.

We also do not accept inspection reports that is primarily a list of deficiency as we do not have adequate information to assess what was covered in the inspection. If this is the case, please provide alternate evidence from a recognised regulatory authority that is current and contain sufficient evidence to cover the scope of your application, otherwise if no evidence is available you will need to submit a certification application for TGA to conduct an on-site inspection.

Slide 13 Inspection reports that are redacted or have been translated by the manufacturer. We do not accept these. You will need to provide a full unredacted report, or if it has been translated by an independent certified translator, you will need to provide a certified translation statement to us.

Another common deficiency is the use of PICS evidence for a manufacturer outside its borders. TGA is a PICS member and we do accept evidence from a PIC/s participating country inspected within their own borders but not if the inspection was performed outside the borders of that country. To give you an example, if the manufacturing site is located in India and Thai FDA conducted the inspection, we will not accept this inspection report as evidence. Alternate evidence from a recognised regulatory authority is required and if there is no acceptable evidence available you will need to submit a certification for TGA to conduct an on-site inspection.

Slide 14 Regulatory inspections list is required to give us an indication on the compliance history of the site, the frequency the site has been inspected by a regulatory authority and if there is a more recent inspection. If the most recent evidence is available but not provided, we may reduce the expiry of your clearance application or apply a condition whereby no extension of the clearance is to be granted.

If the scope of your application is not covered in the latest inspection report, it is highly recommended to provide justification upfront on why the most recent evidence will not be included to avoid a delay, reduced expiry or a condition on your clearance.

Slide 15 Statement that includes details of any regulatory actions from the manufacturer allows us to assess the site's compliance history. The manufacturer needs to provide this declaration and not the sponsor. They will need to provide details on whether there has been any product alerts, import alerts, warning letters or recalls for the entire site, not just for your products. If there has been a regulatory action and this includes both voluntary and imposed, the manufacturer will need to submit a summary of the root cause analysis and investigations conducted, Corrective & preventative actions and the current status of the regulatory action.

Slide 16 Site Master File. Site master file is required to provide information on the manufacturer's operations, facilities and pharmaceutical management system. The most common deficiency for this evidence is when appendices are not included during application submission, causing a delay in assessing your application.

So what can you do? When submitting a site master file, please ensure all the appendices are provided and include a site layout and schematic drawings that is legible. We often receive a site layout or schematic drawings of a water system that has been compressed onto an A4 page and makes it really difficult for us to assess.

Slide 17 List of products. List of products provides information on the drug substance and drug products you intend to supply to Australia. As mentioned earlier, if the list of products can be located in the GMP agreement, please ensure this is clarified upfront in a cover letter, otherwise this will be placed in the incomplete queue. Also, please check the list of products matches the dosage forms in the GMP agreement and the scope of your application. For drug substance applications, the product list may not be required if the API is entered into the application form.

Slide 18 Now, let's move onto GMP agreements – GMP, quality or technical agreements are required as they provide information on the roles and responsibilities of each party in relation to the critical aspects of GMP.

We recognise the growing complexity in pharmaceutical supply chains, wherein multiple manufacturing sites are involved in the manufacture of a single product as shown here in this diagram. Therefore, to help us understand your product's supply chain, it is recommended to understand your agreement and if required provide clarification how the agreement fits into the supply chain and its relevance to the Australian market.

Slide 19 Another common deficiency is when we receive agreements that have not been signed or dated. GMP agreements should be signed, dated and regularly reviewed and kept up to date. Please note a draft agreement will not be accepted unless your application is for a new registration or for a new chemical entity submission. Should this be the case you will need to clarify this upfront via a cover letter. If this is the case a condition may apply to your clearance and expiry of your clearance may be reduced.

In terms of reviewing your contract agreements and ensuring it is up to date, if the agreement does not reference the review period or justify how the agreement is kept up to date, we generally apply the 3-year rule as the review period. If, however, your internal procedure stipulates the review period is more than 3 years then you can provide this internal procedure upfront to us.

Slide 20 As per chapter 7 of the PIC/S guide, The GMP agreement between the contract giver and contract acceptor should clearly specify the responsibilities and communication processes for all outsourced activities. We come across a lot of agreements where the activities or the products covered by the agreement are not clearly defined or it has nothing to do with the Australian market. Please make sure the agreement clearly specifies the activities performed by all relevant parties and provide clarification upfront.

If you do wish to apply for additional dosage forms that is not currently in your agreement, you may provide a statement signed by the Australian sponsor stating that the GMP agreement will be updated to reflect the relevant dosage forms prior to commercial supply to Australia. A condition may be placed on this clearance to ensure the agreement is updated prior to commercial supply and a copy of the agreement may be requested to ensure adherence to the condition.

Slide 21 Chapter 7 of the PIC/S guide also states any activity covered by the GMP Guide that is outsourced should be appropriately defined, agreed and controlled in order to avoid misunderstandings which could result in a product or operation of unsatisfactory quality. We understand different manufacturing sites may use certain terminologies however we come across documents where terminologies are used interchangeably, causing confusion during assessment.

For example, there are various terminologies when it comes to release - release for supply, release for shipment, batch disposition, release for distribution, release to market to name a few and we come across agreements where these terms are used interchangeably. Any ambiguity or terminology needs to be explained to us.

Slide 22 Lets have a look at this example where roles and responsibilities are not clearly defined – all 3 parties have been marked as responsible for the release for supply step. There is no information on how everyone can be responsible for this step. We understand the complexity of a supply chain but you still need to explain to us why and how this is possible and in what way this relates to the products specifically for the Australian market.

Slide 23 Another issue we often encounter is when the release for supply step is conducted by the manufacturer and there is no information on the role and responsibilities of the Australian sponsor. For example, no detail on who is responsible for ensuring compliance and ongoing compliance to market authorisation requirements of the local authority, post market activities, or that the Australian sponsor does not meet the requirements regarding product quality review input and review (stipulated in chapter 1 of the PIC/S guide) or as per annex 15, no information on the shipping responsibilities. As the product sponsor, it is crucial for you to understand the supply chain of the products supplied to Australia and the requirements to ensure you meet the PIC/S guide.

Slide 24 To follow on from the previous slide, if the agreement provided is between the global headquarters and the manufacturer, the roles and responsibilities of the Australian sponsor must still be defined. We understand that as subsidiaries there may be no formal agreement between the global headquarters and the Australian sponsor, however a signed statement from the Australian sponsor that clearly outlines its roles and responsibilities and communication processes for all outsourced activities can be provided. Alternatively, if this is specified in your global procedure, this can also be provided in lieu of the signed statement.

Slide 25 Release procedures provides information on how the authorised person at the site performs the release for supply step. The European system of batch certification by a qualified person is not adopted in the Australian manufacturing principles however a Qualified person meets the definition of an authorised person within the Australian regulatory framework.

A common deficiency with this piece of document is when the site is only responsible for further processing. For example, the site's release procedure suggests they are only responsible for reviewing packaging batch records and the product gets shipped to another site for further processing and not the actual release for supply step.

So what can you do? Understand your supply chain and what manufacturing steps are required for that particular site relevant to the Australian market and the scope of your application reflects correctly to what the manufacturing steps the site can do.

We also get procedures where the document is only a description of how they use the System Interface Procedure and no description on the release for supply process, whether critical records are checked, who is responsible for releasing the product and how this authorised person ensures each batch has been manufactured and checked for compliance with the relevant Marketing Authorisation. It is important to talk to your manufacturer and provide you with a clear outline on who is responsible for the release for supply step and how do they ensure each batch manufactured is checked with the Australian marketing authorisation.

Slide 26 Validation Master Plan. Now this is provided to determine whether equipment, facilities, systems and processes are appropriately qualified. Assessors are frequently going back to the sponsor to request for the summary of the validation status as it is not in the VMP. We understand VMPs may not include all the relevant documents however please ensure you also submit a summary of the validation status which includes a revalidation schedule and documents relevant to the correct building.

Slide 27 Product quality reviews. Reviews are generally conducted on an annual basis to verify the consistency of existing manufacturing process and that it adheres to the PIC/S guide.

To avoid a delay in assessment, please ensure the full document including the appendices and the most recent PQR is submitted with the application. If the substance or product has not yet been subject to a product quality review, you should provide a statement upfront via a cover letter and to also provide the PQR procedure. Otherwise this will be placed in the incomplete queue at receipting stage.

Slide 28 As I briefly touched on earlier, API declarations not provided upfront for the MRA pathway also applies to the CV pathway. If the inspection report you have provided only covered specific APIs or was not covered in the inspection report, then you will need to provide an API declaration during application submission. If you do not have access to the inspection report, it is highly recommended to talk to your manufacturer to have an understanding on what the inspection covered.

Slide 29 Some other common deficiencies when it comes to API declaration is when it is signed by the sponsor and not the manufacturer. We will not accept this as evidence. Make sure this declaration is signed by the manufacturer and provided upfront when submitting your application.

In addition to the deficiency previously discussed, the majority of API declarations we get is just a generic statement taken directly out of the GMP clearance guidance "…manufactured in the same facility (specific buildings) as those inspected and referenced in the inspection report or GMP certificate". We need more information than this- we need to know precisely which building your drug substance is manufactured. The building and suite number or name should be specified in the declaration.

Slide 30 In order to reduce regulatory burden on industry, we accept a Letter of access obtained from another sponsor or manufacturer which allows access to information or evidence of an application that was previously submitted or to an active clearance. For the CV pathway, we still require certain sponsor-specific evidence and often these documents are not provided upfront. Examples of sponsor specific evidence we require are GMP agreement, list of products intended for supply, the latest product quality review relevant to your product and API declaration. Please note however API declarations are only accepted if used in conjunction with an LoA to evidence, not for LoA to clearance. Make sure you understand the type of application you are applying for and submit the sponsor specific evidence upfront to avoid placing your application in the incomplete queue.

There are 3 types of Letter of access used for desktop assessments and we receive a lot of LoAs that is confusing as to what type of LoA you have been granted access to. For example, in the letter provided it states it is for an LoA to clearance granting access to the evidence. This adds confusion whether the sponsor is granting permission to use an existing GMP clearance as an LoA clearance or if it is for LoA to evidence. When you are providing the Letter of access, make sure it clearly states the type of access granted to you so your Manufacturer providing LoA to evidence, Sponsor providing LoA to evidence, or Sponsor providing LoA to clearance.

Slide 31 One common deficiency for LOA to clearance is when the clearance you have been given access to was actually issued using another LoA to clearance. To illustrate what I mean, let's have a look at this diagram. Let's start off with Sponsor A. Sponsor A submitted an application with evidence for a site and the clearance was issued, now let's call this issued clearance the "parent". Sponsor A provides a LoA to clearance of the parent to another sponsor, Sponsor B. The scope for both these clearances were identical and sponsor B provided relevant sponsor-specific evidence. Sponsor B's clearance was then approved. Let's call this issued clearance the daughter. Now Sponsor B then issues an LoA clearance of the daughter to sponsor C. Since the daughter was issued using an LoA to clearance, this will not be acceptable as evidence for Sponsor C's application. Sponsor C will need to obtain a LoA clearance directly from Sponsor A or provide the full set of evidence.

Slide 32 There are a few things you need to be mindful of when you are using a LoA to clearance. LoA to clearance grants a sponsor permission to use an existing clearance as the primary evidence to allow an additional clearance to be issued on the condition the scope of the application is identical or less than the parent scope.

We have identified in many instances when the daughter is not identical or is more than the scope of the clearance being accessed to, so the parent. For example if the parent scope was issued for dosage forms X and Y, and the scope of the daughter clearance has dosage forms X ,Y and an additional dosage form Z, then the daughter scope will need to be amended to match the parent clearance, or if dosage form Z needs to be included in the scope then you can either provide a different LOA to a clearance that supports all the dosage forms or update the type of LoA, so to LoA to evidence instead of LoA to clearance or you can just provide the full set of evidence. Please note that relevant fees may apply if the type of LoA changes and also please communicate with the sponsor granting you to access their LoA and understand what is included in the scope of their application before submitting yours.

Slide 33 To summarise, it is very important that you communicate with your manufacturer before you submit your application to avoid any confusion or delay.

As a sponsor, you need to understand what is covered in the evidence submitted with your application, where your product is manufactured and whether it was specifically covered in the inspection report. If it wasn't then you need to find out how the scope of the inspection report relates to your products and provide any clarification upfront.

It is very important to understand the supply chain of your product specifically to the Australian market and provide supporting documentation and clarification how your products are supplied to Australia.

Any ambiguity in terminology, responsibilities or evidence should be clarified upfront to prevent a delay in processing your applications.

And lastly, if you have any questions please do not hesitate to contact us before you submit your GMP clearance application. Key information is contained on the following webpages.