Consultation submission coversheet (Minor variations to prescription medicines) Page 1 of 2

Consultation submission cover sheet This form accompanies a submission on:

Minor variations to prescription medicines: guidance and application forms

Name and designation XXXXXXXXXXX

Company/organisation name and address

Merck Sharp & Dohme, Level 4, 66 Waterloo Road, North Ryde, NSW 2113,

Australia

Contact phone number XXXXXXXX

I would like the comments I have provided to be kept confidential and not be published: (Please give reasons and identify specific sections of response if applicable)

Yes No

I do not object to publication of my submission, but would like my name to be removed from all documents prior to publication and for my name to not be included within the list of submissions on the TGA website.

Yes No

It would help in the analysis of stakeholder comments if you provide the information requested below.

I am, or I represent, a: (tick all that apply)

Business in the therapeutics industry (please tick sector):

Prescription medicines Complementary medicines OTC medicines

Medical devices Blood, tissues, biological Other

Sole trader Business with ~600 employees

Importer Manufacturer Supplier Industry organisation

Government Researcher Professional body

Consumer organisation Institution (e.g. university, hospital)

Regulatory affairs consultant Laboratory professional

Health professional – please indicate type of practice:

Other - please specify:

If you would like to be kept informed about TGA activities, please subscribe to one of the TGA’s email lists <http://www.tga.gov.au/newsroom/subscribe.htm>.

Consultation submission coversheet (Minor variations to prescription medicines) Page 2 of 2

It would help in the analysis of stakeholder comments if you provide the information requested below.

Suggested improvements, amendments, corrections and areas requiring clarification in the draft guidance documents (please identify which document you are commenting on)

Minor variations to registered prescription medicines: chemical entities

Minor variations to registered prescription medicines: biological medicines

Both documents

Section, page number Comments

see attached document

Suggested improvements, amendments, corrections and areas requiring clarification in the draft application forms

Name of form Comments

see attached document

Comments on the proposal for six new application forms

none

22th

February 2013

Minor Variations Project Team Office of Scientific Evaluation Therapeutic Goods Administration P. O. Box 100 WODEN, ACT 2606

Dear Minor Variations Project Team Comments Concerning the Consultation Paper - Minor variations to registered prescription medicines: Chemical entities

Merck Sharp & Dohme (Australia) Pty Ltd (MSD) would like to take this opportunity to provide comments and suggestions concerning the Therapeutic Goods Administration’s (TGA) consultation paper, ‘Minor variations to registered prescription medicines: Chemical entities’

Background

Before dealing with any specific aspects of this consultation paper, MSD would like to express its general support to the TGA’s recommended changes to the Appendix 12 of the Australian Regulatory Guidelines for Prescription Medicines (ARGPM) related to the minor variations of registered prescription chemical entities. MSD believes that this review of the guidelines will make the TGA requirements more clear and allow the industry to establish more predictable timelines for changes that are regarded as minor variations. Review of the Consultation Paper Having attended the Minor Variation to Prescription Medicines Business Process Review information session for industry at the Rydges Camperdown, Sydney on 5th

October 2012 and following the review of consultation paper, MSD would like to provide the comments on the points listed below.

1.2 Overview of the legislative basis for varying products

Comments on Part 1 General Information

On page 16, last paragraph under the section “Categories and timeframes” the TGA has described the statutory timelines for the evaluation of Category 1, Category 2, Category 3 and self-assessable requests. The same paragraph also states “Requests for variations to ARTG entries under 9D(1) (corrections) or s9D(2) (safety-related requests) have no statutory timeframes”. While the clarification on the Category 1, Category 2, Category 3 and self-assessable requests is much appreciated, MSD is still concerned about the lack of any established timelines for the variations made under 9D(1) (corrections) or s9D(2) (safety-related requests).

The commercial reality is that many of the pharmaceutical companies active in Australia are subsidiaries with head offices in the US, Europe or elsewhere. In addition a large proportion of the medicines currently available in Australia are manufactured overseas and may be manufactured for many other markets throughout the world. There is no indication that this trend is likely to be reversed in the future, and from both an environmental and an economic standpoint this is the responsible approach. In order to implement changes to medicines, including the co-ordination of the changes between the many markets for which the product may be manufactured, and in order to assure continued supply of compliant medicines to the Australian public, predictable timeframes are necessary. As such MSD would like to propose that in the absence of any statutory timelines, the TGA include predicted mean timelines the industry can expect to have their 9D(1) (corrections) or s9D(2) (safety-related requests) approved. This can then be used as a guide by the industry.

MSD has noted that the revised guidelines do not provide any clarity on the time it takes to process a Category 3 application starting from the time an application is received by the TGA to the time it is accepted into evaluation and shows up on TGA eBS. From experience gained from many applications for minor variations over the years, the company has found this time to be quite variable, ranging from 2 weeks to 2 months and at times leading to significant delays in the implementation of the changes. As mentioned above, the ability to maintain a reliable supply of medicines to the Australian market is partly dependent on the ability of the Australian subsidiary to meet predictable approval timelines to enable co-ordination of changes that may affect many markets worldwide. As such MSD would like to propose that as part of this review process the TGA amend the guidelines to provide more clarity on the average processing times for the Category 3 application from the time the product is received by the TGA to the time it is accepted into evaluation.

1.3 Changes to the product information

It is noted that on page 21, the TGA has added additional requirements to how the changes to the product information is to be presented to the authority. The changes are listed below:

• a table explaining how each of the changes relates to the request, including references to any data submitted in support of each change

• an assurance that the PI is the most recent approved version • an assurance that all of the proposed changes to the PI relate to the requested changes to

the ARTG entry, the no other unidentified changes have been proposed or made.

MSD is especially concerned with the first of the above requirements “a table explaining how each of the changes relates to the request, including references to any data submitted in support of each change” and would like to question the need for such a table when the TGA is already being provided with annotated and clean copies of the PI which is often accompanied by comments. This new provision for the inclusion of a changes table would mean an increased

burden on the already stressed time and resources that the pharma industry in Australia is increasingly facing. As this additional step is not likely to improve the safety compliance of the products and as the addition of a changes table just compliments the current practice of submitting a clean and an annotated copy of the PI, MSD would like to urge the TGA reconsider including this requirement as part of Appendix 12.

2.3 How to apply to the TGA

Comments on Part 2 Requesting a correction to an incorrect or incomplete entry in Australian Register of Therapeutic Goods: s.9D(1)

MSD is supportive of the TGAs initiative to include a separate form for the s9D(1) changes. However, the company is not clear on the fee allocations. While the guidelines specify “If the variation is initiated by the Secretary, no fee is payable” (page 29) it does not clarify what fee the industry should be paying if the change is initiated by the company to rectify a mistake which is a result of the TGA administrative error. MSD believes that this circumstance should also be discussed under the “What fees do I pay?” section of guideline and the body responsible for the payment of the fee under this circumstance clearly identified.

While MSD understands that statutory timelines are not feasible for changes under s9D(1), the company would appreciate guidance from the TGA on potential timelines for these changes.

MSD also notes that sponsors are required to provide “details of when the entry became incorrect or incomplete, preferably including a relevant file or submission number” (page 29). However, the company would like to stress that this information may not always be available. Therefore, MSD would like to request that the guidance documents include a discussion on what could be other acceptable forms of evidence for a change under s9D(1) in cases where this information is missing.

3.1 What is a safety-related request?

Comments on Part 3 Making a safety-related request to vary an entry in the Australian Register of Therapeutic Goods: s.9D(2)

MSD believes the statement “…….statements such as ‘the clinical significance of the finding is unknown’ are not sufficient as a warning or precaution” appearing in the last bullet point on page 35 of the consultation document may be subject to misinterpretation. Whilst the statement “the clinical significance of the finding is unknown” per se does not qualify as a warning or precaution, MSD believes the intent behind this is that statements such as ‘the clinical significance of the finding is unknown’ cannot be added to a warning or precaution without supporting data. Therefore the company believes that the intent of the above statement should be further clarified in the proposed guidance.

3.2 Changes to the product information for safety-related requests

The first paragraph under section 3.2 “Changes to the product information for safety-related requests” on page 36 of the consultation document states “If proposed changes to the PI that are safety-related are identified during evaluation of a Category 1 application (Streamlined Submission Process31

In addition, if the Category 1 Application is for a new product, or will result in the creation of a new ARTG entry, it is not possible to make changes to the product information until the product appears on the register following approval of the application. Thus, under the requirement set out in this consultation document, any updates to the safety information in these cases must be made as a safety related notification after approval resulting in delays to the finalisation of the Product Information.

), the sponsor may be asked to submit a separate safety-related request under s. 9D(2).” MSD is concerned that the requirement to submit separate safety-related requests during evaluation of a Category 1 application adds confusion and burden to both sponsors and TGA due to varying versions of the PI being evaluated by the evaluator, Stream Pharmacist, and Delegate.

Where safety signals arise during the evaluation period which require urgent notification MSD proposes that the sponsor be able to notify these immediately (since in any case they may be relevant to the evaluation of data current under review) e.g. by email to the Streamlined Submissions Case Manager with a carbon copy to the Stream Pharmacist and Delegate.

3.3 How to apply to the TGA

Under section on “How to apply to the TGA” (page 36) it states “If you want clarification about which procedure to follow, contact the TGA”. While MSD very appreciative of the TGA gesture the company would still like to seek clarification on the preferred contact person for any such enquiry e.g. Stream Pharmacist, or Case Manager and the preferred means of contact e.g. email or phone.

On page 38 of the consultation document, the last paragraph under the section “What fees do I pay” states “If the TGA determines that it needs to evaluate supporting data during the course of assessing a safety-related request, the sponsor will be invoiced for the balance of the higher fee not yet paid. A new request does not need to be made. If there are multiple changes being requested under s. 9D(2) in the same submission, the TGA will approve any of the changes that do not require evaluation of data, any other changes that require evaluation of supporting data should be lodged in a separate submission”. For the purpose of reducing confusion for the sponsors and with the aim of decreasing the administrative burden on both the sponsor and the TGA that would result from creating a separate application to submit supporting safety data, MSD proposes that sponsors be permitted to submit supporting data without lodgement of a separate submission even in the event of multiple changes, for consistency with cases in which one change has been nominated as changes are often interlinked.

On page 39 of the consultation document under the section “What happens to my request?” it states “If a requirement has not been met (for example, the sponsor has not included a correctly marked-up copy of the proposed new PI), the sponsor will be asked to submit the required information before the request can be processed.” MSD believes it would be beneficial to clarify whether this additional request is associated with a re-payment of fees.

This section goes on to further state “If the Secretary needs supporting data to make a decision (whether the data are submitted at the TGA’s request or on the sponsor’s own initiative), the evaluation will be conducted according to guidelines and procedures set out in Section 3 of the ARGPM.” MSD believes it would be beneficial to update the current guidelines to clarify the particular sub-section of Section 3 that applies to the evaluation of a safety-related request (with evaluation of data). The Section 3 in the current version of the ARGPM (Jun 2004) only provides generic guidance on Category 1, 2, and 3 submissions.

3.4 Safety-related variations identified by the TGA

MSD would like to seek clarification on scenarios where the sponsor may be asked to submit a separate safety-related request during a Category 1 application. While MSD acknowledges Section 3.4 “Safety-related variations identified by the TGA” on page 39 of the consultation document, for requests outside the Streamlined Submission process, the top of the same page also notes that: “Safety-related requests should not be included in streamlined submission process applications, that is, Category 1 and 2 applications. Following the incorrect process is likely to cause delays in approval of important safety-related changes to the product”. MSD feels that this statement is in contradiction to the statement under section 3.2 on page 36 i.e. “If proposed changes to the PI that are safety-related are identified during evaluation of a Category 1 application (Streamlined Submission Process31

On page 39, the paragraph entitled ‘Alignment of product information approved for the same active ingredient’ includes the remark ‘Some sponsors find it useful to mark any recently amended text in the PI with an asterix, as an aid for other sponsors.’ The asterisking of changes of clinical significance in PIs is a requirement of the Medicines Australia Code of Conduct. The relevant section of the code is reproduced below:

), the sponsor may be asked to submit a separate safety-related request under s. 9D(2)”. Therefore, the company would like to urge the TGA to specify the exact circumstances when a safety related application can be sent to the authority without affecting the timelines for any of the related ongoing submissions.

‘3.3 Changes of Clinical Significance and the addition of a Boxed Warning

Changes of clinical significance relating to product safety are likely to influence the decision to prescribe. They include, but aren’t limited to, changes to the approved indication(s), contraindication(s) and precautions and the addition of a boxed warning. Where a change of clinical significance relates to product safety and, in particular, the addition of a boxed warning is incorporated into the Product Information, it should be communicated to relevant healthcare professionals. Changes of clinical significance may be communicated to healthcare professionals by:

• highlighting the change in all forms of the Product Information for a period of 12 months from the date of change with an asterisk (‘*’) and linking to a footnote in type size not less than 3 mm as measured by the height of the font’s lower case ‘e’. The footnote must read: “Please note change(s) in Product Information”, and/or

• providing a prominent statement on Product websites, and/or • sending a Dear Healthcare Professional Letter to relevant healthcare professionals.

A company may decide which mechanism(s) are most appropriate for communication of a change of clinical significance.’

This requirement applies to Product Information used in the promotion of prescription medicines, and is specific to changes of clinical significance as defined by the Code. The intent behind highlighting recent and significant changes to the PI is to assist prescribers and consumers to identify relevant changes to the products they are prescribing or taking, which is appropriate from the perspective of the Quality use of Medicines.

The suggestion of the comment included in the Draft Guideline is that any safety changes may be highlighted using the asterisk, however there does not appear to be a consensus of opinion between industry and the TGA as to what actually constitutes ‘clinical significance’ and whether any and all changes to the safety aspects of the PI need to be highlighted in this way e.g. is the addition of an adverse event to the list of AE’s in the PI clinically significant, particularly if there is no evidence of direct causality?

The inclusion of this comment in the TGA guideline is likely to add to the confusion that already exists regarding the use of an asterisk in the PI. If the asterisk is used in different ways by different sponsors, there is not a consistent message to prescribers and consumers about what it means and the effect of highlighting significant changes is diluted. In addition, it has the potential to add to the administrative burden of both industry and the TGA, as the MA Code requires such changes to be highlighted for a period of 12 months following the change, and under the current guidelines, removal of the asterisk is an approvable change. There needs to be clarity over the use of asterisking in Product Information, and there should be harmonisation of TGA and Medicines Australia requirements. If this is not possible then MSD suggests that this suggestion should not be included in the Guideline until clarity is achieved.

4.1 What types of variations are covered under s9D(3)

Comments on Part 4 Requesting a variation that does not reduce quality, safety or efficacy: s.9D(3)

Section 4.1, page 45 of the consultation document under “Approval” states “The secretary’s approval is required for all variations under s9D(3) of the Therapeutic Goods Act 1989. This means that, even if the data to support the proposed variation do not have to be evaluated by the TGA, the variation must be formally approved before it can be implemented”. While MSD does not have any particular issues with the approval of all applications under s9D(3), the company is unclear regarding what the TGA is basing the approval of the changes made under SAR since no evaluable data is to be submitted with these changes (see page 47). MSD believes that the TGA should elaborate on the basis on which the approval letter for the SAR’s will be issued in the guidance document.

4.2 Self-assessable requests

General Conditions

Further to the comment “No request for variation that requires TGA evaluation of data should be submitted at the same time as the self-assessable request” under “General Condition” on page 46, MSD would like to clarify how soon a Cat.3 application can be made to the TGA following a submission of an SAR for the same product.

On page 47 under the section “What do I need to provide” the fourth dot point states “the estimated date of intended implementation of variation (taking into account the time required for approval)”. From the review of the consultation paper MSD has concluded that all changes made under s9D(3) must be approved prior to implementation. The last paragraph on page 47 clearly states “It is a condition of registration that variations cannot be implemented without prior approval by the TGA”. Therefore, with this being the case, MSD feels that the provision to include an implementation date in the SAR form is now redundant and should be removed. MSD would also like to know whether the TGA will be issuing the application acceptance letters for all changes made as self-assessable requests.

MSD notes that all GMP clearances need to have at least 6 months validity at the time of the application. However, no reasons for this new requirement have been provided by the TGA. MSD is concerned that this condition effectively acts to lower the usability of the GMP clearances by 6 months and especially so for short term clearances such as 1 year clearances where the clearance can only be used in the submission for 6 months at which point the company will need to apply for another clearance on at least an extension. While this is not an issue for the majority of applications, MSD is concerned that there may be occasions where an emergency submission will need to be made to the TGA with lessthan six months validity of the GMP

certificate and requests that TGA consider including an exception to this requirement under specific circumstances, if properly justified.

MSD notes that the TGA has indicated to future inspection of the SAR related data during audits. However, no clarification on how these inspections/audits will be organized or facilitated has been included in the guidance document. As such the company would like to request that a guide to how these audits will be carried out including the dates of the audits be published so that the sponsors could get more clarity on this process.

A Changes to the active pharmaceutical ingredient

MSD is supportive of the addition of a new self-assessable request type: Revision of Certificate of Suitability to the European Pharmacopoeia monograph (CEP) for the API (A13) (page 59).

C Change to, or addition of alternative, site of manufacture of drug products

MSD is pleased that changes to the site of manufacture of the dosage form will now include changes in method as part of this self-assessable request (C1) (page 66). MSD believes that this will provide greater convenience to sponsors since minor changes in method are commonly encountered at alternative sites of manufacture.

MSD also acknowledges and agrees with the new requirement of “Appropriate technology transfer of approved test methods to the proposed site should have been carried out” where a self-assessable request is submitted to change the site of quality control testing and release for supply (C3) (page 68).

D Changes to drug product specifications

MSD notes that in order to change identification tests to near infrared spectroscopy (NIR) for the drug substance and/or excipients (D5) (page 72), the condition that ‘the site of testing must have a previously TGA-approved SOP for introducing NIR as an identification test in finished products’ has been updated to ‘the method development and other data requirements (including data collection, establishment of the spectral reference library, calibration and validation of the method) must comply with the current EMA guideline on use of NIR that has been adopted by the TGA’. MSD believes that this is a very positive move by the TGA and takes into account the practicalities of operating in a global environment.

F Changes to the material of a container /closure system

On page 78 of the consultation paper under the section F1 “Bottles, jars and tubes” the TGA has removed the consequential change to the PI as part of change container/closure system. Therefore, MSD would like to know whether any consequential change to the PI can still be submitted as part of the SAN or does a separate application will need to be made to the TGA for this change.

MSD is not supportive of reductions in shelf life and imposition of more stringent storage conditions no longer being permitted as self-assessable requests under “Changes to the material of a container/closure system (F1-F4)” (pages 77-80). MSD believes that this change will put unnecessary financial burden on the sponsors who will now have to submit this change as a category 3 application.

G Changes to size, shape or components of container/closure system

MSD is not supportive of the statement “No changes must be made to the products shelf life or storage conditions” appearing in sections G1 and G2 (pages 81-83). MSD believes that reductions in shelf-life and more stringent storage conditions resulting in a drug product that continues to meet existing specifications would not compromise its efficacy, safety and quality and should be allowed as a self-assessable request. However, MSD is supportive of specific conditions and explanations being included for blister packs, strip packs and reclosable packages as this adds greater clarity when considering the type of self-assessable request to select. In addition, permission to apply for inclusions of or changes to an outer overwrap designed to prevent ingress or regress of moisture, solvent or gases from a container under G2 is a welcome addition to this self-assessable request category.

H Change to, or addition of, pack size

Under “Change to, or addition of, pack size (H)” (page 84), there appears to be a contradiction between the information box defining “pack size”, which provides a definition for the pack size of pressurized metered-dose preparations or dry powder inhalers, and the specific condition which states “The product must not be a pressurized metered-dose preparation for oral inhalation”. MSD believes that changes in the pack size of pressurized metered-dose preparations should continue to be proposed as a self-assessable request for consistency of application requirements for other dosage forms.

K Changes to product labels

MSD suggests clarification of the statement on page 90 under ‘Specific Conditions’:

• addition or amendment of the terms hypotonic, hypertonic and isotonic in the labels of large-volume injections

The circumstances under which these terms may be added to a product label are understandable, but it is not clear under what circumstances it would be appropriate to change the description of the tonicity of an injectable medicine, unless the tonicity itself had changed. This would seem to result from a change to the formulation, and therefore it should be clarified that this change would not be self-assessable, and perhaps examples provided of where the statement may change without any other change to the product.

MSD notes that the self-assessable changes to product labels (pages 90-92) which involve changes to the colour, design or layout of labels with no change to content now contains more stringent conditions including: – change to layout must not introduce a day-of-week or time-of-day (or similar) dosing schedule panel, although variations to such panels that were previously approved may be allowed, provided that there is no change to the dosing regimen – change to the layout or design of a physician sample pack may include changes in content if this is to ensure compliance with Australian pharmaceutical industry codes of conduct – deletion of repeated text (present elsewhere on a label) from selected side panels is acceptable, provided that the information is not mandatory and its removal is in accordance with the best practice guideline on prescription medicine labeling. Furthermore, for addition of, or changes to a company website address, the website must now contain information about the product (including direct links from the website) that is consistent with the information approved by the TGA for that product. MSD agrees with these changes.

M Other changes

MSD appreciates the addition of a distinct category for changes related to medicines and poisons scheduling.

4.3 Requests that require submission of data

MSD would like to acknowledges the new requirements added to the guidelines requiring the sponsors to submit additional data for changes requiring prior approval including the requirement for at least three batches for all changes (previously 2-3 batches), increased process validation data requirements, at least 6 months validity for GMP clearances, data on polymorphism, inclusion of references to TGO 76 and TGO 77 to name a few. While MSD is agreeable to majority of the changes the company still has some concerns regarding specific requirements that have been introduced in the guidance document. These concerns and possible alternatives are detailed below.

E Changes in synthetic route or manufacturing process for the active pharmaceutical ingredient”

Page 101of the guideline states “If redefining a starting material, justification for the choice of the starting material. Provide the pre-starting material synthetic process and details of controls of starting material impurities, including metal catalysts and residual solvents”. MSD concurs with the TGA that choice of stating material should be well justified and that starting materials need to be well defined (including the impurities, metal catalysts and residual solvents in the synthesis process) as stipulated under section “E - Changes in synthetic route or manufacturing process for the active pharmaceutical ingredient” of the consultation document (page 101).

However, given that the starting material should be a well-controlled and well-defined entity (which may be purchased from a third party in some cases), MSD does not see the value gained from including a lengthy outline of the pre-starting material synthetic process. Furthermore, should the pre-starting material synthetic process be required, MSD would like to urge the TGA to specify how far back in the process are the sponsors required to describe this process. This section also states ‘Where a change is to late stages of synthesis, crystallization, purification or milling, either relevant comparative data of the dosage form…manufactured from at least three batches of pre-variation and at least one batch of post-variation API, or a well-argued justification for not providing such data.’ MSD suggests that the term ‘well-argued’ is somewhat subjective, and raises the question as to what ‘well-argued’ actually means and how it is to be judged. It may be possible to argue a case articulately, that has no scientific merit and is therefore not an adequate justification. MSD suggests it may be more appropriate to use wording such as ‘satisfactory’ or ‘acceptable’. G Changes to the site of manufacture of the active pharmaceutical ingredient Under the change category (page 102-103) “G Changes to the site of manufacture of the active pharmaceutical ingredient ” it states “The Australian licence or GMP clearance letter should cover the relevant manufacturing steps and must have at least 6 months’ validity (before expiry) at the time of application”. MSD notes the new requirement that the relevant Australian licence or GMP clearance letter must now have at least 6 months’ validity (before expiry) at the time of application. However, as stated earlier MSD disagrees with this minimum 6 month requirement given the 45-working day timeframe for a decision to be provided for a Category 3 application. MSD proposes that the condition of registration under Sections 28 of the act that sponsors must ensure evidence of GMP compliance of an overseas manufacturer is sufficient to comply with this requirement. For the requirement “Comparative particle size distribution data from at least three batches of pre-variation API and at least one batch of post-variation API to demonstrate comparability in particle size profile” (page 103) MSD acknowledges the additional requirement of comparative particle size distribution data from at least three batches of pre-variation API and at least one batch of post-variation API to demonstrate comparability in particle size profile. However, the company believes this requirement to be redundant given that now the TGA requires Certificates of Analysis from at least three (previously only one) production-scale batches manufactured at the new site to demonstrate the manufacturer’s ability to produce material that meets the currently approved specifications, including particle size limits and polymorphic form.

I: Changes to the source or manufacturing process of excipients of animal origin

MSD acknowledges the change in the tissue category nomenclature (page 104) to be consistent with the EMA’s categories and the TGA’s Supplementary Requirements for Therapeutic Goods for Minimising the Risk of Transmitting Transmissible Spongiform Encephalopathies (ie

Categories A, B and C). However, this is inconsistent with the tissue categories in Appendix 10 of the ARGPM which are the CHMP categories (ie Categories I, II, II and IV). Therefore MSD will like to suggest that the TGA consider updating Appendix 10 of the ARGPM so that Appendix 10 and 12 are consistent. M Changes to Labels MSD notes the comment ‘The Best Practice Guideline on Prescription Medicine Labelling; should be followed where practicable for safety and quality use of medicine and requests clarification as to how the practicability of the requirements of the guideline are to be judged, and whether sponsors can be compelled to meet these requirements if the TGA disagrees with an assessment by a sponsor that a requirement is not achievable.

MSD would like to express its support for the TGAs decision to separate the changes that would result in a separate and distinct good either via a SAR or Cat.3 route into a common section of the Appendix 12. MSD acknowledges that none of the changes under Part 5, including changes made as self-assessable requests can be implemented prior to TGA approval and that the 45 working days evaluation period applies with usual clock stops for s31 requests.

Comments on Part 5 Applying to make a variation that creates a sepatate and distinct good: s.23

While the TGA has mentioned the Groups Order, MSD would like to urge the TGA to include some examples of common situations under which groupings will apply in the revised Appendix 12 as a guide to the industry.

5.2 Self –assessable requests

MSD acknowledges and agrees with the inclusion of a new requirement on information on use or non-use of human embryos or human embryonic stem cells, or other material sourced from human embryos or human embryonic stem cells, in the manufacture of the product.

5.3 Applications that require submission of Data

B Changes to container type

On page 128 of the consultation document it states “ If relevant, biomaterial safety evidence may be required”. While this statement is acceptable, MSD would like the TGA to specify the circumstances under which such data would be required so that these can be provided to the TGA upfront instead of via a s31 request.

C Replacement of trade name

MSD is happy with the changes proposed to the section on trade name.

6.1 Changes that do not require notification to the TGA

Comments on Part 6 Changes that do not require prior approval

- inclusion or removal of, or changes to, sponsor or supplier telephone/facsimilie number, email address, barcodes (includes 2-D matrix codes, but not quick response [QR] codes)….

MSD requests clarification on the TGA’s policies with regard to QR Codes, as these are not mentioned elsewhere in the guideline. As these become increasingly popular, guidance as to their proper use, and control of information accessed using the codes is relevant and necessary.

We look forward to receiving feedback and comments from the TGA.

With Kind Regards,

MSD Regulatory Affairs

22nd

Minor Variations Project Team

February 2013

Office of Scientific Evaluation Therapeutic Goods Administration P. O. Box 100 WODEN, ACT 2606 Dear Minor Variations Project Team,

Comments concerning the Consultation Paper – Minor variations to registered prescription medicines: Biological medicines

Merck Sharp & Dohme Australia (Pty) Limited (hereafter referred to as MSDA) takes this opportunity to provide comments and suggestions concerning the Therapeutic Goods Administration’s (TGA’s) consultation paper – ‘Minor variations to registered prescription medicines: Biological medicines’. Gratification

MSDA would like to express its general support and gratitude to the TGA’s recommended changes to Appendix 13 of the Australian Regulatory Guidelines for Prescription Medicines (ARGPM) related to the minor variations of registered prescription medicines-biological medicines. MSDA believes that this update to the guidelines further clarifies TGA’s requirements and allows Industry to establish more predictable timelines for changes that are regarded as minor variations. Review of the Consultation Paper

Having attended the minor variation to prescription medicines business process review information session for industry at the Rydges Camperdown, Sydney on 5th

October 2012 and the subsequent release and review of consultation paper, MSDA provides comments on the points listed below.

PART 1 – GENERAL INFORMATION

1.5 Implementing approved variations:

On page 24, the paragraph directly after the above subheading, the TGA states that variations cannot be made without approval from the Secretary and that in a request for a minor variation, sponsors should include their planned approach for implementing the proposed change, including planned timeframes. TGA also quotes a timeframe of 45 working days as the approval timeline for SARs (on page 43)

MSDA is concerned that this means that the date nominated in the application form cannot be less than 45 working days from the date of submission. In the event that the TGA approves / acknowledges a variation in less than 45 working days, there could be several weeks delay in actioning the approval. This is a considerable delay and will lead to difficulties in implementing e.g. artwork changes, minor manufacturing changes, etc. in a timely fashion, which in turn may lead to an escalation in the disruption

of continuity of supply. MSD also invites TGA to comment how it interprets “implementation” i.e. date that an approval is actioned, date that changed product is released to the Australian market?

PART 4 - Requesting a variation that does not reduce quality, safety or efficacy: s. 9D (3)

4.2 SELF-ASSESSABLE REQUESTS:

MSDA welcomes the expanded guidance on the types of changes which can be classified as self-assessable.

C Change to the site of manufacture:

C3 – Change to manufacturer or supplier of excipients or raw materials

On page 63, one of the requirements is a copy of the Australian licence and/or GMP clearance letter. MSDA’s comment - Currently sponsors are not required to hold GMP clearance letters for manufacturers/suppliers of excipients/raw materials used in biological medicine manufacture. It is impractical to obtain GMP clearance letters for a wide number of third party manufacturers/suppliers. Suppliers/manufacturers of excipients/raw materials may not meet GMP clearance criteria as they may themselves be distributors of materials manufactured by third parties. The existing requirement that the raw materials/excipients from another supplier/manufacturer comply with previously approved acceptance criteria, storage conditions and meet validation criteria should be sufficient.

There are raw materials that are lab grade materials with no requirements to meet GMP expectations, and where lab grade may be the only materials available. Supplier information is not currently included in the license (with the exception of animal derived raw materials). In addition, all approved suppliers of excipients are not included.

This information is not currently captured in vaccine licences and represents a shift in regulatory expectations for raw materials/excipients. Typically, CoAs are provided in P.4 for excipients, but represents a "typical" CoA and all approved suppliers are not included.

At the present time the ARTG records include those manufacturers for which we obtain GMP clearances. We also provide specification for which raw materials and excipients must meet and this would be controlled by the DS manufacturer. This should continue to be the case.

Further GMP clearances would add significant work for both sponsor and TGA through audits. This could negatively impact the continuation of supply since audit timelines and closing out of inspections are lengthy. TGA would need to show where this adds value and improves safety.

D Replacement of an in-house reference standard:

MSDA’s comment - Is this a reference standard that is used to determine potency? What is meant by ‘protocol’ – is this a ‘Comparability Protocol’? Additional guidance would be helpful.

E Establishment of a new working cell bank or seed lot

E2 – Change to the storage site for the master cell bank or seed lot, or working cell bank or seed lot

MSDA’s comment – the specific condition that must be met is that ‘the change must be to a secondary storage site only’. What is meant by the term ‘secondary’? Further clarification would be helpful.

G – Changes to Product Labels (p68)

MSDA notes the TGA’s directive to await acknowledgement of Self Assessable Notifications / Requests before implementation of the variation. There have been occasions recently when applying this approach to artwork change SANs has resulted in delay in product reaching market while the sponsor awaited TGA acknowledgement of SAN. The company will continue to be proactive in contacting the TGA when expedited review is required to meet patient / business needs, although we foresee this will place greater burden on TGA reviewers.

Required information: The copy should be actual size and should indicate the colours to be used. MSDA will endeavour to supply full scale labels wherever possible, but on occasion the large size of the pack prohibits to scale printing on A3 paper. If labels are not provided actual size this will be noted on the artwork.

H – Changes to the pack size (p71)

Reducing the number of units (vials, syringes, ampoules, cartridges) in a pack is self-assessable; increasing the number of units in a pack is not. Specific conditions • The change must be the result of either of the following: – Pharmaceutical Benefits Advisory Committee recommendation – deletion of an existing pack size that is no longer to be supplied. MSDA notes that under Appendix 13 – Section 10 ‘Pack Size’, the number of units enclosed in the outer pack may be reduced without prior approval. Thus an alternate pack size containing fewer units may be registered via SAN e.g. a recent application to register a single vial pack size of a vaccine, in addition to the existing pack size (ten units). In the draft guideline, addition of a pack size now appears as Category 3 change (see page 97).

Could the TGA please comment on the rationale for up scaling the requirements for registering an alternate, smaller pack size from SAN to Cat 3? MSDA also notes that on occasion, a sponsor may seek to make available a smaller pack size (i.e. a single unit pack in addition to a 10 unit pack) to improve user benefit. This may have been a sponsor decision and not at the behest of the PBAC (many biologicals are solely private market). For example, clinics may not want to retain 10units of stock of an item they use at a low turnover (particularly for clinics in regional Australia), due to shelf life constraints or expense of holding stock on hand (biologicals may be relatively expensive medicines/vaccines). Marketing and supply decisions should be available to the sponsor to allow them to maintain best service to their customers and Australian patients.

N – Changes to the shelf life or storage conditions of the drug product (p78)

N2 Changes to excursion temperature during manufacture - removal of an excursion temperature or - reduction in the time spent out of refrigeration, including time out of the freezer

only. Specific conditions • For biological medicines that require refrigeration or freezing, stability testing must have been conducted in real time at the specified storage temperature, for at least the requested shelf life. • The time out of refrigeration (which also includes time out of the freezer) during normal manufacturing processes, up to the point of return to the fridge or freezer following labelling and packaging, must have been defined and justified. From that point onward, all storage and shipping conditions must be justified by the real-time stability data; the data for justifying any temperature excursions must include real-time studies of the proposed excursion followed by return to the normal storage conditions for the remainder of the shelf life. Required information • An assurance that data are available for three batches manufactured using the commercial process. • Assurances that all specific conditions have been met, including details of the change. MSDA welcomes the facility to remove excursion temperature or reduce TOR via SAR. MSDA notes the proposed requirement for stability testing in real time at the specified storage temperature for the duration of shelf life. As discussed at greater length later in this document (in relation to changes to Category 3 requirements types C, D and H), the company feels the requirement for real time data until expiry, for 3 production batches, is excessive for variations of this nature.

O - Editorial changes to documentation for the manufacturing process (p80)

Specific conditions • The change must only be to typographical and editorial changes that do not change the performance of the procedure.

MSDA seeks the TGA’s confirmation it will not be mandatory to report all editorial changes to the licence via SAR as soon as they are discovered. MSD contends editorial changes should remain ‘No Regulatory Action’, and the company has internal procedures in place to ensure editorial changes, once identified, are communicated to the TGA in due course. Per current internal MSDA procedures, editorial or typographical changes that do not impact the original intent of the license are recorded and communicated to the agency the next time the license section is submitted subsequently as part of a variation. These current internal procedures align with the specific condition given above.

4.3: REQUESTS THAT REQUIRE SUBMISSION OF DATA (CATEGORY 3)

C Changes to the method of manufacture of drug product (p93)

Required information

• Batch analytical data generated for three full production-scale

batches of drug product manufactured using the proposed process, unless otherwise justified. These data should be compared with data from at least three batches of recently manufactured pre-variation product and the mean, standard deviation and range of historical data. All data should be generated using approved routine quality control methods, unless otherwise justified and details are provided of the non-routine methods used.

Under the current Appendix 12, sponsors are required to submit batch analytical data from “representative’ batches of finished product – at least one batch of full production scale while the other batches should be at least pilot scale manufactured using full production scale equipment unless otherwise justified. MSDA invites the TGA to comment on why it feels it necessary to increase the requirement for batch analytical data from one to three production batches, and why data from pilot scale batches are no longer appropriate.

For many changes to method of DP manufacture MSDA would need to perform process validation at full scale, in which case providing the above is not an issue. However, in instances where the sponsor has used a different process validation strategy, and can provide appropriate justification for this, would the TGA be able to accept deviations from the above requirement? MSDA would undertake to provide material from one full scale production batch, and a commitment to monitor the following two batches and report any OOS results to TGA. If not, there may be interruption of supply to critical medicines while waiting for sufficient production material to be generated and tested.

• Real-time stability data generated for batches produced using the new process (refer to Appendix 14 of the ARGPM). For biological medicine products requiring refrigeration or freezing, stability testing should be in real time at the specified storage temperature, for at least the requested shelf life. The time out of refrigeration (which also includes time out of the freezer) during normal manufacturing processes, up to the point of return to the fridge or freezer following labelling and packaging, must have been defined and justified.

From that point onward, all storage and shipping conditions must be justified by the real-time stability data; the data for justifying any temperature excursions must include real-time studies of the proposed excursion followed by return to the normal storage conditions for the remainder of the shelf life.

MSDA strongly contends that it is excessive relative to the current guidelines to require real time stability data for the duration of shelf life (2-3 years) to support routine changes to method of manufacture. In effect, preparation of all regulatory submissions will need to be put on hold for 2-3 years while real time data is generated! This would inevitably lead to interruption of supply of critical medicines and vaccines to Australian patients. In the EU and US, sponsors would submit comparability data for such changes. This includes initial stability data with a commitment to follow stability until the end of shelf life and to report unexpected results. FDA is now also requesting accelerated or mild forced degradation data. Furthermore, this requirement will effectively prevent release of any product for which there has been a temperature deviation during shipping, as it is not practically feasible to provide real time data for a 3 year shelf life in response to individual shipping temp deviations. Once the 3 years necessary to generate the real time data had elapsed, the quarantined stock would have passed its expiry date and been disposed of (and economic costs incurred). Please also refer to MSDA’s comments on this subject in response to Section H: Changes to shelf life and storage conditions.

D changes to site of manufacture of the Drug Product (p94)

Required information

• Certificates of analysis for three sequential, preferably full-scale batches of drug product that were manufactured at both the currently approved site and the new site. Under the current Appendix 12, sponsors are required to provide CoAs for “representative batches of finished product. At least one batch of full production scale while the other batches should be at least pilot scale manufactured using full production scale equipment from the new site unless otherwise justified.” We acknowledge that for some changes the TGA does require three production batches under the current Appendix 12, with submission of data for the first batch and a commitment to provide data from the second and third batches when available. MSDA invites the TGA to comment on why it feels it necessary to increase the requirement for batch analytical data from one to three production batches, and why data from pilot scale batches are no longer appropriate. Would commitments to provide data once available (as per current situation) no longer be acceptable?

• Relevant comparative data on the product (see ‘C: Changes to the method of manufacture of the drug product’, above). MSDA’s comments in response to Part C are applicable here. MSDA invites the TGA to comment on why it feels the need to increase the requirement for batch analytical data from one to three production batches. MSDA wold undertake to provide material from one full scale production batch, and a commitment to monitor the following two batches and report any OOS results to TGA, as per current requirements. • Relevant stability data for batches produced at the new site (refer to Appendix 14 of the ARGPM). For biological medicine products requiring refrigeration or freezing, stability testing should be in real time at the specified storage temperature, for at least the requested shelf life.

The time out of refrigeration (which also includes time out of the freezer) during normal manufacturing processes, up to the point of return to the fridge or freezer following labelling and packaging, must have been defined and justified. From that point onward, all storage and shipping conditions must be justified by the real-time stability data; the data for justifying any temperature excursions must include real-time studies of the proposed excursion followed by return to the normal storage conditions for the remainder of the shelf life.

MSDA’s comments in response to Part C are applicable here. MSDA strongly contends that it is excessive relative to the current guidelines to require real time stability data for the duration of shelf life (2-3 years) for routine changes to manufacturing site.

H Changes to the shelf life or storage conditions of the Drug Substance or Drug Product (p98)

Note on stability testing

For biological medicine products requiring refrigeration or freezing, stability testing should be in real time at the specified storage temperature, for at least the requested shelf life. The time out of refrigeration (which also includes time out of the freezer) during normal manufacturing processes, up to the point of return to the fridge or freezer following labelling and packaging, must have been defined and justified. This should be based on worst-case storage scenarios and include storage conditions inherent in the manufacturing process and transport.

MSDA contends it is excessive to require real time sequential thermal stress studies [temperature excursion followed by return to the normal storage conditions for the remainder of shelf life] for the duration of shelf life in support of routine manufacturing changes. MSDA notes that potency loss from exposure to conditions above the long term storage condition is taken into consideration as part of setting the product potency specifications at the time of initial registration.

From that point onward, all storage and shipping conditions must be justified by the real-time stability data; the data for justifying any temperature excursions must include real-time studies of the proposed excursion followed by return to the normal storage conditions for the remainder of the shelf life.

For a change in shelf life or storage condition, it is the current expectation of the sponsor that we would submit data covering the full claimed shelf life in EU and US. MSDA would usually use representative

small scale batches to prepare this. Not all studies routinely analyse all expected temperature excursions, depending on the nature of the change being made.

However, if it becomes are requirement to repeat the sequential stress study for every manufacturing change (as it proposed in parts C, D and H of this document), the delay in regulatory approval would be excessive if the study would need to be completed prior to submission of the variation! This will add a further 2-3 years preparation for any regulatory application of this nature, and delay availability of medicines / vaccines to the Australian public.

N Changes to diluents kits or product components

Any changes to product components require the TGA to evaluate the data. This includes any changes to diluents and any change to, or addition of, a component of a biological medicine.

MSDA invites the TGA to clarify whether variations to diluent product itself, without changing the component provided in the kit or composite pack, will now be subject to Category 3 application? Are we correct to assume that a variation to a diluent or component which meets the biological criteria for self-assessment e.g. change to the label on a diluent syringe supplied with a vaccine, can be communicated via SAR as at present?

We look forward to receiving feedback and comments from the TGA.

With Kind Regards,

MSDA Regulatory Affairs