manufacturing transfers of established drug products

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Manufacturing Transfers of Established Drug Products A Challenge in the “New” Regulatory Environment

ISPE Nordic Annual Conference 2015

Anders Sveno – Head of Regulatory Project Management

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A new Regulatory Environment for Established Products

• To register a drug product 50 years ago was very different

• Several new guidances have been issued • ICH• EMA

• Many of these guidelines have been focused on products with New Chemical Entities (NCE)

• For established products, separate requirements are often presented

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Risks When Initiating a TT of Old Established Products

• Different regulatory environment• Specification requirements was different (e.g. no inclusion of degradation products)• Analytical methods not up to date• Manufacturing process using old methodology• Knowledge on important/critical parameters limited

• Changes in product also changes regulatory requirements

• Documentation requirements has changed (i.e. details of the regulatory file)

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Meda – A specialty Pharma Company

• A Swedish pharma company with presence in more than 60 countries/5000 employees

• > 1000 products world wide

• Working with established active substances• Established products (mainly original products)• New launches

• Growth through take over of companies/products

• Several FDF manufacturing sites in-house but also high number of CMO‘s

• Strategy is not to be a manufacturing company

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Different Types of Manufacturing Transfers

• R&D companies (e.g. big pharma)• TT of processes due to lack of capacity/strategy, both API and FDF• Internal expertise • Significant knowledge sharing• Complex molecules or products but significant experience

• Old established products (e.g. Meda)• TT of processes based on strategic decisions• Knowledge of process is mainly at the ”current” manufacturing site• Relatively simple products/processes (not always…) but complexity is due to limited

development information• Preferably the FDF manufacturer handles API sourcing

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What Initiates a Manufacturing Transfer?

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Process and Important Steps of a Transfer

Identify potential suppliers

Compile technical package

Select supplier based on

received offers

GAP analysisIdentify

variations

Data and documentation

needed

Validation strategy

Stability strategy

Submission and regulatory

approval

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Process and Important Steps of a TransferItem Regulatory

FileBatch Record Proposed GAP Justification

Raw materials

Excipient A Excipient A Excipient A None -

Process No information

No overage 2% overage Introduction of overage

Test batch, loss in equipment

Specification Impurities not incl.

- Add according to guideline

Addition of specification parameter

Data to be provided

Analytical methods

Assay -titration

- Assay -HPLC

New method of analysis

Validation of method

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Process and Important Steps of a Transfer

• Bridging stock is a crucial question and depends on medical need as well as costs

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Case study 1 – TT of a Simple Effervescent Tablet

• Agreement included supply from the existing site only for a limited time period

• Existing process• Direct compression of dry powder blend• Old, tailor-made equipment to handle fragile tablets

• Challenges• Similar equipment not available at any of the suppliers• Due to high product volumes an interrupt of supply

could not be accepted• Potentially very high development costs and time• Different timelines for approval in the concerned countries• Very old regulatory dossier

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• A company in Austria, specialized in effervescent tablets offered to use an already developed formulation for the specific product, including a regulatory dossier. Good opportunity but it came with:• New composition• New manufacturing process• Updated specification and methods

• Regulatory dossier (module 3) not fit for purpose• Dossier already close to 10 years old• Written for submission of new product not change in product• Minor differences between available product and Meda product

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• Module 3 was adjusted and considered fit for purpose based on the specific product

• Despite of this a significant number of questions were obtained on the manufacture and control• To perform a bioequivalence study if not further justified• More details on process parameters• Critical parameters required further control• Shelf life/stability studies on intermediates • Validation strategy not fully justified, i.e. more

information on risk assessment

• > 1 year difference in regulatory approval between Sweden and Denmark, difficult to assess bridging stock

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Case study 2 – TT of two Solutions for Injection due to Withdrawn GMP License

• The two products play an important role in the Swedish healthcare• Glycopyrronium bromide – used during surgery• Glycopyrronium bromide/Neostigmine – post surgery

• Manufactured at CMO in UK• MA license changed to exclude sterile manufacture

• Manufacture urgently transferred to Weimer Pharma in Germany

• Analytical testing and release kept at CMO in UK

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• During transfer to Weimer the API supplier stops the manufacture of Glycopyrronium bromide

• New API supplier identified but not introduced immediately

• Concurrent process validation at Weimer in order to release material as rapid as possible

• Focus on stock level in order to set dead-line for submission of new API source• The fluctuating stock suddenly got an explanation…

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• Urgent requirement to bring dossier in compliance• New API supplier• New testing and release site for FDF• New FDF specification

• Discussions with all concerned HA’s → Risk based solution due to medical need but…

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• Variation to transfer manufacture of FDF had to be initiated again

• Still several variations ongoing at the different HA’s• New API• New testing and release site for FDF• New FDF specification

• New manufacturer in France identified, transfer initiated Dec 2013

• Regulatory submission in April 2014

• Regulatory approvals• Sweden - May 2014• Norway – June 2014• Finland – July 2014• Denmark – October 2014

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• Meda general timeline for a manufacturing transfer, 12-18 months

• Key factors to deliver this project in 6-10 months• Manufacturer specialised in the area and experience with similar product• Strong development capabilities and well integrated with production• Regulatory support and department integrated in development and manufacture• State of the art GAP-analysis• Set up of validation designed to minimise number of technical trials• Concurrent validation to release batches to market as rapid as possible• Close collaboration with health authorities in the different countries

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Summary

• Regulatory risks should be assessed before changes to established products are initiated

• Make sure necessary capabilities are available at the new CMO

• A thorough GAP analysis is key to success

• Validation and stability strategies should be risk based

• Close collaboration with the concerned HA’s

• National registrations can result in very different timelines for regulatory approval

• Bridging stock must be closely monitored

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Thank you for your attention!

ISPE Nordic Annual Conference 2015

Anders Sveno – Head of Regulatory Project Management

manufacturing transfers of established drug products

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