Topic 4.

Stability – Challenges and

Considerations for global
development

Topic Owner: Laura P. O’Brien

CMC Focus Group Meeting

May 11th 2012
 Stability Topics & Definitions
 Primary stability study / establishing shelf life & storage
conditions

 Stability data to support pharmacy dispensing / patient

handling practices

 Other stability challenges

 Definitions
 SMF = Small molecule formulations (innovator or generic)
 Bio’s = Biotech products
 HA’s = Health Authorities, e.g., FDA, EMA, PMDA, Health Canada…
 “Sensitive” drug product – protected from moisture, light, temp. (refrig.)

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Primary Stability / Establishing Shelf Life
& Storage Conditions
 Amount of stability data in initial registration submissions
 Requirement for 12 months long term storage data per ICH Q1A (R2)
 How can representative supportive data be used?
How have you succeeded in deviating?
 What do other HA’s accept?

 Submitting stability updates during the review period

 How does the stability update during review process work for FDA
discussion?
• Needs to be pre-negotiated (case by case; pre-NDA topic)
What timing of the stability update submission was accepted?

 Other HA requirements and negotiations?

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Primary Stability / Establishing Shelf Life
& Storage Conditions
 Extrapolated shelf life per ICH Q1E
For FDA:
 Apply ICH Q1E guidance for SMF’s
 No extrapolation for Bio’s;
some flexibility case by case
(ICH Q1E does not apply for Bio’s)

 Other HA requirements?

 Shelf life in Australia with a trend for decrease in Assay

For 2 SMF’s, allowed shelf life based on:
[95.0% release limit – 92.5% shelf life limit1] / [slope @ 30°C storage]

1Therapeutic Goods Order No. 78, 11 (b)

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Primary Stability / Establishing Shelf Life
& Storage Conditions
 Shelf life with a holding period for an intermediate
Any experience with start of shelf life at completion of bulk manufacture
rather than the time when API is first mixed with excipient (impact of an
intermediate holding period on shelf-life)?

EMA NfG Start of shelf-life of the finished dosage form

 Value of accelerated stability requirements in

establishing shelf life?

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 Stability data to support pharmacy
dispensing / patient handling practices
 In-use stability study design and in-use periods
Case study for a sensitive SMF:
• FDA required in-use data to support a 3- to 4- month mail order
supply
• 1-month bottle supply required to be exposed daily for 3-4 months
• Chimney-shape bottle label applied

 How much 25°C in-use time is reasonable between

dispensing and administration of a refrigerated product?
• 1 month for an injectable?

 Are stability data needed to support:

• physicians without refrigerators?
• shipping excursions?

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 Stability data to support pharmacy
dispensing practices
 Which stability assumptions support the beyond-use
date applied by a U.S. pharmacy?
 Unless otherwise instructed, the dispenser will assign a beyond-use
date of one year from the date the drug is dispensed,
or the expiration date on the manufacturer’s container,
whichever is shorter (Ref USP General Notices 10.40.100).

 Stability data needed to address local pharmacy

dispensing requests for a “sensitive” SMF?
 Northern European pharmacies de-blister and repackage in plastic
sachets. In Denmark, 4 weeks stability data in an open container were
requested to dispense a 2-week supply.
 New Zealand & Australia pharmacy requests for 30-day stability data to
dispense in a blister pack:

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Stability data to support patient handling
practices
 Stability data needed to address caregiver / patient
handling?
 “Pill boxes”

 Humid bathrooms

 Open containers

 Hospital pill tray for nurse dispensing

 A child resistant bottle closure may be broken to handle more easily

 Should in-use light exposure of a photosensitive product

be supported?

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 Stability data to support Japan
pharmacy dispensing / patient handling
Japan dispensing by pharmacist:
 Repackaging of blisters into paper bags

 Automated repackaging into One Dose Pack

 Crushing of tablets / opening of capsules:

should also be supported with stability data

“ODP Information Handbook” required; data based on in-use stability study;

not a J-NDA review topic
 In-use stability data have strong impact upon sales
 All pharmaceutical companies provide in-use data
 Literature exists compiling in-use stability data without primary package
for all the drug products in Japanese market.

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 Other Stability Challenges
 Biosimilars
 Can the storage conditions for a multisource product be different from
the innovator’s? (Bio’s are generally refrigerated.)
 Stability performance should not be worse than innovator’s.
 Same labeled instructions for handling / in-use?

 Global stability requirements (site specific stability)

 How much data are needed at new site for approval?
 Consideration for dosage complexity / DP stability on the site-specific
stability data?
 Same shelf life with only 3 months data in submission?

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 Discussion
 Does the shelf life spec apply after dispensing?
 Should water content spec be met in a humid bathroom?
 Should the clinical relevance of a spec be considered?

 What is the scope of the Sponsor’s responsibilities?

 Exclude non-compliance, i.e., label instruction not followed.
 “Reasonable” or “Standard” or “Foreseen” storage & handling?
 Documented frequent practices?
 Exclude “rare” or “unexpected” occurrences – how defined?

 Any different experiences for Devices?

For Drug-device combinations? Other pharmaceuticals?

 Any other stability / shelf life discussions?

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Topic 4

Wrap Up

CMC Focus Group Meeting

March 17th 2011
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Stability Data @ Initial File

 Some companies (small molecule) reported that have successfully
negotiated initial submissions in the US with <12 months data and a
commitment to submit additional data during the review cycle
 Have seen this for oncology products or for products for unmet medical needs
 Additional review material should be submitted early in the review process.
PDUFA V contains language that any updates to a submission must be
submitted within 30 days of the filing date.
 May not apply to supplements with shorter review cycles
 Shelf-life will always be dependent on the strength of the primary stability data
 Biological product has been successful to submit in US with less
than 12 months data and use additional supportive data to gain a
longer shelf-life.
 Noted that the process was ‘locked’ at Phase 2

CMC Focus Group Meeting

March 17th 2011
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Stability Data @ Initial Filing

 General Themes
 Less than 12 month - Can be negotiated – much easier to
negotiate in US than outside US
 With pre-agreement, can submit additional stability during review
in US, EU, Japan
 Requires robust supportive data
• Minimal changes
• Final analytical methods

CMC Focus Group Meeting

March 17th 2011
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Definition of DP Shelf-life
 One example of successful start of shelf-life when drug
product intermediate (API + 1 excipient) is added into the
DP manufacturing scheme – accepted in US and EU
 Was a well-known API (not a novel compound)

 Extensive stability (5 years) on DP intermediate

 Agreed to set shelf-life of 2 years for DP intermediate

CMC Focus Group Meeting

March 17th 2011
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Site Specific Stability

 Various experiences were discussed for small molecule, solid oral,
and may not be required for initial filings in NDA/MAA
 Expectation is that the sponsor demonstrates in the file that the

mfgr site can make the product at commercial site

 SSS data gathered as part of the post-approval stability

commitment
 Several ROW countries will require this

• Brazil appears to be most strict and expects site specific for

the entire supply chain
 Biological products – more conservative approach – Needed!
 Changes in scale and site are of concern for biologicals

CMC Focus Group Meeting

March 17th 2011
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In-Use Stability
 Defined: Would be covered in labeling
 Should be supported by development studies and
primary stability batches at initial and end of shelf-life
 EU guideline requirement
 No experience with different in-use spec than shelf-life
spec
 Future point to consider – qualify with clinical experience
and tox support

CMC Focus Group Meeting

March 17th 2011
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Patient Handling
 Conditions not outlined in labeling
 Not a “one size fits all”, but this could be reasonable
 Supported by 30-days open dish data

 “sensitive” product – support with study where

container is opened once daily (or to match the

dosing instructions)
 Accelerated stress studies can cover most situations

 Advisable to consider the common pharmacy

practices in your stability studies

CMC Focus Group Meeting

March 17th 2011