Dr. Nicholas Cappuccino
Dr. Reddy’s Laboratories, Inc.
This presentation contains a summary of
the opinion and perspective from GPhA
member industry representatives on the
topic of Stability.
This presentation does not necessarily
represent the opinion of the presenter nor
Dr. Reddy’s.
Drug Product Selection of batches
Three primary batches of drug product
Same formulation and same container closure system as proposed for marketing
Manufacturing process used for primary batches should simulate that to be applied to production batches
Two of the three batches should be at least pilot scale batches and the third one can be smaller, if justified.
It should be considered by OGD that batches with minor quantitative differences in formulation may be acceptable, if justified.
Drug Product
Packaging of Stability Batches OGD currently requires that the one stability batch
required should be completely packaged on a production
packaging line
It should be considered by OGD that only one of the
required pilot scale batches be completely packed on
production packaging equipment. Additional pilot or lab
scale batches should be packed in each configuration
only to the extent necessary for sample test
requirements and maybe packed in packaging
equipment that simulates the proposed production
packaging equipment.
Drug Product
Storage Conditions – General Case
If long-term studies are conducted at 25C+
2C/60% RH and significant change occurs at any
time during 6 month testing at the accelerated
storage condition, additional testing at the
intermediate storage condition should be
conducted…
Testing at the intermediate condition is not
required otherwise in Q1A.
Generic industry ANDA requirement should not be more
stringent than for a New Drug Application
Bracketing and Matrixing stability protocol
designs may be applied to ANDA stability
studies conducted according to principles in
ICH Q1A(R2).
Provided that the design of these studies are
done according to the principles described in
ICH Q1D guideline, no prior approval of these
reduced design protocols should be required
by OGD.
Stability data generated per ICH Q1A(R2) guideline principles may be used to propose an expiry date for a product per the ICH Q1E guideline, ―Evaluation of Stability Data‖
In cases where accelerated data show little or no change and little variability, an expiry date of 2X the available data will be granted up to X + 12 months without statistical analysis
In cases where accelerated data show change or are variable, an expiry date of 2X the available data will be granted if acceptable statistical analysis is performed.
Since the new ANDA stability package matches that of an NDA, the practice of granting a tentative 2 year expiry date should be eliminated
Development of ANDA products according to
Quality by Design(QbD) principles should
allow flexibility in meeting typical regulatory
requirements
Exceptions to standard Q1A(R2) requirements for
primary stability studies may be made if justified
from extensive product stability knowledge
gained by QbD
Number of batches
Size of Batches
Similar rather than identical formulations
Test parameters
GPHA proposes 6 months of data from the long term and accelerated storage conditions and intermediate condition, if applicable, is the most that should be required at submission. N.B. This is an exception to ICH Q1A(R2) which requires
12 months of long-term storage data at submission
Before ANDA approval NLT 12 months of data must be available for review upon request of OGD Expiry dating in any event will be based on evaluation of
data per Q1E, thus less than 2 year expiry periods may be granted by OGD if appropriate
Industry experience with 505(b)(1) and 505(b)(2) NDAs reveals that CDER ONDQA often accepts 6 months data at submission with supplementary data supplied during review period if requested by applicant during pre-NDA meetings.
Country No. of
batches
(each
strength)
Batch Size Stability
Each strength and pack
In months
ACC Long
term
Intermed.
Canada 2 Minimum 100,000
(2 batches)
6 6 If ACC fails
Also allowed when
justified One batch
100,000 and one batch of
smaller scale when dose
proportional
Europe (EMA) 2
3
2 batches pilot scale for
conventional dosage forms
3 batches for critical
dosage forms
6 6 If ACC has
significant
change
Minimum—2 batches
100,000 and one batch
smaller scale
The proposed Stability guideline will set US OGD stability standards different than and higher than those of other national regulatory authorities e.g., Canada, EU, WHO, etc.
FDA has been engaged in discussions with other countries regarding possible sharing of information and work in reviewing ―global‖ dossiers from generic companies.
This stability guideline may create a new barrier to achieving the overall goal of improving the timely access to generic medicines to patients in a more cost-effective way utilizing harmonized regulatory standards.
Given the significant effects and actions
necessary to be taken by the generic
industry:
Procuring sufficient API to meet 3 batch
requirement
Additional Stability storage capacity
Additional Facility and Laboratory space
Target date of ANDA filings regarding patent
considerations and development timelines
GPHA proposes that the new requirements become
effective no sooner than 1 year from the date of
issuance of the final guidance.