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.