Keynote New Frontiers for Complex Drug Products and BCS based Biowaivers

Pharmaceutical Equivalence: Opportunities, Challenges, and Solutions for ANDA and 505(b)(2)

Ajaz S. Hussain, Ph.D., Insight Advice & Solutions LLC

[email protected]

2nd Annual Symposium on Development of Generics & 505(b)(2):

‘New Frontiers for Complex Drug Products and BCS Based Biowaivers’

DoubleTree HotelSomerset, NJ

Ajaz S. Hussain | Insight Advice & Solutions LLC 1

mailto:[email protected]

Outline

Greetings from Toronto, Canada; sincere apology for not being with you in person to deliver this talk. At IGPA later today we will be discussing Building a Culture of Quality; a topic that is also relevant to the audience in NJ

Why I firmly believe that for Complex Generics it is “Pharmaceutical Equivalence” that is the ‘Elephant in the Dark’ ?

What I have learned specifically that reaffirms the Why? Examples while at FDA, Examples from Sandoz (Omnitrope® - US

505(b)(2), Generic Enoxaparin and Glatiramer acetate), other examples

How many companies fail to leverage this “billion(s) dollar” opportunity?


Our “generic” paradigm:

Interchangeability with confidence

Pharmaceutical Equivalence

Bio-

equivalence

Practices > Confidence

Therapeutic Equivalence


This paradigm has been tested and “knocked on its head”

“It still is solid” but in need for attention –particularly in the realm of complex generics

“Knocks on the head” Generic Drug Scandal

Failures to detect obvious errors/flaws

Recent failures and manufacturing challenges

Tested – numerous prospective studies to assess therapeutic equivalence


“Knocks on the head” erode confidence and increase nocebo effects!

“Knocks on the head” have occurred When we failed to appreciate a systems approach to development,

review, process validation, and inspections (GLP/GCP/CGMPs)

When we ignored to ask the ‘right question’ and in the ‘right sequence’

When we did not question assumptions we take for granted

Most of these relate to Pharmaceutical Equivalence PE = dosage form (irrespective of color, shape, mechanism of

release,….);

A clear liquid in a bottle is a “solution”: e.g., cyclosporine micro emulsion, and low-permeability excipients (e.g., sorbitol)

Consider current examples….ER failures and AB to BX downgrades

Our incorrect thinking – “BE is the pivotal evidence”; instead of integrating PE,BE, Practices – as in a system


“Pharmaceutical Equivalence” that is the ‘Elephant in the Dark’

Q1/Q2

Q1/Q2/Q3, ……

Today … Color, Shape,…..moving towards same mechanism of release?

Today we are back to “subjectXformulation” interaction – once again in healthy subjects?

Isn't this just an assumption? Which, politely, is not a part of “our elephant” but what comes out of it when we don’t pay attention to PE!

We lack consensus on a set of principles to integrate across multiple, orthogonal, analytical characterization tools for physical attributes and physical performance (e.g., size, shape, charge, flow, plume, …)

This is a “billion dollar” opportunity; but only for certain companies


generics are for minor but not serious illnesses;… and poor people are forced to ‘settle’ for generics.

What do people really think of generic medicines? A systematic review and

critical appraisal of literature on stakeholder perceptions of generic drugs. BMC Medicine 2015, 13:17336 % of the patients reported negative experiences after medication substitution

89 % of pharmacists reported receiving patient complaints regarding use of generic medicine, although 64 % suggested that this was due to a nocebo effect

Only 50.2 % of the surveyed pharmacists agreed that all products that were approved as generic equivalents can be considered therapeutically equivalent.

Just 6 % of pharmacists considered that dry powder inhalers were interchangeable.

While acceptance of generic medications is improving, substantial mistrust and lack of confidence remains, particularly within the patient and, to a lesser extent, physician groups.

Nearly half the patients stated they would refuse generic substitution when it became available if this was just to save the health authority money.

Generic medicines were considered to be poor quality and treated with suspicion.


http://www.biomedcentral.com/1741-7015/13/173/additional

The “how” is very difficult because of “culture” and “mind-set”

Example: Equivalence of Glatopa® and Copaxone®

Characteri-zation of

Brand Copaxone

Thorough understanding of reference listed

drug (Copaxone) required.

Review available scientific, patent,

and regulatory literature on Copaxone.

Characterization by more than 60

physicochemical, biological, and immunological

methods.

Multiple lots (up to 50 for some

attributes) were studied over several

years probing the range and diversity of the commercial

lots, as well as evaluating the

effects of lot aging.

Four-Point Criteria for

Demonstration of Equivalence of Glatopa and

Copaxone

Equivalence of starting materials

and basic chemistry.

Equivalence of structural

signatures for polymerization,

depolymerization, and purification.

Equivalence of physicochemical

properties.

Equivalence of biological and

immunological properties.

http://www.momentapharma.com/AAN-Equivalence-Glatopa-Poster-6x4-PRESS.pdf (accessed 16 September 2015)


http://www.momentapharma.com/AAN-Equivalence-Glatopa-Poster-6x4-PRESS.pdf

To leverage the “billion(s) dollar” opportunity:

Put R back in R&D & recognize it is a “complex” product and process!

Invest in analytics, mathematics & statistics, and large sample sizes; and in systems/integrative thinking and data integration

Get to know the RLD – multiple lots; open the door with large sample size

Ability to justify measured RLD variability is relevant to development of the proposed generic

Exquisite regulatory communication strategy

This is not a ‘complicated process’ for which typical ‘good practices” work (e.g., typical project management approach)

This is a complex process – with multiple interactions and “emergent properties”; treat it as it is - a complex process and plan to anticipate and address “emergent issues” - in technical, regulatory and legal dimensions; at a certain point be prepared for stakeholder (payers, patient groups,..) communications


Related talks that you may find of some interest

Please see past presentations @ http://www.slideshare.net/a2zpharmsci/

Product Quality & Patient Safety USP Workshop, Mumbai, 12 June 2015

Excipient Knowledge Management, Mumbai, 12 March 2015

QbD and CoQ IDMA, Mumbai, 24 March 2015

QbR to QbD to CPV; 16 February 2015

Bioequivalence – Still a Quality Achilles’ Heel? 16 October 2014

A Historical Document on Subject By Formulation Interaction

Voices of/for Patients

Voice of the Patient

Reducing technical and regulatory uncertainty in biosimilar development

Biopharmaceutics Classification System (BCS) & Waiver of Bioequivalence


http://www.slideshare.net/a2zpharmsci/

Keynote New Frontiers for Complex Drug Products and BCS based Biowaivers

Leadership & Management

Transcript of Keynote New Frontiers for Complex Drug Products and BCS based Biowaivers