Topic 2: Managing Excipient

Scientific Regulatory Risks for Adult

and Pediatric IR Formulations

Moderators

Bernhard Boehm, Boehringer Ingelheim

Brian Carlin, FMC BioPolymer

Akm Khairuzzaman, FDA

Laura O’Brien, Boehringer Ingelheim

Thomas Oliver, FDA

Debra Webb, Pfizer

Disclaimer

The slides reflect the comments of the

audience and are not necessarily

representative of the moderators or their

organizations.

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CMC Focus Group Meeting

March 15th 2013

Overview

Excipient Unknowns

Excipients in Pediatric Development

Innovative / Novel Excipients

Excipient Unknown Unknowns Composition & Functionality/Performance

Limited Utility of Pharmacopoeial Attributes

Unspecified excipient

attributes

True variability of

specified attributes

Criticalities in the

Finished product

Not by Design!

Carlin B, J Excipients & Food Chem 3 (4) 2012 143-153

http://ojs.abo.fi/index.php/jefc/article/view/190/176

James Michaels NIPTE/FDA June 2012

Criticality in

Excipient Risk Assessment ICH definition (Severity, Probability & Detectability)

doesn’t include “a point of transition from one state

to another”

ICH definition based

on MIL-STD-1629a

Eg Critical Micelle Concentration Explosive Percolation*

*http://www2.imperial.ac.uk/~mgastner/percolation/percolation.html

Application criticalities?

Excipients may unexpectedly affect CQAs if

there is a criticality in the application

Unanticipated, interactions, scale-up

Not always intrinsic to an excipient

Non-linearities, discontinuities, tipping points

Disproportionate impact of minor excipient

variability governing a critical transition

No evidence of problem in DOE is NOT

evidence of no problem

Examples of Criticalities Percolation thresholds

Disintegrant in insoluble/hydrophobic matrix

• No wicking without contiguous network

Non-linear tablet hardness-force profile

• Contiguous high density regions within compact

Conflicting technological objectives

Overgranulation

Lubrication vs Compaction vs Dissolution

Unidentified Critical Material Attributes • especially with “non-critical” excipients in

‘”simple” formulations (what can go wrong?)

Excipients in Pediatrics

EMA „5-year Report to the European

Commission” on Pediatrics 2012

Safety of excipients for the paediatric

population: […] In an analysis of 84 proposed

PIPs that was carried out in 2009, issues with

excipients were identified in 102 (82%) out of

125 pharmaceutical forms proposed for

children.

Role and Functionality of Excipients in

Pediatric Formulations

Impact on

Solubility

Relative bioavailability

Palatability

Dosing Accuracy

Excipients in Pediatrics:

Mission Impossible?

How to manage complexity: different age groups/ diseases/

treatment duration/ socio-cultural preferences/ …

Different risk/benefit assessments?

How to address varying patient preferences/needs with one

formulation?

Tox assessments for excipients: how detailed should they be?

Novel vs. non-compendial vs. compendial

What is a “sufficient justification”?

How to treat flavors containing ethanol/propylene glycol?

Innovative / Novel Excipients

Do we need novel excipients?

Risk vs. benefit:

Higher degree of unknown

Limited / no experience (regulatory, safety, quality)

Added value?

Unmet needs?

Novel Excipient Example – Regulatory Issue Novel “mixed” excipient in tablet (P.1 target value = 68% of formulation).

Composition of mixed excipient provided as separate table in P.1.

Query received based on: CPMP/QWP/486/95 re: Section 3 Manufacturing Formula where it is required

excipients be 90-110% of nominal quantity in the formulation

Query: In the DP Appendix the allowable ranges for each of the novel excipient’s ingredients had been provided (e.g., 3.5 – 6.0% ingredient Y). The regulator took these ranges and applied the guideline 90-110% to each ingredient as if each ingredient of the mixed excipient were a single excipient in the DP formulation. In so doing, at the extremes of the ranges, the ingredients did not meet the 90-110% requirement.

Excipient supplier’s lab scale process capability data with critical ingredients at extremes of allowed ranges and historical batch data showing typical value for each ingredient in the excipient were used to justify the ingredient ranges

Accepted response required DP manufacturer to state target values of the excipient’s ingredients in the excipient’s composition table provided in P.1. The supplier’s ingredient ranges (provided in DP Appendix) were accepted as initially submitted.

Example for Discussion:

BA & palatability problem for Drug X Performance objectives cannot be met using available

compendial excipients.

How to manage & mitigate risks of using a novel excipient? Under which circumstances is the unmet need so high that it is

worth the resources?

Has a firm performed NonClinical work to support a pediatric excipient?

What are risk management approach differences for: novel -vs- compendial? adult -vs- pediatric?

What novel excipient data can be reviewed in advance to facilitate marketing authorisation of finished product?

IPEC Novel Excipient Safety Evaluation Program

Ground Rules for Discussion 14

CMC Focus Group Meeting

May 15th 2013

Intended as a technical discussion

Intended to facilitate sharing of experience

Not a Q and A for the Agency

Questions regarding specific applications or

requests for a meeting can be sent to:

NewDrugCMC@fda.hhs.gov

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CMC Focus Group Meeting

May 15th 2013

In 2010, five (5) recalls traced to excipient: impurity,

peroxide content, variability in cellulose derivatives and

other natural polymers

What is the proper risk management strategy for

excipient?

Should excipients be chosen differently for pediatric

formulations? (e.g. benzyl alcohol, propylene glycol,

ethanol safety in neonates)

Is an excipient compendial monograph sufficient enough

to ensure product quality?

Do we need novel excipient for pediatric formulation?

Managing Excipient Scientific & Regulatory

Risks for Adult and Pediatric IR Formulation

FDA Guidance on Excipients 16

CMC Focus Group Meeting

May 15th 2013

Guidance for Industry: nonclinical studies for the

safety evaluation of pharmaceutical excipients-

2005.

Safety pharmacology according to ICH S7A:

Standards for all new excipients

Inactive ingredient database (IIG limits) -

http://www.accessdata.fda.gov/scripts/cder/iig/

Managing Excipient Scientific Regulatory

Risks for Adult and Pediatric IR Formulations:

Wrap-Up

Excipient Unknowns

Excipients in Pediatric Development

Innovative / Novel Excipients

Wrap-Up – Excipient Unknowns

Compendial doesn‘t mean it‘s OK

Mfg site, country, region differences even within one

supplier

USP doesn‘t cover functionality or physical testing,

focuses on chemical testing, not designed for fitness

for purpose

How to manage suppliers, no guarantee they won‘t

make changes, change is often inherent from their

ingredient source (yr to yr)

CQAs of excipients (beyond compendia)

• How to set spec limits if cannot obtain samples of excipients

at ranges of their attributes – IPEC has a guide

Wrap-Up – Excipient Unknowns

CQAs of excipients • How to demonstrate absence of impact if one

cannot obtain samples of excipients at extremes of

their attributes Often an issue with continuous manufacturing at center spec

Suppliers are willing to work with pharma

Cost in use vs cost per kilo

• IPEC has a sampling guide under development,

consider sieving, bracketing, blending, etc.

• Ask supplier for portion of batch with

corresponding IPC data for continuously produced

materials

• Try another supplier

Wrap-Up – Excipient Unknowns

Has awareness of excipient criticality increased? Yes, due to insolubilities of APIs; smaller drug loading (greater

excipient loading)

Assumption of non-criticality is dangerous

How to resolve unknowns? Increase exchange of info with suppliers but there may be IP

concerns

Concern of higher prices for tailoring excipients to meet specific

pharma needs or even needs of one pharma co.‘s formulation

If excipient supplier is a member of IPEC, shows they‘re

interested in more than just selling a commodity

Suppliers need pharma to provide feedback on excipient

performance

Wrap-Up – Excipient Unknowns

(cont) If excipient is deemed “non-critical“, DOEs might not be powered

to look at excipient attributes, problem of defining excipient

criticalities when excipient variability is encountered only

sporadically

Consortium between pharma companies (database), academia,

suppliers (NIPTE* is an example)

Non-competitive exchange of info

Sharing of proprietary data is a concern

Cost – what would we be willing to pay to get more info?

*National Institute of Pharmaceutical Technology and Education

Wrap-Up – Excipient Unknowns

How to establish a design space

encompassing excipients? Do we typically qualify multiple excipient suppliers during

development? Not during development (lack of time, resources,

fear of failing a batch needed for clinical supply), excipient issues

can crop up post approval when switching suppliers or within

one supplier‘s sources/sites

Example of excipient supplier: cleans site 1/yr, then mfg one

continuous batch of pharma grade for the year‘s supply, then

mfg demand needs for food grade, then tech grade for rest of

year

Wrap-Up – Excipient Unknowns Purity of Excipients

Labeled entity + impurities ≠ 100%; concomitants , processing

aids, undeclared additives... are part of equation

What do figures on COA mean relevant to continuous

manufacturing?

• COA results may be an ave or composite of 1000 tons of

manufacturing at steady state

• If drums of material are numbered consecutively, suppliers can

trace a specific drum back to the nearest IPC testing

Pharma strives to control API characteristics but ignores

excipients even though often the API drug load is 5% or less

Example: pure dicalcium phosphate won‘t make tablets, need

the impurities for the excipient to work

Wrap-Up – Excipient Unknowns

Constant composition vs constant performance Example: some suppliers deliberately vary composition to obtain

constant performance (colorants). Constant color is more

important than constant composition.

New USP metals testing: USP going forward with limits proposed as draft in ICH

Required to test DPs if cannot justify via data from excipient

suppliers

Source of excipient is important – e.g., harvested from trees

(cellulose) or seaweed (carrageenan) and mined excipients (talc,

titanium/iron oxides)

Wrap-Up – Excipients in

Pediatric Development Peds is last place to introduce a novel excipient,

concern about clinical bridging to adult safety

and efficicacy data Consortium to share tox data (EUPFI, starting STEP database)

How to develop a global ped formulation? Water supply a concern

Pharmacokinetics varies across ethnicities in adults, it‘s worse in

children

Multiple peds formulations often required

Age of ability to swallow varies

Complexity of mixing with food & drink

Wrap-Up – Excipients in

Pediatric Development Flavors in ped formulations:

Concern with propylene glycol and ethanol

How much is acceptable? No knowledge of

acceptable levels, just what maximum is not

acceptable

Interact with PDCO early, FDA may not be as

amenable to early discussions (prior to

EOP2) unless company submits a specific

question

Wrap-Up – Innovative / Novel

Excipients Risk/benefit

Target indication can influence risk/benefit

What is required to register a novel excipient?

If never used in peds (but used in adults) is it novel? Yes

due to new population group, need to justify excipient

and levels used, individual tox assessments may be

necessary, do we need a ped IIG?

Designation of “ novel“ may be unclear: i.e., coprocessed

excipient made of precedented ingredients?

IPEC developing coprocessed excipient guide