Implementation of ICH Q3D in Product

Development.

Presentation by Dr. Laurence. J. Harris (Lhasa

consortium member and Pfizer Colleague) at the

3rd Annual Impurities: Genotoxic and Beyond

Summit, 12 - 13 June 2019, Munich, Germany.

Outline

• ICH Q3D background knowledge.

• Implementation.

– tools developed to support implementation;

• flexible procedural guidance.

• risk assessment template.

• template for submission of the risk assessment summary.

• fit for purpose analytical methodology.

• Excipients.

• Using prior knowledge (data) to make the risk assessment process more efficient.

• Case histories.

– example risk assessments.

– control strategies.

• Conclusions / Learnings.

ICH Q3D background

• ICH Q3D is the “Guideline for Elemental Impurities”

• Applicable to new finished drug products (as defined in Q6A and Q6B) and new drug products containing existing drug substances.

• Does not apply to drug products used during clinical research stages of development.

– applicable to the commercial product. However, the principles can be usefully applied earlier in the development process.

• Because elemental impurities do not provide any therapeutic benefit to the patient, their levels in the drug product should be controlled.

• Approved guideline was published Dec 2014.

– 3yr implementation timeline for existing marketed products (Dec 2017).

– applicable to new drug products after ~18M (mid 2016).

– aligned Pharmacopoeial requirements established e.g. USP<232>.

• Useful resources;

– FDA “Guidance for Industry” 2018.

– ICH training modules (see next slide).

background

Elemental impurity PDEs background

Resources

ICH training materials

Training Module 0: Introduction

Training Module 1: Other Routes of Administration

Training Module 2: Justification for Elemental Impurity Levels Higher

than an Established PDE

Training Module 3: Acceptable Exposures for Elements without a PDE

Training Module 4: Large Volume Parenteral Products

Training Module 5: Risk Assessment and Control of Elemental

Impurities

Training Module 6: Control of Elemental Impurities

Training Module 7: Converting between PDEs and Concentration Limits

Training Module 8: Case studies

Training Module 9: Frequently Asked Questions

Overview article: A. Teasdale et. al, Pharmtech Europe, 2015(3), p12ff

background

Elements, limits and control options

• The guideline lists 24 elements that need to be considered in a drug

product focussed risk assessment (RA).

– elements are divided in different classifications based upon toxicity /

“abundance” - which also aids the RA process.

• Permitted Daily Exposures (PDEs) are established for each element

based on oral / parenteral / inhaled routes of administration.

• A control threshold (30% of the PDE) has been established to help

assess the significance of a measured or predicted daily intake of each

element.

– if the RA fails to establish that an EI is consistently < the control

threshold then controls should be established to ensure that the EI does

not exceed the PDE.

• Drug product manufacturer has a range of options available to

demonstrate risk of exceeding established limits is negligible.

background

Component approaches are generally preferred

7

Option 3

Finished Product Analysis; measure the

concentration of each element in the

finished drug product and compare to the

PDE

Option 2a

Common permitted concentration limits of

elements across all drug product components

for a drug product with a specified maximum

daily intake

Option 1

Common permitted concentration limits of

elements across all drug product components

for drug products with maximum daily intake

of <10 grams

Option 2b

Different permitted concentration limits of

elements in individual components of a drug

product with a specified maximum daily intake

background

The risk assessment

• The RA drives the decision to analyse components of the DP or the DP itself.

• Don’t test the drug product for all 24 EIs and then consider risks!

• A combination of risk analysis and available supportive data leads to a robust control strategy.

Water

Drug

Substance

Excipients

Manufacturing

Equipment Containers

Closures*

EI in DP

background

(Co, V <0.2% in 316L &

Ni ~ 11% in 316L)

*Jenke et al, PDA J Pharm Sci Technol Vol. 69(1), p 1-48

(2015) & PDA J Pharm Sci Technol Vol. 67(4), p 645-57

(2013)

Elements to be considered in the RA background

Implementation

• What are my deliverables?

1. a documented risk assessment that is held at the manufacturing

site and available for inspections.

2. summary of the risk assessment in the CTD.

3. controls established that are consistent with the RA & CTD

summary.

4. on-going re-evaluation of the RA if there are significant changes

throughout the product lifecycle.

implementation

Implementation of ICH Q3D in development;

Challenges

• Each project is very different!

– route of admin, dosing, speed of development, parallel formulations,

multiple different excipients, switching API route of synthesis etc.

• Pharmaceutical organizations are generally large and Global so

there are a lot of people to train!

• Guideline though fairly complex is clear.

• It is very new, so industry and regulators are all on a learning

curve.

– expect to have queries on your submissions.

• Drug products with routes of administration not covered by the

guideline e.g. topicals.

implementation

Implementation of ICH Q3D in development

• A successful implementation will benefit from;

– sponsors and change agents.

– procedural guidance and training.

– RA tools that drive a consistent approach.

– templates for generation of RA summaries required for the CTD.

– access to data that helps to reduce the testing burden.

– fit for purpose (generic) analytical methodology (ICP-MS).

implementation

Tools - flexible procedural guidance

• Internal guidance document based upon ICH Q3D.

– training delivered to analytical project leads.

– awareness training delivered to formulators, process chemists, regulatory strategists.

• If a project team follows the procedure they will meet all required deliverables.

• Flexibility around control options, but the “component approach” is encouraged / preferred.

• Q3D “lite” for early phase materials

– no RA mandated, any testing is focussed on gathering data for API (typically class 1, 2A and added catalysts), compendial excipients, fit for purpose analytical methods used.

• Q3D “compliance” expected for late phase projects

– targets established for API and DP when the RA shows they are necessary

– typically added catalysts are monitored via the specification, especially catalysts added at late stages of the route.

implementation

Tools - risk assessment template

• Excel based template has been developed.

– probably a very similar format & content across all companies!

• Project analyst inputs formulation details.

– excipients, mass of each individual component used, route of administration, daily intake etc.

• Project analyst selects elements that need to be considered.

• Based on the information provided above the Excel template calculates concentration limits for each element of concern.

– the excel gives the concentration limits for options 1, 2a and 3 for each EI.

• Any known elemental impurity data* for each component is then entered e.g. concentration of Pb in Magnesium Stearate is X ppm.

• Excel then converts that value (in ppm) to a daily intake (in micrograms/day) and compares to the PDE and 30% control threshold.

*data from testing or published literature

implementation

Tools - templated approach to submission of

the risk assessment summary

• Developing a template text for project teams is recommended to drive some level of consistency.

• A typical template text would include the following;

1. a statement that a risk assessment has been completed.

2. list all of the potential sources of EI considered.

3. discuss any potential EI risk originating from manufacturing equipment, utilities, container closure system.

4. test data on key batches of drug substance for any intentionally added elements (reagents / catalysts).

5. discuss whether excipient origin, any test data, database or literature data suggests any risk of EI contamination in the drug product.

6. a reference to any data used that isn’t generated in-house.

7. data generated by testing the drug product for any elements of concern (3 commercial lots or 6 pilot scale lots).

8. analytical technique used to generate any supportive or batch data.

9. statement about key validation criteria used e.g. linearity, accuracy, LOQ.

10. a summary table of key data and a clear statement of any controls required (engineering, specification etc.) for specific EIs.

implementation

Analytical methodology (ICP-MS)

• ICP-MS methodology has been extensively used within

industry.

– generic method has been established aligned with

USP<233>.

– acid digestion (in microwave) is preferred approach to

sample preparation.

– internal Standards with similar ionization potential have

been established for each Q3D element of concern.

– minimum of a 3 point calibration curve established.

– recovery established by use of spiked samples.

implementation

Analytical methodology (ICP-MS)

• FDA Guidance for Industry;

– https://www.fda.gov/media/98847/download

implementation

Excipients – the greatest unknown?

• In 2014 there was very little data available and excipients were considered

to be a significant risk

excipients

Early example of data sharing for excipients*

• Literature (testing has already been done for you) = published

data.

– *Li et al., Journal of Pharmaceutical Sciences, Vol. 104, 4197 - 4206

(2015) - FDA/IPEC/Industry.

– 24 Elements, 205 excipient samples, > 4900 determinations.

– overall low EI levels. Some Pb, Cd, As in mined/marine derived

excipients.

• Data sharing (testing has already been done for you) = published

data.

– mutually beneficial for drug product manufacturers to analyse the EI

content of excipients and pool the data.

excipients

A proactive action from the pharma industry

Facilitate more scientifically driven elemental impurities risk

assessments under ICH Q3D, and reduce unnecessary testing

as part of the elemental impurities risk assessment efforts.

“A database of shared excipient elemental impurity determinations, with

equivalent provenance to published literature”

Elemental Impurities Data Sharing Initiative excipients

The growing consortium

The database and the consortium was established in 2016.

Elemental Impurities Data Sharing Initiative

Independent 3rd party to host and blind data.

- data on excipients NOT suppliers.

Quality is critical.

- standards (“acceptance criteria”) for method validation.

- active data management (outliers etc.)

Relevance.

- sufficient number of relevant excipients.

- data for relevant elements.

- multiple excipient samples, from a range of suppliers.

Data is accessible to industry and regulators

The database contains the results of 2304 analytical studies for 264

excipients.

excipients

Excipient relevance based on 2016 FDA

novel approved drugs list

22 Novel drugs approved in 2016

20 excipients used > once

90% (18 of these 20) have ≥ 3 studies in the database*

https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugInnovation/ucm592464.htm

excipients

*value in 2019 is 100%

Excipient relevance based on 2018 FDA

novel approved drug list

49 novel drugs approved in 2018

42 excipients used > once

86% (36 of these 42) have ≥ 3 studies in the database

39 excipients (93%) used > once are covered in the

database

Notes;

1. A list of excipients used in 49 novel drugs was

generated using label information available

through Drugs@FDA service.

2. These comprised of 30 oral, 17 parenteral, 1

topical and 1 inhaled formulation.

3. Water for injection and tablet coatings were not

considered.

https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugInnovation/ucm592464.htm

excipients

Elemental impurities excipient database1. Identify all excipients in the drug product

2. Search the database for each excipient

3. Review and export relevant elemental impurity results

Retrieving data from the database is easy! risk assessment

It is easy to export all data required to assess excipient risk in a new

formulation in approximately 10 minutes.

Element

Cmax for

Excipient

1 (ppm)

Cmax for

Excipient

2 (ppm)

Cmax for

Excipient

3 (ppm)

Cmax for

Excipient

4 (ppm)

Cd

Pb

As

Hg

Co

V

Ni

1. Identify the elements of concern based

upon the risk assessment

2. Search for the excipients in the Lhasa

elemental impurities excipients database

3. Confirm that each excipient in the

formulation has been analysed for each

element of concern

4. Extract the maximum observed value from

the database

5. Assess how much confidence to place in

the dataHow many batches tested?

From many different suppliers?

Is the highest value recorded sensible (not a sig.

outlier)?

Case History 1 – solid oral drug product case histories

4 standard excipients, API (10%), film coat (EI data available from supplier), Pd used in the API

synthesis.

Element

Cmax for

Excipient

1 (ppm)

Cmax for

Excipient

2 (ppm)

Cmax for

Excipient

3 (ppm)

Cmax for

Excipient

4 (ppm)

>76 lots

tested

4

suppliers

18 lots

tested

3

suppliers

9 lots

tested

3

suppliers

≥50 lots

tested

4

suppliers

Cd 0.2 0.2 0.2 0.2

Pb 0.2 0.27 0.2 0.2

As 1 1 0.2 1

Hg 0.9 0.2 0.2 0.9

Co 1.5 0.6 0.2 1.5

V 3 10 1 3

Ni 6 22 1 6

µg/day

from

Excipient

1

µg/day

from

Excipient

2

µg/day

from

Excipient

3

µg/day

from

Excipient

4

Calculation based on: 4 x 25mg tablets (approx. 1

g of drug product) and composition of each tablet.

0.115 0.057 0.006 0.002

6. Calculate the maximum Cd

contribution from excipient 1

convert micrograms per gram to grams

per day

7. Repeat for all excipients

8. Repeat for all elements of concern

case histories

Element

Cmax for

Excipient

1 (ppm)

Cmax for

Excipient

2 (ppm)

Cmax for

Excipient

3 (ppm)

Cmax for

Excipient

4 (ppm)

µg/day

from

Excipient

1

µg/day

from

Excipient

2

µg/day

from

Excipient

3

µg/day

from

Excipient

4

µg/day

Film

coat*

Sum

µg/day

%

Oral

PDE

>76 lots

tested

4

suppliers

18 lots

tested

3

suppliers

9 lots

tested

3

suppliers

≥50 lots

tested

4

suppliers

Calculation based on: 4 x 25mg tablets (approx. 1 g of drug

product) and composition of each tablet.

*supplier data used

Cd 0.2 0.2 0.2 0.2 0.115 0.057 0.006 0.002 0.015 0.195 4 %

Pb 0.2 0.27 0.2 0.2 0.115 0.077 0.006 0.002 0.015 0.215 4 %

As 1 1 0.2 1 0.573 0.287 0.006 0.010 0.045 0.921 6 %

Hg 0.9 0.2 0.2 0.9 0.516 0.057 0.006 0.009 0.090 0.678 2 %

Co 1.5 0.6 0.2 1.5 0.860 0.172 0.006 0.015 0.150 1.203 2 %

V 3 10 1 3 1.720 2.867 0.030 0.030 0.300 4.947 5 %

Ni 6 22 1 6 3.440 6.307 0.030 0.060 0.600 10.44 5 %

9. For each element sum the individual contributions across all excipients

10. Compare to the PDE and 30% control threshold

case histories

Element

Cmax for

Excipient

1 (ppm)

Cmax for

Excipient

2 (ppm)

Cmax for

Excipient

3 (ppm)

Cmax for

Excipient

4 (ppm)

µg/day

from

Excipient

1

µg/day

from

Excipient

2

µg/day

from

Excipient

3

µg/day

from

Excipient

4

µg/day

Film

coat*

Sum %

Oral

PDE

>76 lots

tested

4

suppliers

18 lots

tested

3

suppliers

9 lots

tested

3

suppliers

≥50 lots

tested

4

suppliers

Calculation based on: 4 x 25mg tablets (approx. 1 g of drug

product) and composition of each tablet.

*supplier data used

Cd 0.2 0.2 0.2 0.2 0.115 0.057 0.006 0.002 0.015 0.195 4 %

Pb 0.2 0.27 0.2 0.2 0.115 0.077 0.006 0.002 0.015 0.215 4 %

As 1 1 0.2 1 0.573 0.287 0.006 0.010 0.045 0.921 6 %

Hg 0.9 0.2 0.2 0.9 0.516 0.057 0.006 0.009 0.090 0.678 2 %

Co 1.5 0.6 0.2 1.5 0.860 0.172 0.006 0.015 0.150 1.203 2 %

V 3 10 1 3 1.720 2.867 0.030 0.030 0.300 4.947 5 %

Ni 6 22 1 6 3.440 6.307 0.030 0.060 0.600 10.44 5 %

• 9 lots at commercial scale

• All class 1 and 2a elements < 30% of PDE

• Pd used in API synthesis routinely measured at <30% of control threshold in the API

• No specification based controls proposed in the CTD

case historiesTest data on the finished drug substance &

product was also generated

Case History 2 case histories

• Solid oral drug product, < 1g / day intake.

• API loading = 21%.

• The same 4 standard excipients.

– Data available from the Lhasa database for 96, 57, 18 & 9 batches of each excipient for class 1 and 2A elements.

• Film coat (EI data generated was in-house).

• No added catalysts used in the API synthesis.

• All elements of concern are an order of magnitude < 30% control threshold.

• Negligible risk.

– no specification controls required for any elements in either API or DP.

• >10 API lots tested by ICP-MS.

• 4 commercial process DP lots (for each tablet strength) tested by ICP-MS, data supports the conclusion

of the risk assessment.

• No regulatory queries received to date for this CTD submission relating to elemental impurities

• There are multiple similar examples from the past 3 years, with essentially the same

overall risk level.

Conclusions / learnings / outlook.

• Simplify the risk assessment as much as possible, be pragmatic and focussed.

• Supplement the risk assessment with as much data as possible.

– invest and develop ICP SMEs.

– use all available published data / databases.

• Expect questions on the content of your regulatory submissions.

– generally asking for more data and / or detail.

• A good risk assessment will tell a compelling story, the need for controls (or not) should be obvious.

• For solid oral DP using well precedented excipients at <10 gram daily intake then it is very common to not require any DP specification controls.

– it is possible to envisage much more extensive reliance on available data and much less reliance on testing.