Elemental Impurities:

An Industry Perspective

Ernest Parente, PhD

Mallinckrodt Pharmaceuticals

May 17, 2016

2016 GPhA CMC Workshop

Overview

Risk Assessment

The Supplier Interface

The Contractor Interface

Contract Laboratories

Contract Manufacturers

The Laboratory Interface

Managing the Lab

Lab Best Practices

Notice: Opinions expressed are those of the author not necessarily those of Mallinckrodt Pharmaceuticals.

Mohammed Abubakr’s

Circular Periodic Table

Quality Risk Management

While well-known in other industries, the concepts and methods of Quality Risk

Management are only slowly gaining acceptance as a tool in establishing product

quality specifications in the pharmaceutical industry1.

“Zero Risk Tolerance” culture

Lack of understanding of how to identity, quantify and mitigate risk

Risk Management Strategy

Risk Assessment

• Identify risks, probability of harm and severity of harm

Risk Control

• The purpose of risk control is to reduce the risk to an acceptable level.

• Includes decision making to reduce and/or accept risks.

• What can be done to reduce or eliminate risks?

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1. See International Conference on Harmonization (ICH) Guideline Q9 “Quality

Risk Management,” Step 4, 9 Nov 2005 .

EI Quality Risk Management

Basic Concept of Risk Assessment as Related to the Permitted Daily Exposure

(PDE) Limit of Elemental Impurities in Drug Products

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1. Identify risk

2. Probability of risk

3. Severity of harm

4. Detection of risk

1. Identify possible elements present

2. Evaluate using PDE Control Threshold1

3. Defined by the PDE for each element

4. Sensitive Methods (e.g., ICP-MS)

Risk Concept Elemental Impurity Risk Assessment

Risk Control

The “risk” is that an identified Target Element could potentially exceed the PDE.

Think of the Control Threshold as an “action limit” that signals that a remediation

or control may be needed to mitigate risk

To clarify, Control Threshold is not another compliance limit. Rather, it is a tool to

justify a Quality Risk Management decision.

1. The Control Threshold is defined in ICH Q3D, “Guideline for Elemental Impurities”

as 30% of the element PDE.

Risk Assessment & Control Strategy

Identify:

Conduct an assessment to identify known

and potential sources of elemental

impurities that may find their way into the

product

Evaluate:

Compare the observed or predicted levels

with the established PDE

Summarize and Document the

Risk Assessment: Consider the

significance of the observed or predicted

level for elements potentially present

Control:

Implement a control strategy, if needed,

to ensure elemental impurities in the drug

product do not exceed the PDE.

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Risk Assessment

What is needed for Ingredient/Product risk assessment?

IDENTIFY a list of Target Elements

1. ICH recommended elements (route of administration)

2. Elements used or likely to be present identified on Supplier Questionnaire

3. Elements listed on Certificate of Analysis (CoA)

4. Literature search

5. Other sources of information

EVALUATE results against the element PDE limit for Target Elements.

Are elements above or below PDE Limit?

Above or below the Control Threshold?

• If above, consider reducing risk or establishing a control

• If below, no additional action may be needed

If close to the Control Threshold, is variability a factor?

• 95% confidence that Control Threshold will not be exceeded?

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Risk Assessment

If sufficient, “reliable” information isn’t available, testing may be needed.

Testing Strategy: (1) Test finished product, (2) Test Ingredients or (3) Both

• If significant risks are identified in the packaging or manufacturing assessment,

the summation strategy may not be an option.

• Liquids will need a finished product method to assess inorganic leachables

Determine appropriate Target values (J Values)

Recommended – ICP-MS test methods validated to USP <233> standard or

validated as “suitable for the intended use.”

CONTROL elements or materials identified during the Evaluation.

If the Risk Assessment identifies elements above the Control Threshold,

develop a control strategy.

• Control “Key” ingredients or test product

If below the Control Threshold:

• No testing required

• Possible periodic testing/re-evaluation performed for Lifecycle Management

• Re-evaluate for change control

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Drug Product Compliance Strategy

Pros

Assured compliance because ingredients

are controlled (QbD)

No OOS/CAPA or destruct at the batch

level

Easier to develop methods for single

ingredients than finished products

Once ingredients are tested, compliance

can be calculated for varying products

and strengths

May be able to get information from

suppliers to reduce testing

Cons

Initial large workload to

develop/validate methods for

ingredients (more ingredients than

products)

On-going incoming raw material

testing may be required

(routine/periodic testing)

Assumes metal impurities from

product manufacturing process are

controlled by GMPs (wear products)

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Test ingredients, not products, and use

summation to demonstrate compliance

Drug Product Compliance Strategy

Pros

Low initial development cost

Holistic approach including contributions

from ingredients, the manufacturing

process and packaging

May be able to get information from

suppliers to support product lifecycle

management

Cons

Possible OOS/CAPA or destruct at

batch level

• Not possible to rework product

Complex failure investigations

More difficult to develop methods?

Added risk for skip testing approach

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Test Products not ingredients

So Far – So Good… Or Is It?

Situation 1: A man parachutes from a plane

three times and lands successfully without

harm or incident.

Conclusion : There is no risk in skydiving.

Situation 2: The man continues to skydive

until one day his parachute fails to open and

he tragically crashes to his death.

New Conclusion: There actually is risk in

skydiving.

Maybe this risk could have been mitigated if

there was:

Quality control on the airplane

Quality control on the pilot

Quality control on the skydiver

Quality control on the… parachute!

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Risk Assessment –

Testing Finished Products

Question: If the EI burden for three, full-scale finished product batches is

consistently below the 30% PDE Control Threshold, can it be concluded there is no

need for any knowledge of what’s in the ingredients?

Point 1 to consider: It is not QbD approach.

Point 2 to consider: Testing quality into the finished product is not a GMP

approach.

The Wrong Answer: If you think the answer is “Yes,” you didn’t learn anything

from the parachuting story.

The Right Answer: If you know what to test for, testing every batch of finished

product is a “control strategy” that eliminates the risk of releasing sub-standard

product. However, it is hard to justify the process as a “good” risk assessment

strategy since it doesn’t assess/control risk factors.

Take home message: It important to know what’s in the ingredients even if you

test the finished product.

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Target Selection

Based on route of administration and formulation

Target (Concentration Limit) = Permitted Daily Exposure (PDE) / daily dose

Assume, Limit of Quantitation (LOQ) = 0.1 x Target (i.e., 0.1J)

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20 g/day Limit 10 g/day Limit 5 g/day Limit

Element

PDE (Oral)

(µg/day)

Target

(µg/g)

LOQ

(µg/g)

Target

(µg/g)

LOQ

(µg/g)

Target

(µg/g)

LOQ

(µg/g)

Cd 5 0.25 0.025 0.5 0.05 1.0 0.1

Pb 5 0.25 0.025 0.5 0.05 1.0 0.1

As 15 0.75 0.075 1.5 0.15 3.0 0.3

Hg 30 1.5 0.15 3 0.3 6 0.6

If below the LOQ, use the LOQ in the Summation calculation as “worst case”

LOQ must be sufficient low to permit assessment of 30% PDE Control Threshold

Comparison of Targets and LOQs for

Different Maximum Daily Doses

Evaluation – Summation Approach

Selecting J and Doing the Math

The LOQ is defined by the lowest validation recovery value. The USP <233>

Accuracy Range (0.5J - 1.5J) may need to be expanded to assess the 30% PDE

Control Threshold.

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Use LOQ

Highest

Contribution

>30% PDE

Doses per day 10 tablet

PDE Limits Oral

Components

Daily Max

Dose (mg)

found

(µg/g)

exposure

(µg/day)

found

(µg/g)

exposure

(µg/day)

API 600.00 6000.00 <0.05 0.3 <0.25 1.5

Excipient 1 100.00 1000.00 <0.05 0.05 <0.25 0.25

Excipient 2 30.00 300.00 <0.05 0.015 <0.25 0.075

Excipient 3 80.00 800.00 <0.05 0.04 <0.25 0.2

Excipient 4 100.00 1000.00 <0.05 0.05 <0.25 0.25

Excipient 5 90.00 900.00 <0.05 0.045 <0.25 0.225

Total 1000.00 10000.00 0.5 2.5

PDE (µg/day): 5 5

% of PDE consumed: 10.0% 50.0%

SUPERTABS, 600 mg

LOQ = 0.1 J LOQ = 0.5 JQuantity per

dose

(mg/tablet)

Pb Pb

Assume (1) All values below LOQ

(2) 10 g/day Target

Material Supplier Interface :

The Mostly Current State

Many suppliers currently make a commitment to “comply,” but few are

providing useful, reliable, quantitative data on EI in materials.

Kicking the can down the road:

“Big Pharma Supply is well aware of the full litany of USP, FDA, EMA, ICH etc. etc.,

regulations. While we are sure our products do not contain any of the elements on

the periodic table, we are evaluating our material and assure you we will comply with

all of the regulations past, present and future by January 1, 2018.”

While encouraged by the commitment…

The regulation is for drug products not ingredients. So, while the materials need

to be suitable for the intended use, there is nothing per se for them to comply

with. It’s really about customer service.

Finished products need to comply by January 1, 2018. There is no

implementation date for ingredients. To be useful for product compliance,

information on ingredients is needed… now.

Material Supplier Interface:

The Desired State

It is important for drug product manufacturers and ingredient suppliers to

partner on compliance.

Wish Lists of Information from Suppliers:

Supplier Questionnaire disclosing the use of catalyst, metal-containing reagents

used and other elements potentially present.

Quantitative data for three, full-scale batches for target elements of interest.

Indication of the method and LOQ for each element tested.

Confirmation that appropriate methods were used for testing and that they were

validated to the standards appropriate for the intended use (e.g., USP General

Chapter <233>).

Samples of three batches of the material with CoA for confirmatory testing.

How often the supplier will test and how the information will be reported?

• Typical values

• Highest acceptable values

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Laboratory Testing Options

Option 1 : Develop ICP-MS testing capability at manufacturing sites

Pros : Ready access to testing

Cons : Significant capital investment in equipment and facilities requiring

specialized technical expertise

Option 2: Centralize testing at an in-house “Center of Excellence” for ICP-MS

Technology

Pros : Optimize capital investment, technical expertise and economy of scale, in

control of test schedule

Cons : Logistics issues in shipping samples and managing a multi-site workload

Option 3: Use an external contract lab for testing

Pros : No capital investment, no technical expertise needed

Cons : Cost?, logistic issues in shipping samples, problem resolution may be

more complicated, testing priority outside of internal control

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Contract Lab Interface

Important to develop clear expectations on both sides up front on roles and

responsibilities and costs.

Some initial questions for discussion

What capabilities are available (ICP-MS KED capable, ICP-OES, AA, etc.)?

Does the lab specifically have experience in USP <232>, <233> and ICH Q3D

compliance testing?

Have they ever been audited by FDA?

Do they have experience in preparing reports for regulatory filings?

What are the lab deliverables?

Testing results report

Method validation report

Who will do the risk assessment? SOP available?

• Decision on Target elements and LOQs

• Decision on testing product or ingredients

Control Strategy Justification Report

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Contract Manufacturer Interface

Important to develop clear expectations on both sides.

Define roles and responsibilities in a Quality Agreement, Supply Agreement or

Contract up front.

Sponsor ultimately responsible for developing an “approvable” regulatory

submission and on-going compliance program

Information needed for filing :

• Supplier Questionnaire and CoA

• Manufacturing, Packaging and Product/Ingredient Risk Assessments

• Method Validation Reports (compliant with USP <233>)

• SOP for Risk Assessment

• Justification for Control Strategy

– Test Ingredients and use summation option or Test finished product

– Test every batch or skip test

– No testing needed (change control monitoring)

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Contract Manufacturer Interface

Some contractor manufacturers will test in-house, but many indicate they plan

to out-source finished product testing (40-50%) to a contract lab.

Two levels of contractors to manage

Manufacturing contractor and Lab sub-contractor

Define responsibilities and costs

Who will manage the contract lab?

Who is responsible for failures and failure resolution? Cost?

• If ingredients are not controlled, failures at the batch level can occur.

OOS and CAPA procedures

• If skip testing is used and the product is in distribution, a failure could trigger a

field alert (3 day notification)

Bottom Line:

High level of transparency needed at both levels of contractors.

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Managing the Lab Workflow

Validation Protocol

Issue: Each method validation needs to be conducted under an approved protocol

Challenge: Hundreds of “very similar” protocols are involved requiring approval

The Approach: Develop an “umbrella” protocol with a provision for “moving parts.”

Thus, only one, general, pre-approved protocol is needed to cover most situations.

The elements and limits are given in the ICH Q3D guideline

Validation Acceptance Criteria are specified in the USP <233>

The ICP-MS testing conditions are more or less standardized

The “moving parts” are the sample preparation procedures. One procedure

generally can cover many test articles. So, there is a limited number of sample

preparation procedures.

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Managing the Lab Workflow

Test Methods

General Method – Since many of the methods are similar, a general test method

can be created that references appropriate sample procedures.

Validation Reports

Calculation Template – A large amount of data are generated for each validation

report. Consider developing an Excel template that automates all of the report

calculations, linearity plots, etc.

Training and Method Transfer

Skill-based training

Include end user (e.g., Quality Control) in the method validation process

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Documentation Strategy

Deliverables: Separate reports or sections in one report

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Manufacturing

Risk Assessment

Packaging

Risk Assessment

Ingredient/Product

Risk Assessment

Risk Assessment Summary

& Control Strategy

• Material CoA

• Supplier Questionnaire

• Product Formulation

• Rationale for Target Elements

• Ingredient Test Results

• Product Test Results

• Calculations

• Review of Process

• Materials of Contact • Materials of Construction

• Potential Leachables

• Methods and Specifications

• Regulatory Submission

Change Control

Include EI assessment as part of change control

procedures

Process Changes (Validation Report)

Material Changes

Include EI as part of the Vendor Certification

Program

Changing one material can affect many processes

or products

Documentation strategy feeds into the Change

Control and Lifecycle Management strategy.

(e.g., effect of packaging material change or

excipient supplier change).

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Life-Cycle Management

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Case Study:

Teflon Stir Bar

Problem:

Occasional Out-of Trend (high) results

are observed for Cobalt for a parenteral preparation (PDE 5 µg/day).

Root Cause Investigation:

Occurred during a validation study, so there were data suggesting the high

recovery result was suspect

Problem isolated to Teflon-coated, ALNICO magnetic stirring bar used in the

microwave digester (ALNICO – acronym : Aluminum-Nickel-Cobalt)

Apparently with some low and unpredictable frequency the stir bars fail and result

in a high Co values

Lesson Learned :

Due to the nature of “trace analysis,” false positives will occur.

CAPA : While it may not possible to completely prevent reoccurrence, once the

root cause has been identified measures can be put in place to remediate the

suspect result (contamination or real result).

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Lab Best Practices – Clean and Green

1. As little as 50 picograms of certain

elements can have an adverse

effect on results.

2. Even a “clean room” does not cover all sources of contamination.

3. PPE, like gloves, serve to minimize contamination.

4. Consider using plasticware instead of glassware. Pre-treat Pyrex

digestion vessels using the digestion acids and cycle before use.

5. Store items in zippered plastic bags to minimize contamination.

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Lab Best Practices

6. If bottle top dispensers are used, before use dispense some of the

liquid to rinse the dispenser tip to minimize contamination.

7. Use plastic spatulas or coated spatulas (Teflon, PTFE) to dispense

solids.

8. Keep items and samples covered as they move about the laboratory.

9. Use high purity acids. Trace metal grade acids are usually suitable

and a good alternative to ultra high purity grade acids which are

expensive.

10. For very low level detection, KED mode can eliminate interferences

due to residual carbon (e.g., vanadium).

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THANK YOU FOR YOUR ATTENTION!

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Acknowledgements:

Thanks to my colleagues at

Mallinckrodt Pharmaceuticals:

Dr. David A. Fay

Christy M. Nichols

Eileen L. S. McClendon

Jared L. Zobrist

Roy Alexander’s 3-D Periodic Table

More than you ever wanted to know about periodic tables:

The INTERNET Database of Periodic Tables, The Chemogenesis Web Book, http://www.meta-

synthesis.com/webbook/35_pt/pt_database.php