How to implement ICH Q3D of elemental impurities in 5 steps

Directive ICH Q3D aims to limit the presence of potentially toxic elemental impurities (also known as heavy metals) in pharmaceutical products intended for human use.

This directive is linked to changes in the pharmacopoeias (Ph.Eur. & USP) with the introduction of new, safer, more selective and precise analytical methods with greater reproducibility and better recovery.

DEADLINE INFORMATION

June 2016 ICH Q3D applicable to new products

December 2017 ICH Q3D applicable to licensed products

1. STEP 1 - BASELINE INFORMATION

2. STEP 2 - DEFINITION OF STRATEGY TO FOLLOW

3. STEP 3 - ANALYTICAL PLAN

4. STEP 4 - CONTROL STRATEGY

5. STEP 5 - LIFE CYCLE MANAGEMENT

3

INDEX

INDEX

4 BASELINE INFORMATION

STEP 1 - BASELINE INFORMATION

One of the major challenges in the implementation of ICH Q3D is communication with suppliers. The supplier, in most cases located in another country, is not familiar with the standard and, furthermore, it is the MAH itself that has final responsibility for the implementation. This means that you must not only collate, but also check that the information provided by suppliers is valid.

At this stage you have to collect all available information on those elements that could contribute to the presence of elemental impurities in the final product:

At this stage it is necessary to collate at least the following information:

Component Information

Final product

Unit formula (qualitative-quantitative)

Specifications

Available analytical data

Stability data

Active pharmaceutical ingredient (API)

Number of suppliers of API

Information about the suppliers /Questionnaire

Origin of the API

Source of supply

Presence of catalysts

Specifications

Analytical data

Elemental Impurities in drug product

Manufacturing equipment

Drug Substance

Water ExcipientsContainerClosureSystem

BASELINE INFORMATION 5

Excipients

Number of suppliers of excipient

Information about the suppliers / Questionnaire

Origin of the excipient (mineral, animal, synthetic)

Source of supply

Presence of catalysts

Specifications

Literature review

Analytical data

Packaging material

Summary of Product Characteristics / Composition

Study of extractables and leachates if applicable

Literature review

Process (Equipment)

Process flow

Equipment Materials

Aggressive processes at the level of kinetic energy, pH, temperature, etc...

Maintenance and qualification of equipment

Services

Purified Water / Water for Injection Grade.

Steam

CIP/SIP processes

Compressed air

Dependence on third-parties is a critical parameter that determines the time, above all for multi-product CMO’s. Therefore, facilitating the information collection work means a reduction in time and costs.

Once all the information is collected and validated, we face the next big question: What strategy should I follow to implement ICH Q3D?

6 DEFINITION OF STRATEGY TO FOLLOW

STEP 2 - DEFINITION OF STRATEGY TO FOLLOW

Well, with all the information collated and validated... What should I do?

The strategy to be followed will be decided on the basis of the information available. The variability in the application of the standard depends on the API, processes, excipients, etc. The choice of one or other strategy requires a high level of expertise.

A. Final product strategyRisk analysis is based on the levels present in each medicinal product plus the possible interaction with the packaging material.

Focus on the end product.

Packaging material: Level of risk determined by the nature of the product (oral solids, liquids, suspensions, or semi-solids) and packaging material composition.

Materials Element to considerABS (acrylonitrile butadiene styrene) Mg

Glass AI, Ba, Ca, Fe, Mg, Si, Zr

PC (polycarbonate) Ca, Si, Zn

PET (polyethylene terephthalate) Co, Sb

PE (Polyethylene) AI, Ca, Cr, Pb

PES (polyethersulfone) None

PP (polypropylene) AI, Ti

PMMA/Acrylic (polymethyl methacrylate) Ca, Mg, Si

PTFE (polytetrafluoroethylene) Ca, Fe

Elastomers AI, B, Ca, Mg, S, Si, Zn

Multi laminaria polyolefins Cr, Pb

PVC (polyvinyl chloride) Ca, ZnSilicone Si

Dennis R. Jenke and coll - PDA Journal Of Pharmaceutical Science and Technology - Vol 26 No. 1 2015 (3)

Elemental Impurities in drug product

Excipients(Mined vs. synthetic)

Drug Substance(Metal Catalysts)

Container Closure System

(Packaging)

Manufacturing(Equipment/Process)

Facilities/Utilities(Water/Air)

Focus of theassessment

DEFINITION OF STRATEGY TO FOLLOW 7

First screening to establish elemental impurities of interest.

Based on data from 3 commercial batches or 6 pilot batches, the EI must be translated to units of total daily amount, also taking into account the total daily amount of the medicinal product.

Daily dose of EI = Impurities concentration (ug/g) per maximum daily dose (g/day)

B. Components strategyThe risk analysis is based on the levels of elemental impurities in each component which could contribute EI to the medicinal product.

The component information (literature references, suppliers, in some cases extrapolation of data can be performed, analysis of some of the components).

Calculate the amount of each of the EI in the components, depending on the % that is in the formulation and based on a maximum daily dose of the medicinal product.

The level of each EI is to be determined as the sum of the contribution of each component so as to determine the final amount in the medicinal product.

Amount of EI in the medicinal product = n∑ Ci x Mi i=1

The choice of one or other strategy will depend on the needs and resources of each MAH. Each case is different; therefore an expert should advise on the pros and cons of each strategy. OK, so once the information is obtained and validated and the strategy determined, what is it necessary to analyse? What procedures are used?

Elemental Impurities in drug product

Excipients(Mined vs. synthetic)

Drug Substance(Metal Catalysts)

Container Closure System

(Packaging)

Manufacturing(Equipment/Process)

Facilities/Utilities(Water/Air)

Evaluate potential contributions of elemental impurities

Risk Assessments for these three categories may be applicable to multiple products and manufacturing locations

For some dosage forms the potential for elemental impurities is higher

Lower Risk

Most likely sources

8 ANALYTICAL PLAN

STEP 3 - ANALYTICAL PLAN

Once the information is compiled and validated, and the strategy for the implementation of directive ICH Q3D on Elemental Impurities is defined, a few aspects of the analytical plan have to be considered:

The analytical procedures will be based on some of these methods:

Procedure 1: ICP-AES/OES

Procedure 2: ICP-MS

Alternative procedure: e.g. Flame - AA, Graphite - AA, Cold Vapor Atomic Absorption Spectroscopy (CVAAS) - Hg, may be used provided that they are validated.

It is necessary to take the decision to perform the analyses internally or by a third party (CRO): issues to consider:

Required investment: facilities, equipment, etc.

Difficulty for inexperienced analysts.

Sample digestion / sample preparation can be problematic during the development of methods.

Price

AA - GH

Flame - AA

Graphite - AA

ICP - OES

ICP - MS

Scope of the analytical plan:

What elements do I have to analyse?

How many samples do I have? What volume of samples do I have?

What level do I want to reach?

Which analytical technique is the most appropriate?

What is the associated cost?

ANALYTICAL PLAN 9

Analytical testing: Screening & Validation:

In some cases, finished product or raw materials would require screening with an appropriate technique: ICP-MS is the preferred technique (lowest detection limits achieved)

Drawbacks of ICP-MS are the requirements of highly equipped facilities and trained personnel, as well as high costs associated to mainteinance.

When testing, the ICH Q3D requires that the screening is performed in at least 3 representative batches produced in an industrial scale or at least 6 representative batches produced in a pilot scale.

Costs can be reduced through an appropriate selection of the elemental impurities to be tested as well as the analytical methodology to apply.

All the methods used for analytical testing of elemental impurities must be validated, but the extent of the validation should be fitted to the intended purpose (i.e. screening test for a risk assessment would require validation for the limit of quantification, specificity and recovery data; whereas a screening to comply with a specification as control strategy would require full validation information such as robustness, accuracy, precisión, etc.)

We offer the best service with our partner Kymos Laboratories, which is a GMP, EU and FDA certified analytical lab with a vast experience in this topic.

Testing itself is not acceptable as a risk assessment: A scientific risk assessment determines the potential risk of variability in the obtained results and batches tested.

Therefore, testing provides useful information for the risk assessment but it cannot substitute it!

Subsequent to screening and risk analysis further development and validation of the method may be necessary for some elemental impurities.

STEP 4 - CONTROL STRATEGY

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In the case of the presence of any elemental impurity, its significance is considered on the basis of its determined or predicted value and compared with its PDE value. ICH Q3D establishes a control limit of 30% of the PDE value for each elemental impurity.

At this stage the maximum concentration value must be defined from the PDE value according to the different conversion strategies (1, 2A, 2B and 3) defined in ICH Q3D.

The following table shows the actions to perform according to the value obtained.

EI estimated at the end of the RA Actions Control strategy

EI not present Document No action required

EI < 30% PDE Not additional action to be implemented Adequate existing controls

30% PDE < EI < PDEDefine additional controls to control those that do not exceed the PDE level

Specification on the medicinal product or components (API and excipients)

Modification of the manufacturing process that provides decrease in EI

Selection of the most appropiate packaging materials

EI > PDE

Define additional reduction controls or Evaluate the patient´s safety and establish a rationale to justify higher EI content

In some cases it could be acceptable

Justify before health authorities

ICH Q3D requires re-evaluation when there is any change in the manufacturing or packaging process, changes of suppliers, or in the facilities.

CONTROL STRATEGY

STEP 5 - LIFE CYCLE MANAGEMENT

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If ICH Q3D has made one thing clear, it’s that it is in no way “elementary”. The implementation of this directive is a living process that the MAH should always bear in mind.

With increasing the knowledge of the product and its process, new developments, modifications and/or variations throughout the life of the product up to its future discontinuation, the study of elemental impurities in today’s product will form part of the quality system, change controls and continuous improvement on the part of the holder.

In the case of changes to the product and/or components which are potential sources of elemental impurities, it must be re-evaluated. These changes may be (but not limited to):

Changes to synthesis route.

Changes of manufacturers.

Changes in the processes.

Changes to the packaging materials

Facilities.

All of these changes will be subject to change controls and if necessary, regulatory variations.

LIFE CYCLE MANAGEMENT

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