Management of Design Changes through the Product Lifecycle

Executive Summary Situation There is significant variability as to how companies manage device design changes. This is supported by the survey conducted by IPAC-RS. Target Regulators, member companies and therefore patients would benefit significantly if industry adopted a common framework for the management of device changes. Proposal It is proposed to adopt a common framework for the management of device changes. This framework is based upon a risk based approach to product development as defined in ICH Q8, Q9 and Q10. It is evident that given the scope of potential changes for an undefined number of devices that it is impossible to develop definitive guidance. The purpose of the guidance defined is to be indicative of what sponsoring companies should consider.

1 Introduction The International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS) is an international association of innovator and generic companies that develop, manufacture or market orally inhaled and nasal drug products for local and systemic treatment of a variety of debilitating diseases such as asthma, chronic obstructive pulmonary disease and diabetes. IPAC-RS member companies are primarily involved in the development of “Combination Products”, so are very interested in medical device design guidance and the impact upon “Combination Products”. We are committed to advancing consensus-based, scientifically driven standards and regulations for these products, with the purpose of facilitating the availability of high-quality, safe, and efficacious drug products to patients. The current members of IPAC-RS are: 3M, AstraZeneca, Boehringer Ingelheim, Catalent, Chiesi, GlaxoSmithKline, MannKind Corporation, MAP Pharmaceuticals, Merck & Co., Inc., Mylan, Novartis, Pfizer, Sunovion, Teva, and Vectura Ltd. Aptar Pharma, Medspray, Rexam, SHL, and West are supplier members. IPAC-RS has several working groups. The objective of the IPAC-RS Device Working Group is to understand and promote best practices for orally inhaled and nasal drug product device design. In response to concerns from IPAC-RS member companies about the consistency of the approach adopted for the management of device changes through the product lifecycle, IPAC-RS established a Copyright © 2013 International Pharmaceutical Aerosol Consortium on Regulation & Science (IPAC-RS). All Rights Reserved. 1

sub-group to review the consistency across industry of the management of device changes throughout the product lifecycle. The group determined that the most effective method to establish and validate the consistency, or lack thereof, of management approaches across industry was to conduct a survey to establish a baseline of current practices for a range of typical scenarios that could be encountered throughout the lifecycle of a “Combination Product”. The objective of the Device Survey was to assess current attitudes toward device changes in order to: •

Establish a view on the ‘as is’ situation in relation to device changes,

•

Facilitate a move towards consensus on the appropriateness of in-vivo and in-vitro testing,

•

Highlight areas where regulatory requirements may differ from what is perceived to be technically required.

A full description of the methodology adopted and the results of the survey are presented in Appendix 1. It is evident from the results that the hypothesis as to the lack of consistency in how members companies both manage the change process and how they notify regulatory authorities of such changes is validated. It was further concluded that Risk Management, as defined by ICH, does not appear to be informing decision making. The survey supports the premise that the development of guidance utilising a risk based management approach to evaluate and manage device changes for OINDP could be of significant value to all stakeholders (i.e. patients, regulators & industry). The remainder of this document describes an approach to realise the previously stated objective.

2 Scope All “Combination Products” post start of Pivotal Clinical Studies, pre and post market authorisation, are within the scope of this proposal. There is no distinction made between Innovator and Generic Drug Products. For both types of products, developers must demonstrate that as the product evolves through the product lifecycle, the link between the “Combination Product” tested in the clinical setting, for which market authorisation was granted, or is intended, must assure that the safety, quality and efficacy of the drug product is not changed. Formulation, Primary Pack and process changes, other than those related to the drug delivery system, are out of scope (see Section 4.5). It is important to note that the proposed guidance relates to product lifecycle management of device changes. The development of generic substitutable or product line extensions is out of scope. Copyright © 2013 International Pharmaceutical Aerosol Consortium on Regulation & Science (IPAC-RS). All Rights Reserved. 2

3 A Risk Based Approach to Design Changes through the Product Lifecycle The risk based approach proposed for the management of device changes through the product lifecycle is based upon ICH Q8, Q9 & Q10. ICH Q9 states “Fundamental to this process is the concept of quality risk management. It is important to understand that product quality should be maintained throughout the product lifecycle such that the attributes that are important to the quality of the drug (medicinal) product remain consistent with those used in the clinical studies. An effective quality risk management approach can further ensure the high quality of the drug (medicinal) product to the patient by providing a proactive means to identify and control potential quality issues during development and manufacturing. Additionally, use of quality risk management can improve the decision making if a quality problem arises. Effective quality risk management can facilitate better and more informed decisions, can provide regulators with greater assurance of a company’s ability to deal with potential risks and can beneficially affect the extent and level of direct regulatory oversight. Two primary principles of quality risk management are: • •

The evaluation of the risk to quality should be based on scientific knowledge and ultimately link to the protection of the patient. The level of effort, formality and documentation of the quality risk management process should be commensurate with the level of risk.

3.1 Definitions Combination Product – The combination of a device and a drug product. Critical Quality Attribute – “A physical, chemical, biological or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality.” • Drug Product Critical Quality Attribute (DP CQA) – An attribute of the drug product that has a consequence for the safety and/or efficacy of the drug product e.g. emitted dose, fine particle mass, assay, impurities. These attributes typically define the release specification of a Drug Product. • Device Critical Quality Attribute (Device CQA) – An attribute of the device that directly impacts a Drug Product Quality Critical Attribute (e.g. metering of the formulated drug product, presentation to the airflow path in a reproducible and reliable manner will directly impact emitted dose) – please note that this is not a formal ICH definition but is drafted to align with the principles of the ICH definition with respect to safety and efficacy. Critical Process Parameter (CPP) – “A process parameter whose variability has an impact on a critical quality attribute and therefore should be monitored or controlled to ensure the process produces the desired quality.” Copyright © 2013 International Pharmaceutical Aerosol Consortium on Regulation & Science (IPAC-RS). All Rights Reserved. 3

•

•

Drug Product Critical Process Parameter (DP CPP) - A unit manufacturing operation (e.g. filling) or a single manufacturing step/process parameter of a unit manufacturing operation (e.g. sealing dwell temperature) that has the potential to directly impact a Drug Product Quality Critical Attribute Device Quality Critical Process Parameter (Device QCPP) - A unit manufacturing operation (e.g. injection moulding) or a single manufacturing step/process parameter of a unit manufacturing operation (e.g. ultrasonic weld energy) that has the potential to directly impact a Device Critical Quality Attribute.

3.2 Drug Product Critical Quality Attributes of Common OINDPs The next section defines the typical Drug Product Quality Critical Attributes for an orally inhaled and nasal drug product irrespective of whether the medicament is for topical or systemic drug delivery. The oral inhaler and nasal spray were selected as they are the two primary combination products that IPAC-RS design, develop and manufacture. As per the definitions (see Section 4.1) these are the attributes of the drug product that determine the safety and/or efficacy of the medicament. Table 1

Typical Drug Product Critical Quality Attributes for OINDPs

Critical Quality Attribute

Oral Inhaler

Assay Impurities Emitted Dose Emitted Dose Uniformity Aerodynamic Particle Size Distribution (APSD) or Droplet Size Distribution Droplet Size Distribution or Particle Size Distribution Airflow Resistance/Resitivity Plume Geometry Extractables Leachables Foreign Particulate Matter Microbiological Quality

Nasal Spray

× × ×

×

It is the responsibility of a sponsoring company to define and justify the Drug Product CQAs for their Combination Product. It is important to consider whether demonstration of the equivalence of the Drug Product CQAs following a design change is sufficient to demonstrate that the drug product is equivalent in respect

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of clinical safety and efficacy. The design change must also be considered in terms of whether the change will impact upon; •

How the target patient population may interact with the drug product to assure delivery of a Drug Product CQA (e.g. airflow resistance of the oral inhaler is increased, patient inspiratory effort is increased such that a subset of the target patient population can no longer aerosolise a passive oral inhaler).

•

Whether the design change could elicit as physiological change that would not be detected by standard in-vitro test methods (i.e. Quality Control Test Method) as described by the Drug Product CQAs described in Table 1 (e.g. a change to the method of actuation of a nasal spray product causes the soft palate to close, a change to the external mouthpiece form of a oral inhaler changes the patients oropharyngealeal geometry).

In addition, to the standard in vitro Quality Control methods it may be appropriate to utilise more discriminating methodologies associated with lung cast and nasal cast models in association with inhalation manoeuvres that are more representative of the target patient populations. These approaches should be considered in the context of the design change proposed and their potential to provide more discriminating data.

4 Device Changes Decision Tree The diagram provided below describes the decision process flow that defines what, if any, testing may be conducted to verify any change through the drug product lifecycle – see Scope Section 2. It is evident that given the scope of potential changes and the range of different devices that it is impossible to develop definitive guidance. The purpose of the guidance is to be indicative of what sponsoring companies should consider. It is acceptable to conduct testing to validate multiple changes (see Section 4.3 & 4.4). However, it must be recognised that such an approach increases the risk that non-equivalence between design revisions will be determined and that the source of the non-equivalence will not be immediately evident. It is also possible, but less likely, that two changes may offset their impact upon a Drug Product Critical Quality Attribute and further change at a later date may result in non-equivalence and the source of the issue will be harder to define.

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Figure 1: Managing Device Change: A Decision Tree

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It is the responsibility of the sponsoring company to determine the design and type of clinicval bridging study required.

4.1 In Vitro Test Protocol When considering device changes the key objective must be to demonstrate equivalence of the drug product post change with reference to those DPCQAs that have the potential to be impacted (i.e. emitted dose, emitted dose uniformity, APSD Profile and fine particle mass uniformity). Similarly, changes to Device Critical Quality Attributes, Drug Product Quality Critical Process Parameters and the Device Critical Quality Process Parameters that have the potential to impact a Drug Product Critical Quality Attribute may be assessed using the same test methodology. Key consideration must be given to whether the methods being utilised to assess the potential impact upon a Drug Product CQA are sufficiently differentiating cognisant of:

•

how the target patient population may interact with the drug product to assure delivery of a Drug Product CQA ; and

•

whether the design change could elicit a physiological change that would not be detected by standard in-vitro test methods (i.e. Quality Control Test Methods).

The test protocol should use a risk based assessment to determine: a) The Drug Product Critical Quality Attribute(s) that has potential to be impacted b) The Drug Product Critical Quality Attribute(s) that are not impacted c) The rationale for (a) and (b). Consideration must be given to any changes in Drug Product Critical Process Parameters, Device Critical Quality Attributes and/or Device Critical Process Parameters and their potential to impact a Drug Product Critical Quality Attribute. d) What, if any, supporting evidence exists that can be used to understand potential for the proposed change to impact the Drug Product Critical Quality Attribute(s). This supporting evidence may be data generated by the sponsoring company or may be information in the public domain (i.e. Scientific Literature, IPAC-RS Publications et.). e) A pre-defined test protocol, based upon the potential risk and acceptance criteria for each of the impacted Drug Product Critical Quality Attributes, that provide assurance that the safety and efficacy of the Drug Product has not been compromised. These protocols should be sufficiently powered to evaluate the impact of any change using an appropriate statistical method.

4.1.1

Stability Assessment Requirements

Stability testing, including an assessment of assay and impurities, should only be considered necessary if: Copyright © 2013 International Pharmaceutical Aerosol Consortium on Regulation & Science (IPAC-RS). All Rights Reserved. 7

•

the primary pack is an integral part of the drug delivery system e.g. reservoir Dry Powder Inhaler, Nasal Spray Pump;

•

the change proposed has the potential to alter how the formulation is protected from water, light, oxygen etc.; and/or

•

the component(s) to be revised are in intimate contact with the formulation for more than the transient time to deliver a dose.

For changes where the primary pack is integral to the drug delivery system it is recommended that long term stability evaluation should be conducted. Changes could be implemented on the basis of shorter term predictive accelerated stability studies but a commitment to longer term studies would be required. For all other instances it may be appropriate to conduct accelerated predictive stability studies that assess impact upon specific Drug Product Critical Quality Attributes. A protocol defining the tests to be performed, a rationale for including the tests defined (the rationale should consider how the change impacts upon the ability of the drug delivery system to protect, meter and dispense the medicament) and acceptance criteria, that assure the safety/efficacy of the drug product has not been compromised, should be pre-approved by the sponsoring company before adoption of the design revision.

4.1.2

Mechanical Function & Mechanical Safety Assessment

The Mechanical Function and Mechanical Safety Assessment should evaluate attributes of the design, based upon a risk assessment, that could be compromised by the inclusion of the change proposed. For example, replacement of a type of polymer for a component under load, may cause the part to fail on long term storage or at extremes of the design as described by the variance in the detailed engineering drawings. This assessment should also be cross-referenced with the Design FMEA to ensure that the integrity of the individual components that may be subject to change and the overall product assembly are not compromised (the Risk Priority Number is not higher than the originally acceptable limits). A protocol defining the tests to be performed, a rationale for including the tests defined and acceptance criteria, that assures that the safety and efficacy of the drug product has not been compromised, should be pre-approved before adoption of the design revision.

4.2 Patient Handling Studies Any Patient Handling/Human Factors Study must be designed to consider: • What is the design change(s)? Copyright © 2013 International Pharmaceutical Aerosol Consortium on Regulation & Science (IPAC-RS). All Rights Reserved. 8

•

What, if any subset, of the patient populations ability to use the design maybe compromised?

It must be recognised that these studies are primarily qualitative and as such are not statistically powered to elucidate whether the revision of a design issue will impact usability of the device. It is highly recommended that sponsoring companies continuously monitor patient feedback from all clinical studies.

4.3 In Vivo Test Protocol Definition For orally inhaled and/or nasal drug products for delivery of medicaments by systemic absorption it may be appropriate and clinically relevant to demonstrate equivalence by means of a pharmacokinetic study. Systemic pharmacokinetic data have a well-established role in the bioequivalence evaluation of orally administered systemically acting drugs but there is doubt about its applicability to inhaled topically acting drugs. Whereas pharmacokinetic data clearly have a role is establishing bioequivalence in terms of systemic safety, there is a need to better understand the relevance to efficacy. Therefore, it may only be possible to demonstrate that the inhaled topical medicaments have the same safety/efficacy by conducting both a pharmacokinetic and pharmacodynamic study. Consideration should be given to power the study appropriately to demonstrate the study objectives.

5 Regulatory Notification It is evident from the survey that sponsoring companies are unclear of how to inform the regulatory authorities of design changes through the product lifecycle. The proposal outlined in Section 4.3 defines a series of key decision points that drives sponsoring companies to determine whether they need to undertake programmes of work to support the device changes that they would propose. The proposal for the mechanism whereby sponsoring companies notify the regulatory authorities uses the same framework – see Table 2

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Potential to impact how the target population and/or patient/HCP may interact with the device x

x

Potential to elicit a change in physiological response that would not be detected by standard in-vitro methods x

Potential to impact a Drug Product CQA, Device CQA etc.

Design Phase Post Approval Post Phase IIb - Approval

x

Update IND/CTA, if Registered Detail is impacted, when transitions from Phase IIB to Phase III Recorded in NDA/ IMPD Update IND/CTA, if Registered Detail is impacted, when the new design is studied in the clinic

x

Table 2 Risk Based Framework for Notifying Regulators

US: Annual update EU: Type IAIN change

US: CBE 30 EU: Type IA or IB change

Recorded in NDA/ CTA x

x x x

x x

Updated IND/CTA, if the Registered Detail is impacted, when the new design is studied in the clinic

US: PAS EU: Type II EU change

x Recorded in NDA

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6 Conclusion The proposal presented has been developed in the context of a Device Survey conducted by IPAC-RS that clearly demonstrates a lack of uniformity in approach. It is evident that all parties involved in the design, development and product lifecycle of “Combination Products” (i.e. patients, sponsoring companies and regulators) would benefit significantly from the development of guidance such that common standards for the management of change through the product lifecycle can realised. The approach outlined in this proposal has been developed cognisant of the concept of a Risk-Based Approach to Product Development as described in ICH Q8, Q9 and Q10. The proposal defines a risk based approach that enables device changes to be implemented post start of pivotal clinical through the product lifecycle on the basis of a supporting data package that is targeted at assuring that the safety/efficacy of the drug product is not compromised.

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Appendix 1:

IPAC RS – Product Lifecycle Device Change Management Survey Methodology The IPAC-RS Product Lifecycle Device Change Management Survey presented 15 scenarios that related to a series of common types of changes. These included material of construction changes, introduction/replacement of a supplier, scale up through the industrialisation phase of a programme and design revisions that member companies may determine to implement for a variety of reasons. Respondents were provided with information about each of these scenarios in turn and asked to indicate the following for each scenario: •

what activities they would undertake in support of the change proposed cognisant of the phase of the development process. These activities are classified as either being non clinical or clinical.

•

whether their decision to conduct these activities would be driven from a technical and/or a regulatory perspective.

•

how they would notify the agency of any change.

Non-clinical activities that could be selected by respondents included: • • • • • • • • • • • • •

mechanical verification, device robustness, physiochemical parameters, dimensional measurements, filling line trials, emitted dose, dose content uniformity, Aerodynamic Particle Size Distribution – ACI or NGI, Aerodynamic Particle Size Distribution – Lung Cast Model, Pack Integrity, Spray Pattern/Plume Geometry, extractable/leachables, other.

Clinical testing activities that could be selected included: • • • • • •

user handling study, design validation, pharmacokinetic bioequivalence study, pharmacodynamic bioequivalence study, clinical efficacy, clinical safety study,

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• •

flow profile measurement, other.

The survey was open for completion from May 2010 through January 2011. The preliminary results are based on responses obtained by September 2010; at that point, 125 responses had been obtained. Figure 1 presents a summary of the demographics of the respondents to the survey

Results The results showing how a sponsoring company would respond to each of the scenarios are provided in the following format; •

Two graphs are presented for each scenario, one graph summarizes results for non-clinical activities and one summarizes results for clinical activities.

•

Each bar represents the response to a particular test. The abbreviated test name is given below the bar.

•

The height of the bar gives the numbers of respondents that would do the test as a percentage of the total answering the question.

•

The blue, orange and red portions represent the proportion that would perform the test for technical only, regulatory only or technical & regulatory reasons respectively.

Abbreviations used are as follows: Non-Clinical Test Abbreviations MechVer Mechanical variation DevRob Device robustness Phy&Dim Physiochemical parameters and dimensional measurements Filling Filling Line Trials

PD BE

EmMass DCU APSD

ClinEff ClinSaf FlowProf

Pharmacodynamic Bioequivalence Study Clinical Efficacy Study Clinical Safety Study Flow Profile Measurement

Other

Other – to be specified

LungCast

Clinical Test Abbreviations UserH User Handling Study DevVal Device Validation (Function) Study PK BE Pharmacokinetic Bioequivalence Study

Emitted Mass (Shot Weight) Dose Content Uniformity Aerodynamic Particle Size Distribution – ACI or NGI Aerodynamic Particle Size Distribution

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PackInt Spray EXs LEs Other

– Lung Cast Model Package integrity related tests Spray Pattern/ Plume Geometry (MDIs) Extractables characterization Leachables characterization Other – to be specified

Complete Results of IPAC-RS Product Lifecycle Device Change Management Survey Scenario 1 DPI operating button change

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Scenario 2 Addition of a mdi dose counter

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Scenario 3 DPI mouthpiece change

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Scenario 4 Capsule to multi-dose DPI

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Scenario 5 DPI components change for automisation

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Scenario 6 Base elastomer manufacturing change

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Scenario 7 Polymer additive source/supplier change

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Scenario 8 Mouthpiece material change

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Scenario 9 Ink change

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Scenario 10 Primary Pack manufacturing plant relocation

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Scenario 11 MDI valve & filling process change

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Scenario 12 New material conditioning process

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Scenario 13 Moulding process change

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Scenario 14 Injection mould scale-up

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Scenario 15 Ultrasonic welding process change

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Summary of Results The following general observations can be made from a review of the responses to all scenarios: •

Clinical testing was almost as common as in-vitro testing for design changes, while for material & process changes, in-vitro testing was much more common.

•

Several respondents would use long-term stability testing (>6 months) at 40 C/ 75% RH to support changes. It was unclear whether companies would conduct short term accelerated stability studies to implement a change and commit to longer stability studies in parallel.

•

Mechanical testing, device robustness, and dimensions were seen by many as key elements for most changes.

•

Shot weight, DDU, ACI and spray pattern were often done regardless of whether there was a perceived technical need.

•

The lung cast model and flow profile measurement were not used often.

•

Extractable and Leachable testing were primarily conducted for material and process changes, but frequently also conducted for pure design changes.

•

Device validation and user handling studies were the most common clinical studies.

•

About half of respondents would do clinical work purely for regulatory reasons

The survey revealed considerable variance regarding: (1) whether to test in the context of a device change; and (2) if so, what types of tests should be conducted; as well as (3) the rationale for testing. There was also uncertainty about the regulatory pathway that should be taken to obtain approval of a proposed change. It was concluded from the survey that there was a lack of consistency in the approach being adopted. It was evident that Risk Management, as defined by ICH, does not appear to be informing decision making. It was unclear whether the driver of the inconsistencies noted was that respondents answered based on what they would do or what they believed should be done. Additional work could be conducted to understand the inconsistency in approach (e.g. a subanalysis to determine whether inconsistency was driven by region, background or experience of the respondents). However, it was concluded that given the variability observed that this would be unlikely to affect the overall conclusion. The survey suggests that the development of an agreed framework for guidance utilizing a riskmanagement based approach to evaluate and manage device changes for OINDP could be of a significant value to all stakeholders (i.e. patients regulators & industry).

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