IQA - Drug Product Review and Recommendations

Mayra Pineiro-Sanchez, Ph.D. Quality Assessment Lead

Division of Immediate Release Products II Office of Lifecycle Drug Products (OLDP)/OPQ/CDER/FDA

2017 AAM CMC Workshop May 23-24, 2017

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Disclaimer This presentation reflects the views of the speaker and not necessarily those of the FDA or other government agencies

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Integrated Quality Assessment

Drug Product Review and Common Deficiencies Drug Substance

Drug Product Development

Formulation Development

Drug Product Controls

Container Closure

Stability

Case Study

Scope – Solid Oral Dosage Forms

Outline

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ANDA Integrated Quality Assessment

IQA

Process Reviewer (OPF) Manufacturing process and controls

Drug Product Reviewer (OLDP) Drug Substance

Facilities Reviewer (OPF)

Biopharmaceutics Reviewer (ONDP)

Microbiology Reviewer (OPF)

Drug Product Reviewer (OLDP) Drug Product

Application Technical Lead: Provides day-to-day leadership to the review team and oversight of the scientific review

Regulatory Business Project Manager: Serves as review team regulatory and process leader

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Reference to Drug Master File (DMF). DMF evaluation is performed by the DMF team

Drug substance review in the IQA includes the evaluation of critical aspects of the API

ANDA submission should reflect a risk-based approach through clear understanding of the drug substance attributes that can have an impact on the quality, safety and manufacturability of the finished drug product

Drug Substance

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Physicochemical Properties: Knowledge of physicochemical properties/critical quality attributes of the drug substance that may impact drug product quality, performance, patient safety, and/or efficacy (e.g., PSD, chirality, polymorphism, aqueous solubility as a function of pH, hygroscopicity, melting point)

Common Deficiencies: The API is said to not have any polymorphic forms but

literature reports indicate otherwise

Polymorph characterization is incomplete

Aqueous solubility as a function of pH is not included and dose/solubility volume is not determined

Hygroscopicity is indicated but no supporting data is included

Drug Substance

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Control of Drug Substance (Specifications and Methods) Complies with the USP monograph as a minimum requirement

Additional tests should be established based on a risk-based approach (e.g., water, polymorph, particle size) and in consultation with the DMF holder

Impurities should be characterized and classified as process and/or degradation products and should be controlled per ICHQ3A recommendations

Genotoxic impurities should be controlled based on the threshold for toxicological concern per current Agency recommendations

USP compendial items – USP Method verification per USP <1226> or full validation for in-house method per USP <1225> with adequate USP equivalency data

Non USP items - In-house methods should be completely validated per USP <1225>

Methods adopted from the DMF holder or other – include method verification and method transfer reports per USP <1224>

Drug Substance

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Common Deficiencies (Specifications and Methods): The drug substance controls are not in line with most current USP and

appropriate justification is not included

Tests for critical drug substance attributes are not included (polymorphism, stereochemistry, particle size, water content, etc.).

Proposed limits for impurities are above ICHQ3A and no justification is provided

The potential for genotoxic impurities is not addressed

Incomplete method validation for in-house methods

Method labeled as USP. However, differences observed between the USP method and the method described are not justified based on USP <621>

USP equivalency data not provided or failure to demonstrate equivalency based on USP system suitability

Forced degradation studies with under/over degradation and/or mass balance not established

Drug Substance

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Reference Standards, Container Closure System & Stability USP reference standard – Lot number and certificate of analysis (COA)

Non-USP reference standard - COAs and copies of structural elucidation and characterizations (FT-IR, NMR, MS, UV, elemental analysis, etc.) either from DMF holder or the ANDA applicant should be provided

Confirmation that the proposed container closure system provides appropriate protection

Indicate the storage conditions at the drug product manufacturing facility

Common Deficiencies: Qualification data for reference standards not included Traceability of in-house standards to USP not demonstrated Reference standards used for method validation not qualified

Drug Substance

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Drug Product Development

Expectation:

Takes a risk-based approach to product development

Demonstrates product understanding

Establishes a Quality Target Product Profile (QTPP)

Identifies Critical Quality Attributes (CQAs) (will focus on those relevant to drug product review)

Mitigates high risk CQAs through formulation design, process/product understanding and optimization

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Drug Substance Controls established using a risk-based approach

In general overages are not a recommended practice

Excipients Perform excipient compatibility studies to address the potential for

chemical reactivity of excipients (or impurities in excipients). Ratio of excipient to API should be representative of the proposed formula

Grade and level of excipients are evaluated through formulation development/product performance studies

The use of stabilization agents is justified

Compendial excipients are controlled based on current USP/NF

A risk-based approach is used to justify the inclusion or lack of testing beyond USP recommendations

Formulation Development

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Common Deficiencies:

Compatibility studies do not reflect the chemical stability of the API in the formulation (i.e., testing for impurities is not performed, ratio of excipient to API is inadequate)

Supporting data to justify the use and level of a stabilization agent not provided

Drug product contains FD&C yellow #5 (Tartrazine) - Tartrazine is known to cause allergic reactions in some patient population

Formulation Development

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Compendial products: Comply with the USP monograph as a minimum requirement

General requirements for Solid oral dosage forms:

Description, identification, uniformity of dosage units USP <905>, disintegration time (ODT), assay, impurities per ICHQ3B(R2), dissolution

Additional tests are established based on a risk-based approach (e.g., water content, polymorph, microbial testing)

Drug products should comply with USP <467> Residual Solvents

Controls may be modified for stability studies with justification

Analytical Methods & Methods Validation

USP compendial products– USP Method verification per USP <1226> or full validation for in-house method per USP <1225> with adequate USP equivalency data

Non USP products- In-house methods should be completely validated per USP <1225>

Control of Drug Product

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Common Deficiencies: Additional testing beyond compendial requirements not considered

Impurities identified as process impurities appear to increase and no justification provided

Controls for known degradants reported in the literature not included

Water content limit proposed is not supported by data

Scored tablets with a functional score configuration not evaluated per current Agency guidance

Trending observed on stability not discussed

Representative chromatograms not included

Reference standards for drug product degradants not appropriately qualified

Control of Drug Product

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Container closure (including bulk containers) should provide adequate protection over the proposed shelf-life

Compliance with USP <661> and <671> should be demonstrated

Certificates of compliance with applicable 21 CFR for indirect food additives should be included

Adequacy of the proposed packaging configuration for ODTs (e.g., HDPE bottles, blister pack) should be demonstrated

Common Deficiencies: Container closure is said to comply with USP <661> and <671> but supporting

data not included

Moisture permeation data for the blister packs not provided

Studies to confirm the tablet integrity during transportation of ODT drug products packaged in HDPE bottles not performed

Container Closure

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Stability data upon submission: Six months accelerated and long term (three drug product

lots with two lots of API)

Bulk packs when intended for re-packagers

In-use stability data for drug product intended for alternative administration (e.g., tablets dispersed in liquids, capsules contents (pellets, beads, granules) sprinkled on soft foods) or based on a risk-based approach

Stability

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Common Deficiencies: Controls for stability changed without justification (e.g., parameters not

expected to change during storage may not need to be tested, increase in impurity limit should be within acceptable limits (ICHQ3B(R2)), increase in water content is not justified)

Evaluation of assay and impurities fails to show mass balance

Stability protocol fails to include accelerated testing of validation lots when a scale-up is proposed

Failure to use risk-based approach to generate in-use stability data

Note: Tighter dissolution requirements may be suggested by Biopharmaceutics – data from retained accelerated stability samples at six months or long term at 24 months should be provided to confirm the drug product can meet the recommended limit

Stability

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Physical Attributes Low solubility

Hygroscopic

Exhibits Polymorphism – ten crystalline solid state forms, and an amorphous form. Forms exhibit differences in solubility

Applicant uses hygroscopic anhydrous crystalline form (not the most stable form)

Notes:

Manufacturing process involves dry granulation with roller compaction

Scale-up proposed = 10X

Initial Assessment Physical stability of the drug substance in the drug product is considered a HIGH RISK

as the drug substance exhibits polymorphism and the form that the Applicant utilizes is known to absorb water and convert to the hydrate form

It is reported that moisture absorption can transform the polymorph into a less soluble form, thus monitoring of water content along with polymorphic forms in the in-process, final and stability samples should be performed

Case Study (Drug Product X)

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Data in the Original Submission Batch data for API with test for hygroscopicity with limit of NLT X, XRD to

confirm polymorphic form and test for water content

Controls for polymorph not included for release and stability of the finished drug product

Agency Requests Establish a range for hygroscopicity test

Include characteristic 2-theta values for polymorph ID test

Perform studies to establish potential for interconversion in the DS and DP

Evaluate the potential presence of polymorphic mixtures before and after milling and during storage

Establish the polymorphic composition of the drug product upon release and stability and compare the results to the drug substance content and to un-expired and un-stressed RLD samples

In-use stability studies for DP stored in HDPE bottles

Case Study

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Findings Data generated to support a range for acceptable hygroscopicity of the API

Polymorph ID test revised to include 2-theta values of desired form and absence of 2-theta values of unwanted form

Studies to demonstrate interconversion acceptable for DS and manufacturing process

An increase of unwanted polymorph form was observed on stability. Additional studies demonstrated that dissolution was negatively impacted by a X% or higher content of the unwanted polymorph

In-use stability studies show an increase in interconversion

Control strategy Limit water content in API and finished product (excipients)

No scale-up of commercial lots

Establish a quantitative polymorph test to monitor the polymorph content in the API, (in-process) and during release and stability of the finished drug product

Case Study

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ANDA review involves multiple disciplines through an integrated quality assessment process

The drug product discipline will evaluate critical aspects of the drug substance and drug product formulation development, container closure and controls for release and stability

Taking a risk-based approach to product development is crucial in order to demonstrate product understanding and achieve a successful control strategy

Closing Remarks

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Susan Rosencrance Ph.D., Director OLDP

Peter Capella Ph.D., Director DIRPII, OLDP

Bing Wu Ph.D., Branch Chief DIRPII, OLDP

Damaris Maldonado M.S., Master Reviewer DIRPII, OLDP

Acknowledgements

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Thank You!