cmc biologics pathway_draft8

Edward NarkeRegulatory Managing Director

DS InPharmatics

Journey in the Development of Biologics Through End of Phase 3

The CMC Pathway

The CMC Journey in the Regulation of Biologics

Our Goals

• To better understand the FDA’s CMC requirements and expectations for biologic manufacturing and product testing

• To better visualize a cost-effective, risk-managed approach to manage these manufacturing processes and products through clinical development into market approval

• To better appreciate the challenges involved with controlling safety, potency, and impurity profiles for these products

Process Overview of Biologics

Virus inactivation

Virus removal

Harvest

FiltrationFiltration

Chromatography column (Size Exclusion) Chromatography column

(Ion Exchange)

Chromatography column (HIC)

WCBBioreactor (fermentation)

Filtration

Sterile filllyophylization

What makes Biologics Special?

Biologics have Expected

• Primary, secondary, tertiary,

quaternary structure

• Size

• Charge

• Hydrophobicity

• Folding (S-S bonds)

• Glycosylation

• Bioactivity

• Heterogeneity

& Unwanted:

• Aggregation

• Incorrect folding

• Truncation

• Amino acid modifications oxidation, deamidation,

glycation, etc.

A Big Picture Approach is Desirable

Pre-clinicalPhase 1

Phase 2Phase 3

Phase Development

Not So Obvious

How much test method validation, product characterization, stability? How tight should specs be? Do I need a bioassay?

Unambiguous Requirements

Validated Test Methods

Complete Product Characterization

Final Specifications

Expiry Date Assigned

Bioassay Related to Function

Full Change Control Program

Question?

• What are some critical items to open an IND and most common reasons why INDs get placed on Clinical Hold, and how to avoid this.

Product Characterization? • Inadequate characterization data provided

– Identity*, heterogeneity/variants (size, charge, hydrophobicity, glycosylation), aggregates, etc.

– Process-related impurities (HCPs, DNA, antibiotics, chemicals)

• Specifications inadequate to control quality– Inadequate spectrum of release tests– Acceptance criteria too wide

• What to do?– Evaluate product as much as feasible before starting

nonclinical and clinical studies

Methods for Product Release

• Assay Methods not suitable for intended purpose– SEC for Aggregates– Potency Assay

BioActivity Assays?

• Absence of bioactivity/or Potency assay specification

– Critical quality attribute for proteins– Proteins inactivated by various conditions– Potency assay required to evaluate and control product quality– Inability to assure consistent dosing of product between lots;

safe dose

• What to do?– Develop and implement a relevant & quantitative

bioactivity and or potency assay and set a meaningful specification

Viral Safety? – Cell banks or animal-derived raw materials not

appropriately tested for endogenous or adventitious agents (mostly viruses, retroviruses)

– Manufacturing scheme not validated for its ability to remove or inactivate retroviruses

• Transmission of infectious viruses to humans• No information on country of origin of ruminant

derived materials used in manufacturing

– Concern over TSEs; BSE

Viral Safety? – What to do?

Retroviruses• Estimate retrovirus particle load in cells &

unpurified bulk; potential particles/product dose• Document ability of process to adequately remove

retroviruses

Exogenous viruses• Evaluate potential presence of viruses• Include 2 robust, orthogonal viral reduction steps

Pharmaceutical Process-Related Impurities Major Safety Concern for

the FDA!

The FDA can place your clinical study in ‘clinical hold’ for the following CMC reason:

MAPP 6030.1 – “if there are any reasons to believe the manufacturing or controls for the clinical trial product present unreasonable health risks to the subjects … such as a product with an impurity profile indicative of a potential health hazard or an impurity profile insufficiently defined to assess a potential health hazard”

Impurity Safety Assessment For Biologics Product-Related Impurities

Protein AggregationKnown immunogenecity

Amino Acid Changes Immunogenecity (e.g., oxidation of methionine)

Glycosylation Changesimmunogenecity

FDA Guidance For Industry CMC IND Content For Phase 2 and 3 1999

“Impurities should be identified, qualified, and quantified, as appropriate. Suitable limits based on manufacturing experience should be established.”

“For peptides and proteins, characterization should include data on the amino acid sequence, peptide map, post-transitional modifications (e.g., glycosylation, gamma carboxylation), and secondary and tertiary structure information, if known.”

Design of the Manufacturing Process!

“The extent of purification of recombinant DNA products should be consistent with the intended use of the product. Drugs and biologics which are to be administered repeatedly or at high concentrations should be adequately pure to prevent the development of undesired immune or toxic reaction to contaminants.The purification process should be designed to specifically eliminate detectable viruses, microbial and nucleic acid contamination and undesirable antigenic materials.”

1985 FDA Guidance: Production and Testing of Recombinant DNA-derived Products

List All Actual/Potential Impurities!

• Process-related impurities Cell-substrate (DNA, HCP, proteases, endotoxins) Cell-culture (cell-substrate [DNA, HCP, protease];

endotoxin; media components – antibiotics [tetracycline, gentamicin], hormones [insulin, IGF-1, transferrin], serum)

Purification (enzymes [DNase/RNase]; resin leachates; surfactants; residual cleaning agents]

Product-related impurities

FDA Guidance for Review Staff and Sponsors: Gene Therapy 2004

Identify the “Critical Impurities”!

‘Critical Impurity’: That which must be controlled to a defined level to assure appropriate quality and/or safety!

Impurity that impacts patient safety risk Impurity that is difficult to consistently remove Impurity that varies from batch-to-batch or

changes with time (case by case)

Risk Management of Impurities

Goal: Determine how you will demonstrate to regulatory agencies adequate control of the specified impurities!

Impurity Control Mechanisms Process validation In-process action limit monitoring End product specification release/stability testing Combination of above

Determine Acceptance Limits

What to Base Acceptance Limits On

• Known toxicity information • Required regulatory targets/specs • Levels consistent with clinical materials• Company-specific requirements

Specifications: Early Development

• Acceptance Criteria Generally Broad (Focus on Safety/Efficacy)– Define safety limits, where possible, with regulatory

guidance– Example: LAL ≤5 EU/kg/dose – Tighten specifications as manufacturing experience

increases

• Employ Quantitative Methods Where Feasible• Push the Envelope With Toxicity Studies to

Underwrite Safety• Understand the Impact of Process Changes on

Product Quality

Specifications Through Development

• Specifications Are Expected to Change – Changes to Analytical Methods– Evaluation of Stability Data– Changes to Formulation– Process Changes and Process Capability– Enhanced Understanding (Characterization)– Increased Manufacturing Experience– Process Validation and Clearance Studies

Specifications Through Development

While acceptance criteria generally get tighter with increased manufacturing experience, there may be some cases where widening the criteria may be acceptable.

• Analytical Testing May Decrease for Late Phase Products – May remove tests following process validation/clearance

• Examples: Viral Testing and DNA

– May remove tests based on process consistency• Examples may include monitoring of oxidation/acidic variants

Specifications: Late Development

• In General, Expect to Tighten Specifications– Methods Are Fully Validated and Locked Down– Extensive Manufacturing Experience– Link Between Product Quality & Clinical Outcome– Statistically Relevant Pool of Data– Enhanced Understanding of Product Stability

• Internal Targets – Reflect Process Capability– Product quality may still be high outside of internal targets

• Make Specifications Relevant

Designing Relevant Specifications

• The Good– Supported by appropriate, well designed analytical methods– Address all the quality attributes that impact safety and efficacy– Underwrite safety and efficacy through end of shelf life– Reflect a thorough understanding of the molecule and the process

• The Bad– Analytical methods inappropriate, poorly validated, lacking specificity – Contain tests that are irrelevant to product quality–Lack tests for

critical quality attributes due to poor characterization– Lack relevance to clinical experience– Driven by analytical or process capability– Contain tests performed “because we can”

The Perfect Process

Early Phase Development• Phase 1 Study with Pilot-Scale Material: Process Not Optimized• Acceptance Criteria for Clips/Truncations Very Wide• Process May Not Optimized for Removal of Aggregates• No Assay for Acidic Species or Oxidation • Clinical Data Shows Good Safety and Efficacy

Later Phase Development• Methods Optimized: More Sensitive and Quantitative• Clinical Samples Re-evaluated With Optimized, Quantitative Methods• More Results Define Further Knowledge• Specifications Based on Process Capabilities and Relevant Clinical

Experience• Targets Set on Patient Safety Considerations and Process Capabilities

– Plan Ahead –Understanding of process capability will increase over time as you

gain experience.

A Few Key Questions

• What are some of the major challenges that are faced in meeting CMC filing requirements?

• What are the some strategies that are applied to address the major challenges?

Assay Methods for Product Release?

• Assay methods not suitable for intended purpose

Examples:– SEC for aggregates: Sample treated to

reduce aggregates before running column– SDS-PAGE gels under-loaded– Potency assay: “what is active”

COMPARISON OF NONCLINICAL & CLINICAL LOTS?

– Product used in animal toxicology studies not comparable to product intended for clinical

• Can’t rely on Tox studies establishing safety (special emphasis on impurities, degradants, aggregates)

– What to do?• Do key Tox studies on appropriate material;• Do side-by-side comparisons of non-clinical and

clinical lots• Evaluate potential safety impact of differences

between Tox and clinical lots

Stability Testing?

– No stability data or testing plan• Product stable throughout nonclinical studies• Product will be stable for duration of clinical studies

– Stable under conditions of use (diluted, etc.)• Product changes that would result in safety risk

– e.g., release of untargeted toxin– e.g., release of radiolabel– e.g., aggregation– e.g., loss of sterility

Insufficient Information Submitted?

– Clinical trial material not yet manufactured• No release or characterization data on the actual

product to be administered to patients• Uncertain that product suitable for clinical use

– Problem exacerbated by limited set of specifications and wide acceptance criteria; limited understanding of critical product characteristics

– What to do?• Manufacture clinical lots, provide release data before

submitting IND

Collecting the Data as the Journey Continues

Key question: How and when to invest to really get to know the manufacturing process and its outcome

Marginal conditions: Seek out regulatory authority advice. It’s all about involving the agency as a partner

Milestones: A reality check for your CMC regulatory approach at any transition

What Is ‘Potency’?

‘Potency’ = the assessment of ‘biological activity’

Impacted by both molecular conformation and by molecular variants!

Potency is Invaluable in Biologic Manufacturing!

• Parameter of product quality release testing (‘active content’)

• Tool for assessing lot-by-lot manufacturing consistency during normal manufacturing operations

• Tool for assessing product stability• Tool for demonstrating product comparability

after a manufacturing process change

BioAssays/Potency: Required Measurement for Biologics

• 21 CFR 610.10“Tests for potency shall consist of either in vitro or in vivo

tests, or both, which have been specifically designed for each product so as to indicate its potency in a manner adequate to satisfy the interpretation of potency given by the definition in 600.3(s)”

21 CFR 600.3(s)“The word potency is interpreted to mean the specific ability

or capability of the product, as indicated by appropriate laboratory tests or by adequately controlled clinical data obtained through the administration of the product in a manner intended, to effect a given result”

Regulatory Expectations For the Choice of Bioassay/Potency

“ A correlation between the expected clinical response and the activity in the biological assay

should be established in pharmacodynamicor clinical studies.”

ICH Q6B Specifications for Biologics

When Must a Biologic/Biopharmaceutical Have a

Potency Bioassay?

“Potency assay (i.e., ability to induce immune response such as proliferation of responder cells, cytotoxicity or any other correlation with biological activity) is to be in place at Phase 1/2, and established at Phase 3”

Regulatory Expectations During Product Development for Tumor Vaccines, Raj Puri, FDA

What About Setting Potency Specifications?

Regulatory guidance on setting potency specs

- limited! (as with other specifications)

“The permissible range of values in potency assays that reflects adequate biological activity of a product should be based on

experience……”FDA PTC MAbs 1997

Development Phases

Controlling Quality and Basis for QTPP?

• Do I have a reliable process that is reproducible?

• Do I have a reliable, specific and sensitive analytical method?

• What are the physical chemical properties? Can it be readily formulated-delivered and maintain stability?

Pre-IND

Initiating Phase 1

Early Clin Dev

Transition Ph2 to Ph3

POC to Registration

Continuous Improve

Key Questions

Conditions/Features

Basis/Considerations

Milestone/Result - Further Actions

Development PhasesBasis for QTPP?

• How do I want to (need to) deliver the drug?

• What, if any, are the key properties of the drug that could confound clinical results?

• Can I produce a compliant and convincing CMC package?

Pre-IND

Initiating Phase 1

Early Clin Dev

Transition Ph2 to Ph3

POC to Registration

Continuous Improve

Key Questions

Conditions/Features

Basis/Considerations

Milestone/Result - Further Actions

Example of Release Specifications For a Marketed Biologic

Implications of New Regulations?

• What about Refuse to File

• Actions for BLAs

Refusal to File BLA for Protein Product?

• Facility not ready for inspection during the time frame of the review clock

• Lack of process validation

• No stability data on product intended for commercial use

Summary?

• Implications of Regulations?

• Principles for selecting effective development and regulatory CMC strategies in an evolving regulatory environment?

• How Much Information?

• What is the best way to use opportunities to consult with the Agency?

What you don’t know can hurt you….

• “…there are known knowns; there are things we know we know. We also know there are known unknowns; that is to say, we know there are some things we do not know. But there are also unknown unknowns – the ones we don’t know we don’t know.”

Thank you …