May 2008 P Pekos

Preparing an INDApplication: CMC

Principles & Content OutlinePeter Pekos, President

Dalton Pharma ServicesMay 13, 2008

May 2008 P Pekos

• Integrated synthesis laboratories • Research library • cGMP manufacturing suites • Biopolymer synthesis laboratory • Secure, controlled environment • Analytical laboratory

• over 80 employees

• 42,000 sq ft facility in Greater Toronto Area • Adjacent to Toronto’s York University • Proximity to Toronto area pharma, biotech, medical research facilities

Company Profile

• 26 at Ph.D. / M.Sc. level

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Services

Contract Research

Custom Synthesis

Contract Analysis

API Manufacturing

Sterile Filling

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Drug Development Support

Batch Records

AnalyticalSmall Focused LibrariesBulk intermediates & impurity standards

Process Optimization & Scale Up

API Manufacturing (GMP)

• Method Development• Method Validation• Stability Programs• Impurity Identification

Regulatory Support• CMC• IND• NDA

Lead Optimization

SAR elucidation

Prodrug synthesis

Sterile Filling (GMP)

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Disclaimer

Views presented here are provided toillustrate the general process and issues ofpreparing for an IND

Each therapeutic development program maydiffer in the details particular to that drug

Be sure to consult all laws, regulations andguidances that apply to your situation

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Business Of MedicalManufacturing

All the issues common to any manufacturingbusiness, plus…• Your product acts DIRECTLY on your consumers• Most products are inherently dangerous• Simple to use and to misuse• Highly intrusive regulatory environment

Conversely, the regulatory environmentprovides for a process to manage businessrisk as well as risk to the public• Consider each Health Authority as a resource to

consult with, not an adversary!

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Investigational New DrugApplication

IND regulations exempt the investigation of anew drug (or new drug use) from theregulations governing the production andmarketing of a commercial drug product.

Seeks to balance protection of the public withthe need to introduce new therapies.

Current regulations at 21 CFR 312.22 and312.23 contain the general principlesunderlying the IND submission and thegeneral requirements for an IND's contentand format

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IND regulation of CMC

Balancing protection with investigation leadsto a graduated, “bootstrapping” approach• Early studies provide limited data to assess risk

vs. benefit, consistency and control, etc., sominimize the initial human exposure

• As the program develops, the accuracy, precision,and breadth of your data is expected to improveover time

• By the time of a marketing application, thesponsor must demonstrate they are ready andable to meet the full requirements for a marketeddrug

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FDA View on Early CMC Data

“It is recognized that modifications to themethod of preparation of the new drugsubstance and dosage form, and evenchanges in the dosage form itself, arelikely as the investigation progresses. Theemphasis in an initial Phase 1 CMCsubmission should, therefore, generally beplaced on providing information that willallow evaluation of the safety of subjectsin the proposed study.”GUIDANCE FOR INDUSTRY. CONTENT AND FORMAT OF INVESTIGATIONALNEW DRUG APPLICATIONS (INDs) FOR PHASE 1 STUDIES OF DRUGS,INCLUDING WELL CHARACTERIZED, THERAPEUTIC, BIOTECHNOLOGY-DERIVED PRODUCTS (Nov 1995)

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Causes for “Clinical Hold” basedon CMC section of your IND

Unknown or impure components Chemical structures of known or highly likely toxicity Product that cannot remain chemically stable throughout the

testing program proposed Product with an impurity profile indicative of a potential

health hazard or an impurity profile insufficiently defined toassess a potential health hazard

Poorly characterized master or working cell bank Refer to 21 CFR 312.23(a)(7)

(see http://www.fda.gov/cder/guidance/phase1.pdf)

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Basic CMC Strategy for IND

Develop pre-clinical data or cite research toanswer these two questions:• Does the chemistry of either the drug substance

or the drug product present any signals ofpotential human risk?

• Does the manufacturing of either the drugsubstance or the drug product present any signalsof potential human risk?

Continue to address these questionsthroughout your development program!

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INTRODUCTION TO cGMP

Legal basis for cGMP What does that “c” mean? General Principles

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FD & C Act; 501 (a) (2) (B)

“A drug shall be deemed adulterated if:• … the methods used in, or the facilities or

controls used for its manufacture, processing,packing or holding do not conform to or are notoperated or administered in conformity withcurrent good manufacturing practice to assurethat such drug meets the requirements of this Actas to safety and has the identity and strength, andmeets the quality and purity characteristics, whichit purports or is represented to possess.”

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cGMP Legal Principles

Quality must be built into product• By “taking care” in making medicine• Can’t test quality into product

Missing or inadequate cGMP risk harm• Products(s) may be adulterated (defects need not

be shown before action brought)• Firm is responsible

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cGMP Legal Principles

Non-compliance may lead to your productfailing to meet your label claims:• Super-potency or sub-potency• Contamination• Misbranding• Bioavailability (e.g., altered pharmacology)• Safety and efficacy

The mere risk of harmful consequencesjustifies legal action and remedy!

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cGMP Legal Principles

“c” = “Current” = Dynamic• Standards evolve over time, e.g., ICH efforts of

the past decade, and US process overhaulunderway right now**http://www.fda.gov/OHRMS/DOCKETS/98fr/E7-23292.pdf

“Good” Practices• Minimal acceptable standards• Not necessarily “best practices”

• Unless “best” is, in fact, the current minimal

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cGMP Legal Principles

Feasible and valuable• No “percentage” in practice threshold

• Doesn’t have to be “predominant”• Enforceable even if no one else is currently

practicing it• Although a stronger case is made if someone else

has adopted that practice

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cGMP Scope

Any ingredient (including excipients) Finished dosage forms administered to

humans and/or animals• OTC, Rx products• Biologics, veterinary drugs• Drugs undergoing study (IND)

Manufacturers, test laboratories, packagers(including pharmacies), and warehouses

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Excluded from cGMP

Drug products compounded per Section 503Pharmacy Compounding (FDAMA)

Position Emission Tomography (PET)agents, but draft rule published in 2007suggests these will be covered too:• May be met by producing PET drugs in

accordance with the United States Pharmacopeia(USP) general chapter on compounding PETradiopharmaceuticals

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General cGMP Responsibilities

Prepare, review, approve and distribute SOP Ensure adequate qualifications, training, and

experience for personnel operating under cGMP Follow SOP and MBR Review MBR and executed BR Evaluate all deviations, investigate and resolve

critical deviations Ensure sanitary facilities Calibrate and maintain equipment and facilities, and

document that maintenance Review and approve validation protocols and reports Establish a change control process

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General Quality Principles

Quality is everyone’s job Sponsors must establish a

quality system Responsibilities must be

clearly stated Real-time quality records Investigate all deviations Quarantine before release

Establish a QualityControl Unit (QCU)• Independent of

production management• Responsible for QC and

QA (QA could be doneseparately)

• Notification process fordefects, recalls,inspections, and seriousGMP deficiencies

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Quality Control Unit

Must be involved in allquality issues

Must review andapprove all quality-related documents

(See: Quality SystemsRegulation, 21 CFRpart 820)

Cannot delegate mainresponsibilities• Lot release or rejection• Establishing raw

material, WIP, packagingand labeling acceptancesystem

• Batch record review priorto release

• Deviation investigationresolution

• Quality audits andvalidation reviews

• Stability data

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Content of IND

Item 7: CMC[21 CFR 312.23 (a) (7)]

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Item 7 of the IND: CMC

7.1 Introduction 7.2 Drug Substance 7.3 Drug Product 7.4 Diluent (if applicable) 7.5 Placebo (if applicable) 7.6 Test Procedures 7.7 Environmental Assessment

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Introduction: Section 7.1

Drug Substance/Productdescription:• chemical name, structure,

physical, chemical, and/orbiological characteristics,and generic name (ifavailable) and internal IDcode.

Names and amounts ofDrug Substance(s) used inProduct

Names and amounts ofexcipients, includingpreservatives or deliveryenhancers

Container/closuredescription

Diluent used to administerproduct, if applicable

Name, address, anddescription of each locationused in the manufacture ofthe Product andSubstance(s)• Reference existing IND or

DMF if available, if not,provide, floor plans,equipment lists, andmaterial flows for eachlocation

Summary flow chart ofmanufacturing process

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Drug Substance: Section 7.2

A brief process description:list reagents, solvents, andcatalysts used. A detailedflow diagram isrecommended.

Methods and specs foridentity, strength, quality,and purity• Reference Standard(s)• Brief description of the test

methods• Proposed acceptable limits• Recommend including CofA• Validation data and

established specs may berequested for biotech orhuman/animal source drugs

Full name and streetaddress of eachmanufacturing location

Information on the stabilityof the Drug Substanceduring the tox & clinicalprograms• A brief description of the

stability program and testmethods

• Preliminary tabular databased on representativematerial may be submittedin lieu of final data

• Neither detailed stabilitydata nor the stabilityprotocol should besubmitted

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Drug Product: Section 7.3

Citing USP-NF may be sufficient List components & quality level

• Active Pharmaceutical Ingredients• Excipients (including alternatives)

• Everything used in themanufacturing process, not justappearing in the final formulation

• For novel excipients, additional infomay be necessary.

• Summary table of composition The full name and street address of

each manufacturing location Brief description of manufacturing and

packaging procedures• Include sterilization process for sterile

products• Flow diagrams are recommended• Specify Container/Closure system

proposed for clinical studies

Methods & specs used for identity, strength,quality, and purity:• Reference Standard(s)• Brief description of methods used• Proposed acceptable limits• Recommend including CofA• Assess bioactivity for biotech drugs• Validation data and established specs may be

requested for biotech or human/animal sourcedrugs.

Information on the stability of the DrugProduct during the tox & clinical programs• A brief description of the stability study and the

test methods in the container/closuresystem and clinical storage conditions

• Preliminary tabular data based onrepresentative material may be submitted.

• Neither detailed stability data nor the stabilityprotocol should be submitted

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Label information (7.3.9)

A copy of all labels and labelling to be providedto each investigator:

A mock-up or printed representation of theproposed labelling.• Investigational labels in USA must carry a caution

statement as required by 21 CFR 312.6(a).• “Caution: New Drug - Limited by Federal (or United

States) law to investigational use.” NB: Label production and use regulated! NB: Other nations have different rules for labels!

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Dilulent/PlaceboSections 7.4 & 7.5

A brief general description of thecomposition, manufacture, and control of any• Diluent used to reconstitute the product, if needed• Placebo to be used in the proposed clinical trial(s)

Recommend using diagrammatic and/ortabular information where possible

NB: Placebo lots require the same care asactive lots and consume similar time andresources!

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Environmental Impact Section

Most investigational drugs able to claimcategorical exclusion from an environmentalassessment under 21 CFR 25.24

Possible exceptions: Cytotoxics or processesthat create large volume of hazardous waste.• See Guidance for Industry for the Submission of

Environmental Assessments for Human DrugApplications and Supplements, November, 1995.

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Electronic IND Submissions:eCTD format

Differs substantially from paper outlinedescribed here, but same principles apply

Still optional for CDER submissions May offer long term advantages for eventual

marketing applications, but technology andprocess is still evolving

Consult current CDER guidance:http://www.fda.gov/cder/regulatory/ersr/ectd.htm

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Other CMC Considerations

Investigator’s Brochure references CMC info Integrate the Tox and Clinical protocols with CMC via

the Pharmacy Manual• Storage, handling, and disposal of the drug• If required, preparing/compounding the drug for

administration (e.g., reconstitution with Diluent)• Specifications and stability limits for any contact materials

(e.g., IV bags, catheters, syringes, pumps, etc.)—oftenoverlooked, risking clinical timeline

Combination products (e.g., with device) governedby additional rules, see:http://www.fda.gov/oc/combination/

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cGMP Resources

Internet WWW site by DMPQ• http://www.fda.gov/cder/dmpq• CGMP regulations and ongoing changes• Division subject contacts• Medical gases• Active pharmaceutical ingredients• Human Drug cGMP Notes• Etc.

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Other Web Resources

ICH website (future of harmonizedregulation?)• Quality guidelines:• http://www.ich.org/cache/compo/276-254-1.html

CDER handbook (useful background, but notcurrent)• http://www.fda.gov/cder/handbook/

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Thank you

Special Acknowledgement toMark Winnett