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Phase 1 Appropriate Quality Management Systems

Webinar Presented by Lisa Helmonds,

Vice President, MWA Consulting, Inc.

July 17, 2019

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AGENDA

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➢ Review the current FDA Guidance

for Industry: CGMP for Phase 1

Investigational Drugs

➢ Identify Critical SOPs Required for

Phase 1 Products

➢ Discuss Pros and Cons of Using

Electronic Systems versus Paper

➢ Provide Recommendations for

Implementing a Compliant Phase 1

QMS 3

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DRUG DEVELOPMENT TIMELINE

GLP

GLP

GCP

GMP

PHARMACEUTICAL QUALITY MANAGEMENT (PQS) SYSTEM

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Six (6) Systems that need to be in a state of control

1. Facilities and Equipment

2. Laboratory Controls

3. Materials

4. Packaging and Labeling

5. Production

6. QUALITY SYSTEM touches all the others

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GRADED APPROACH TO COMPLIANCE

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Early Research• GLP animal supplies• Record details of material manufacture

including vendors lot numbers in notebook.

Other IND/Clinical Support Data• Good science• Good laboratory records of experiment• Report reference to source data in IND files

Phase 1 Clinical Materials• CGMP for Phase 1 Investigational Drugs:

FDA July 2008

Phase 2 Clinical Materials thru Commercial Launch

• cGMPs CFR 21 Parts 210 and 211 apply• Continuum of compliance as development

progresses7

Phase 1 Phase II Phase III

BiobatchCommercial Mfg


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➢ Implement CGMP for the manufacture of each batch of investigational drug used during phase 1 clinical trials to ensure product safety, integrity, strength, purity and quality (SISPQ)

➢ Establish manufacturing controls based on identified hazards for the manufacturing setting.

➢ Follow good scientific and Quality Control (QC) principles to assess risks to patient, product quality and data integrity.

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RECOMMENDED CGMP FOR PHASE 1 INVESTIGATIONAL DRUGS

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A. Personnel should have:

➢ Education, experience, and training to enable everyone to perform their assigned function.

➢ Appropriate experience to prepare the phase 1 investigational drug

➢ Familiarity with QC principles and acceptable methods for complying with CGMP.

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B. QC Function

Ensure each manufacturer establishes a written plan that describes the role of and responsibilities for QC functions.

➢ Examining materials used in the manufacture of a phase 1 investigational drug

➢ Review and approval of manufacturing procedures, testing procedures, and acceptance criteria


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B. QC Function (continued)

➢ Releasing or rejecting each batch of phase 1 investigational drug based on a cumulative review of completed manufacturing records and other relevant information

➢ Investigating unexpected results or errors that occur during manufacturing or from complaints received

➢ Initiation of corrective action, if appropriate.


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B. QC Function (continued)

➢ Assign an individual(s) to perform QC functions independent of manufacturing responsibilities, especially for the cumulative review and release of phase 1 investigational drug batches.

➢ For some manufacturers, the Quality Control Function as described in this guidance may be assigned between a quality control and quality assurance group and may be integrated into a more comprehensive quality system.


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C. Facility and EquipmentFacilities

➢ Sufficient space, clean environment, appropriate construction.

➢ Appropriate lighting, ventilation, and heating.

➢ Appropriate cooling, plumbing, washing, and sanitation.

➢ Use of procedural controls to promote orderly manufacturing to prevent contamination, cross contamination and mix-ups.


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C. Facility and Equipment (Continued)Equipment

➢ Appropriate equipment to maintain an air cleanliness classification suitable to the operation performed in the area.

➢ Appropriate equipment that will not contaminate the phase 1 investigational drug that is properly maintained, calibrated, cleaned, and sanitized at appropriate intervals.

➢ Identify all equipment used for a particular process and document such use in the manufacturing record.


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D. Control of Components, and Containers and Closures

➢ Establish written procedures describing the handling, review, acceptance, and control of material

➢ Control materials (e.g., segregated, labeled) until you have examined or tested the materials, and released them for use in manufacturing.

➢ Handle and store such materials to prevent degradation or contamination.


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D. Control of Components, and Containers and Closures (Continued)

➢ Identify and trace all materials used in the manufacture of a phase 1 drug from receipt to use in the manufacture of each batch.

➢ Keep a record (e.g., log book) minimally containing:• Receipt date• Quantity of the shipment• Supplier's name• Material lot number • Storage conditions• Corresponding expiration date


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➢ Establish acceptance criteria for specified attributes on each material based on scientific knowledge and experience for use in the specific phase 1 drug.

➢ Examine the certificate of analysis (COA) and/or other documentation on each lot of material to ensure that it meets established acceptance criteria for specified attributes.


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➢ For human and animal derived material include information on sourcing and/or test results for adventitious agents, as appropriate.

➢ For incomplete documentation for a material for a specified attribute, test for the incomplete specified attribute of the material.

➢ Perform confirmatory identity testing for each batch of the API or drug substance.


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E. Manufacturing and Records

➢ Follow written manufacturing and process control procedures.

➢ Keep a record of manufacturing data that details the materials, equipment, procedures used, and any problems encountered during manufacturing.

➢ Retain records sufficient to replicate the manufacturing process.


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E. Manufacturing and Records (Continued)


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➢ For phase 1 drugs, if a batch is initiated but not completed, include an explanation of why manufacturing was terminated in the record.

➢ A record of changes in procedures and processes used for subsequent batches along with the rationale for any changes.

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E. Manufacturing and Records (Continued)


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➢ Keep a record of the microbiological controls and procedures that were implemented for the production of sterile-processed phase 1 drugs.

➢ Follow the recommendations for use of aseptic techniques and the control of in-process materials, components, and container closures designed to prevent microbial and endotoxin contamination.

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F. Laboratory Controls Testing

➢ Ensure laboratory tests used for materials, in-process material, packaging, drug product are scientifically sound, suitable and reliable for the specified purpose.

➢ Perform tests under controlled conditions.

➢ Follow written procedures describing the testing methodology.

➢ Maintain records of all test results, procedures, and changes in procedures.


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Method Development


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Method Validation: Phase 1 Phase 2 Phase 3 NDA

Linearity X X X X

Specificity X X X X

Forced Degradation:

Acid pH — X X X

Basic pH — X X X

Heat — X X X

H2O2 — X X X

UV Light — X X X

Accuracy X X X X

Repeatability X X X X

Intermediate Precision — — X X

Reproducibility (if needed) — — X X

Robustness:

Mobile Phase pH — — X X

Mobile Phase Composition — — X X

Detector Wavelength — — X X

Column — — X X

Solution Stability — — X X

Limit of Detectionc X X X X

Limit of Quantitationc X X X X

Method validation package — — — X

c = As applicable to type of method used.

Related Substances:

Method Validation X X X X

Identification — — X X

Qualification — — X X

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F. Laboratory Controls (Continued)Testing

➢ Perform laboratory testing of the phase 1 drug to evaluate quality attributes.

➢ Monitor specified attributes and ensure acceptance criteria is applied appropriately.

➢ Establish specifications for known safety-related concerns.

➢ Calibrate and maintain laboratory equipment to established written procedures.


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➢ Verify that the equipment is in good working condition when samples are analyzed (e.g., system suitability).

➢ Retain a representative sample from each batch of phase 1 investigational drug.

➢ Retain both the API and phase 1 investigational drug in containers used in the clinical trials.


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➢ Retain twice the quantity necessary to conduct release testing, (excluding testing for pyrogenicity and sterility) if required at a later date for testing/investigation.

➢ Appropriately store and retain the samples for at least two years following clinical trial termination, or withdrawal of the IND application.


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F. Laboratory Controls (Continued)

Stability

➢ Run a stability study using representative samples of the phase 1 drug to monitor the stability and quality the drug during the clinical trial (i.e., date of manufacture through date of last administration)


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G. Packaging, Labeling and Distributing

➢ Suitably package the Phase 1 drug to protect it from alteration, contamination, and damage during storage, handling, and shipping.

➢ Establish written procedures for controlling packaging, labeling, and distribution operations.

➢ Use appropriate measures (e.g., product segregation, label reconciliation, verify operations by a second person, confirmatory laboratory testing, QC review) to achieve effective control.


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G. Packaging, Labeling and Distributing (Continued)

➢ Assure the drug product’s stability during the studies.

➢ Transport the phase 1 drug according to labeled conditions.

➢ Keep a detailed distribution record of each batch of phase 1 drug to allow full traceability if a recall is necessary.


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H. Recordkeeping

Keep complete records relating to the quality and operation of the manufacturing processes, including but not limited to: ➢ Equipment maintenance and calibration ➢ Manufacturing records and related analytical

test records ➢ Distribution records QC functions➢ Component records➢ Deviations and investigations ➢ Complaints


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H. Recordkeeping

➢ Retain records for at least two years after a marketing application is approved for the drug

➢ If an application is not approved for the drug, retain records until two years after shipment and delivery of the drug for investigational use is discontinued and FDA is notified.


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Multi-Product Facilities

➢ Manufacture only one phase 1 investigational drug at any given time, in an area or room separate from unrelated activities.

➢ If you must use the same area or room for multiple purposes, be sure cleaning and procedural controls are in place to ensure that there is no carry-over of materials or products, or mix-ups.


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Multi-Product Facilities (Continued)

➢ Ensure the area design/layout promotes:

• Orderly handling of materials and equipment

• Prevention of mix-ups

• Prevention of contamination of equipment or product by substances, previously manufactured products, personnel, or environmental conditions.

➢ Procedural controls could include:

• Procedures for clearing the room of previous product materials

• Product and component segregation

• Unique product identifiers.


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Multi-Product Facilities (Continued)

➢ Periodically evaluate the implemented procedural controls for their effectiveness.

➢ Take appropriate corrective action when indicated by the evaluation or when other events warrant.


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Biological and Biotechnological Products

➢ Carefully control and record the manufacturing process and testing to reproduce a comparable phase 1 Investigational Product.

➢ Properly store retained samples.

➢ Ensure appropriate equipment and controls in manufacturing are in place to ensure personnel safety.

➢ Use testing for safety-related purposes such as viral loads, bioburden, detoxification of bacterial toxins, virus clearance and removal of residual substances as appropriate.


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Adventitious Agent Control

➢ Evaluate for susceptibility to contaminate the environment with biological substances, including microbial adventitious agents

➢ Discuss containment issues for specific cases with the applicable Center within FDA before starting to manufacture product.

➢ Multi-product facilities should have cleaning and testing procedures that ensure prevention and/or detection of contamination by adventitious agents

➢ Use dedicated equipment and/or disposable parts (e.g., tubing), when possible.

➢ For multi-product areas, establish procedures to prevent cross-contamination, and to demonstrate removal of the previously manufactured product from shared equipment and work surfaces


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Gene Therapy and Cellular Therapy Products

➢ Manufacture phase 1 investigational cell and gene therapy products according to this guidance as much as possible.

➢ If this guidance can’t be followed include your justification for adopting additional controls or alternative approaches in the records.

➢ Monitor manufacturing performance to ensure product safety and quality when investigational gene and cellular therapy products are manufactured as one batch per subject.

➢ Periodically conduct and document internal performance reviews when manufacturing multiple batches of the same phase 1 investigational drug, to assess whether the manufacturing process is optimal to ensure overall product quality.

➢ Based on the review, make appropriate modifications and corrective actions to control procedures and manufacturing operations.


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Sterile Products/Aseptically Processed Products

Additional controls (FDA Guidance on Sterile Products Produced by Aseptic Processing, Sept. 2004)

➢ Aseptic manipulation under Class A, ISO 5 conditions

➢ Process simulation study using growth media➢ Environmental monitoring during processing➢ Disinfecting area prior to operations➢ Training personnel in aseptic techniques➢ Demonstrating sterilization methods are

suitable➢ Demonstrating that the test article doesn’t

interfere with sterility tests➢ Etc.


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Anything that compromises the safety, identity, quality, and purity of the drug product

➢ Cross contamination (adulteration)• components, API, in-process or drug product

➢ Contamination• Insect or rodent infestation, external

contamination, etc.

➢ Mix-up (adulteration)• Placebo vs. active• Wrong active• Different dosage forms in the same container

➢ Misbranding• No label, wrong label, incorrect information

➢ Absence of written procedures

WHAT IS NOT GMP NEGOTIABLE?

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CRITICAL SOPS REQUIRED FOR PHASE 1 PRODUCTS

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Quality Systems SOPs

• SOP Format and Content

• Document Control

• Good Documentation Practices

• Record Retention & Disposal

• Training Program

• Change Control

• Deviation Management System

• Corrective Action Preventive

Action Program

• GxP Contract Service Provider (CSP)

Qualification

• Oversight & Management of CSP

• Clinical Product Complaints

• Dealing with Research Misconduct

• Data Integrity Policy

• GxP Consultants


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Quality Assurance Operations SOPs

• QA Responsibilities

• Batch Record Review and Disposition

Release of Clinical Trial Material (CTM)

• API, Drug Product, Packaging

Specifications/COA

• Material Review Board (MRB)

• Master Batch Record (MBR) Review and

Approval

• Retrieval of Clinical Supplies

• Analytical Methods Validation

• Stability Program

• GMP Material Destruction

• Use of Notebooks

Most Likely are Outsourced to CRO


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Clinical Operations SOPs

• Authorizing Clinical Sites to Receive

Investigational Product (IP)

(includes IP release form)

• Clinical Trials.GOV

• Transfer of Sponsor Obligations for

Conduct of Clinical Trials (TORO)

• Safety Reporting

• Developing, Approving, and

Amending Clinical Study Protocols

• Management of Clinical Study

Protocol Deviations

• Developing, Approving, & Revising

Informed Consent Forms

• Maintaining Sponsor Trial Master Files

• Financial Conflict of Interest and

Disclosure

• Review of Study Data

• Pre-Study Evaluation and Site Selection

• Site Initiation Visits

• Interim Monitoring Visits

• Clinical Study Closure Visits



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Medical Writing SOPs

• Preparing Investigator Brochures

• Preparing Clinical Study Reports

• Preparing Abstracts and

Publications

Regulatory SOPs

• IND Annual Reports

• Final Study Report Approval

Process

• Communication with Regulatory

Agencies

• Investigator Submissions Form

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• Implementation of Single Patient

INDs



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Biometrics and Data Management SOPs

• Electronic Data Transfers

• Data Management SOP

• Blinding and Accidental Unblinding of

Treatment Assignments (non-safety)

Drug Safety SOPs

• Receipt, Handling, & Reporting of

SAE for Investigational Product

• Medical Monitoring

• Safety Reporting of Non-Clinical

Data

• Data Safety Monitoring

Boards/Committees


ELECTRONIC SYSTEMS VERSUS PAPER SYSTEMS

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Paper Systems Pros Paper Systems Cons

• Labor intensive to print/scan/file

• Space needed for filing hard copies

• Need to maintain both electronic

and paper files since most

documents from CSP are emailed

• Routing documents for approval is

time consuming

• Potential for lost documents

• Tracking and ensuring training is

complete is a manual process and

can be delayed

• Can start study using paper

documents immediately

• Not committed to a particular

electronic system too soon

• Not dependent on IT hardware

or servers

ELECTRONIC SYSTEMS VERSUS PAPER SYSTEMS

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Electronic Systems Pros

• Many Part 11 compliant validated

systems available for small

companies available include

Document management, Training,

and Quality Issues/CAPA modules.

• Ease of document

routing/approval/retention

• Ease of tracking training

• Ease of handling deviations/CAPA

• Several designed specifically for

startups with cost constraints

• Audit trails for change controls and

traceability

Electronic Systems Cons

• Requires a great deal of meticulous

effort and forethought

• User Requirements

• PQ testing

• Many documents to produce

• Risk assessments required

• Must be Part 11 compliant validated

system

• Still need people to implement and

maintain SOPs

• Implementing an electronic QMS

during study start up can be disruptive.

• Cost of EQMS

RECOMMENDATIONS FOR IMPLEMENTING A COMPLIANT PHASE 1 QUALITY MANAGEMENT SYSTEM

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➢ Start QMS implementation at least 6-9 months before you start your clinical study.

➢ Hire experienced consultants to provide regulatory and quality guidance early if you do not have a RA/QA FTE.

➢ Train your senior management in GxPs prior to study start.

➢ Be sure to have the Sponsor’s SOPs in place before starting the study.

➢ Document what elements are outsourced to a CRO, CMO, etc.

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RECOMMENDATIONS FOR IMPLEMENTING A COMPLIANT PHASE 1 QUALITY MANAGEMENT SYSTEM

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➢ Outsource to reputable companies.

➢ Qualify your CMO/CROs prior to using them for your study.

➢ Having no QMS is in place can negatively impact the study results.

➢ Remember ensuring patient safety and data integrity are key to all phases of a clinical study.

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POTENTIAL PITFALLS

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When a phase appropriate QMS is not in place, there are potential compliance risks:

➢ Patient safety can be jeopardized.

➢ Loss of critical documentation to support regulatory submissions.

➢ Data integrity issues due to poor documentation practices can negatively impact the outcome of your study.

Summary

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➢ Reviewed the current FDA Guidance for Industry: CGMP for Phase 1 Investigational Drugs

➢ Identified Critical SOPs Required for Phase 1 Products in your facility

➢ Discussed Pros and Cons of Using Electronic Systems versus Paper

➢ Provided Recommendations for Implementing a Compliant Phase 1 QMS

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REFERENCES

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➢ 21CFR 11 Electronic Records; Electronic Signatures➢ 21 CFR 210, 211 – cGMP in Manufacturing, Processing,

Packing, and Holding of Drugs and Finished Pharmaceuticals

➢ ICH Q7 – Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients

➢ ICH Q10 – Pharmaceutical Quality System➢ FDA Guidance for Industry: CGMP for Phase 1

Investigational Drugs

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QUESTIONS

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THANK YOU

THE MWA TEAM

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