FDA Perspective on Process Validation for Biotech Products · PDF fileISPE Process Validation Conference 12 –14 September 2017 Bethesda, MD 1 FDA Perspective on Process Validation

ISPE Process Validation Conference12 – 14 September 2017

Bethesda, MD

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FDA Perspective on Process Validation for Biotech Products

Zhihao Peter Qiu, Ph.D.Chief, Division of Inspectional Assessment

Office of Process and FacilitiesOffice of Pharmaceutical Quality

U.S. FDA, Center for Drug Evaluation and Research

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Outline

• Overview of the 2011 Guidance for Industry Process Validation: General Principles and Practices

• Regulatory Requirements for specified biological products submitted under Biologics License Applications (BLAs)

• An integrated CMC review and inspection for BLAs

• Overview of pre-license and pre-approval inspections

• Examples of 483 Observations/Case Studies


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Statutory and Regulatory Requirements for Process Validation

• Section 501(a)(2)(B) of the Act (21 U.S.C. 351(a)(2)(B)) A drug . . . shall be deemed to be 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 not operated or administered in conformity with current good manufacturing practice to assure that such drug meets the requirements of this Act as to safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess.

• 21 CFR 211.100(a): There shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess…

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Drug Quality Principles

• Quality, safety, and efficacy are designed or built into the product.

• Each manufacturing step should be adequately controlled to assure final product meets all quality attributes.

• Testing of in-process and final product cannot adequately assure drug quality.


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2011 Process Validation Guidance

• For purposes of this guidance, process validation is defined as the collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality product.

• Process validation involves a series of activities taking place over the lifecycle of the product and process. This guidance describes the process validation activities in three stages.

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Three Stages Process Validation

• Stage 1 – Process Design: The commercial process is defined during this stage based on knowledge gained through development and scale-up activities.

• Stage 2 – Process Qualification: During this stage, the process design is evaluated to determine if the process is capable of reproducible commercial manufacturing.

• Stage 3 – Continued Process Verification: Ongoing assurance is gained during routine production that the process remains in a state of control.


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Stage 1: Process Design

Objective: Design a process suitable for routine commercial manufacturing that can consistently deliver quality product:1. Building and capturing process knowledge and understanding, which

can include:– Early process development and small scale experiments

– Development of laboratory or pilot-scale models

– Design of Experiment (DOE) studies

– Risk analysis tools

– Computer simulations

2. Establishing a strategy for process control, which can include:– Process controls to reduce input variability and/or adjust for variability

during the manufacturing process

– Appropriate in-process monitoring and operational limits, especially for attributes that are not readily measured or characterized

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Stage 2: Process Performance Qualification (PPQ)

Objective: Evaluate the process design and determine if it is capable of reproducible commercial manufacture:a. Design of facilities and qualification of equipment

and utilities• to assure proper facility design and qualification prior to

PPQ

b. Process Performance Qualification (PPQ)• combines actual facility, utilities, qualified equipment,

and trained personnel with the manufacturing process, control procedures and components to produce commercial batches


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Stage 3 - Continued Process Verification

• Objective: Provide continual assurance that the process remains in a validated state for commercial manufacturing. Some related activities:– System in place to detect and characterize

variability, and determine root cause– Monitoring, assessing, and adjusting variability as

needed– Gathering data to improve/optimize manufacturing

process– Facility and equipment maintenance

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PPQ: NDA/ANDA vs BLA

• NDA/ANDA: – PPQ must be successfully completed before

commercial distribution of a drug product – Facilities must be ready for inspection at the time of

submission• BLA:

– Complete commercial scale PPQ studies prior to submission

– submit PPQ data in an application – Facilities must be ready for inspection at the time of

submission and manufacture the complete product during PLI/PAI within the review cycle


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What is a Biological Product?

Section 351 PHS Act,as amended by FDAMA

“Biological Product” – a “virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product, … applicable to the prevention, treatment, or cure of a disease or condition of human beings.”

*Biological Products are regulated by CBER and CDER

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“Specified” (definition from 21 CFR 601.2):

• Therapeutic recombinant DNA-derived products

• Monoclonal antibody products for in vivo use

• Therapeutic synthetic peptide products of 40 amino acids or less

• Therapeutic DNA plasmid products

• Specified biological products are regulated by CDER• Include biosimilar products regulated under BsUFA

What is a “specified” biologicalProduct?


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Unique Requirements for BLAs

• Product and facility must meet standards prior to license issuance (21 CFR 601.4)

• Complete commercial scale process validation studies and submit data in an application (2011 PV Guidance)

• Facility ready for inspection and is manufacturing the BLA product

• Provide production schedules for the complete product • 2-4 months after the submission

• No Type II DMFs for DS sites

Note: BLA combination products are regulated under 21 CFR 600s, 210/211, and 820

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Integration of Functions forBiotech Products

• CMC review and inspection responsibilities are shared between Office of Biotechnology Products (OBP) and Office of Process and Facilities (OPF)

• A team approach to review and inspection

• Enables a continuous process in regulatory review and inspection

• Allows for a better assessment of the firm’s process understanding and quality oversight


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Integrated Review and Inspection• Office of Biotech Products (OBP)

• Leads in the overall assessment for product quality:

• Approves manufacturing process and final specifications (except microbiology)

• Active participants on inspections

• Product specific elements, data verification, conformance to standards and commitments in the BLA or supplement

• Office of Process and Facilities (OPF)

• Leads in the overall assessment for CGMP compliance

• Leads the pre-license inspection team

• Responsible for evaluating CGMP compliance status of a firm and conformance and commitments in the BLA or supplement

• Leads in microbiology and facilities assessments of drug substance and drug product sections of applications and supplements

• Assess cross contamination controls

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Process Validation for Biotech Products

• Data for commercial scale PPQ batches

• Equipment cleaning validation

• Columns and membrane lifetime validation

• Sterilization validation

• In-process hold time validation

• Media fill for aseptic processing

• Filter validation

• Shipping validation

• Test method validation


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Assessment of Manufacturing Facility during a Pre-License Inspection

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Inspection Types

• Pre-License Inspection (PLI) - announced, generally required for approval of an original BLA – DS and DP Manufacturing and critical testing sites are subject to

inspection by CDER– Other associated establishments listed in the BLA are covered by

ORA investigators

• Pre-Approval Inspection (PAI) – announced, could be waived– Triggered by major changes as described in Prior Approval

Supplements involving changes that have a substantial potential to have an adverse effect on the identity, strength, quality and purity or potency of the product (21 CFR 601.12)

• Surveillance and Post-Approval Inspection – announced or unannounced– ORA with CDER product reviewer participation

• For Cause Inspection


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• To meet statutory obligation in the FD&C and PHS Acts

• To assess compliance with CGMPs and applicable sections of the 21CFR 600, 21CFR 210 and 211, and 21CFR 820, if applicable

• To verify compliance with commitments made in the BLA or Supplement

• Evaluate process consistency for safe, pure and potent products

Purposes of Pre-License/Pre-approval Inspections

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Regulatory Authority• 21 CFR 600.20– Inspectors

– Inspections by an officer of the FDA with special knowledge of the manufacturing methods and controls

• 21 CFR 600.21 –Time of Inspection

– Inspection conducted while the establishment is in operation and is manufacturing the complete product for which a biologics license is desired

• 21 CFR 601.20 – Biologics licenses; issuance and conditions

– Product examination - compliance with requirements

– Availability of product for examination and inspection during all phases of manufacture

– Inspection - compliance with requirements (establishment)

– One biologics license to cover all locations; each location subject to inspection by FDA

Note: FDA enforces laws enacted by Congress and issues regulations as authorized by Congress to implement its statutory authority. The regulations can create binding obligations and have the force of law.


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Objectives of Pre-ApprovalInspection Program

Compliance Program 7346.832

• Readiness for Commercial Manufacturing– Verify that the applicant has demonstrated ability to operate with

integrity and in compliance with CGMPs

• Conformance to Application– Assure adherence to application commitments

• Data Integrity Audit– Assure the authenticity and accuracy of data submitted in

applications

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Assessment of PV during PLIsStage 2

• Design and qualification of facilities, equipment and utilities – Conduct facility walkthrough

– Verify data for equipment qualification and PM

– Verify monitoring data for facilities and utilities

• Process Performance Qualification (PPQ)– Verify PPQ data and data for all commercial batches

– Observe at scale manufacturing process and testing


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Assessment of PV during PLIsStage 3

• Ongoing assurance is gained during routine production that the process remains in a state of control– Assessment of departures from the validated state

through deviations and investigations

– Effectiveness of corrective and preventive actions

– Overall state of control

– Audit of results from continued process monitoring

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Examples of BLA PLI 483 Observations


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Incomplete Process ValidationExample 1

• Application:

– PAS for the addition of two DS manufacturing suites (A and B) for product X.

• Observations:

– No process validation (PPQ) campaigns were performed in Suite B.

– Three PPQ runs were performed using only one cell culture campaign.

• Outcome:

– Application was CR’ed

– Additional PPQ runs were completed in resubmission

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Incomplete Process ValidationExample 2

• Application: – Original BLA using two DS manufacturing suites (X and Y) for

product A

• Observation:– No process validation (PPQ) campaigns were performed in Suite Y

• Outcome: – Application was amended to withdraw Suite Y

– BLA was then approved


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Inconsistent Manufacturing ProcessExample 1

• Application:

– Original BLA

• Observations:

– Three successful PPQ batches

– 40 additional batches were manufactured since the completion of the process validation batches

– Great than 50% post PPQ batches were rejected or terminated

• Outcome:

– A Withhold recommendation was entered and application was CR’ed

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Inconsistent Manufacturing ProcessExample 2

• Application:

– Original BLA

– PLI conducted at a CMO site

• Observations:

– Discrepancies between manufacturing process described in the application and batch records

• Manufacturing processes: manual vs. automatic operations

• IPC sampling procedures and locations

• Equipment qualification

• Outcome:

– Application was amended to correct errors.

– Additional studies were performed to provide data to support the application


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Examples of Facility 483 Observations

• Inadequate facility maintenance – Utility areas found in disrepair (corrosion, leaking pipes, diagrams

not updated after changes)

• Inadequate environmental monitoring

• Inadequate facility cleaning and pest control- Pests found in manufacturing areas - Facility not clean and well-maintained - No efficacy studies for sanitizing agents

• High bioburden counts for water used as final rinse for equipment cleaning

• No monitoring of process gases

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Examples of Equipment 483 Observations

• Deficient equipment qualification and requalification

– Numerous bioreactor runs were contaminated due to incorrect installation of components, valves, sampling devices, slope of condensate lines

– Bioburden and biofilm problems due to faulty drain design

• Inadequate validation of sterile hold time for bioreactors

• Ineffective schedules and procedures for preventive maintenance of equipment

– large number of production process deviations due to equipment failures

• Inadequate hold time validation

– Inadequate validation of dirty, clean, sterile hold times involving equipment, e.g., bioreactors, purification vessels, UF/DF membranes systems, formulated bulk drug substance storage vessels, etc.


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Examples of Aseptic Processing 483 Observations

• Inadequate smoke studies

– Missing set-up activities, dynamic conditions, interventions

• Inadequate media fill procedures

– Failure to simulate the entire aseptic operations, product contact equipment

– Missing vials

– Inadequate investigations of failed runs

• Inadequate environmental monitoring

– No EM for set-up activities

– Inadequate personnel monitoring

• Inadequate aseptic practices

– Excessive movements

– Inadequate glove disinfection

• Inadequate design and constriction of facility and equipment

– HEPA filter failures

– Inadequate validation of sterile hold time for product contact equipment

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Examples of Laboratory Controls 483 Observations

• Failure to maintain complete data derived from all testing

– incomplete, inaccurate or falsified laboratory records

– re-test samples without justification

– unauthorized “trial” runs prior to tests that were used in the reported test results.

• Failure to prevent unauthorized access and changes to data

– No audit trail function

– Shared password for analysts or under “system administrators”

– Electronic Records can not be saved and may potentially be changed prior to the completion of the test/run

• Failure to train employees on their particular operations and related CGMP practices

• Release tests for API and DP reported in the submission were not performed


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Summary

• Regulatory Requirements for BLAs– Submit commercial scale process validation data in the application– Availability of product for examination and inspection during all phases

of manufacture

• Regulatory review of biotech product submissions is an integrated process – involves quality assessments and establishment inspections to ensure

product quality– Performed by both reviewers/investigators from CDER

• Pre-License inspection is required for BLAs and supplements (for new facilities) – Evaluate product quality and observe manufacturing operations– Verify process validation data submitted in the BLA or supplement– Adherence to CGMPs

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Contacts:

Zhihao (Peter) Qiu, Ph.D.

DIA/OPF/OPQ/CDER/FDA

White Oak Building 51, Room 4304

10903 New Hampshire Ave.

Silver Spring, MD 20993

phone 301‐796‐6655

e‐mail: [email protected]


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Documents

FDA Perspective on Process Validation for Biotech Products · PDF fileISPE Process Validation Conference 12 –14 September 2017 Bethesda, MD 1 FDA Perspective on Process Validation