1Application of Quality Risk Management Principles during Review and Facility Inspections

Patricia F. Hughes, Ph.D.Team Leader

Biotech Manufacturing TeamDivision of Manufacturing and Product Quality

Office of ComplianceFDA-CDER

July 28, 2009WCBP CMC Strategy Forum, CASSS

ICH Q9

Quality Risk Management (QRM)

Definition as described in ICH Q9: A systematic process for the assessment, control,

communication, and review of risks to the quality of the drug product across the product lifecycle.

Risk is the combination of probability of occurrence of harm and the severity of that harm.

ICH Q9

QRM

Risk associated with quality must be managed to protect patients from harms. Quality must be maintained throughout product

lifecycle Quality attributes must remain consistent with those

used in clinical studies QRM involves the identification and control of

potential quality issues during development and manufacturing

ICH Q9

QRM

Two primary principles: The evaluation of the risk to quality should be based

on scientific knowledge and ultimately link to the protection of the patient; and

The level of effort, formality, and documentation of the QRM process should be commensurate with the level of risk

5Goal in Manufacturing

To establish commercially successful processes that are capable of producing consistently a high quality product with a high degree of assurance (low or no failures). Regulatory oversight is intended to ensure product

quality and is managed through Application approval process Establishment inspections (pre-approval and

CGMP)

6QRM: During Review

Reviewers use QRM principles to determine if the applicant has: Identified potential risks to product quality attributes or

process consistency Ensured appropriate controls are in place Demonstrated the effectiveness of the controls

through process validation at scale

7Role of the Biotech Manufacturing Team in the review of submissions and in pre-approval

inspections

BMT reviewers in OC/DMPQ conduct reviews of BLAs and supplements and lead pre-approval inspections.

Submissions are assessed from the following perspectives: Microbial control strategy during drug substance

manufacturing Sterility assurance for sterile drug product

manufacturing Microbial Product Quality Attributes

8Purpose of Pre-approval Inspections

Assess the CGMP compliance status of manufacturing facilities during the pre-license or pre-approval inspections Systems based approach

Assess that the products manufactured comply with the standards established in the BLA Verify information and data in the submission (BLA or

PAS) to the FDA (data integrity) Evaluate the capabilities of the manufacturing processes

to consistently produce products that are safe, pure and potent as established in the license application Assess in process controls

9QRM and Inspections

Degree of oversight on inspection depends on the several risk factors Overall compliance status and history of the company

or facility Results or previous audits/inspections

Complexity and novelty of the site, manufacturing process, product and its therapeutic significance

Previous recalls, product defects or manufacturing problems

Major changes of building, equipment, processes, key personnel

Experience with manufacturing of a product

10

Microbial Control in Biotech Product Manufacturing: Risks

Biotech processes are susceptible to microbial contamination because of the type of buffers, column resins, cell culture raw materials, cell culture /fermentation conditions, etc. Cell culture processes are susceptible to adventitious

viruses that can lead to cell death Bioburden resulting from microbial proliferation can

cause protein degradation, loss of potency, immunogenicity, protein heterogeneity, change impurity profiles and lead to inconsistent processes.

Bioburden can increase endotoxin levels Bioburden must be controlled in the pre-sterile filtration

step and not compromise the sterility assurance of the final drug product manufactured using in aseptic processing.

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Benefits of Risk Management of Microbial Control

Better control of the process and product quality Fewer batch deviations/investigations and possible

failures Better management of change control Regulatory relief

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Sources of Microorganisms

Raw Materials Cell culture and cell banking

Complex raw materials (serum, peptones) Purification

Reusable resins Reusable filters

Cell substrates Microbial contamination

Manufacturing Environment Water Air Personnel Equipment

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Mitigating Microbial Contamination Risks

Reduce opportunities for the ingress of microbial contaminants

Eliminate contaminants at critical step in the process Validate critical manufacturing steps to eliminate and

prevent ingress of adventitious agents.

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Examples of Purification Review Issues No microbial monitoring or inadequate monitoring during

manufacturing Unknown risks to the quality attributes of the product

Root cause failures in product stability cannot be assessed adequately

No established microbial limits during purification Microbial intermediates reported to contain high levels

of bioburden Risks to protein through microbial degradation Presence of uncontrolled impurities due to different

microorganisms that can effect the validated purification process

Effect on the stability of the product due to the presence of degradative microbial enzymes

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Examples of Purification Review Issues

Inadequate control of hold conditions for process intermediates Risks:

Increases in bioburden during hold time Unsupported hold conditions may lead to process

and intermediate quality variability

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Examples of Review Issues during Drug Product Manufacturing

Sterility Assurance of Drug Product Sterilization of components, containers and closures

Inadequate evidence sterility assurance Aseptic Processing

Three media fills not completed Inadequate bracketing worst-case not assessed

Stability Container closure integrity not adequately validated

Lack of controls Sensitivity of test method worst-case not simulated

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Facility: Key Control Elements

Design Environmental control Disinfection

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Raw Materials: Key Control Elements

Segregation, testing and pre-treatment of at-risk raw materials

Cell bank characterization, handling and storage

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Raw Materials

Raw materials from natural sources (peptones, soytones, yeast extracts, etc.) may be a source of bioburden, including viruses and mycoplasma May need to be handled in segregated/dedicated

areas and treated before use in manufacturing Culture media and media components should be

evaluated before use for the presence or absence of endogenous or adventitious agents.

Consideration should be given to pre-use treatment to reduce possibility of facility and process contamination (e.g., inactivation procedures such as sterilization, pasteurization, 0.1micron filtration, irradiation, etc.)

These materials should be kept to a minimum and have satisfactory documentation on the origin of material

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Equipment: Key Control Elements

Use of specialized equipment and surface finishes smooth and polished

Cleaning studies and validation to prevent carryover Sterilization/sanitization and inactivation of microbial

contaminants

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Process: Key Control Elements

Microbial and mammalian derived products Closed and open operations Segregation of pre-viral and post-viral operations Effectiveness of Cleaning, Sterilization, Sanitization, and

Inactivation steps

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Risks associated with products derived from different expression systems

Mammalian cell lines Carriers of viruses Expansion of viruses can occur in cell culture

Cross contamination with viruses from different cell lines inadequate inactivation, cleaning, sterilization, change

over procedures, etc. Susceptibility of many cell lines to contamination from

adventitious agents Cross contamination from raw materials, facility, equipment,

personnel Viral inactivation methods are specific for each process and are

used where terminal sterilization is not feasible Based on known and potential viral contaminants and load

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Risks associated with different expression systems

Microbial Endotoxins and other specific microbial derived

impurities may be of concern in multi-product manufacturing

The impurities are biochemical in nature Addressed with process design and cleaning

validation studies Mammalian viruses are not known to expand in

microbial cells. Risk of cross contamination of microbial cells with

mammalian viruses is not likely

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Viral Risks to Cell Culture Processes

Contamination of cell cultures processes by adventitious agents continues to be a major risk to the industry Firms will typically inform and meet with the FDA

when an establishment experiences a contamination by an adventitious virus

Events are devastating and can lead to drug shortages

Prolonged shut down of the facilities for decontamination

Important actions include Quality risk management

Risk assessment, control, communication, review

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Multi-product Manufacturing: Risk Assessment

Consider the ability of microorganisms to:

Ingress into a process through raw materials, facility, personnel, equipment, process

Survive and proliferate Produce microbial toxins/degradative enzymes

(proteases, etc.) Cross contaminate and carryover to other processes

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Recent 483 Observations

Inadequate QRM for the production process:

Multiple lots of drug substance were released which had unacceptably high levels of bioburden during the final purification steps.

In addition, bioburden limits have not been established for each step in the purification process.

Risks: Effect of impurities on the validated process Effect of microorganisms on the product Effects of microbial by products on the stability

of the product

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Recent 483 Observations

Inadequate QRM for the production process: Fermentation lots [xxxxx] contained two morphotypes

in the fermentation harvest cultures instead of a monoculture.

The root cause investigation for the appearance of the two morphotypes was inadequate.

Risks: Instability of the expression system may affect

process consistency Appearance of contaminating microorganisms

must be ruled out

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Recent 483 Observations

Inadequate QRM of the production process:

Hold times for four column eluates [column steps x, y, z] have not been adequately validated microbiologically.

No microbial limits are established Results show high bioburden levels (>1000

cfu/mL) Risks:

Effect of impurities on the validated process Effect of microorganisms on the product Effects of microbial by products on the stability

of the product

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Recent 483 Observations

There is no assurance that adequate microbial controls are in place during [drug substance] manufacturing. For example,

During the harvest of the unprocessed bulk, sublots of Lot xxxx (H9, H10, H11, H12, H13, H14) and Lot yyyyy (H7) exceeded the established action limits for bioburden.

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Risk Management of Microbial Controlduring Review and Inspections

Microbial control is fundamental to the manufacture of a quality product.

Product quality can only be assured if appropriate microbial risk management measures are in place: quality is built in the design of the facilities,

equipment, processes manufacturing and cleaning processes

raw materials are appropriately screened and selected based on microbial quality characteristics

appropriate analytical methods are in place to monitor and control and adjust a process.

Application of Quality Risk Management Principles during Review and Facility InspectionsQuality Risk Management (QRM)QRMQRMGoal in Manufacturing QRM: During ReviewRole of the Biotech Manufacturing Team in the review of submissions and in pre-approval inspectionsPurpose of Pre-approval InspectionsQRM and InspectionsMicrobial Control in Biotech Product Manufacturing: RisksBenefits of Risk Management of Microbial Control Sources of MicroorganismsMitigating Microbial Contamination RisksExamples of Purification Review IssuesExamples of Purification Review IssuesExamples of Review Issues during Drug Product ManufacturingFacility: Key Control ElementsRaw Materials: Key Control ElementsRaw MaterialsEquipment: Key Control ElementsProcess: Key Control ElementsRisks associated with products derived from different expression systemsRisks associated with different expression systemsViral Risks to Cell Culture ProcessesMulti-product Manufacturing: Risk Assessment Recent 483 ObservationsRecent 483 ObservationsRecent 483 ObservationsRecent 483 ObservationsRisk Management of Microbial Controlduring Review and Inspections