Type V DMF Process Flow

Each project will follow validation life cycle

All internal

Semi-Internal/External

Facility, equipment, and instruments, technology

Type V DMF Process Flow

Approaching the black hole in 5 phases 07 APR 14

Type II DMF

Operation Phase

Establish and conduct routine monitoring procedures for:

Sampling

Specifications and OOS handling

Material cost per test X frequency

Investigation cost

Labor: time at PR, LC and QS levels X frequency

Failures and product cost

Testing

Development Phase

Material cost per test X frequency

Labor: time at PR, LC and QS levels X frequency

Validation Cycle

Define Quality Attributes

Development

Establish Preliminary Method, Procedures and Validation Protocol

Method Validation

Note book study yields preliminary data

Refine, finalize method, procedures and validation protocol

Validation

Execute, collect data, complete validation

Operation and Routine Monitoring

Long term

Change Control and Periodic Validation

VMF

Writing and Editing

II C: Validation

Micro Efficacy of Steam Sterilization

II C: Routine Monitoring of Micro for Steam Sterilized Article

Determine test procedure

Establish final test method and validation protocol

Determine test frequency

• Daily/weekly/Monthly/Semi-annually with Steam Sterilization validation

Execution of validation

Assessment of non-confirming data and its impact on steam sterilization process, validation, product disposition (more frequent test will lower the product risk, increase cost)

Compile Organize Data

Review and Editing

Validation Report, assessment of organisms recovered comparing to Steam Sterilization organism

Time and labor

• Internal
• External

• QS working with LC
• Summarize each project

Write VMF

II A: Description of Process and Product

Time and labor

• Internal
• External

II D2: Routine Monitoring of Micro WFI

Hard to put a $

Determine test procedure

Determine test frequency

• Weekly $100 per week=$20/day

II B: Thermo Qualification of cycles

Assessment of non-confirming data and its impact on steam sterilization process, validation, product disposition (more frequent test will lower the product risk, increase cost)

-Detection of leaking valve, put 3 weeks of product in quarantine

-Investigation

II D2: EM WFI Bioburden

1.2 years $29,600

II C: Develop Micro Efficacy of Sterilization Cycle

Establish final test method and validation protocol

Level V 30 hours

Level VI 8 hours = $1600

Define Attributes

Execution of validation

• Time - All internal

- Semi internal

- All external

• Resource - All internal

- Semi internal

- All external

$100 per day X 5 X 52 weeks = $26000

-Determine attributes based on regulatory & industry knowledge, manufacturing process, form validation parameters

Preliminary Method & Procedure selection

II G: Sterility testing methods and release criteria

Validation Report

Level V 40 hr, level VI 8 hr = $2000

• Time - All internal

- Semi internal

- All external

• Resource - All internal

- Semi internal

- All external

1 month

-Method selection, example, TSA, SDA, R2A plate count or swab Technique. Develop sampling and testing method, possible validation for recovery rate for organism recovery and quantity recovery, could be a combination of many, elect method(s) for notebook study

Note Book Study

• Time - All internal

- Semi internal

- All external

• Resource - All internal

- Semi internal

- All external

• Material and equipment instrument requirement

Set time period, carry out of validation with method selected. Determine whether using method selected will acceptable result.

-If not, identify root cause, propose corrective actions.

-If validation success can be assured, proceed to validation

III B 2:

Packaging of the Product

II F: Endotoxin Test and Method

II D2: Mirco EM, WFI Bioburden

9 months $18,500

Define Attributes

-Determine attributes based on regulatory & industry knowledge, manufacturing process, form validation parameters

• Time - All internal

- Semi internal 1 month

- All external

• Resource - All internal

- Semi internal -LC Level III 20hr, Level VI 10 hr $1000- $150 from EPC

- All external

Order a book $150

Preliminary Method & Procedure selection

• Time - All internal 3 month

- Semi internal

- All external

• Resource - All internal -LC level III 60hr, Level VI 20 hr $2500

- Semi internal

- All external

-Method selection, membrane filteration. Develop sampling and testing method, possible validation for recovery rate for organism recovery and quantity recovery, could be a combination of many, elect method(s) for notebook study

Note Book Study

Planning Phase

• Time - All internal level III 2.5 hr per day, three months = $7760

- Semi internal

- All external

• Resource - All internal

- Semi internal

- All external

• Material and equipment instrument requirement -new pump $2300

-test supply $36 per day = $4860

Set time period, carry out of validation with method selected. Determine whether using method selected will acceptable result.

-If not, identify root cause, propose corrective actions.

-If validation success can be assured, proceed to validation

Form a general plan to determine

Decision we make here will significantly impact all the following steps

Resource

Project Identification

$$$$ Prior and post submission

• Identify and understand the requirements of items in VMF

II D1: Bioburden of Bulk

Need to have an over all understanding of needs

Micro rapid test?

• Identify various current stage of items covered in VMF

To reduce/eliminate challenges and gaps may face when DMF is reviewed by FDA

-A firm instead of an individual

-Needs detail understanding of requirements

-Long term commitment

-Help in planning assessment, the earlier the better

-Method selection

-Review before and after critical steps

-Compile/review DMF, content and format, submission

LC Tech

QS/Regulatory Support

Microbiologist

-Has some GMP understanding

Internal -Existing

-New staff

External - Consultant

- Contract labs

• Formulate the course of mitigation

Human

Based on above

new/change in facility equipment,

human - time and rate

Accumulation of overall work scope

$$$

Time

From the start to finish

III B # : Radiation dose map

Take longer

Learning curve

Assurance of successful submission is lot

May not be $ saving after all

Maybe the best option

• utilize internal and external expertise
• give flexibility, control,
• Retain knowledge
• Team collaboration

Team on site

Significant cost

NTI still have to make hard decisions

Not very practical - space, retention of knowledge, less control

May or may not save significant time

All external

II E: Container-Closure Packaging Integrity

VMF Submission

III B 4: Radiation Microbial Methods and controls

III B 1: Radiation Process

FDA Review Time

Regulatory Fees

Type II DMV

A parallel path to the black hole

III B 5: Sterile Article Expiration date