What is FMEA and How to Use it

Failure Modes and Effects Analysis is the subject of an international standard, IEC 60812-Analysis techniques for system reliability-Procedure for failure mode and effects analysis (FMEA)

The only international standard that applies for FMEA is IEC 60812, which shows general application, but does not show the use of the tool in risk management.An extension to the FMEA allows analysis of the criticality of a failure, such an analysis is called FMECA or Failure Mode and Effects Criticality Analysis

Most medical device companies use FMECA, although they incorrectly label it as “FMEA”

Failure Modes and Effects Analysis was developed as a tool to explore the effects of failure of components on the reliability of various products.The tool was developed as a tool for use in the field of reliability engineering to explore where more rugged components would be required to obtain desired product life

The title of the standard, Analysis techniques for system reliability-Procedure for failure modes and effects analysis (FMEA), reflects its correct use

Use of FMEA
As an input to the Risk Management process FMEA should be used to:

Solvency II

Solvency II is a new, stronger EU-wide requirement on capital adequacy and risk management for insurers with the aim of increasing protection for policyholders. The strengthened regime should reduce the possibility of consumer loss or market disruption in insurance.

Solvency I was a minimum harmonization directive introduced in the early 1970s. It allowed for differences to emerge in the way that insurance regulation was applied across Europe leading to different regimes. It was also primarily focused on the prudential standards for insurers and did not include requirements for risk management and governance within firms.

Solvency II aims to achieve consistency across Europe on the key ideas of:

• Market consistent balance sheets;
• Risk-based capital;
• Own risk and solvency assessment (ORSA);
• Senior management accountability; and
• Supervisory assessment.

The Solvency II Directive states that the new regime will go live on 1 November 2012 when it will replace the Solvency I requirements and the current regulatory regime for insurance supervision for firms in the UK. The European Commission’s (EC) proposals for the Omnibus II Directive include an amendment to the implementation date by two months to 1 January 2013.

The new regime will apply to all insurance firms with gross premium income exceeding €5m or gross technical provisions in excess of €25m. Some insurance firms will be out of scope depending on the amount of premiums they write, the value of technical provision or the type of business written.

Solvency II principles and rules apply to Lloyd’s of London syndicates in full. Due to its specific nature, some of the Solvency II requirements are being considered for their application to Lloyd’s.

European process

Solvency II is being created with a four-level process or the ‘Lamfalussy processes

Process validation process

Following processes to be validated are

– Aseptic filling processes
– Sterilization processes
– Clean room ambient conditions
– Sterile packaging sealing processes
– Lyophilization process
– Heat treating processes
– Plating processes
– Plastic injection molding processes
– Routine end-product tests have insufficient sensitivity to verify the desired safety and efficacy of the finished devices
– Clinical or destructive testing would be required to show that the manufacturing process has produced the desired result or product
– Routine end-product tests do not reveal all variations in safety and efficacy that may occur in the finished devices
– The process capability is unknown, or it is suspected that the process is barely capable of meeting the device specifications

Process Validation steps

1. Determine the need to validate
2. Determine what to validate (IQ, OQ, or PQ)
3. Write a validation protocol
4. Conduct the protocol and collect the data
5. Analyze the data
6. Improve the process, as warranted, based on the data and analysis
7. Prepare a report
8. Maintain the documentation as a quality record

Types of Process Validation

Prospective
– Validation conducted prior to the distribution of either a new product, or product made under a revised manufacturing process, where the revisions may affect the product's characteristics.

There are three phases of prospective
validation:
– Installation qualification (Process equipment consistently operates within established limits and tolerances)
– Process performance qualification (The process is effective and reproducible)
– Product performance qualification (The finished product produced by a specified process meets all release requirements for functionality and safety)

Concurrent
– A subset of prospective validation conducted with the intention of ultimately distributing product manufactured during the validation study

Retrospective
– Validation of a process for a product already in distribution based upon accumulated production, testing and control data


In this validation there is an assumption, typically unmet, of complete records
– Customer complaints not investigated
– Investigations without adequate corrective action
– Scrap and rework not fully documented
– Inadequate process variability records

Sponser Meeting with FDA some facts

There are many meetings which a sponser can have with FDA related to the product being developed and to be approved by FDA. But it can be categorized in to 3 base categories.

Type A: Critical Path (Urgent) meetings – Clinical hold, Safety Issues, Site disqualification, etc (within 30 days)
Type B: Procedural meetings – Pre-IND meeting, EOP2, pre-NDA, etc (within 60 days)
Type C: Miscellaneous meetings – CMC issues, mid-P3, early-review, mid-review, etc ( within 75 days)
Formal meetings are not the only way you communicate with the FDA: comment requests, emails, telecons with the RPMs, etc.

Why meeting FDA?

- Sponsors have the right to request a meeting with the FDA review division
- These meetings are specifically to help prescription drug approvals
–Not granted if FDA perceives that an IND is not being planned
–More for issue resolution while product development than scientific rationale
–Clarification and discussion, not “interrogation”
- Pre-submission meetings (pre-IND, EOP2, pre-NDA) meetings are considered critical by FDA compared to mid-cycle meetings (mid-P3, mid-review, etc)

Time for meeting
1. Developed “final product” idea
–Finished formulation
–Target indication(s) and population(s)
2. CMC information
–Characterization
–Manufacturing and packaging (cGMP)
–Stability studies
3. Basic non-clinical studies (GLP)
–Acute and sub-acute toxicology
–Pharmacology
–In vitro toxicity tests
4. Ready to initiate clinical studies
5. Have sufficient GMP level investigational product
6. The pre-clinical studies demonstrate MTD, NOAEL, major expected adverse events
7. Scientific rationale for mechanism of action is available
8. Clinical development plan is proposed