EO Batch Release Your Way to Full Validation

I have had several early-stage device company clients who are interested to get to “First In Man” (FIM) clinical use without breaking the bank. My job is to save the client enough money so they can pay my fee and have money left over for other things (like a great Christmas Party).

If device sterilization is a requirement, you do not need to perform a comprehensive (full) sterilization validation study before FIM. You can ensure adequate sterility assurance on a “batch release” basis, and save the time (and money) needed to perform a full validation.

 For ethylene oxide (EO) sterilization of devices with a “nonpyrogenic” label claim, the following sequence of tests and batch releases can be performed to achieve full validation status per ISO 11135-1.

0. Presterilization Bioburden Enumeration and Extraction Efficiency

1. Clinical Batch Release #1 (maximum load) – fractional cycle + full cycle

– inoculated device sterility testing for FIM-representative devices after fractional cycle

– candidate process challenge device (PCD) sterility testing after fractional cycle

– bioburden resistance testing for FIM-representative devices after fractional cycle

PCD sterility testing after exposure to full cycle only 

– EO residual testing for FIM-representative devices at 48 hours after end of full cycle aeration

– LAL endotoxin testing for FIM-representative devices after full cycle

– FIM human use devices exposed to fractional and full cycles

– Temperature and humidity probes monitor both cycles

Note: If all acceptance criteria are met, the FIM devices are acceptable for human use from a product sterility standpoint. Also, the PCD to be used for routine lot release going forward is selected.

  

2. Clinical Batch Release #2 (maximum load) – half cycle #1 + full cycle 

– PCD sterility testing after exposure to half cycle only

– PCD sterility testing after exposure to full cycle only 

– EO residual testing for FIM-representative devices at 24 hours after end of full cycle aeration

– LAL endotoxin testing for FIM-representative devices after full cycle

– FIM human use devices exposed to fractional and full cycles

Temperature and humidity probes monitor both cycles 

3. Clinical Batch Release #3 (maximum load) – half cycle #2 + full cycle

– PCD sterility testing after exposure to half cycle only

– PCD sterility testing after exposure to full cycle only

– EO residual testing for FIM-representative devices at 0 hours after end of full cycle aeration

– LAL endotoxin testing for FIM-representative devices after full cycle

– FIM human use devices exposed to fractional and full cycles

– Temperature and humidity probes monitor both cycles

At this point EO residuals testing can be discontinued if a dissipation curve can be created from the 0, 24 and 48 hour results that demonstrates acceptable levels of residuals per ISO 10993-7.

4. Clinical Batch Release #4 (maximum load) – half cycle #3 + full cycle

– PCD sterility testing after exposure to half cycle only

– PCD sterility testing after exposure to full cycle only

– LAL endotoxin testing for FIM-representative devices after full cycle

– FIM human use devices exposed to fractional and full cycles

– Temperature and humidity probes monitor both cycles

At this point, full validation status has been achieved for the maximum load!

Subsequent Batch Releases (maximum load) – full cycle only

– PCD sterility testing after exposure to full cycle only

– LAL endotoxin testing for FIM-representative devices after full cycle

– FIM human use devices exposed to full cycle

To validate a “minimum load”, another combined half cycle and full cycle is required with temperature and humidity probes. The acceptance criteria for the minimum load should be that the temperature and humidity profile should be equivalent or better than it was for the “maximum load”.  If the minimum load is judged to be a worse case (runs colder, larger ranges across the load, etc.) then 2 additional half/full cycle combinations must be performed before the minimum load cycle can be considered validated.

Quality Policy and Objectives

Does your organization’s Quality Policy inspire you, or tire you?

First, let’s review US FDA and ISO 13485 requirements and ISO 14969 guidance. After that, I am sharing my current “state of the art” model for a Quality Policy and corresponding Quality Objectives.

Quality Policy Definitions

ISO 9000:2005 – Overall intentions and direction of an organization related to quality as formally expressed by top management.

US FDA 21 CFR 820 – Quality policy means the overall intentions and direction of an organization with respect to quality, as established by management with executive responsibility.

US FDA 21 CFR 820.20 Management responsibility

(a) Quality policy. Management with executive responsibility shall establish its policy and objectives for, and commitment to, quality. Management with executive responsibility shall ensure that the quality policy is understood, implemented, and maintained at all levels of the organization.

ISO 13485, 5.3 Quality policy

Top management shall ensure that the quality policy

(a) is appropriate to the purpose of the organization,
(b) includes a commitment to comply with requirements and to maintain the effectiveness of the quality management system,
(c) provides a framework for establishing and reviewing quality objectives,
(d) is communicated and understood within the organization, and
(e) is reviewed for continuing suitability.

NOTE: ISO 9001:2008 has same requirements except (b) says: includes a commitment to comply with requirements and continually improve the effectiveness of the quality management system.

ISO 13485, 5.4.1 Quality objectives

Top management shall ensure that quality objectives, including those needed to meet requirements for product, are established at relevant functions and levels within the organization. The quality objectives shall be measurable and consistent with the quality policy.

ISO 13485, 5.4.2 Quality management system planning

Top management shall ensure that the planning of the quality management system is carried out in order to meet the requirements given in 4.1, as well as the quality objectives.

GUIDANCE – ISO 14969

The quality policy establishes

— a commitment to quality and the continuing effectiveness of the quality management system to meet customer and regulatory requirements,

— the context for quality objectives, and

— the relationship of the organization’s objectives to the customers’ requirements.

It is important that the organization’s quality policy be considered when preparing the overall organization policies related to its business operations (e.g., marketing, sales, finance) in order to ensure that all organization policies are consistent and supportive of each other.
The quality policy should communicate the organization’s commitment to quality and its overall vision of what quality means to the organization’s business and customers. In order to demonstrate that the organization is committed to implementing its quality policy, it will need to identify clear, overall quality goals for the business that are directly relevant to the organization and its customers.
Top management’s commitment to the quality policy should be visible, active, and effectively communicated. For example, a publicly displayed copy of the quality policy signed by top management is one method to show that commitment to both employees and customers. Another method is to present and discuss the quality policy at organization meetings throughout the year. Top management’s commitment is best communicated through its decisions and actions.
All employees need to understand the quality policy and how it affects them. Top management should ensure that the organization decides on the methods which will be used to achieve this understanding.
The quality policy also needs to be reviewed from time to time to determine if it accurately reflects the current quality related goals and objectives of the organization. This review is often carried out during the management review required in 5.6.

Are you still there? Here is what you have been waiting for:

Drum roll please…
Here is a draft Quality Policy that I typically suggest to new clients for consideration.

___________________________________________________________________

ACME MEDICAL, INC. QUALITY POLICY

Acme Medical is committed to providing innovative XYZ DEVICES that meet customer and regulatory requirements.

We maintain an effective quality system by managing product risk and executing objectives related to:

  1. Product development and improvement.
  2. Quality system planning and improvement.
  3. Supplier quality assurance.
  4. Personnel training and competence.
  5. Regulatory compliance and internal/external audits.
  6. Process effectiveness and efficiency.

____________________________________________________________________

I put the Quality Policy in the top-level Quality Manual document that I call “QSM1: Quality System Overview”.  My second Quality Manual document is “QSM2: QS Glossary”, and my third/last Quality Manual document is “QSM3: QS Objectives”.

The framework for the QS Objectives is established by the 6 headings in the Quality Policy. In the QS Objectives document (my QSM3), SMART objectives are listed under each heading.

I suggest re-casting the objectives annually and reporting accomplishments quarterly. In my opinion, the current-year objectives/accomplishments should always fit on one page. Don’t make this too complicated.

Nowadays, quality audits are not restricted to compliance. Compliance is the easy part; we need a quality management system that works, a system that is effective, and hopefully efficient too!

The QS Objectives should be the basis for assessing process effectiveness (and efficiency). They should be used by the process owners to guide them towards continual improvements. They are also used by quality auditors (internal/external) to evaluate process effectiveness.

# Current Quality Policy from Fortune 500 Medical Device Company
We will exceed our customers’ expectations by striving without reserve for unsurpassed product quality, reliability, and patient safety through effective, agile and compliant processes.
We will continuously improve our quality management systems, comply with all applicable regulatory requirements, and deliver excellence to customers through our products, processes, services, and relationships.”

ISO 13485:2016 Quality System Process Risk Management

ISO 13485:2016 has a broader view of risk management than in the past. Risks are to be considered in terms of the impact on medical device safety and performance, and in terms of meeting regulatory requirements. For managing quality system process risks, rather than adding a “Risk” section to each Standard Operating Procedure (SOP) as some have suggested, I added a new section to my Quality Manual to address risks for each quality system process, i.e. each SOP. The format of my new Quality Manual risk section is shown below. A row is included in the table for each SOP.

Since my Quality Manual already lists the SOPs, this makes sense to me. And by having all of the risk assessment and control information in this single document, it seems easier to manage than sprinkling risk assessment/control information into each SOP.  Here is how I show risk management in my Quality Manual process interaction diagram.

QSM1 Process Flow, 21 Lucid.png