Validation Deviations

Validation deviations are just a part of life when you are working through validation protocols and test scripts; it’s highly unlikely that you will ever complete a full validation project without raising the odd validation deviation here and there.

So what is a Deviation or Exception?

It’s quite simple it’s an error or a failure which occurs during Verification of Validation.
Types of Deviations

There are three main types of deviations that can occur during a validation project they are:

    Critical
    Non-critical
    Simple

Simple Deviations

Simple deviations are usually classified as documentation or protocol errors, these errors are usually found prior to execution or are “obvious” errors or typos. These deviations have no impact on the validation and offer to real risk to the validation process.

Examples of simple deviations include:

    Wrong test selected for product
    Incorrect specification for product
    Loss of power to the equipment being tested

Non Critical Deviations

Non-critical deviations are errors in the protocol or execution of the validation which have no impact on the validation, there errors are normally found during or after the execution. It is good practice to carry out an assessment to determine if the deviation has any impact. There is no real need to document the risk or lack thereof.

Examples of non-critical exceptions include:

    Operator not trained to perform the operation
    An interruption in the computer system or the equipment’s performance

Critical Deviations

Critical deviations are errors which have an impact on the validation, these errors are found during or after execution. It is good practice in this scenario to carry out an assessment to determine the impact if any.

Examples of critical exceptions include:

    Acceptance criterion failure
    An interruption in the computer system or the equipment’s performance

Deviation Process Flow

SME involvement throughout the deviation process is critical. You cannot document enough, even if all of it does not make it into the final event write up. A CAPA may not be needed for simple events, but consider a CAPA if there are many of them or the same ones repeatedly.

General Process Considerations

It is advisable to commence with the resolution process as soon as the event is observed. Involve the SME’s/QA throughout the process as appropriate and get agreement on next steps and/or results prior to execution, or after the completion. Immediately notify the relevant SME/QA if there is any potential Product/Material impact. Conduct a risk assessment to determine the impact and actions to be taken.
Types of Deviations

Typographical errors
These errors are found prior to execution or are “obvious” errors or typos.

External Issues
Failures caused by factors external to the process or system under test.

Execution Errors
Failures to follow instructions within the Test Document or referenced procedures.

Document Generation Errors
Incorrect detail in procedures, acceptance criteria or referenced documentation.

Acceptance Criteria Failures
Pre-defined acceptance criteria have not been achieved.

Things To Consider When It Comes To Qualifying Autoclaves

Autoclave Validation / Qualification is mandatory for all machines used for biological sterilization, in the biomedical and pharmaceutical industries. Sterilization can be accomplished by either physical or chemical means. The principal physical means is autoclaving; other physical methods include boiling and dry heat.

Chemicals used for sterilization include the gases ethylene oxide and formaldehyde, and liquids such asglutaraldehyde . Of all these sterilants, autoclaving is the fastest and most reliable, which is why the regulators always scrutinize autoclave validation / Qualification activities.

Here are 10 items to consider when qualifying autoclaves.
1. Testing of Steam for Porous Product Sterilization

Before commencing temperature testing the correct conditions must be satisfied. The first condition for sterilization of porous product is saturated steam quality. The ideal for steam sterilization is dry saturated steam and entrained water (dryness fraction ≥ 97%). The largest heat transfer occurs when the steam is at boundary conditions. If the steam is dry or contains gas then it cannot condense and its effectiveness is reduced.
2. Equipment Used for Testing

The equipment used must support 21 CFR Part 11 and must be of adequate accuracy. Testing with equipment that is not appropriate can be a major problem so also buy from a trusted vendor. As a small temperature range is required for accuracy (A few degrees) the accuracy of the equipment is very important for the overall measuring chain.
3. System Description of Autoclave

The first impression is very important when the qualification of critical equipment such as an autoclave is at stake. A good description of the system in a protocol shows that you understand how the process works and which critical points you need to keep under control. This description must contain the programs that are used, how they work, how many, where the control probes are located and what regulates this process.
4. Operating Instructions, Calibration and Maintenance

Before the temperature is tested it must be checked whether the operating instruction are valid, whether the instruments are calibrated and what was changed in the system since the last qualification occurred.

Operating Instructions must include parameters of sterilization, the scheme item and position of the control probes in the chamber. The emphasis is on the calibration of instruments because small errors in temperature can affect the Fo value to a great extent.
5. Procedure

One of the most common mistakes is inaccurate testing procedures. The test procedure must be unambiguous and accurate and must not leave the possibility for different interpretations.

Ambiguous: Put the thermocouple in a glass bottle.

Unambiguous: Put the thermocouple in a glass bottle at the contact between the bottom of the bottle and the side of the bottle (This is the most critical place to collect condensate).
6. Load

The most common objections are about loads. That they are not sufficiently described and that regular production does not reflect the qualified load being used.

This can be avoided by item photographing and releasing the same patterns in the protocol and work instructions. This will avoid the arbitrary interpretation of descriptive configuration.

Although sometimes this may seem trite the differences in the temperature profiles of the solution and air filters can be great. Pay special attention to the worst case loads and explain the rationale (mostly filter and silicone hose).
7. The Position of the Thermocouples

The position of the thermocouples must be unambiguous and precise to avoid different interpretations by individuals that perform tests or inspections. You do not want to enter into a debate about where the thermocouple is positioned.

Of course, the critical areas must be covered, and this must be explained in the rationale. When sterilizing liquid loads studies must be done to define coldest and warmest point for min and max load.
8. Acceptance Criteria in the Heat Penetration Tests

Since there are differences in the standards (e.g. PDA Technical Report and EN 285) it would be best if all eligibility criteria are taken into account. Special emphasis should be on equilibration time and temperature because it is a requirement for a good Fo.
9. Deviations

Deviations cannot be forgotten as they may be encountered regularly throughout the qualification process. A robust deviation management process should exist as they may impact the quality of the product. Good handling of deviations help us to improve our qualification, though they are often viewed negatively and not as a mechanism for process improvement.
10. Reports

The report should be accurate as it eliminates the use of data from the protocol and the ability to find errors in them. The report should contain the time and the date of tests, parameters, results related to temperature, BI results , positions of thermocouples, Fo and comparison of results from initial and previous qualification in order to see in which direction the process is moving.
Zeljko Joksimovic
Senior Expert Associate for Validation

Tips On How To Investigate Laboratory & Manfacturing Sterility Failures

Sterility can be defined as the freedom from the presence of viable microorganisms. However, the conditions that guarantee absolute sterility are usually too harsh for active ingredients, and the definition of sterility for a medicinal product must be defined in functional terms.

What do you do when you encounter a sterility failure?

It depends on your perspective!

If you are a Lab Technician you get worried and cry……….if you are a Lab Manager you get furious and try to find out who messed up………if you are QA you reject the batch…………….and if you are part of the manufacturing unit you reject the batch.
How can you settle all these concerns methodically?

The problem can be solved by conducting root cause of the failure.

Investigate:

    What went wrong?
    Where did it go wrong?
    What went wrong?
    How did it go wrong?
    How can it go wrong?
    What & who all are involved?

Investigate the Procedure
The investigation shall be done by a team of professional experts based on company specific written procedures and SOP’s.

Conduct based on Risk
Sterility Failure investigation shall be conducted on a System based Approach.
Laboratory System Investigations

Culture Media

    Media Preparation Details (in-house / ready to use / dehydrated media)
    Negative controls results (passes / fails)
    Growth promotion test results (passes / fails)

Sterilizer & Sterilization

    Media sterilization details
    Sterilizer filter Integrity testing records
    Sterilizer Qualification Reports – any cold spots?

Test Procedure

    Test Procedure / SOP
    Sterilizer filter Integrity testing records
    Analytical manipulations done during testing : Reconstitution / Mixing of the Product

Test Equipment

    Open Sterility Equipments -Requires independent Sterilization and assembly
    Closed Sterility Equipments- Ready to use containers

Test Samples

    Sample Transportation and Handling Procedures
    Records of Sanitization / Decontamination of the sample surface

Analyst

    Qualified
    Training Records
    Self Assessment During Stress Conditions
Environmental Monitoring

    Trend Analysis: Recent Out of Trend data
    Comparison of the recovered organism with that of data bank
    Identification of the organism to species level
    Any typical or atypical organism observed
Cleaning & Disinfection

    Records of preparation of the solution
    Filter integrity testing records
    Reports of disinfection agent effectiveness on the recovered organism



Test Environment

    Sterility Performed in a Uni-Directional Air Flow unit in a classified cleanroom
    Investigate reports for : Preventive maintenence , Air velocity, differential pressure, leak rates , sanitization cycles, cleaning records
    Sterility Performed in an Isolator

Top Tips for Pharmaceutical Automation and Validation

Automation is generally considered as a risky subject because of the specialized and technical nature of work. If there is no understanding of how automation is made and designed, it will be very uncompromising to develop an automation system validation strategy. Several studies of software projects have recorded success rates of less than thirty percent, where it was measured based on the schedule, meeting cost estimates, and satisfying requirements.

There are many ways to do automation projects poorly, but just a few ways to do them correctly. The availability of enhanced software tools and techniques makes it visible and testable for the application to the mainstream of the project. This article focuses on new practices and tools to reduce the complexity of the process.
Structure of Automation Projects

Pharmaceutical automation is tough, but when successful, it is very rewarding.

This is the formula for success:

    Meeting schedule milestone and cost estimates;
    Sustaining automation requirements and quality standards;
    Make automation system work right away;
    Satisfying the owners of the business or facilities.

Since, the automated systems will be integrated to the production equipment; this can greatly affect operations, maintenance, profitability, and safety of the finished production facility.

The pharmaceutical industry is regulated by the U.S. Food and Drug Administration (FDA) and the international Ministry of Health. These regulations apply to the manufacturing of drugs and medical devices including the use of computers to manufacture these products.

Since then, the industry’s automation professionals have developed the business processes to support a cradle to grave, life-cycle approach to automation. The industry has had a lot of opportunity over the years to apply business processes to support the delivery of automation.
Beating the Odds

Improve your chances of success with planning, requirements, testing, and documentation. In pharmaceutical automation projects, define and fix your requirements. Have a robust plan, attain management support, and keep the discipline to execute the plan.

There should be organization, consistency, and coordination all throughout the project. Tasks and requirements should be well-defined in the different phases such as design/review, procurement/delivery, and commissioning. Documents are software’s deliverables and these should be specified and given proper resources.

Existing organizations involve in the project such as QA, engineering, maintenance, validation, regulatory affairs and production committees, should be made aware of the scope of their functions and responsibilities. In the later part of the article, we will discuss in detail some techniques and pointers to have a smooth implementation flow.
Conditions Encountered In Project Management

Design specifications should be detailed and complete. Project managers should work hard to complete all information needed. A structured approach that begins with a plan can increase your odds of success. An automation validation master plan defines at a high level the expectations for quality, requirements, testing, documentation, review, and approval. It would also cover expectations for security, change control, maintenance strategy, contingency planning, and periodic reviews.

Since manufacturing facilities are very complicated, design policies should be clearly established recognizing the interest of various stakeholders to attain balance for an efficient operation. The other main part of the plan is to get it approved by the business leaders. In the preliminary planning of a proposed automation upgrade project, controlling cost was identified as the primary issue with getting approval.

For example, the automation team will probably be asked to significantly reduce the estimated cost for the proposed project.  If you have a robust plan, obtain management support, and maintain the discipline to execute the plan, you can achieve your targets. Define the requirements before you start the design, and get the key stakeholders to agree to them. Communicate broadly and keep the requirements fixed during the course of the project design, implementation, and through start-up.
Control Strategy

Along the way, changes cannot be avoided and they would affect the project design, costs, and schedule. A well-established and effective control process is very important. To maximize control, define and fix your requirement.

Accurately define the automation project requirements with the help of the users of the automation system. They should be measurable and testable identifying the industry, tools, and development needs.
Testing

Tests should show the expected functionality of the equipment. Comprehensive and quantitative tests should be created in accordance with the actual specifications to achieve their purpose. The success of testing depends, in part, on good requirements. If a process automation professional has solid and fixed requirements, it would be a lot easier. Inappropriate testing will increase cost and extend the development time. Testing reduces start-up issues.

If a developer does too little testing during the development process, there will be mistakes in the process control application code. The software will then have to be fixed later in the development process or during start-up of the manufacturing equipment in the facility. The sooner a designer catches a mistake, the cheaper it is to fix. Appropriate testing can reduce overall project cost and reduce rework during start-up.
Author

Mark Richardson
IT Quality Specialist
Premier Infrastructure

Disinfectant Testing and Validation

A controlled manufacturing cleanroom environment requires a sound disinfectant testing program. Disinfectants utilized in routine cleaning must be validated to confirm their effectiveness for use. Proper rotation of the disinfectants can be determined based on the data collected in this study.
Why should I choose Microtest Laboratories to perform my disinfectant validation study?

• Microtest is a high-quality laboratory that has been performing microbiological work for more than 25 years.
• Our specialized microbiology group possesses years of experience performing qualification work on many different surface types using a wide range of disinfectants.
• Microtest has an internal collection of ATCC organisms ready for use onsite, plus the ability to identify and cryopreserve client environmental isolates.

How do I know which method to follow for my disinfectant testing study?
Tube Dilution Method

• For clients with new facilities with little or no environmental trending history.
• Utilizes ATCC strains and some environmental isolates, where applicable.
• Isolates are directly inoculated into the desired concentration of disinfectant being tested.
• Studies of this sort allow a facility to begin production with some assurance that their disinfectants can kill specific microorganisms of concern.
• Initial screening of disinfectants does not validate that they are effective on hard surfaces.

Coupon Testing Using the Swab Recovery Method

• For established facilities with environmental programs and trending.
• Coupons are prepared from the actual surfaces present in the client's clean room environment.
• The disinfectants are sprayed on the surfaces using the method and contact time that are captured in the client's cleaning procedures.
• To ensure implementation of a proper disinfection program, the FDA recommends the use of the facility's environmental isolates. However ATCC organisms may be used as well.

Microtest can create a proposal for your disinfectant validation study with the following information:

• Quantity of surface materials found in your facility
• Quantity of environmental isolates/ATCC strains to be utilized in study
• Quantity of disinfectants to be challenged against in study
• Quantity of time-points to be challenged in the study (time disinfectant sits on a given surface)