Sunday, May 31, 2009

Outsourcing stability services

Outsourcing stability services can provide a competitive advantage to pharmaceutical companies of all sizes by improving a product’s speed to market. Handling stability programs is often extremely time-consuming work involving a number of responsibilities, including initiating and maintaining stability studies, tracking pull dates, testing the samples and reporting the results.

Outsourcing stability testing allows large pharmaceutical companies to turn to stability contract labs for their expertise in handling stability programs, with benefits that include cost savings as well as rapid and efficient generation of stability results. Outsourcing thereby enables these pharmaceutical companies to focus internal resources on core competencies and new drug development. Smaller pharmaceutical and biotechnology companies can benefit from outsourcing because it eliminates the need for large capital expenditures on analytical equipment and stability chambers or rooms. In addition, these companies can rely on contract stability labs for their knowledge and analytical resources and for data generation, interpretation and reporting.

How can a pharmaceutical company be sure that it’s choosing the right lab to perform stability testing? What should a company look for when it outsources? Let’s explore some guidelines for choosing the best outsourcer for your company’s stability-testing needs.

Investigation and Audit
When searching for the right stability contract lab, it’s important to carefully evaluate the company you plan to entrust with your product. The following are some critical considerations:

• How long has the company been in business?
• Is the company financially stable and able to serve you over the long term?
• How much experience does the lab have with your particular dosage form?
• Does the company have scientific expertise?
• Does it have adequate equipment and capabilities?
• Is the company committed to outsourcing?
• Does the company have a strong service record?
• Is the company responsive and flexible?
• Is the company GMP/GLP compliant?

Computerized monitoring system

There are many ways to find answers to these questions. Meeting with the contract lab’s sales team and taking a tour of the facility will allow you to see the company’s operations first hand and give you an opportunity to ask questions. Many labs also have web sites, annual reports and financial presentations where more detailed information can be obtained. The Internet, trade magazines and other publications are also extremely useful tools for comparing contract labs and to help determine their capabilities and the dosage forms to which their expertise is most suited. Also, word-of-mouth and referrals from those who have worked with specific contract labs can help confirm your decision.

While consideration of these important factors will provide information about the company as a whole, you must also evaluate the outsourcer’s operating procedures specific to its stability services. There are a number of factors to consider when evaluating a contract lab’s stability services, as outlined below.

Responsiveness to Regulations
When regulatory guidelines are revised, contract labs must be flexible enough to accommodate the changes. Recently, the International Conference on Harmonisation (ICH) regulatory guideline QIA was revised (R2) when QIF “Stability Data Package for Registration Applications in Climatic Zones III and IV” was incorporated. The main changes included:

1) Adjustment of intermediate storage conditions (previously 30°C ± 2°/60% RH ± 5%); acceptable relative humidity was changed to 65% ± 5% for drug substances, drug products and drug products packaged in semi-permeable containers.
2) 30°C ± 2°/65% RH ± 5% can be used for long-term storage instead of 25°C ± 2°/60% RH ± 5% for drug substances and products.
3) 30°C ± 2°/35% RH ± 5% can be used for long-term storage instead of 25°C ± 2°/40% RH ± 5% for drug products packaged in semi-permeable containers.

A knowledgeable contract lab can help you determine the best course of action for incorporating the revised guidelines into your stability program. One point about the revised guidelines to keep in mind: if 30°C/65% RH is used as a long-term storage condition (item 2 above) rather than as an intermediate storage condition, then, if samples at the accelerated storage condition (40°C/75% RH) fail specifications, you won’t have any backup samples at an intermediate storage condition to test if required. Consequently, using 30°C/ 65% RH as an intermediate storage condition and keeping 25°C/60% RH as a long-term storage condition may be a more conservative choice. However, this can always be discussed with the contract lab’s stability team.

These changes will have a significant impact on contract labs storing stability samples. Contract labs should have the ability to accommodate new conditions, as well as maintain the old conditions for clients that still require them. Accommodating these various requirements means more capital expenditures for the contract lab, since more storage space will be needed. This underscores the need for assessing a lab’s current and future stability storage space.

Does the lab have room to expand its stability areas, and can it accommodate changes quickly to meet its clients’ needs? Is the contract lab you are evaluating working with clients to ensure that all the new changes have been addressed? Does the contract lab communicate efficiently and effectively with clients? You need to know the answers to these questions before you proceed.

Reach-in stability chambers

Effective Stability Sample Tracking
Managing thousands of stability samples and timelines requires a solid stability-sample tracking system to ensure that all samples are handled appropriately. Before samples are placed into the stability chambers, they should be labeled with information such as the product name, product code, lot number, quantity enclosed, date of manufacture and storage conditions. Properly identifying each sample is essential to prevent confusion when pulling stability samples from the chambers.

Reliable stability software can also make a significant difference when tracking pull dates and sample locations and quantities. When using either off-the-shelf or customized sample-tracking software applications, it is important to comply with FDA regulations for audit trails and security compliance in order to meet inspection regulations. Auditors today are increasingly concerned with the integrity and security of stability software, preferring programs that comply with regulatory guidelines.

You should also investigate a contract lab’s procedures for submitting samples for stability testing. Contract labs should also have a system in place to track the flow of all samples placed into or removed from each stability storage location. This will help document small spikes in temperature and humidity due to opening the stability chamber or room doors.

Overall, a reliable stability-sample tracking system is critical. Does the contract lab you’re evaluating have an effective and reliable system?

Effective Stability Protocols
To obtain a clear picture of how to handle each study, a contract lab should establish a detailed stability protocol for each project. This protocol specifies all information needed to conduct the stability study and testing in accordance with each client’s needs. It should include the client name; product information (including product codes/lot numbers and packaging information); a list of tests, test methods and acceptance criteria; and detailed information about sample storage conditions. In addition, the times when samples are to be pulled should be clearly stated, as should the number of samples to be pulled per interval. Information on storage and testing sites, company-specific tolerance for pull dates and references to standard stability operating procedures should also be included.

Because contract labs deal with many different products, each of which could have different regulatory requirements for stability, it is important that the lab be aware of specific regulatory guidelines for a range of dosage forms and packaging configurations (e.g., HDPE bottles vs. semi-permeable membranes). Nasal sprays, for example, require a number of pump functionality tests, such as spray content uniformity, spray pattern and droplet size distribution. Also, depending on the dosage form, samples may be placed in stability in different orientations, such as inverted and upright or horizontal and upright. The stability samples should also be labeled with the sample orientation if more than one orientation exists. Therefore, it is important to specify the orientation of the samples in the protocol and on the pull schedules.

Establishing an effective protocol will help ensure that each study runs smoothly. Both the contract lab and the sponsor should approve the protocol to ensure agreement on all the details of the stability study. If changes to stability protocols need to be made, they should be controlled via a defined process established by the contract lab. This ensures that all versions of the stability protocol will be tracked with a detailed history of the changes. Does the contract lab in question use established and effective protocols?

Ability To Transfer Client Methods
Before any stability testing can be performed, the contract lab must have working test methods. Validated client methods can be transferred to the lab in two ways: via Inter-Lab Qualifications or through Method Transfers. Inter-Lab Qualifications are performed if the pharmaceutical company has an analytical lab. The pharmaceutical company and contract lab simultaneously test a specific lot
of samples using the same method, and then compare results. The contract lab is then evaluated based on the pharmaceutical company’s acceptance criteria.

When a pharmaceutical company does not have a lab or its lab is committed to other uses, Method Transfers are performed. For an effective Method Transfer, a contract lab generates a Method Transfer protocol, tests samples based on client methods and determines if the results are within acceptable limits. These limits are generally established by the contract lab together with the pharmaceutical company. Both parties review each other’s standard operating procedures, along with the regulatory guidelines, and then agree on the acceptable limits. Since contract labs deal with many clients, they should be efficient at transferring methods.

Temperature and humidity validator

Stability-Chamber Monitoring
Whether the contract lab uses reach-in chambers or walk-in rooms for sample storage, routine calibration and validation must be performed to ensure that stability chambers are reliable and that samples are subjected to defined conditions. Temperature and humidity within each chamber must be continually monitored and documented with an automatic chart recorder or electronic monitoring system. A qualified contract lab employs a 24-hour paging system to alert personnel if chamber conditions go out of specification or if water leaks onto the shelves. A generator should also be available to provide backup power in the event of power failures.

Extended exposure to significantly changed temperature or humidity can put significant stress on the samples, and can lead to inaccurate and even failing results. Therefore, it is essential that the temperature and humidity within each stability storage unit be closely monitored and the chambers be re-validated routinely. This is another critical element when evaluating a contract lab’s stability program. Ideally, labs should have a suitable backup plan if a chamber should break down and cannot be repaired within a few hours. If possible, samples should be moved into another qualified stability chamber with the same storage conditions and documented appropriately. If this is not possible, then the impact of the change in temperature and/or humidity on the samples should be assessed accordingly.

Does the contract lab in question have consistent, reliable chamber monitoring and maintenance? Does it have a schedule for re-validating the chambers? Is there a designated team handling the stability chambers and rooms? What is the contract lab’s contingency plan if a chamber breaks down?

Comprehensive Reporting
Proper reporting of stability results is critical for keeping clients up to date after each testing interval; results can be used to track trends and predict shelf life. A summary of the entire stability study, from start to finish, should include the contract lab’s expert opinion on the results, as well as study trends and the predicted shelf life for the samples. These summaries are particularly valuable in long-term studies, which can last as long as five years. Be sure to evaluate your potential contractor’s reporting practices to ensure you’ll receive testing results in a timely and organized fashion.

When choosing a contract lab for outsourcing your stability testing, look for a company that is highly qualified and committed to teamwork. By choosing th

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