Stability testing is an important aspect of any drug development project, and it is a requirement for manufacturing FDA-approved drug products. The information from such development studies is used to determine acceptable shelf life, proper storage conditions and suitable packaging. Essential information regarding product quality over its useful lifetime is gathered about potency, impurity levels and integrity of the delivery scheme (oral or otherwise). Conducting a stability testing program is no trivial task; these studies can last as long as five years. Considering that a typical stability protocol may include three product lots, four dosage strengths and three storage conditions, a large amount of data will be generated during the course of a cGMP-regulated stability study.
Pharmaceutical companies frequently contract these programs to an outside testing facility because they don't have the Resources in house. Their expectations of the contract laboratory are high. There is substantial financial risk in placing such a long-term study with an outside organization. Mishandling a project one, two or three years into a study is very costly in both money and time. A single delay can cost a sponsor many millions of dollars. What do sponsor companies look for to ensure that their stability programs will be executed correctly?
When selecting a contract laboratory, consistency of service and performance is a key issue for most pharmaceutical companies. Because risk is high, a company will sometimes opt to place a study at a contract research organization (CRO) with which it has worked in the past, even if the service was less than adequate. Some like the familiarity of a known entity rather than working with a new laboratory, even though the new laboratory may provide better service or be in a more convenient location. Reducing risk requires effort for both the sponsor and the CRO. Sponsors invest time and effort in conducting site audits. This is costly both for the sponsor and the CRO, but there are benefits in what each can learn from the other. CROs running projects for multiple sponsors can learn a great deal about optimum quality procedures and documentation, enabling them to learn from many masters of these arts. Likewise, sponsors sometimes pick up new information from the CRO that helps keep their own goals rigidly compliant. In this article, we will share our experiences with multiple sponsors about their primary areas of concern.
When placing a study with a contract laboratory, the sponsor has the burden of assuring that the data was generated in a compliant fashion. Therefore, the sponsor will hold the contract laboratory to a very high standard and will be looking for the same things an FDA inspector would look for.
Sponsors audit facilities prior to placing a study, and the audit frequently entails a two-pronged approach. Prior to the visit, the sponsor may ask the CRO to complete a questionnaire to give the auditor a better snapshot of the facility and to allow him/her to use on-site time more efficiently. The sponsor must obtain enough information to be able to qualify or disqualify a laboratory, and the laboratory must convey the appropriate information if it wants the project. However, questionnaires to assess laboratory capacity and capability are difficult to design. Questionnaires designed for contract manufacturing often are used to assess laboratory function, but this approach doesn't always provide an accurate picture of the laboratory, because the focus of the two activities is very different. In these cases, the on-site visit becomes more crucial. In addition to the initial audit, pharmaceutical standard operating procedures (SOPs) require routine audits on an ongoing basis, usually annually, though some may occur at less frequent intervals.
Sponsors look for laboratories that are able to maintain sample integrity, analyze samples in compliance with cGMP requirements, and provide quality assurance services. Intertwined with these three prime areas of interest is a list of intangible assets. These intangible assets aren't on a checklist or a questionnaire but often will be noticeable to the auditor.
In managing a stability program, control of the sample and its local environment is crucial. From the time a sample enters the building to its disposal, sample integrity must be maintained. Sample integrity includes identity and purity. The sample and its package should not be compromised in any fashion throughout the study. Auditors will examine sample storage areas in search of organization, adequate segregation, security and documentation.
A well organized, clean space will ensure adequate segregation. Areas littered with boxes, bottles, paperwork and other paraphernalia tends to leave the auditor doubting the lab's tracking capability. Auditors are concerned that their samples may get placed with samples from other sponsors or that samples from different studies will be mixed. Well-labeled bins or well-marked shelves with dividers help ensure adequate sample segregation. Keeping tested samples segregated from untested samples provides added assurance for well-maintained samples. Sponsors will look for validated sample tracking systems. Laboratory information management systems (LIMS) are useful in providing tracking, but if a LIMS is not implemented, then a paper system must ensure that the samples can be tracked throughout the life cycle and that all aspects of their handling and environment are well documented.
Sponsors need to feel confident that their samples will be analyzed using validated methods and tested on qualified instruments by trained scientists in a well-documented fashion. They will look for systems that ensure these things. Not only must the method be validated, but the laboratory will need to provide certification that it can run the method. Instruments must be qualified, meaning that installation qualification, operational qualification, and performance qualification have been completed. In addition, auditors will ask about routine maintenance and verification procedures. Not only do auditors expect detailed SOPs describing these activities, they expect necessary documentation of their satisfactory completion to be available.
Auditors will ask for evidence that an adequate number of qualified persons will be involved with the study and that these persons have the appropriate education, experience and training. CROs must also be able to provide an organization chart. Pharma sponsors want to be confident that qualified scientists will execute their project, so they will scrutinize the training program and documentation to ensure that regulatory requirements are met. Auditors will ask about initial training for instrument operation, specific training in methods performance and ongoing training. Job descriptions and curricula vitae provide evidence about scientists' job responsibilities, education and the experience they possess to perform these responsibilities. Since training continues after starting a job, records of ongoing operational training, as well as annual regulatory training, will also be expected.
The most frequently requested SOP is the procedure for out-of-specification (OOS) investigations. This SOP is always highly scrutinized and sponsors examine the process closely. The Barr decision of 1993 mandated that investigation of results that fall OOS be documented thoroughly. The analyst must determine with the supervisor whether a laboratory error occurred. Any additional data generation must be planned, documented and approved prior to execution. Sponsors seek comfort in knowing that aberrant results are dealt with in technically sound fashion and that corrective or preventive actions are put in place when necessary.
Key to every laboratory is the regulatory oversight function of a Quality Assurance unit. QA serves the laboratory by auditing processes, data, reports and protocols. In addition, QA must maintain a working knowledge of the regulations and ensure that laboratory operations are in compliance. Sponsors will look for a QA unit that is independent of the laboratory and reports directly to management. They will look for sound auditing and reporting practices. Sponsors also expect that deviation trending, investigations, and follow up on corrective actions (when necessary) are part of the process.
Currently, of foremost interest is compliance to 21CFR Part 11, which covers use of, and requirements for, electronic records and electronic signatures. The industry is focusing its attention and resources on bringing operations into compliance; however, compliant applications are not universally available at this time. In these cases, sponsors look for a gap analysis document showing a proactive approach to meeting this requirement. The sponsor will want to know where deficiencies exist, how deficiencies are handled currently, and the plan to meet compliance. Computerized systems are an integral part of most operations, and regulations require validation of these systems. The sponsor has a vested interest in these systems performing adequately, so software validation documentation must be provided for sponsor examination.
An exemplary record with the FDA provides an additional boost in the confidence level of sponsors, and auditors are extremely interested in the results of any completed FDA inspections. Laboratory systems that can withstand FDA scrutiny are sound and are a good indicator of future performance. Results of these inspections, as well as the laboratory response, will be examined.
Sponsors need assurance that laboratories are providing services in compliance with GMPs. It's a given that most contract organizations are going to operate with a complete and detailed set of SOPs based upon regulations that allow for a wide range of interpretations and philosophies. Auditors collect information regarding the systems the laboratory follows. However, sponsors are also looking for other intangible qualities that often can be the deciding factor among competing laboratories, including responsiveness, trust and scientific expertise.
Everyone will agree that good communication is necessary for the success of any contract relationship. This particular topic arises in any discussion about outsourcing. However, its importance should not be trivialized. Sponsors look for those who can communicate, and the communication process begins with the first contact. To ensure success, both parties should state their expectations up front. Establishing the rules in a clear, concise manner at the beginning prevents misunderstandings and frustration. Decisions about data presentation and report format made prior to the start of the study also ensure seamless flow of work.
As sponsor scientists rely on the laboratory to complete their projects, they expect the laboratory to provide timely responses to their inquiries. Sponsors need to know that their project, their question, their concern is the laboratory's top priority, and the contract laboratory scientists believe the favor should be returned!
Showing a propensity to respond in a timely fashion will also set the tone for data delivery. Sponsors want to know how quickly or how slowly their data will be available. The window to complete testing can be tight. Sponsors expect that timelines will be met, particularly with stability samples for which the analysis schedule is preset. Of course, when schedule adjustments must be made, immediate notification is expected. Sponsors appreciate honesty; they would rather be told a realistic timeline instead of one the client might expect but the laboratory can't deliver.
Sponsors appreciate confidentiality and professional treatment of their studies. They also appreciate the scientific expertise and insights provided with the data. A good partnership with a CRO can actually enhance the project for the sponsor, particularly for smaller or "virtual" pharma companies. Sponsors who are able to talk directly with the scientific staff and get immediate information regarding their study feel more confident about the attention given to their work.
The success or failure of a study placed with a CRO is very dependent on the relationship established among all the individuals involved. For CROs, learning how a sponsor will manage and what it will expect, and then establishing that relationship, is the biggest challenge. Sponsors hire CROs to complete studies for which their in-house resources are unavailable. The sponsor's technical staff has to be assured that the work will be done to its specifications, and these vary greatly from sponsor to sponsor. Some expect the CRO to provide in-depth technical advice, while others expect the CRO to be simply "another pair of hands," completing the work to the letter according to the instructions. In either case, sponsors are looking for a laboratory that will work within their respective cultures. Thus, the service a CRO provides is expected to be flexible, not only in handling studies but also in responding to emergencies.
Essentially, the laboratory should be able to function as if it were just down the hall from the sponsor. In reality, such a geographic relationship is seldom the case. Thousands of miles may separate the two; however, in today's age of the fax, the Internet, Webcast capability, video conferencing and teleconferencing, geographic distance is less important. Still, some sponsors put merit on having a laboratory nearby, and close proximity can enable same-day delivery of samples or data. If a problem arises, the sponsor can access the laboratory easily. Some sponsors feel an added comfort level employing a laboratory within driving distance.
When about to begin a stability program, whether a sponsor elects to outsource or keep it in house, the facility must have a secure, controlled environment that will maintain sample integrity. The facility should have laboratory procedures that provide training, qualified instruments, validated methods and controlled documentation. The quality assurance unit must have intact systems. Above all, the sponsor must feel confident that the laboratory can execute the protocol in a timely fashion, in line with the regulations, and that the final data package provided is good quality.
Sponsor Expectations for Stability Programs
Some guidelines for sponsor inspections
By Margaret B. Voelz
Published August 22, 2005
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