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Communication between contract analytical laboratory and client is extremley important when out-of-specification (OOS) results arise.
The contract analytical laboratory (CAL) plays such a key role in the support of its clients that the quality of communication between the CAL and client is arguably just as important as the quality of the science in supporting the production of biopharmaceuticals. Communication is just as important when out-of-specification (OOS) results arise. It is always to the manufacturer's advantage if the CAL has the resources, back-up, and communication channels available to provide an assured service when results are OOS.
For any biotech company considering using a contract analytical laboratory (CAL) to support its product development or manufacturing, the science on offer must be of the highest standard; the laboratory must be competent to carry out all of the analytical procedures required.
Analytical competence, however, is only one part of the story. Communication is extremely important in supporting the production of high-quality biopharmaceuticals. This is especially true when the results of an analysis indicate a problem with the product, as in the case of out-of-specification (OOS) results.
Having identified a suitable partner laboratory, the first point of communication between the manufacturer and the CAL should be with the latter's quality assurance unit. This will be to ascertain the quality standards in operation, to receive copies of the letters of approval from the MHRA or the FDA, and to view at first hand the laboratory's facilities, not just for carrying out analysis, but also, for example, for receiving, storing, and disposing samples.
Assuming the CAL has the necessary quality systems in place, the discussions should focus on agreeing on the contents of a confidentiality agreement and technical agreement. The CAL is likely to have many other clients, so the manufacturer may wish to establish how potentially sensitive information will be protected from other companies' auditors. Confidentiality agreements may be prepared by the manufacturer or by the CAL, but in either case, must be agreed on by each party.
In Europe, EU Directive 2003/94/EC (the so-called "Orange Guide") makes it clear that a written contract is needed to define duties and obligations between the parties for good manufacturing practice (GMP) analysis. It is arguably impossible for a contract to cover every eventuality, but the more detailed the contract, the better. Nonetheless, the inspection authorities in the UK have noted, for example, that the contract should not only indicate that the laboratory will inform the client of OOS results, but also state how and when the results should be notified. Similarly, the contract would not only state that samples should be disposed of, retained, or returned, but also would specify how and within what period of time.
Either party may prepare the technical agreement. A CAL-prepared agreement often takes a generic approach to analytical testing, whereas manufacturer-prepared agreements are more likely to be written to cover specific analyses on specific products.
Regardless of authorship, both parties must check the contents of any agreement closely, because not all demands that are sensible in theory are actionable in practice. For example, the manufacturer may ask for the destruction or return of all documents, records, and data that belong to them. However, with the dependence of the modern laboratory on IT systems that are backed up every day, the destruction (i.e., deletion) of electronic records is a nearly impossible task. Understanding and accepting the requirements and limitations of both partners from the outset is critical for maintaining a good working relationship in the long run.
Although contracts form the structure of the communication, and the legal basis for carrying out work and resolving disputes, true communication is a two-way activity. Both sides should feel comfortable requesting information from each other. The client can help the CAL by sending as many details as possible with the sample to be analyzed. Safety data sheets should be sent where appropriate, with details of the testing requirements and disposal instructions. From the laboratory's perspective, it is always better to receive too much information rather than too little, yet it is surprising how often clients appear comfortable sending samples with the simple, but inadequate, instruction "for testing."
That said, the CAL should be flexible and ready to receive sample information in electronic or paper format. Many CALs can copy data from a spreadsheet into a laboratory information management system (LIMS), or have a standard sample submission form available. When such a form has been designed by the CAL, it can be expected to request all the details the CAL needs. If the CAL does not have a form, then it should be suggested that it creates one.
Good communication is most important on the few occasions when an analysis does not progress as planned. These occasions can be broadly divided into two main categories: a deviation from the agreed methodology or an OOS result.
The technical agreement often will reference the methodology and procedures to be followed for the requested analysis. Hence, a deviation is defined as "a departure from an approved instruction or established method." The CAL should have a "deviations" standard operating procedure (SOP) to be followed in such circumstances.
However, deviations from methodology must be accepted and approved by the customer before starting the analysis. The laboratory must discuss the deviation with the client and provide evidence to validate that the deviation is appropriate. Such deviations should be detailed on the test report.
If the deviation is to a customer method, and is to become permanent, then a change control process needs to be instigated. The change control process should also be documented in an SOP. The change can then be validated by submitting analytical data to the client with a copy of the draft new method for after review, the client must provide documented approval that the change provides an improvement to the method.
Whenever results are OOS or out-of-trend, a formal investigation must be undertaken. The investigation invariably starts with a thorough review of the raw data. Assuming no errors are noted, then the CAL should contact the client to discuss the next course of action.
It may be that no further action is required. Clients may occasionally (and without notice to the CAL) request the analysis of known OOS samples to test the competency of the CAL, or to confirm an in-house result. Clearly in these two cases, the OOS result is to be expected.
However, when the OOS is unexpected, further investigations will be required.
FDA's Guidance on OOS Results
The FDA's most recent guidance on investigating OOS test results provides some significant additions to previous guidance.1 Its most significant changes from previous guidance are the following;
The guidance addresses investigations of OOS results in the laboratory phase, including responsibilities of the analyst and supervisor, and when indicated, the expansion of an investigation outside of the laboratory to include production processes and raw material, as appropriate.
The new guidance is a bit confusing in certain parts, however, and from the perspective of the CAL, there are one or two surprising omissions. In the FDA guidance, an OOS result is defined as,
"all test results that fall outside the specifications or acceptance criteria established in new drug applications, drug master files (DMFs), official compendia, or by the manufacturer. The term also applies to all in-process laboratory tests that are outside of established specifications."
Interestingly, Section II of the FDA guidance states, "The responsibility of a contract testing laboratory in meeting these requirements is equivalent to that of a manufacturing firm." Later, in Section III it is stated, "For contract laboratories, the laboratory should convey its data, findings, and supporting documentation to the manufacturing firm's quality control unit (QCU), who should then initiate the full-scale OOS investigation."
These two statements appear to contradict each other, suggesting on the one hand that the CAL has equal responsibility with the manufacturer, and on the other that it is only responsible to the manufacturer. In practice, of course, investigating OOS results is usually a mutual decision, prompted by the reporting of results by the CAL, proposal of follow-up investigation by one or both parties, and agreement of the contractual basis on which the work is being carried out.
The new guidance is surprisingly lacking in detail as to how OOS results should be classified and followed up. It merely notes that, "the source of the OOS result should be identified either as an aberration of the measurement process or an aberration of the manufacturing process."
From the laboratory's perspective, it is far more useful to drill down to the detail and assign the error more specifically (e.g., dilution error or wrong sample weight used). Our own laboratories would always seek to assign a conclusion to any investigation (i.e., calculation error, method error, equipment error, technician fault, or genuine OOS). This affords the opportunity to analyze OOS results for specific trends to highlight potential weaknesses in our own quality system, and also provides greater assurance to the client that an OOS result reported as arising from manufacturing error is indeed genuine.
Section III of the guidance states that, "corrective action to prevent recurrence" should occur whenever laboratory error is identified as being the cause of an OOS result. However, this author is in favor of the term "preventive action," which is used later in the section.
Leaving aside the semantics, where the laboratory has shown that there has been a fault in the production process rather than the testing process, there is more investigative analysis that the laboratory can undertake to establish the root cause of the OOS result.
It helps if there has been a history of good communication between the CAL and client. Investigating an OOS result may necessitate the client disclosing sensitive, proprietary information to the CAL so that they can make sense of what has gone wrong. It may be necessary to open up manufacturing facilities to the CAL so that samples can be taken and processes be understood.
Whoever does the investigation, it is always clear that the OOS result must be taken seriously, and acted on. Testing into compliance is both unscientific and objectionable. The guidance notes make it clear that when there are no laboratory or calculation errors identified and there is no scientific basis for invalidating the initial OOS results in favor of acceptable retest results, then, "all test results, both passing and suspect, should be reported."
It goes on to say, "It is critical that the laboratory provides all individual results for evaluation" as "averaging the result(s) of the original test that promoted the investigation and additional retest or resample results obtained during the OOS investigation is not appropriate." This practice "hides variability," according to the guidance and which goes on to say that, "relying on averages of such data can be particularly misleading when some of the results are OOS and others are within specification." Anyone familiar with the USA versus Barr Laboratories case of 1993 will recognize the importance of not ignoring OOS results, and why testing into compliance is unacceptable.2
Whether out of specification, or more usually, in specification, one of the most important pieces of communication between the CAL and client is the actual result of any analysis. Modern LIMS allow for the production of secure, electronic copies of certificates of analysis (CoA), which permit the CoA to be e-mailed directly to the client's inbox, rather than relying on the slower postal service. In some cases, the laboratory may be able to grant the contract-giver access to secure parts of its IT infrastructure or LIMS for live results. The client can view the progress of the analysis from sample receipt through to the final result.
If this is the case, and if appropriate, then the requirements of 21 CFR Part 11 should be obeyed, with the appropriate use of automatic password ageing, unique identifiers, limiting access, and audit trials. The complexities of 21 CFR Part 11 are such that no further detail can be entered in here.
The raw data, copies of the CoA, and all associated correspondence can now be archived for the period agreed in the technical agreement.
Throughout all processes, each party could have informal questions, so requests for information should be quickly answered. CALs often have a dedicated customer- service team, or customer managers who should be the first point of contact for all queries. The customer service team should be the customer's advocate with the laboratory should additional support be needed.
There are other potential sources of discussion between a CAL and its customers. These might include, for example, requests from the customer for an audit, a laboratory tour, or debarment statements. One would hope that there was never a need to register a complaint about the CAL's service, but it might be useful to know in advance what systems the CAL has in place for dealing with and responding to complaints. On a more positive note, the CAL may want to conduct a customer-satisfaction survey, and the cooperation of clients in completing such surveys is likely to be beneficial to both parties.
Communication between the CAL and client is an essential part of the working relationship. Although it might be tempting to make a choice of partner laboratory on initial considerations of price, the long-term consequence of this decision should always be kept in mind. Communication is particularly important when out-of-specification results arise. It is always to the manufacturer's advantage if the CAL has the resources, back-up, and communication channels available to provide an assured service when things are working well, and perhaps more importantly, the investigative resources to respond promptly and expertly when results are OOS.
Adrian Kirk is a quality manager at RSSL Pharma, Reading Science Centre, Berkshire, UK, +44(0)1189868541, email@example.com
1. US Food and Administration. Guidance for Industry. Investigating out-of-specification (OOS) test results for pharmaceutical production. Rockville, MD; 2006 Oct. Available from: www.fda.gov/cder/guidance/index.htm.
2. United States v. Barr Laboratories, Inc., 812 F. Supp. 458 (DNJ 1993).