The acquisition of qualification packages increases the availability of internal resources. The supplier takes over components of the qualification, e.g. installation tests leading to as-built documentation (normally Good Engineering Practice), the implementation of specific function tests and accompanying documentation, initial calibration, etc. These kinds of services which include risk analysis, evidence of implementation (trace matrix), design qualification, installation qualification, operational qualification even the performance qualification and similar services, are provided as standards by suppliers of the pharmaceutical industry.
The following points must be observed when all-inclusive qualification packages are awarded with the order.
Contract giver/contract acceptor agreements
Before qualification packages are ordered, an intensive analysis of the supplier's existing qualification strategy is required. A reconciliation of definitions and contents must be made to avoid the unnecessary duplication of work. Example: during risk analyses, checks must be carried out to determine whether it is a Failure Mode and Effect Analysis (FMEA) with Risk Priority Numbers (RPN) or a Hazard Analysis of Critical Control Points (HACCP). The type and scope must be precisely defined and laid down.
In order to determine the costs and ensure planning reliability, the qualification scope must be defined at an early stage together with the order. This requires a certain amount of experience as no functional descriptions/flow charts (also known as Functional Design Specification - FDS), valve control plans, program structures, or similar information are available at this point. A list of qualification requirements that describe around 95 % of the qualification activities should be developed for regular orders. Therefore, analyses that are intended to verify the completeness of qualification packages are frequently difficult to perform.
The qualification packages and accompanying formats are standardized by suppliers and adaptations to individual qualification strategies must be negotiated. Today, the scope and depth of the qualification is generally determined by current GMPs a risk analysis, trace matrix, or similar. This basis may only be developed once the order has been placed: depending on the circumstances this may lead to other expenditure and additional costs.
The maximum processing times for the approval of documents must be specified in the contract. The times allocated for the checking of test plans or similar are often too short. The checking of test protocols often requires several iterative steps that were not envisaged in the planning. As the first step, checks are carried out to determine whether the harmonized formats and specifications were complied with. Parallel checks are carried out to verify whether all contents of the user requirements and the risk analysis have been implemented in test protocols/test cases. To gain a clearer overview, these are carried out using implementation matrices (trace matrices). The initial content check is then carried out by the qualification team. Afterwards, it is often necessary to review the test plans for the first time. The reviewed plans are then checked in a second step (initial check to verify adoption of submitted corrections) and corrections are made to the semantics and elaboration of the test cases.
A check of the supplier's qualification resources should be carried out as project delays may lead to bottlenecks in resources. Suppliers also sometimes use external service providers resulting in additional interfaces in the coordination process. Generally in these cases the communication channels must be checked to ensure, for example, that agreements with qualification service providers are binding (additional costs and work).
It must be determined whether the supplier will only be compiling the test plans or whether the supplier will also be involved in the tests. Both options have benefits. The tests should be carried out by in-house personnel to achieve a maximum transfer of expertise between the supplier and the purchaser. This could be linked with a training course for the operating and maintenance personnel. If resources are scarce and schedules are tight, it may be advisable to include the test implementation in the order, which means that only the test plans will need to be reviewed in-house. At this point, the allocation of roles for the tests should be agreed, e.g. how is a mutual check principle (four-eye principle) understood. However, the basic principle always applies that test plans may only be implemented once they have been approved.
The temporal and spatial sequence of the IQ/OQ tests must be arranged. This includes the agreement as to whether tests may be carried out directly at the supplier's premises (Factory Acceptance Test, FAT) and whether these may be assessed as IQ or part-OQ. In principle, these kinds of strategies must be described in the qualification protocol and possible risks assessed. One advantage of carrying out the IQ at the supplier's premises is, for example, that shortfalls in the documentation are easier to address and resolve. During the FAT, it is also feasible to test IQ/OQ test plans that have not yet been finally approved to guarantee a complete test run and check the test design for the last time.
The certificates required (filter, oils, material, seals, etc.) must be stated in the user requirements with the order as otherwise this may lead to delays during subsequent processing, and possibly culminate in disassembly of the materials used (seals). It is also sometimes necessary to define the contents of the certificates in order to ensure that, for example, material certificates such as 2.1B or 2.2B are sufficient for the qualification.
A binding project plan must be agreed that provides a detailed description of which documents must be available for approval and review and when. It is self-evident that milestones in the qualification also need to be secured contractually.
For orders placed abroad, the language to be used in the test plans must be specified in writing. As the verification of the tests is carried out at premises of the purchaser, who will generally also want to use the test plans for change controls or requalifications, the purchaser's language must be used.
It is expedient to check the test plans of previously completed projects or standard packages by the supplier in order to discuss layout and content issues prior to ordering. As a rule, it is desirable to include references to test documents in test descriptions, and then of course append these to the test cases as raw data or reference them clearly. It is important that raw data (flow diagrams, function flow charts) that is used to carry out tests also carries inspection marks. Furthermore, use of the term "complete" in test protocols must be scrutinized as it is difficult to provide evidence of "completion". It is more useful precisely to limit the term to where, for example, evidence is required only for all product-contact areas, or the test is carried out using lists that have been agreed in advance.
The rules for handling changes and deviations must be established. For example, how should these be integrated in the documentation, and when must the customer be informed?
Sanofi-Aventis Pharma AG, Germany
FDA Regulatory Compliance Consulting, USA
This text is a brief excerpt from chapter 6 “Qualification” of the GMP MANUAL.