Product-specific documents

Product specification documents and analytical test methods—In preclinical development, these are important documents and they evolve along with the development phases. Drug substances and products for clinical trials are tested based on these documents, and so are the stability samples. It is critical to ensure that the analyst will perform the right tests against the right specifications with the correct version of the test method. Therefore a mechanism must be in place to control these documents. This can be done manually or with TIMS. A manually controlled system would require the analyst to sign out hard copies of the documents from a central location. After the testing is done, the analyst would have to return these controlled documents to the... 

For products that are prepared extemporaneously at a regular basis or even for a limited stock, a product specific documentation (product file) is needed. This will include specifications, instructions, and records but also a pharmaceutical assessment of safety data, toxicity, biopharmaceutical aspects, stability, and product design. The product file should also include a product review as soon as a product is used repeatedly or over longer periods. 

Validation of processes and systems is fundamental to achieving these goals. It is by design and validation that a manufacturer can establish confidence that the manufactured products will consistently meet their product specifications. Documentation associated with validation includes ... 

Compliance members, with the help of analytical members of the preapproval audit inspection team, audit the following product-specific documents ... 

TABLE I Analytical Documentation Key Product-Specific Documents during Development... 

Finally, the laboratory expends significant effort communicating results to both internal and external customers. Production, quaUty assurance, and purchasing all have various information needs ranging from the simple pass /fail decisions to statistical summaries of the data and suppHer product quahty. Customers expect to receive lot analyses in the form of a COA and often also want their own product-specific information on the document as well. This information can automatically be appHed to the COA if entered into the LIMS. Often, a quaUty-conscious customer wants information about the product in the form of process capabiUty or control charts. Using LIMS, these charts can be provided on demand. 

Product specifications should specify requirements for the manufacture, assembly, and installation of the product in a manner that provides acceptance criteria for inspection and test. They may be written specifications, engineering drawings, diagrams, inspection and test specifications, and schematics. With complex products you may need a hierarchy of documents from system drawings showing the system installation to component drawings for piece-part manufacture. Where there are several documents that make up the product specification there should be an overall listing that relates documents to one another. 

Produce procedures which regulate the specification of design (input) requirements and the documentation of product specifications and drawings. 

Do maintain the design requirement document even after you have produced the product specification. 

The product specification should provide all necessary processing requirements that need to be implemented when carrying out particular processes however, some of the requirements may need to be defined in separate process specifications which are invoked by reference. You may need to develop your own process specifications, but there are many national standards that may suit your needs and they come with the added benefit that they have been proven to work. The quality plan or procedures should not contain any further product requirements but may provide the verification methods to be employed, the precautions to be observed and the recording requirements to be met. You need to identify in your production plans each of these documents at the stage at which they should be applied, otherwise there is the possibility that they may be overlooked. 

In defining your inspection and test requirements it is necessary not only to specify what inspections and tests are required and when, but also to define the acceptance criteria and the frequency of inspection and test. Are the acceptance criteria those defined in the product specification or are the limits to be closed to gain better control over the process Is every product to be inspected or are the quantities so large that it would be economically unviable If sampling is to be performed what are the acceptance criteria Answers to these and other questions need to be provided by your documented inspection and testing requirements. 

The documents that define the calibration process themselves are derived documents and therefore will be governed by your control procedure. They do not need to be listed along with all your other control and operating procedures in the index of quality system documents. A separate index of calibration methods should be maintained. Calibration methods are like test and inspection procedures, they are product specific. 

If a quality record was intended to be any document generated or used by the quality system, the definition would surely have indicated this. If we decompose the definition further, requirements for quality are defined in ISO 8402 as the expression of the needs or their translation into a set of quantitatively stated requirements for the characteristics of an entity to enable its realization and examination. Clearly, such a requirement would be a contract, product specification, design requirement, etc. This implies that any product verification records are quality records, but it rules out any recorded information as being a quality record. 

GPMP is concerned with the manufacture of medicines, and includes control of ingredients, plant construction, process validation, production, and cleaning (see also Chapter 22). QC is that part of GPMP dealing with specification, documentation and assessing conformance to specification. 

Only three countries, Tunisia, Uganda and Zimbabwe, do not issue a GMP certificate. The drug regulatory authorities in these three countries do conduct GMP inspections, but do not issue a specific document which indicates that a manufacturing plant has attained GMP standards. The MCAZ does, however, provide a GMP certificate at the manufacturer s request to facilitate international registration and export of products. In Malaysia, various types of certificates are issued GMP certificates Certificate of Pharmaceutical Product for export and Certificate of Free Sale for medical devices and cosmetic products. Cyprus has no clear criteria for issuing a GMP certificate instead. 

This document contains information related to the liquid aseptic fill operation used in the manufacture of (product name), USP, at ABC Pharmaceutical Industries located at (provide postal address). Additional information to support the liquid aseptic filling validation includes but is not limited to environmental monitoring and controls, as well as product-specific testing such as bioburden and sterility testing. The main subsections are ... 

Essentially, a user should be able to contact their excipient distributor and request a particular excipient, and the distributor should perform all of the sourcing activities, such as elucidating the exact grade of material required, if not already specified provide documentation generated by the manufacturer [product specifications or data sheets, typical C of A, material safety data sheets (MSDS)] and obtain samples of representative lots of the excipient free of charge for the user. 

The product requirements are reviewed before the contract or tender is accepted. Product requirements are defined and communicated to the personnel responsible for the quality production. The unresolved and ambiguous issues are resolved and documented. The changes made in the product specifications are approved before execution of the order. Provisions are made for removing absolute drawings, procedures, work instructions, and specifications from all work areas to ensure that they are correctly authorized versions. Provisions are made for emergency changes necessary to prevent the production of nonconforming material. 

Now I would like to turn to some of the issues of operations within the manufacturing process itself and speak to certain process controls that are expected. In a chemical synthesis sequence, as I mentioned above, intermediates will need to be fully characterized. That characterization will then lead to a set of specifications for the intermediate, that is, its level of purity, its form, etc. Test procedures that demonstrate that the intermediate meets specifications must be established. Some intermediates are deemed to be more important than others and are given specific designation, such as pivotal, key, and final intermediates. In those cases, it is necessary to demonstrate that the specific and appropriate structure is obtained from the chemical reaction and that the yield of the intermediate is documented and meets the expected yield to demonstrate process reproducibility and control. Purity of the substance is to be appropriately documented. And, finally, in reactions which produce pivotal, key, and final intermediates, side products or undesirable impurities are identified and their concentrations measured and reduced by appropriate purification procedures so that the intermediate meets in-process specifications. Thus, those important intermediates become focuses of the process to demonstrate that the process is "under control" and functioning in a reproducible and expected manner. All of these activities ultimately are designed to lead to the production of the actual active ingredient which is referred to then as a "bulk pharmaceutical agent." That final product will need to be completely characterized which then will document that it meets a set of specifications ("Final Product Specifications") for qualification as suitable for pharmaceutical use. 

The final product specifications must contain a specific identity test. The full set of physical properties and physical constants that are characteristic of the substance must be measured and their appropriate values documented. And, very importantly, the purity of the final product must be demonstrated by a suitable chromatographic method. That chromatographic method must be able to measure the presence of impurities at concentrations of hundreds of a percent in order to be appropriate or acceptable for this purpose. Impurities present in the final product must be characterized. Those impurities which occur in final product at greater than 0.1% must be identified and tested for their biological properties, including toxicity, mutagenecity, etc. Ordinarily, impurities present in concentrations of 0.01 to 0.1% can be recorded as unidentified impurities, and impurities which occur at concentrations less than 0.01% are ordinarily just noted. 

Determine product variability under constant processing conditions Prepare process transfer documents Finalize product specifications... 

Acceptance Criteria/Rationale. The acceptance criteria for each measurable attribute (which can be lifted from the specification document) is important and should always be shared. Likewise, it is recommended that a rationale be provided for each criteria. For example, why must the final product moisture content be 70-80% What if it is 83% The reasoning is that it is better to consider this question before being asked by FDA during an audit, thereby avoiding a situation in which the answer provided may not be the best. 

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