Documentation and recording of changes during development

Here you will find answers to the following questions:

  • Which documents must be compiled as a minimum requirement during development?
  • What is a "product specification file"?
  • Which changes have to be recorded and evaluated during development?
  • Which requirements regarding form and content should development documents generally fulfill?
  • For how long must development documents be archived?

Systematic and complete documentation of all quality-relevant activities performed is of great importance even in the early phases of development, because this forms the basis for further process development and optimisation, process validation, and the submission file for marketing authorisation (for example, the development report). Particular emphasis is placed on traceability and the rationale behind every change.

Beginning with the first manufacturing run of investigational medicinal products, Annex 13 of the EU-GMP Guideline requires a product specification file, which is continually updated to reflect the latest status, whereby traceability to previous versions must be guaranteed. This dossier should contain all the necessary information for compiling detailed instructions (figure 16.E-1).

Figure 16.E-1 Product specification file in accordance with the EU-GMP Guideline

Product specification file

All necessary information for compiling detailed instructions for:

  • Processing
  • Packaging
  • Quality control
  • Batch release
  • Storage conditions
  • Shipment

Figure 16.E-2 Documents in development  

Documents in development (in accordance with the EU-GMP Guideline Annex 13 and the FDA Guideline on the preparation of investigational new drug products):

  • Description of the QA system
  • Specifications for
    • Starting materials (active pharmaceutical ingredients and excipients)
    • Primary packaging materials
    • Intermediate products
    • Bulk material
    • Finished products
  • Product Specification File
  • Written instructions for manufacturing and packaging
  • Batch manufacturing record and batch packaging records
  • Preliminary manufacturing parameters and in-process controls
  • Yield calculation
  • Records of testing or examination of raw materials
  • Data on the quality of blinded reference medications
  • System for the identification (de-coding) of "blinded" preparations
  • Release protocol ("technical green light" and "regulatory green light")
  • Shipping orders from the sponsor
  • Acknowledgement of receipt for investigational drug shipments
  • Detailed inventory of investigational medicinal products (delivery note, recovery, etc.)
  • Records of destruction, destruction certificates
  • SOPs:
    • Use, cleaning, calibration, and maintenance of equipment
    • Changes to specifications, batch production instructions and processing instructions
    • Release of investigational drugs
    • Additional labelling of clinical samples in case of extension of the expiration dating period
    • Self-inspections
    • Compilation, distribution, handling, and storage of randomisation codes in the packaging of investigational drugs
    • Recovery, forwarding and recall of clinical samples
    • Shipment, retrieval and destruction of clinical samples

Annex 13 of the EU-GMP Guideline also names additional documents that must be available during development. However, this list is certainly not exhaustive, since in order to comply with GMP, a large number of additional documents is also required, such as a sanitation programme and zonal concept, gowning procedures, cleaning procedures, and qualification and calibration documents, which are not mentioned explicitly in Annex 13. The documents required in development are listed in figure 16.E-2. To avoid annoyances, misunderstandings, and increased workload when searching for data in later stages, a uniform formal and content-related layout of records should be adopted already in the development phase. This makes handling of documents easier, for example:

  • in review,
  • in the compilation of documents for marketing authorisation,
  • for inspections.

Important points for the formal layout are as follows:

  • Unambiguous identification of every document, for example using version numbers, compilation or approval date
  • Possibility of completeness check for each document using page/full page specifications and directory of all inserts or annexes
  • Identification of the author and/or overall responsible person

For content layout, the following applies: Regardless of whether the documentation refers to laboratory controls, stability testing, qualification, validation, calibration, maintenance or cleaning work, or batch manufacturing, the principle of GMP-conformant documentation applies throughout:

1. Create a plan or specification with targets

2. Carry out the activity and collect raw data

3. Evaluate results, compare against targets, and draw conclusions

Depending on the type of document, this "3-step" procedure can obviously be further refined, for example, to form the "eight basic elements of qualification and validation documentation" (in accordance with the FDA Validation Documentation Inspection Guide):

  • Define goals/acceptance criteria
  • Perform tests
  • Document results
  • Verify accuracy
  • Compare against acceptance criteria
  • Draw conclusions
  • Document and approve results
  • Conduct periodic evaluations

In addition to these formal aspects, some rules of thumb should be met for all quality-relevant documentation in development (see figure 16.E-3 and chapter 15 Documentation).

Figure 16.E-3 Rules of thumb for documentation during development

Rules of thumb for documentation during development

  • The title, contents, and purpose of each document must be clear and unambiguous.
  • Each document, its author (or the responsible person) and the compilation or approval date must be clearly identifiable.
  • Document: What, who, when, why, and with what purpose each step is executed (plan) or was executed (record).
  • If individual aspects do not apply for a product or project, are evaluated as non-critical, or are not (/were not) included for any other reason, these points should not simply be omitted in the documentation, but instead a rationale for this decision should be briefly documented, even if this appears to be self-explanatory when the documentation is compiled. In the case of a change in personnel or for inspections, these reasons are otherwise not traceable, and suspicion of the "sin of omission" is threatened.
  • Critical points must be addressed in the documentation and must not be concealed. If possible, comment of the expected effects.
  • Document all results fully. At the end, however, it is important to include not simply a number, but an interpretation and conclusion(s).
  • Do not describe the same operations in different documents, but instead use cross references to other source documents (SOPs, instructions, policies, etc.) - note the version number!
  • In the raw material specifications or product specifications in development, it must be clearly defined which test criteria are release-relevant and which tests serve only to improve understanding of the starting material or product.
  • Master plans such as qualification or validation master planes, or master records for the manufacturing ("batch production record" or "processing instructions" in accordance with the EU-GMP Guideline) are not prescribed in development. Both document types, however, can prove very useful and time-saving in later stages of development.

Archiving periods

In accordance with article 9 of the EU-GMP Directive 2003/94/EC, batch documentation of investigational medicinal products must be archived for at least five years following completion or formal termination of the last clinical trial in which the affected batch was used. Similarly, the requirements of the EU-GCP Guideline 2001/20/EC (Art 13, paragraph 4), stipulate that the register of released investigational products must be available to the responsible authorities for a period which may "in any event be not less than five years". Measured against the total duration of the development project, these time periods are still somewhat short. In practice, even longer archiving periods are usually required:

  • Assuming that a preparation successfully overcomes all difficulties and hurdles of development, the batch documentation for all clinical samples must be available for compilation of the submission file for marketing authorisation. However, the submission of applications for marketing authorisation in different countries can take several years. In some countries, submission therefore may take place many years after the first clinical trials are completed.
  • The batch documentation must be archived so that it can be easily retrieved within a useful period of time in the case of inspections (for example, pre-approval inspection, PAI).
  • If an investigational product is not developed by the sponsor himself, it must be contractually defined for how long the manufacturer is required to archive the batch documentation.
Change Control - Recording and evaluating changes

It is the nature of pharmaceutical development that for example, the formulation, manufacturing process, equipment, packaging material, specifications and test methods are subject to ongoing changes in order to achieve the objective, namely a product that is ready for the market. As a part of this process, deviations occur, for example from the (provisional) manufacturing or control procedures or from preliminary specifications, due to lack of experience at early stages. On the other hand, some changes are also made deliberately, for example, to manufacturing instructions, processes, methods, or specifications, in order to improve product or process characteristics.

However, since changes of this type should not be the result of chance, but instead should follow a rationale, changes to product specifications and manufacturing procedures must be recorded in accordance to a SOP and their effects, for example, on stability and bioequivalence, must be evaluated. All changes should be justified, approved, and recorded (see Annex 13 of the EU-GMP Guideline, "Principle"). As soon as the first clinical samples are manufactured, it is particularly important to assess every subsequent change in terms of its possible influence on the study results. Finally, it must be ensured that the quality of the clinical samples within a study remains consistent and comparable between different studies. This change history also simultaneously documents the development history of the medicinal product. The main points in this development history are ultimately presented to the regulatory authorities in the form of a Development Report.

The regulatory requirements for change control in the development phase refer only to product specifications and batch production instructions or processing instructions. In comparison, the change control requirements in the production environment are considerably more extensive (chapter 19.C Change control).


Systematic and complete documentation of all quality-relevant activities performed is of great importance even in the early phases of development, because this forms the basis for further process development and optimisation, process validation, the production process and the submission file for marketing authorisation (for example, the development report). The traceability and rationale for each change are particularly important.