Generation and Control of Specifications for Intermediate, Bulk & Finished Products and Packaging Materials & Retention of Documents.(EudraLex 4)
All types of document should be defined and adhered to. The requirements apply equally to all forms of document media types. Complex systems need to be understood, well documented, validated, and adequate controls should be in place. Many documents (instructions and/or records) may exist in hybrid forms, i.e. some elements as electronic and others as paper based. Relationships and control measures for master documents, official copies, data handling and records need to be stated for both hybrid and homogenous systems. Appropriate controls for electronic documents such as templates, forms, and master documents should be implemented. Appropriate controls should be in place to ensure the integrity of the record throughout the retention period.
Documents should be designed, prepared, reviewed, and distributed with care. They should comply with the relevant parts of Product Specification Files, Manufacturing and Marketing Authorisation dossiers, as appropriate. The reproduction of working documents from master documents should not allow any error to be introduced through the reproduction process.
Documents containing instructions should be approved, signed and dated by appropriate and authorised persons. Documents should have unambiguous contents and be uniquely identifiable. The effective date should be defined.
Documents containing instructions should be laid out in an orderly fashion and be easy to check. The style and language of documents should fit with their intended use. Standard Operating Procedures, Work Instructions and Methods should be written in an imperative mandatory style. 1 Alternatively the certification may be based, in-whole or in-part, on the assessment of real time data (summaries and exception reports) from batch related process analytical technology (PAT), parameters or metrics as per the approved marketing authorisation dossier.
Documents within the Quality Management System should be regularly reviewed and kept up-to-date.
Documents should not be hand-written; although, where documents require the entry of data, sufficient space should be provided for such entries.
Good Documentation Practices
Handwritten entries should be made in clear, legible, indelible way.
Records should be made or completed at the time each action is taken and in such a way that all significant activities concerning the manufacture of medicinal products are traceable.
Any alteration made to the entry on a document should be signed and dated; the alteration should permit the reading of the original information. Where appropriate, the reason for the alteration should be recorded.
Retention of Documents
It should be clearly defined which record is related to each manufacturing activity and where this record is located. Secure controls must be in place to ensure the integrity of the record throughout the retention period and validated where appropriate.
Specific requirements apply to batch documentation which must be kept for one year after expiry of the batch to which it relates or at least five years after certification of the batch by the Qualified Person, whichever is the longer. For investigational medicinal products, the batch documentation must be kept for at least five years after the completion or formal discontinuation of the last clinical trial in which the batch was used. Other requirements for retention of documentation may be described in legislation in relation to specific types of product (e.g. Advanced Therapy Medicinal Products) and specify that longer retention periods be applied to certain documents.
For other types of documentation, the retention period will depend on the business activity which the documentation supports. Critical documentation, including raw data (for example relating to validation or stability), which supports information in the Marketing Authorisation should be retained whilst the authorization remains in force. It may be considered acceptable to retire certain documentation (e.g. raw data supporting validation reports or stability reports) where the data has been superseded by a full set of new data. Justification for this should be documented and should take into account the requirements for retention of batch documentation; for example, in the case of process validation data, the accompanying raw data should be retained for a period at least as long as the records for all batches whose release has been supported on the basis of that validation exercise.
The following section gives some examples of required documents. The quality management system should describe all documents required to ensure product quality and patient safety
There should be appropriately authorised and dated specifications for starting and packaging materials, and finished products.
Specifications for starting and packaging materials
Specifications for starting and primary or printed packaging materials should include or provide reference to, if applicable:
a) A description of the materials, including:
- The designated name and the internal code reference;
- The reference, if any, to a pharmacopoeial monograph;
- The approved suppliers and, if reasonable, the original producer of the material;
- A specimen of printed materials;
b) Directions for sampling and testing;
c) Qualitative and quantitative requirements with acceptance limits;
d) Storage conditions and precautions;
e) The maximum period of storage before re-examination.
Specifications for intermediate and bulk products
Specifications for intermediate and bulk products should be available for critical steps or if these are purchased or dispatched. The specifications should be similar to specifications for starting materials or for finished products, as appropriate.
Specifications for finished products
Specifications for finished products should include or provide reference to:
a) The designated name of the product and the code reference where applicable;
b) The formula;
c) A description of the pharmaceutical form and package details;
d) Directions for sampling and testing
e) The qualitative and quantitative requirements, with the acceptance limits;
f) The storage conditions and any special handling precautions, where applicable;
g) The shelf-life.