Goals
When you have completed this module, you should be able to:
a. Perform an audit of a documentation system
b. Use a range of tools and information, including the contents of this unit to support the audit of a documentation system
c. Understand and apply appropriate GMP standards/regulations to an audit of a documentation system
d. Recognize compliance or non-compliance of documentation systems to applicable regulations
Explanation of Topic
Introduction
Good documentation is essential for providing assurance that drug products are safe, pure, effective and of the highest quality. It is expected from any pharmaceutical processes. Through the use of established documentation systems, the company and its suppliers are able to provide a complete written record or proof of all activities used in producing a quality drug product.
This module is focusing on written documentation but data may be recorded by electronic data processing systems, photographic or other reliable means. If electronic systems are used the requirements for the documentation in principle is the same.
Good Documentation Practices for Written Documentation
Good documentation practices should be universally used in all documents that are considered part of GMP documentation.
General Documentation Practices
All required data should be recorded directly into production batch records, applicable logbooks, forms or worksheets. Before signing a document or confirming that an activity was performed, the person signing should both read and understand the step in the process or the statement. Initials and signatures of individuals working in that department should be maintained. Entries may not be made in advance or for another person. Entries may not be backdated. Unfamiliar terms should be defined within the document.
Recording information in the document itself
Only permanent ink, preferably blue or black, should be used to complete a document.
Red ink might be used to highlight proposed changes in a document. All recorded information should be clear, legible, and accurate.
Using a white correction fluid or writing over an entry to correct an error is not acceptable.
If a correction is necessary, the incorrect information should be crossed out using one line.
The correct information should be entered near the incorrect information accompanied by the initials of the person making the correction and the date the correction was made.
[Example of CORRECT way to correct errors]
[Example of INCORRECT way to correct errors]
If repeated information is required for several lines in a document, e.g., initials, no ditto marks (“) or arrows (¯) should be used. Initials should be entered each time they are required.
Recording data
All data should be recorded directly onto the production batch record, appropriate record, logbook, form or worksheet. Errors, which are corrected based on information contained in another source document, must be referenced or the source document must be attached. Personnel who verify calculations must do so independently.
Numerical data
Numerical results must be reported using the same number of significant figures as required by the specification or standard.
Required significant digits to four places: 23.42
Wrong: 23.424
Wrong: 23.4
Analytical data rounding should follow the appropriate site SOP. Rules for rounding other numerical data are found below:
Rules for Rounding Numbers
For numerical data other than analytical data:
Ø If the digit to the right of the digit to be retained is less than 5, do not round up to the next higher digit.
Example: 3 significant digits required
Result: 23.74 Round to: 23.7
Ø If the digit to the right of the digit to be retained is 5 or greater, round up the result to the next higher digit.
Example: 3 significant digits
Result: 23.77 Rounded: 23.8
Errors/Correction in Documentation
Using “whiteout”, correction fluid, correction tape or writing over an entry to correct an error is not acceptable. Errors must be corrected with a single straight line through the error and must be initialed and dated. If the reason is not obvious, a full explanation for the correction must be given by the individual making the correction on the page where the correction is made. The explanation must be initialed and dated. When an entry is made or changed after the date it occurred it must be accompanied by:
Ø Initials of the person making the entry.
Ø Date the entry was made.
Ø Explanation of why the entry was late and documentation used to support the entry if applicable.
Time
Times may be expressed differently in different regions. Below are two examples.
International conventions for recording dates vary (e.g., 2/12/05 may represent February 12th, 2005 in the US or December 2, 2005 in the EU). The time and date format a site uses should be consistent throughout the sites, as applicable and clearly understood by any person who accesses the information later.
Batch records
Comments made to clarify data or statements must be initialed and dated. Extended downtime during a production operation that prevents in-process checks from being performed must be noted with an explanation on the batch record, i.e., “in-process checks delayed due to shift change” or “machine down for repairs preventing in-process checks from being performed”. Errors, which are corrected based on information contained in another source document, must be referenced or the source document must be attached.
Reasons for problems must be explained in detail, initialed, dated and written on the corresponding pages.
Examples:
Ø Writing “line down” (indicating a production line is down) on a batch sheet is not sufficient. Briefly explain the reason the line is down.
Ø Writing “problem” on a batch sheet is not sufficient. Briefly provide information that clarifies what the problem is.
If a source external to the batch record is used to change data or statements, explain the source of information. Only authorized personnel are allowed to review and approve batch records.
Corrections to batch records should be made by the person who made the original entry.
If this is not possible (e.g., the person no longer works at the site), efforts should be made to reconstruct the data using other viable or appropriate data sources.
Different sites may have different documentation rules regarding batch records.
Non-applicable pages of information
If a complete sheet of information on a document is not required by the process, a single diagonal line may be drawn from corner to corner. On the line “N/A” (Not Applicable) should be entered with the person’s initials and date. If there are multiple pages that are not used, the site should have a defined procedure outlining the actions to be taken.
Figure: Non applicable pages of information
If critical data are not recorded, a deviation report must be initiated. The deviation report form number must be included on the applicable page(s) of the batch record. Critical data include equipment readings, time, temperature, pressure, and in-process checks. If changes or corrections are necessary to the batch record, they must be explained and approved by quality. Formal documentation, i.e., a memo or signed change request form, must be kept for each change.
Corrective Actions for Documentation Deficiencies
Document deficiencies may be classified. If a documentation deficiency is considered critical it should be investigated following local procedures.
Deficiencies
Critical deficiencies are those deficiencies that impact the batch. Examples are:
a. Missing entries that cannot be reconstructed at the time they are found (with impact to the batch).
b. Unauthorized changes to approved documents
c. An incorrect entry that includes wrong information or documentation of an event that did not occur.
d. An incorrect response or no response to an in-process or out of specification result.
Examples of deficiencies that do not impact the batch are
a. Missing entries that can be and are reconstructed.
b. Incorrect reactions to an in-process or out of specification result, which is identified and is corrected.
c. Poor documentation practice, which includes non-critical documentation errors, such as not dating, signing and explaining a cross out.
d. Mathematical errors that were not corrected and include incomplete information that can be reconstructed.
e. Signature without a date, or information without a signature.
Types of Documentation Systems that are Audited
Documentation systems that should be routinely audited are:
Ø Equipment assembly, cleaning and use log.
Ø Component, drug product container, closure, and labeling records.
Ø Master production and control records.
Ø Batch production and control records.
Ø Production record review.
Ø Laboratory record systems including electronic data systems and analytical methods.
Ø Distribution records.
Ø Annual Product Reviews
Ø Complaint files.
Ø Validation and qualification systems of processes and equipment.
Ø Equipment calibration and maintenance records.
Ø Environmental monitoring records.
Ø Training records.
Components of Documentation Systems
All documentation systems should have approved and established SOPs that govern how the particular documentation system is managed. The topics that should be included, at a minimum are:
Ø Document control and distribution.
Ø Approving bodies and date of approval.
Ø Timeline for review and revision.
Ø A tracking and follow-up method.
Ø Assurance of training regarding documentation.
Ø A description of the purpose of the system.
Ø Storage and retrieval information.
Ø Directions for handling atypical occurrences within the system.
Documentation may consist of logbooks, worksheets, electronic data, highly controlled paper documents, equipment readout or charts.
Revision of Documents
GMP document revisions should be properly controlled through a formal revision system as part of the document management system. Documents should be approved, signed and dated by appropriate and authorized persons, as defined in procedures approved by Quality Assurance. As part of the document management system there should be a method in place to assure that GMP documents are revised regularly to comply with the
GMP requirement that states that all documents should be complete and accurate.
When revised documents are issued, there should be a method in place to promptly remove superseded revisions from the area. Only official records and procedures should be used by personnel.
If approved documents (e.g., validation reports, released batch records, etc.) need to be amended, only appropriate personnel who have proper authorization may amend the documents. There should be a system in place to manage proposed amendments to approved documents.
Retention of Documents
The site should have a record retention schedule for different types of documents. All records associated with a manufacturing lot should be retained for a minimum of one year after the drug product expiration date. Validation records or other records that are not specific to batches or lots may have to be retained longer.
Records may be retained as original copies or true copies, e.g. microfilm, scanned copies, etc. Documents may be stored off site but must be easily retrievable. Original raw data of manufacturing and the laboratory should be retained according to site procedures.
Signatures on Documents
Signatures on documents can signify different roles. One person may sign a “done or performed by” section on one document and the “checked by” section in another document. It is important to understand the distinctions.
Figure: Signatures on Documents
Electronic data
If data is recorded in electronic systems, detailed procedures relating to the system in use should be available and the accuracy of the records should be checked. Only authorized persons should be able to enter or modify data in the computer and there should be a record of changes and deletions; access should be restricted by passwords or other means and the result of entry of critical data should be independently checked. Batch records and other critical documents electronically stored should be protected by back-up transfer on magnetic tape, microfilm, paper or other means. It is particularly important that the data are readily available throughout the period of retention.
Responsibilities of Quality Unit/QA for Documentation
The Quality Unit/QA should review and approve all appropriate quality-related documents including production records as part of the release process, procedures and specifications.
Summary
Documentation provides a data trail that shows that the manufacture of the drug product was in complete control. It is the formal proof that all steps, tests, and activities needed to produce a quality drug product were performed.
To ensure that the data trail is complete a documentation system should be well managed.
It should be all inclusive from generation of documents to revision and removal of documents from a system.
Documentation systems that should be audited are any systems that can impact the quality of the drug product. These include not only direct manufacturing documentation but also the supporting information necessary to show that the drug product process is in compliance.
Key Parameters in Auditing a Documentation System
Prior to the audit
a. Review the types of documentation systems in use at the site
b. Determine if there are any outstanding corrective actions from either internal audits or regulatory inspections involving documentation.
During the audit of the documentation system
Ensure that the documentation system is operating in full compliance.
Ø Verify that all documentation within a system applies good documentation practices.
Ø For production, laboratory or training documentation,
a. Verify that personnel activity indicated in current SOPs is actual practice.
b. Verify that data added to process documents is correct and current with the process.
c. Verify that the system is working correctly by asking to retrieve a previously generated document
d. Verify that there is a procedure in place for double checking data if required for that documentation system.
Ø Verify that access to documentation is restricted to authorized personnel.
Ø Verify that all documentation contains approvals by appropriate personnel.
Ø Verify that completed documentation is reviewed by appropriate personnel including a quality representative.
Ø Verify that document distribution and circulation is controlled.
Ø Verify that documents are identified with appropriate control and access statements.
Ø Verify that the site has a method for assuring that only current versions of documents are used.
Ø Verify that documents are reviewed or revised either on a scheduled frequency or as needed, whichever is the shorter time interval.
Ø Verify that there are SOPs for managing each documentation system. This should include review and approval process for documents including those which require change control management.
Ø Verify that personnel understand the differences when signing in different capacities.
Ø Determine if documentation discrepancy/deficiency classifications are used by an audited site.
Ø Determine the criteria for each classification.
Ø Verify that the same criteria apply if electronic systems are used.
Review the quality system.
Ø Verify that there is an established and approved Quality System/Quality Policy
that is endorsed by management.
Ø Verify that the Quality Unit is independent of manufacturing.
Ø Verify that one of the Quality Unit’s responsibilities is to approve all
appropriate quality related documents.
Ensure that personnel have received adequate training on new or revised versions of documents.
Ø Ensure that training is documented.
Ø Verify that the training program incorporates requirements for temporary employees and consultants.
Ensure that documents are revised according to a written procedure.
Ø Verify that superseded documents are removed when a new procedure is issued.
Ø Verify that revisions to documents are only made by authorized personnel.
Ø Verify that documents are reviewed and/or revised according to a established frequency.
Ensure that documents are retained according to a site retention schedule.
Ø Verify that the site has a retention schedule.
Ø Verify that documents can be easily retrieved.
Ø Verify that manufacturing records are held for a minimum of one year past expiration dating.