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Documentation and Records

1 Documentation System and Specification

Regarding revision of documents, the company should define e.g. in a SOP when and how documents are revised. Issuing a new table listing all existing documents/SOPs after a defined period of time (not necessarily 2 years) is acceptable. The revision history of the document shall be traceable over the retention period.

No pencil, no white out and no crossing out should be used when dealing with GMP relevant documents.

Figure 1 Suggested retention periods

Suggested retention periods are:

general production, analytical, control and distribution records

 

7 years *

clinical batches for an IND or NDA
(see also chapter 19 Tools for Quality Assurance)

LC +

1 year

batches for bioequivalence testing

LC +

1 year

product development reports

LC +

1 year

development and validation reports of analytical test procedures

LC +

1 year

process validation reports

LC +

1 year

equipment IQ, OQ and PQ reports

LC +

1 year

supporting systems (e.g. utilities, computerised systems)

LC +

1 year

training records

 

7 years

For clinical trials and demonstration batches LC + 1 year should be considered.

Note: LC means "life cycle" of the product where shelf life is included. "Life cycle" means the process starting with the user requirements, continues through design, realisation, qualification, process validation and maintenance until the stadium of not in use.

*after the date of the record)

An overview of the different specifications to be established is given below:

Figure 2 Overview of the different specifications to be established

Link to 21F-1.jpg

Figure 3 Types of Specification

Item

Type of Specification

API Starting Materials

  • Internal specification mandatory.
  • More details may be needed compared to RM.
  • Pharmacopoeia requirements not needed..

Raw materials

  • Internal specification mandatory.
  • Pharmacopoeia requirements not needed

Intermediates

  • Internal specification optional.
  • Pharmacopoeia requirements not needed.

API's

  • Pharmacopoeia mandatory. For non-compendial APIs refer to Q6a.
  • Additional internal specifications optional if stipulated by customers.

Labelling

  • Pharmacopoeia and internal specifications mandatory concerning text of labels.
  • Material specification optional.

Packing material

  • Printing see labelling.
  • Material specification mandatory.

Process aids including utilities (product contact materials)

  • If such materials are critical, the use of internal or public specifications (e.g. technical standards like ISO, EN etc.) is advisory.

IPC

  • In order to avoid the necessity of doing OOS-
    Investigations on deviating in-process controls, ranges need to be established - e.g. by defining upper / lower control limits and action limits for the purpose of process monitoring.
  • It is recommended to mention this exception in the applicable SOP.

2 Equipment Cleaning and Use Record

It is recommended to use a log system (different documents) for the chronological record in order to see:

  • for which purpose and batch the equipment has been used
  • from whom and how (cleaning method used) it has been cleaned (when appropriate)
  • any maintenance that was done referring to who did it, what and how it was done (a reference in the batch record should be made, if maintenance was performed during production).
  • the status before and after maintenance, even when the equipment was found to be o.k.

This requirement is valid for major equipment only (see ICH Q7a 6.52 - chapter E.6 ICH Q7A: Good Manufacturing Practice for Active Pharmaceutical Ingredients).

It is important to describe the exact type of repair of the equipment in the record. Status of equipment should be recorded and checked.

Status of cleaning and maintenance should be recorded and checked, preferable in a log.

Cleaning and maintenance may be documented in a database (electronic records) which then should comply with ICH Q7a sections 6.10 and 6.18.

A plant or unit log instead of individual equipment records should also be applicable if the equipment is firmly incorporated into a plant or unit (installed and piped for permanent use) even if this plant/unit is not dedicated but used for production of different API's in campaigns.

If the records of cleaning, maintenance and (re)use are included in the batch record, it may be recommended that this information is written on the first pages and that critical entries are double signed. The review of the batch record will then be easier.

If the cleaning and maintenance records are not part of the batch record, a reference to the appropriate documentation or database should be placed in the batch record.

The objective of this record keeping is to trace what particular equipment was used in manufacturing a particular batch and what status it had at the time of usage.

Figure 4 Documentation on the usage, cleaning and maintenance of equipment

Entries in a equipment log book

  • Process step, product and batch number
  • Cleaning method with details of who performed the cleaning
  • Maintenance activities with details of who performed the maintenance, as well as the status before and after maintenance
  • Repair activities

3 Records of Raw Materials, Intermediates, API Labelling and Packaging Materials

The objective of this record keeping is to trace the above Materials back to the suppliers production records and trace forward until the API-batch delivered to individual customers in case of any failure occurring in the supply chain.

The responsibilities for a final decision regarding rejected raw materials etc. should be defined in a procedure.

The approved master of a label need not to be a label itself but may consist of a approved set of relevant data used by or sent to a label printer. A 0-copy of the label may be filled together with the batch record to proof compliance with such master.

Figure 5 Required information on materials used

Required documentation for raw materials

  • Name of the manufacturer
  • Identity and quantity of each shipment and batch
  • Name of the supplier
  • Identity or control number of the supplier, if known
  • Goods receipt date and internal goods receipt number
  • control record and results
  • Records that can be used to trace back the material

4 Master Production Instructions
(Master Production and Control Records)

Review and signing by two people is sufficient but not restricted to that number.

The review has to be performed by the people/functions appropriate for this task. This may involve R&D, QC, Production, engineering and probably also regulatory affairs as well as SHE (safety, health, environment) departments.

It is possible to use, at different production locations, different Master Production Records derived from the same basic receipt (see figure 6.)

Figure 6 Contents of the master batch production records in accordance with ICH Q7A

Content of the master batch production records

Name of the intermediate or API to be manufactured and if applicable, internal reference code of the API/intermediate

List of raw materials and intermediates with sufficiently specific names or codes, in order to identify particular quality attributes

Precise specification of the quantity or ratio of each raw material or intermediate used, including unit of measure. If the quantity is not established, the calculation for each batch size or production rate should be included. Variations to quantities should be specified where justified.

The manufacturing location and the equipment to be used

Reference to manufacturing instructions, including:

  • Sequence of processing steps to be followed,
  • Ranges for the process parameters to be used,
  • Instructions for sampling and in-process controls, if applicable including acceptance criteria
  • Time limit for execution of individual processing steps and/or the overall process.

The expected yield range in suitable phases of processing or at particular times.

Any specific notes and precautions (or cross references to these), if necessary.

If applicable instructions for the storage of intermediates or APIs, the labelling and packaging materials.

5 Batch Production Records
(Batch Production and Control Records)

An investigation has to be set up at every critical deviation when the origin of the deviation or when the impact on the product quality isn't known. A SOP on investigations of critical process deviations should define what is to be understood by critical. Compare other (related) batches with the same deviation (see figure 7).

Figure 7 Contents of the batch records in accordance with ICH Q7A

Content of batch records:

  • Date and, if applicable, times
  • Identity of the equipment used
  • Specific identification of each batch of raw materials, including weights, measures, and batch numbers
  • Any sampling performed
  • Signatures of persons who executed critical operating steps and persons directly supervising or checking these
  • Results of in-process controls and laboratory tests
  • Actual yield in the corresponding phases or times, if applicable
  • A representative label of the API or intermediate, if this is for commercial sale
  • Any deviations noted, its associated evaluation and investigation (or reference to these, if investigation reports are contained in a separate document)
  • Results of release testing

6 Laboratory Control Records

Graphs, charts and spectra can be added to the control record or can be stored separately. In the latter case these documents should be easily retrievable.

These documents should be signed and dated by the person who performed the test. A reference to the identification of the sample analysed should be included.

The secondary review of the original records only needs to be done when the complete analysis of a sample of a batch has been performed. This can be done on a sheet/record where all results have been summarised.

Modifications of analytical methods should be subject to change control and considered for revalidation prior to introduction.

7 Batch Production Record Review

"Established specifications" can not always be limited to pharmacopoeia specifications, also additional in-house specifications could apply.

During a batch record review check for

  • missing records and out-prints
  • incomplete entries
  • illegible corrections
  • equipment maintenance, breakdown and replacement
  • valid calibrations and service intervals of test equipment (as a useful cross check to routine control of test equipment)
  • reports on OOS-results
  • completeness of deviation reports
  • impact of reported deviations on product quality
  • compliance with specifications, parameter ranges or acceptance criteria including tighter customer specifications
  • usage decision

Summary

The compilation, approval, distribution and administration of documents should be defined. The use, cleaning and maintenance of larger equipment has to be documented in a traceable record (log book). Master batch records should be approved by the quality unit. The issuing of batch records based on master records must be controlled. Batch and test records must be reviewed according to a written defined procedure. It is possible for the quality unit to delegate the review of batch and test records for intermediates (if they are not for commercial use) and for non-critical manufacturing and control record.



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