PRINCIPLE
Documentation is a part of management information system, and good
documentation constitutes an essential part of the quality assurance. Clear
documentation is fundamental for ensuring that each personnel receives clear
and detailed description of the relevant job assignment to minimize the risk
of misinterpretation and error, which are normally associated with habits of
communication by oral practice only. Specifications, Master Production
Document/Manufacturing Formula, procedures, methods and instructions, reports
and records must be free from errors and available in writing. The legibility
of documents is of paramount importance.
GENERAL
Specifications describe in detail the requirements with which the
products or materials used or obtained during manufacture have to conform. They
serve as a basis for quality evaluation.
Master Production Documents, Master Processing Procedure and Master
Packaging Procedure (Manufacturing Formulae, Processing and Packaging
Instruction) state all starting materials and packaging materials used and lay
down all processing and packaging operations.
Procedures give directions for performing certain operations e.g.
cleaning, clothing, environmental control, sampling, testing, and equipment
operations.
Records provide a history of each batch of product, including its
distribution, and also of all other relevant circumstances pertinent for the
quality of the final product.
Document should be designed, prepared, reviewed and distributed with
care. They should comply with the relevant parts of the manufacturing and
marketing authorization dossiers.
Documents should be approved, signed and dated by appropriate and
authorized persons.
Documents should have unambiguous contents; title, nature and purpose
should be clearly stated. They should be laid out in an orderly fashion and be
easy to check. Reproduced documents should be clear and legible. The
reproduction of working documents from master documents must not allow any
error to be introduced through the reproduction process.
Documents should be regularly reviewed and kept up-to-date. When a
document has been revised, systems should be operated to prevent inadvertent
use of superseded documents.
Document should not be hand-written; although, where documents require
the entry data; these entries may be made clear, legible, indelible
handwriting. Sufficient space should be provided for such entries.
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.
The 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
pharmaceutical products are traceable. They should be retained for at least one
year after the expiry date of the finished product.
Data may be recorded by electronic data processing systems, photographic
or other reliable means, but detailed procedures relating to the system in use
ought to be available, and the accuracy of the records should be checked. If
documentation is handled by electronic data processing methods, 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 password
or other means and the result of entry of critical data should be independently
checked. Batch records electronically stored
should be protected by back-up transfer on magnetic tape, microfilm, paper or
other means. It is particularly important that the data ready available
throughout the period of retention.
DOCUMENTS REQUIRED
Specifications
There should be appropriately authorized and dated specifications for
starting and packaging materials, and finished products; where appropriate,
they should be also available for intermediate or bulk products.
Specifications for Starting Materials
The specifications for starting materials should include, if applicable:
a description of the material, including
the designated name and the internal code reference;
the reference, if any, to a pharmacopoeial monograph;
the approved suppliers and, if possible, the original producer of the
material;
microbiological standards, if any;
directions for sampling and testing or reference to procedures;
qualitative and quantitative requirements with acceptance limits;
storage conditions and precautions; and
the maximum period of storage before re-examination.
Specifications for Packaging Materials
The specifications for packaging materials should include, if
applicable:
a description of the material, including
the designated name and the internal code reference;
the reference, if any, to a pharmacopoeial monograph;
the approved suppliers and, if possible, the original producer of the
material;
microbiological standards, if any; and
a specimen of printed materials, including colour;
directions for sampling and testing or reference to procedures;
qualitative and quantitative requirements with acceptance limits;
storage conditions and precautions; and
the maximum period of storage before re-examination.
Specifications for Intermediate and Bulk Products
Specification for intermediate and bulk products should be available if
these are purchased or dispatched, or if data obtained from intermediate products
are used for the evaluation of the finished product. The specifications should
be similar to specifications for starting materials or finished products, as
appropriate.
Specifications for
Finished Products
Specifications for finished products should include :
the designated name of the product and the code reference;
the formula or reference to;
a description of the pharmaceutical form and packaging details,
including pack size;
directions for sampling and testing or reference to procedures;
qualitative and quantitative requirements with acceptance limits;
storage conditions and any special handling precautions, where
applicable; and
the shelf-life.
Production Documents
The documents in production essentially are :
Master Production Document which contain the production formula of a
product in its dosage form and strength irrespective of the batch size;
Master Production Procedure consisting of Master Processing Procedure
and Master Packaging Procedure which contain a detailed procedure for
processing and packaging respectively of a product in its dosage form,
strength and specific batch size. The Master Production Procedure requires
validation before it is authorized for use; and
Batch Production Records consisting of Batch
Processing Record and Batch Packaging Record which are reproductions of their
respective Master Production Procedure and contain all data and information
related to the production of a batch of product. The Batch Production Records,
the procedure as out-lined in the Master Production Procedure, is sometime not
given in detail.
Master Production Document
A formally authorized Master Production Document should include the
product name, dosage form, strength and description, the writer's name and
department, name of verifier and list of document distribution and contain the
following data:
general information describing the type of primary packaging material to
be used or its alternative, statement of the product stability, safety
precautions during storage and other precautions to be taken during processing
and packaging of the product;
product composition or formula for one dosage unit as well as for a
sample of batch size;
a complete list of starting materials whether they remain unchanged or
become altered during processing;
specification of starting materials;
a complete list of packaging materials;
specification of primary packaging materials;
processing and packaging procedures;
list of equipment which may be used for processing and packaging;
in-process control during processing and packaging; and
product shelf-life.
Master Processing Procedure
A formally authorized Master Processing Procedure should exist for each
product and batch size to be manufactured. The Master Processing Procedure
should include:
the name of the product, with a product reference code
relating to the specification;
a description of the pharmaceutical form, strength of the product and
batch size;
a list of all starting materials to be used, with the amount of each,
described using the designate name and a reference which is unique to that
material; mention should be made of any substance that may disappear in the
course of processing;
a statement of the expected final yield with the
acceptable limits, and of the relevant intermediate yield, where applicable;
a statement of the processing location and the principal equipment to be
used;
the methods, or reference to the methods, to be used for preparing the
critical equipment (e.g. cleaning, assembling, calibrating, sterilizing);
detailed stepwise processing instructions (e.g. checks on materials,
pre-treatments, sequence for adding materials, mixing times, temperatures);
the instructions for any in-process controls with their limits;
where necessary, the requirement for bulk storage of
the products; including the container, labelling and special storage conditions
where applicable; and
any special precautions to be observed.
Master Packaging Procedure
There should be formally authorized Master Packaging Procedures for each
product for each batch size as well as pack size and type. This should normally
include, or have a reference to, the following:
name of the product;
description of its pharmaceutical form, and strength where applicable;
the pack size expressed in terms of the number, weight or volume of the
product in the final container;
a complete list of all the packaging materials required for a standard
batch size, including quantities, sizes and types, with the code or reference
number relating to the specification of each packaging material;
where appropriate, an example or reproduction of the relevant printed
packaging material, and specimens indicating where to apply batch number
references, and expiry date of the product batch;
special precaution to be observed, including a careful examination of
the area and equipment in order to ascertain the line clearance before
operations begin;
a description of the packaging operation, including any significant
subsidiary operations, and equipment to be used; and
details of in-process controls with instructions for sampling and
acceptance limits.
Batch Processing Record
A Batch Processing Record should be kept for each batch processed. It
should be based on the relevant parts of the currently approved Master
Processing Procedure. The method of preparation of such records should be
designed to avoid transcription errors. The record should carry the number of
the batch being manufactured.
Before any processing begins, there should be recorded checks that the
equipment and work station are clear of previous products, documents or
materials not required for the planned processing, and that equipment is clean
and suitable for use.
During processing, the following information should be recorded at the
time each action is taken and, after completion; the record should be dated and
signed in agreement by the person responsible for the processing operations:
the name of the product;
dates and times of commencement, of significant intermediate stages and
of completion of processing;
name of person responsible for each stage of processing;
initials of the operator of different significant steps of processing
and, where appropriate, of the person who checked each of these operations
(e.g. weighing);
the batch number and/or analytical control number as well as the
quantities of each starting material actually weighed or measured (including
the batch number and amount of any recovered or reprocessed material added);
any relevant processing operation or event and major equipment used;
a record of the in-process controls and the initials of the person(s)
carrying them out, and the results obtained;
the amount of product yield obtained at different and pertinent stages
of processing; and
notes on special problems including details, with signed authorization
for any deviation from the Master Processing Procedure.
Batch Packaging Record
A Batch Packaging Record should be kept for each batch packed. It should
be based on the relevant parts of the currently approved Master Packaging
Procedure and the method of preparation of such records should be designed to
avoid transcription errors. The record should carry the batch number and the
planned quantity of finished product that will be obtained.
Before any packaging operation begins, there should be recorded checks
that the equipment and work station are clear of previous products, documents
or materials not required for the planned packaging, and that equipment is
clean and suitable for use.
The following information should be entered at the time each action is
taken and, after completion; the record should be dated and signed in agreement
by the person(s) responsible for the packaging operations:
the name of the product;
the date(s) and times of the packaging operations;
the name of the responsible persons carrying out the packaging
operation;
the initials of the operators of different significant steps;
record of checks for identity and conformity with the Master Packaging
Procedure including the results of in-process controls;
details of the packaging operations carried out,
including references to equipment and the packaging lines used;
whenever possible, samples of printed packaging materials used,
including specimens of the batch coding, expiry dating and any additional
overprinting;
notes on any special problems or unusual events
including details with signed authorization for any deviation from the Master
Packaging Procedure; and
the quantities and reference number or identification
of all printed packaging materials and bulk product issued, used, destroyed or
returned to stock and the quantities of obtained product, in order to provide
for an adequate reconciliation.
Procedures and Records
Receipt
There should be written procedures and records for the receipt of each
delivery of each starting, primary and printed packaging material.
The records of the receipts should include:
the name of material on the delivery note and containers;
the “in-house” name and/or code of material [if different from a)];
date of receipt;
supplier’s name and, if possible, manufacturer’s name;
manufacturer’s batch or reference number;
total quantity, and number of containers received;
the batch number assigned after receipt; and
any relevant comment (e.g. state of the containers).
There should be written procedures for the internal
labelling quarantine and storage of starting materials, packaging materials and
other materials, as appropriate.
Sampling
There should be written procedures for sampling, which include the
person(s) authorized to take samples, the methods and equipment to be used, the
amounts to be taken and any precautions to be observed to avoid contamination
of the material or any deterioration in its quality (see Chapter 7, Sections
7.26. – 7.30.).
Testing
There should be written procedures for testing materials and products at
different stages of production, describing the methods and equipment to be
used. The tests performed should be recorded (see Chapter 7, Section 7.15.)
Others
Written release and rejection procedures should be available for
materials and products, and in particular for the release for sale of the
finished product by the head of Quality Management (Quality Assurance).
Records should be maintained of the distribution of each batch of a
product in order to facilitate the recall of the batch if necessary (see
Chapter 9).
There should be written procedures and the associated records of actions
to be taken or conclusions reached, where appropriate, for:
validation e.g. process, procedures, analytical
procedures, computerized systems;
equipment assembly, qualification and calibration;
maintenance, cleaning and sanitization;
personnel matters including training, clothing, hygiene;
environmental monitoring;
pest control;
complaints;
recalls; and
returns.
Clear operating procedures should be available for
major items of manufacturing and test equipment.
Log books should be kept for major or critical equipment recording, as
appropriate, any validations, calibrations, maintenance, cleaning or repair
operations, including the dates and identity of people who carried out these
operations.
Log books should also record in chronological order the use of major or
critical equipment and the areas where the products have been processed.
