Documents required

1. 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 and packaging materials

2. Specifications for starting and primary or printed packaging materials should include, 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 possible, the original producer of the products;
·         ?a specimen of printed materials;

b) Directions for sampling and testing or reference to procedures;

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
3. Specifications 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 for finished products, as appropriate.

Specifications for finished products
4. Specifications for finished products should include:
a) The designated name of the product and the code reference where applicable;

b) The formula or a reference to;

c) A description of the pharmaceutical form and package details;

d) Directions for sampling and testing or a reference to procedures;

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.

Manufacturing formula and processing instructions
Formally authorized Manufacturing Formula and Processing Instructions should exist for each product and batch size to be manufactured. They are often combined in one document.  The Manufacturing Formula should include:
a) The name of the product, with a product reference code relating to its specification;

b) A description of the pharmaceutical form, strength of the product and batch size;

c) A list of all starting materials to be used, with the amount of each, described using the designated 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;

d) A statement of the expected final yield with the acceptable limits, and of relevant intermediate yields, where applicable.

The Processing Instructions should include:
a) A statement of the processing location and the principal equipment to be used;

b) The methods, or reference to the methods, to be used for preparing the critical equipment (e.g. cleaning, assembling, calibrating, sterilizing);

c) Detailed stepwise processing instructions (e.g. checks on materials, pretreatments, sequence for adding materials, mixing times, temperatures);

d) The instructions for any in-process controls with their limits;

e) Where necessary, the requirements for bulk storage of the products; including the container, labeling and special storage conditions where applicable;

f) Any special precautions to be observed.

Packaging instructions
There should be formally authorized Packaging Instructions for each product for pack size and type. These should normally include, or have a reference to, the following:
a) Name of the product;

b) Description of its pharmaceutical form, and strength where applicable;

c) The pack size expressed in terms of the number, weight or volume of the product in the final container;

d) 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 specifications of each packaging material;

e) Where appropriate, an example or reproduction of the relevant printed packaging materials, and specimens indicating where to apply batch number references, and shelf-life of the product;

f) Special precautions to be observed, including a careful examination of the area and equipment in order to ascertain the line clearance before operations begin;

g) A description of the packaging operation, including any significant subsidiary operations, and equipment to be used;

h) Details of in-process controls with instructions for sampling and acceptance limits.

Batch processing records
A Batch Processing Record should be kept for each batch processed. It should be based on the relevant parts of the currently approved Manufacturing Formula and Processing Instructions. 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 process, 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:
a) The name of the product;

b) Dates and times of commencement, of significant intermediate stages and of completion of production;

c) Name of the person responsible for each stage of production;

d) Initials of the operator of different significant steps of production and, where appropriate, of the person who checked each of these operations (e.g. weighing);

e) The batch number and/or analytical control number as well as the quantities of each starting material actually weighed (including the batch number and amount of any recovered or reprocessed material added);

f) Any relevant processing operation or event and major equipment used;

g) A record of the in-process controls and the initials of the person(s) carrying them out, and the results obtained;

h) The amount of product yield obtained at different and pertinent stages of manufacture;

i) Notes on special problems including details, with signed authorization for any deviation from the Manufacturing Formula and Processing Instructions.

Batch packaging records
A Batch Packaging Record should be kept for each batch or part batch processed. It should be based on the relevant parts of the Packaging Instructions and the method of preparation of such records should be designed to avoid transcription errors. The record should carry the batch number and the quantity of bulk product to be packed, as well as 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 operations, 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:
a) The name of the product;

b) The date(s) and times of the packaging operations;

c) The name of the responsible person carrying out the packaging operation;

d) The initials of the operators of the different significant steps;

e) Records of checks for identity and conformity with the Packaging Instructions including the results of in-process controls;

f) Details of the packaging operations carried out, including references to equipment and the packaging lines used;

g) Whenever possible, samples of printed packaging materials used, including specimens of the batch coding, expiry dating and any additional overprinting;

h) Notes on any special problems or unusual events including details with signed authorization for any deviation from the Manufacturing Formula and Processing Instructions;

i) 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. (M.H.R.A., PIC/S GMP Guide)


Equipment cleaning and use log
·         A written record of major equipment cleaning, maintenance (except routine maintenance such as lubrication and adjustments), and use shall be included in individual equipment logs that show the date, time, product, and lot number of each batch processed.

·         If equipment is dedicated to manufacture of one product, then individual equipment logs are not required, provided that lots or batches of such product follow in numerical order and are manufactured in numerical sequence.

·         In cases where dedicated equipment is employed, the records of cleaning, maintenance, and use shall be part of the batch record.

·         The persons performing and double-checking the cleaning and maintenance shall date and sign or initial the log indicating that the work was performed. Entries in the log shall be in chronological order.

·         This section requires written designation of which equipment is ‘‘major.’’ The intent of the regulations is not to include small items such as ladles, scoops, stirrers, and spatulas. The exclusion of ‘‘no major’’ items from the recordkeeping requirement does not, however, exclude them from the requirements that they be properly cleaned.

·         Because the log is for a repetitive operation, the record may be initialed rather than signed. Note that a separate log, which may be a completely separately bound volume, or consecutive pages in a bound or loose-leaf format, or a number of individual records or logs is required for each piece of major equipment that is not dedicated to the manufacture of a single product.

·         The issue of signatures and initials has involved considerable industry–FDA interaction. As new computerized technology became available it was possible to move to paperless control of manufacturing processes. These computerized controls had several advantages over manual systems:
1.      More consistent control.
2.      Only approved (trained) personnel could perform a process.
3.      Processing could be prevented until any prior steps or checks were performed.
4.      Precise recording of the times of operations were possible.

·         Electronic signatures/initials frequently involve a personal password and a personal magnetic card with a secure system to manage allocation and review.

Packaging and labeling records
These records shall include the following:
(a) The identity and quantity of each shipment of each lot of components, drug product containers, closures, and labeling; the name of the supplier; the supplier’s lot number(s) if known; the receiving code as specified in  and the date of receipt. The name and location of the prime manufacturer, if different from the supplier, shall be listed if known.

(b) The results of any test or examination performed including those performed as required by and the conclusions derived there from.

(c) An individual inventory record of each component, drug product container and closure and, for each component, a reconciliation of the use of each lot of such component. The inventory record shall contain sufficient information to allow determination of any batch or lot of drug product associated with the use of each component, drug product container and closure.

(d) Documentation of the examination and review of labels and labeling for conformity with established specifications.

(e) The disposition of rejected components, drug product containers, closure, and labeling.

Laboratory records
Documentation is important in all types of activities in an organization but in a laboratory it is extremely critical.

(a) Laboratory records shall include complete data derived from all tests necessary to assure compliance with established specifications and standards, including examinations and assays, as follows:
(1) A description of the sample received for testing with identification of source (that is, location from where sample was obtained), quantity, lot number or other distinctive code, date sample was taken, and date sample was received for testing.
(2) A statement of each method used in the testing of the sample. The statement shall indicate the locations of data that establish that the methods used in the testing of the sample meet proper standards of accuracy and reliability as applied to the product tested. (If the method employed is in the current revision of the United States Pharmacopeia, National Formulary, Association of Official Analytical Chemists, Book of Methods, or in other recognized standard references, or is detailed in an approved new drug application and the referenced method is not modified, a statement indicating the method and reference will suffice.)



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