1. Purpose
This document provides guidelines for the way in which the commercial manufacture and packaging of Active Pharmaceutical Ingredients (API) and formulated drug products should be documented.
2. Scope and Applicability
This Guideline describes documentation systems comprising:
– Master Formula
– Batch Production Record
– Batch Packaging Record
– Check-lists
– Computerized Systems
This Guideline applies to all APIs, formulated and packed drug products Manufactured.
3. Definitions
3.1 Starting Materials
Any material used in the production of an API, intermediate or a formulated product, but excluding packaging material. Starting material can be further defined as follows:
– Excipient – material used in the production of a formulated product (excluding APIs)
– Raw Material – material used in the production of an API or Intermediate. A raw material may be further classified as either a CRM (Contributory Raw Material) or an NCRM (Non contributory raw material) dependant on it’s role in the synthesis
3.2 Packaging Materials
Any material employed in the packaging of an API, intermediate or formulated product, excluding any packaging material used for transportation or shipment. Packaging materials are referred to as primary or secondary according to whether or not they are intended to be in direct contact with the product.
3.3 Master Formula
A Master Formula is a compendium of information that describes all aspects of the manufacture, packaging and control of an Active Pharmaceutical Ingredient (API) or formulated drug product.
It may exist as a single document or, more likely, as a series of separate documents maintained by functional groups within a manufacturing site. All Master Formulae are based on Chemistry, Manufacturing and Control (CMC) information registered in the markets that will be supplied with the API or formulated drug product.
In the case of products manufactured within a market for supply only to that market, i.e. local products, this CMC data may be supplied by the regulatory department of the local marketing company.
4. Responsibilities
4.1 It is the responsibility of Dossier Management Group (DMG), to produce CMC documentation that describes the manufacture and packaging of each commercial Active Pharmaceutical Ingredient (API) and formulated drug product or by a contractor on behalf of the contract giver site, that is consistent with the information approved by regulatory authorities in the markets for which the product will be supplied.
Note: CMC documentation does not include information about printed packaging components. For products manufactured within a market for supply only to that market, i.e. local products, this responsibility is with the marketing company concerned.
4.2 It is the responsibility of Dossier Management Group (DMG), to make the currently approved CMC documentation available to manufacturing sites and packaging sites, by the controlled distribution of the documents. For products manufactured within a market for supply only to that market, i.e. local products, this responsibility is with the market concerned.
4.3 It is the responsibility of the contract giver to supply CMC information to the contractor(s) it manages.
4.4 It is the responsibility of the manufacturing sites and packaging sites to prepare local, i.e. site specific, master formulae that are consistent with the CMC documentation and use these as a basis for the creation of master batch documents.
4.5 It is the responsibility of the manufacturing sites and packaging sites to document all manufacture and packaging on batch specific copies of their master batch documents, in line with cGMP requirements and expectations.
5. Guideline
5.1 Chemistry, Manufacturing and Control (CMC) Documentation
5.1.1 Contents
The documents (either electronic or paper copies) must comprise the minimum requirements reflecting market requirements. Contract giver should provide similar documentation to site contractors that are responsible for making their product(s).
5.1.2 Identification of Documents
All documents to be distributed must have a title describing the purpose of the document and documents must contain:
– Product name or material name
– Date of issue
– Edition/version reference
Information on markets for which the documents are applicable must be available. The document(s) must be paginated and have identifiers (e.g. product name, code number and edition/version number) on each page. Documents will be distributed electronically. Documents provided within a secure, internationally accessible information management system should contain the above identifiers either within the document or available as data associated with the document and accessible to any viewer of the document.
5.2 Manufacturing Documentation issued by Manufacturing/Packaging Sites
5.2.1 Master Formulae
Each site manufacturing and/or packaging its commercial products must create Master Formulae based on the CMC documents. The Master Formulae must be consistent with the relevant parts of the CMC documentation for the product, taking into account the requirements of the markets that the site supplies.
5.2.2 Master Batch Production Record
Site manufacturing a commercial API or formulated drug product must prepare product specific Master Batch Production Records relevant to manufacturing activities conducted at the site, based on the Master Formulae created by the site. The Master Batch Production Record must have a logical layout and be easy to follow. Documents must be identified with the company name as described in Section 5.1.2. They must be approved/issued through a controlled system. Master Production Batch Records may be prepared in local language. Contents and layout of the Master Batch Production Record should be as follows.
5.2.2.1 Starting Materials
Starting materials should be identified by their standard names and code numbers. The quantities for the specific batch size should be given with sufficient precision.
5.2.2.2 Instructions
Appropriate details of each process step must be described in chronological order and in sufficient detail to assure consistency from batch to batch.
The equipment to be used must be identified and any necessary settings specified. Appropriate environmental requirements for processing must be specified where necessary (e.g. temperature, humidity, air classification, etc). References to Standard Operating Procedures and check-lists must be given when applicable.
Checks and double-checks to be made must be indicated, where these are required. In-process controls, including alert/action/specification limits must be included. Any samples required must be included. Appropriate reconciliation checks and yield limits for major processing steps must be specified.
A statement of theoretical weight or measure for major processing steps must be included. A statement of theoretical yield including the maximum and minimum percentages of theoretical yield must be included. The identity of individual major equipment items and lines used must be identified.
5.2.2.3 Format and Layout
Sufficient space should be provided where data are to be entered, e.g. starting and finishing times, material control numbers, equipment settings, process parameter, observations, calculations and confirming initials.
Space should be provided for documenting the name and batch number of the preceding product prepared in major pieces of equipment to be entered, and for documenting verification of equipment cleaning. Alternatively, this information can be recorded in equipment logs, providing that the retention and disposal of such logs satisfy the requirements given in Section 5.3 – Retention and Disposal.
5.2.3 Master Batch Packaging Record
Site packaging a commercial API or formulated drug product must prepare Master Packaging Records relevant to the packaging activities conducted at the site, based on the specific Master Formulae prepared by the site.
In the case of some products, e.g. APIs, parenterals, primary packaging, including labeling of the primary container, is carried out as an integral part of the manufacturing process.
In such cases the Master Batch Packaging Record, or equivalent documentation, may be integrated within the Master Batch Record. The Master Batch Packaging Record must have a logical layout and be easy to read and follow.
Documents must be identified with the company name as described in Section 5.1.2. They must be approved/issued through a controlled system.
The contents and layout of the Master Batch Packaging Record should be as follows.
5.2.3.1 Materials
Bulk materials and packaging materials should be identified by their standard names and code numbers. The standard quantities of bulk material and packaging materials, including labels, required per unit should be given.
5.2.3.2 Instructions
The equipment to be used must be identified and any necessary settings specified. Appropriate environmental requirements for processing must be specified where necessary (e.g. temperature, humidity, air classification, etc). References to Standard Operating Procedures and check-lists should be given when applicable. Appropriate details of each packaging step should be given. Reconciliation* of printed packaging materials and yield calculations of the finished product should be requested and acceptance limits should be given. (* This may not be necessary when label verification is performed on line.) In-process control instructions should be included.
5.2.3.3 Format and Layout
Sufficient space should be provided where data are to be entered, e.g. starting and finishing times, material control numbers, equipment settings, calculations and confirming initials. Space should be provided for documenting the name and batch number of the preceding product packed to be entered, and for documenting verification of equipment cleaning and line clearance. Alternatively, this information can be recorded in equipment/line logs, providing that the retention and disposal of such logs satisfy the requirements given in Section 5.3 – Retention and Disposal.
5.2.4 Checklists/Generic cGMP Documents
5.2.4.1 Preparation
Where Master Batch Production/Packaging Records contain steps or stages that are common to several products, check-lists/generic cGMP documents may be prepared. They should comprise the details which other-wise would be repeated unnecessarily in the Batch Records. Documents should be identified with:
– Company name
– Date of issue
– Signature of approving/issuing persons
– Edition/version reference
– Reference to a superseded edition, if applicable
The document(s) should be paginated and have identifiers (e.g. code number and edition/version number) on each page. Examples of procedures where check-lists/generic cGMP documents can be of use are: line-clearance procedures or dismantling, cleaning and assembling of a machine. Sufficient space should be provided for entering data and confirming signature(s). The check-lists/generic cGMP documents should be approved/issued through a controlled system. The same processes as those used for Master Batch Production/Packaging Records may be used.
5.2.4.2 Use in Production
Before use, the check-list/generic cGMP documents should be clearly identified by product name, code number and batch number for the batch to be produced or packaged. All completed, dated and signed check-lists/generic cGMP documents should be attached to the respective batch documentation.
5.2.5 Batch Specific Copies of the Master Batch Production Record
5.2.5.1 Preparation
Each batch of APIs and formulated product must have a unique batch/lot number assigned. A batch specific copy to be used during the manufacture of a batch must be prepared from the Master Batch Production Record by e.g. photocopying or computer printing. The actual batch number must be entered on all pages of the copy. The individual responsible for preparing the batch specific copy should confirm by signing, the hard copy or by an electronically sign off if a validated computerized system is used, that the correct Master Batch Production Record has been copied/printed, that the correct batch number have been entered and that the copy/printout is completely legible before the Batch Production Record is given to the production department.
5.2.5.2 Use in Production
Upon receipt the production department should check that the received Batch Production Record is the one intended. During production all recordings required in the Batch Production Record should be entered concurrently, as the operations are performed. Data entries, calculations and checks performed should be confirmed as correct by signing or double signing as specified. Double-checking is required at least for charging-in, calculations and line clearance.
If an erroneous entry is made, it should be crossed out but left legible. The corrected entry should be signed and dated.
If the reason for the error is not immediately evident, a brief explanation should be documented at the time of the correction. Any temporary, unplanned deviation from the instructions should be documented at the time of occurrence and the reasons for the deviation investigated according to local procedures. Release of the batch (es) will be dependent on the outcome of these investigations.
Planned, but temporary, deviations from approved instructions should be handled through local change control procedures. Permanent changes to approved instructions should be handled by local change procedures.
Records created during processing, e.g. completed checklists, generic cGMP documents, diagrams, charts and graphs, should be identified by product name, batch number, date and signature and be attached to the batch documentation. After completion of each major stage in the production process the Batch Production Record should be checked by responsible or other appointed person.
The check should verify that the Batch Production Record has been correctly filled in and that the process parameters are within specified limits. The completed Batch Production Record, including any associated documentation (e.g. deviation reports), should be sent to Quality Assurance/Quality Control for evaluation and approval.
5.2.6 Batch Specific Copies of Master Batch Packaging Records
5.2.6.1 Preparation
For each specific batch or part of a batch to be packaged, one copy of the Master Batch Packaging Record must be produced by e.g. photocopying or computer printing. The actual batch number must be entered on all pages of the copy.
The amount of materials for an intended quantity to be packaged must be entered on this copy. The accuracy of this copy must be confirmed. The individual responsible for preparing the batch specific copy should confirm by signing, the hard copy or by an electronically sign off if a validated computerized system is used, that the correct Master Batch Production Record has been copied/printed, that correct quantities of material and correct batch number and expiration date (if applicable) have been entered and that the copy/printout is completely legible before the Batch Production Record is given to the production department.
5.2.6.2 Use during Packaging
The guidance given in Section 5.2.5.2 is applicable to the use of batch specific copies of the Master Batch Packaging Records. Specimens of container labels should be attached to the Batch Packaging Records, including those applied to containers used for storage and transportation of APIs, intermediates, and bulk/finished drug products.
5.3 Retention and Disposal
All Documentation identified in this Guideline falls within the definition of ‘GMP Documentation’ and its retention and disposal must be managed in accordance with approved procedure.
5.4 Documentation of Manufacture by means of Computerized Systems
When computerized systems are used, entirely or partly, for documentation of manufacturing the following additional prerequisites must be satisfied.
5.4.1 The instructions and recording of the manufacturing procedures must give the corresponding information as a paper-based system according to Section 5.2 above.
5.4.2 Traceability of materials used and recall of the history of the manufacturing must be equivalent to those exhibited by a paper-based system.
5.4.3 The personal responsibility for data entered into the documentation must be secured (by combination of password and identification number interlocked to each other or by other means of the same security).
5.4.4 It must not be possible to change or delete data entered into the system after the acceptance by the person entering it. Any correction thereafter must be recorded and previous entry must be readable and traceable.
5.4.5 The computerized documentation system must be validated according to established procedures. This must also include computerized systems inter- linked with the documentation system.
5.4.6 Retention of documentation must be secured by back-up systems of sufficient durability or otherwise by print-outs.
5.4.7 Previous versions of software used must be supported to assure that documentation conforms with the requirements of Section 5.3 – Retention and Disposal.