1. Purpose
The purpose of this guideline is to define the content of Batch Specific Documentation (BSD), the process by which BSD is produced and the use to which it is put. BSD in this context refers to the Certificate of Analysis, (CofA) and the Certificate of Manufacture (CofM).
The Standard for Batch Specific Documentation that is described within this guideline can be summarized as:
Standard Certificate Formats:
– Certificate of Manufacturing
– Certificate of Analysis
– Certificate of Analysis under Mutual Recognition Agreement (MRA)
Electronic Signatures for all Batch Specific Documentation No transcription of analytical results by Packing Site – use Production Site data and CofA directly Certificates available as Adobe PDF files
2. Scope and Applicability
This Guideline is applicable to all Operations sites issuing CofA and C of M.
For materials distributed to other sister sites or customers for commercial use. BSD used for compliance, importation, financial and regulatory purposes is within the scope of this procedure.
For product received from an external source, the Operations Site concerned should require the same standard of documentation.
3. Definitions
3.1 Certificate of Analysis (C of A)
A batch specific document issued by a manufacturer, vendor or exporter that contains all of the information given on a Certificate of Manufacture (CofM) but in addition also has the analytical results and specification limits for the referenced batch.
3.2 Certificate of Manufacture (C of M)
A batch specific document issued by a manufacturer, vendor or exporter that attests that the batch meets the specifications and has been produced in accordance with the requirements of the Regulatory Authority approval and with cGMP.
3.4 Batch Specific Documentation (BSD)
BSD refers to the Certificate of Analysis, (CofA) and the Certificate of Manufacture (CofM).
3.5 Certificate of Analysis for Mutual Recognition Agreements (MRA)
A batch specific document issued by the fabricator/manufacturer in the exporting country to accompany batches transferred between countries having an MRA in force with one another. This certificate attests that the batch meets the specifications and has been produced in accordance with the requirements of the
Regulatory Authority approval and with cGMP. In addition to the clauses required for a standard CofA it also contains references to the importing country and the Manufacturing and Marketing Authorizations.
3.6 QA/Compliance Unit
An organizationally distinct group established within a Production Site that provides assurance to line management that the site has established and is maintaining the necessary systems and procedures required to comply with the internal and external standards of GMP as appropriate. Sometimes referred to as QA throughout this guideline.
3.7 Supply Agreement
The supply of product to Marketing Companies and Distributors within individual countries is managed by the supply organizations associated with each of the production sites. There is a single Supply Agreement between each of the supply points and their customers, the supply agreements are managed by the supply point account managers.
3.8 Market Specific Requirements
These are the market specific requirements for the provision of BSD to customers and are held as an appendix to this guideline (Appendix VIII). These requirements are for customers external to the company, they are not for internal
Operations supply – when bulk finished products are shipped between Operations manufacturing sites for further processing CofA are always needed.
4. Responsibilities
4.1 It is the responsibility of the QA/Compliance Unit Manager to generate a CofA or CofM upon request.
4.2 It is the responsibility of each Operations QA/Compliance Unit to put in place procedures for the generation and issue of CofA and CofM. There must be a record kept of the recipient.
4.3 It is the responsibility of each Supply Point Account Manager working in coordination with the Supply Point QA and supply organizations to ensure that the market specific requirements for provision of BSD are discussed and agreed with the receiving customer for a particular market.
In a European context the issue of any BSD presupposes that Annex 16 Chapter 2.1 of EU Directive 2003/94 is fulfilled: Each batch of finished product must be certified by a Qualified Person within the EC/EEA before being released for sale or supply in the EC/EEA or for export.
5. Guideline
The process for agreement, generation and delivery of BSD is shown schematically in Appendix I.
5.1 Document Types
The type of batch specific documentation to be supplied varies depending upon the customer’s needs. It can range from no documents through to a CofA signed with a wet-ink signature.
The options for providing BSD to external customers are, in descending order of preference;
i) No documentation.
ii) Certificate of Manufacture.
iii) External Certificate of Analysis.
iv) Certificate of Analysis for Mutual Recognition Agreement markets.
An Internal CofA is used to support transfer of bulk-finished products between manufacturing sites. A Raw Material CofA is used for API, intermediates and excipients.
The standard language to be used is English.
5.2 Certificates for Registration Samples
The registration and license renewal processes for products may require the company to send samples to the Regulatory Authorities. These samples require BSD to be provided. In all cases CofA should be provided, CofM are not acceptable. However the normal market specific CofA for finished product, including electronic signature is acceptable. In exceptional circumstances it may be necessary to produce a version that is signed manually i.e. wet ink signature.
5.3 Signatures
When BSD is required it must be signed. If it is generated by a validated data management system e.g. LIMS, then an electronic signature is acceptable and there is no requirement to further sign the documents with ink. Only in exceptional circumstances should a document be manually signed.
The vast majority of markets and customers will accept an electronically signed document.
5.4 Exchange of Certificates between QA units
When materials are made at one manufacturing site and then shipped to another site, for further processing, two key pieces of information must be transferred between the QA units of the sites involved:
* The analytical results.
* The confirmation that the batch has been made in full compliance with GMP and Marketing Authorization/ NDA requirements.
Analysis of the drug substance or finished product usually takes place at the manufacturing site and is not repeated at the subsequent processing site.
Analytical results are transferred to the next site in the processing chain either via a Raw Material CofA for transfers of drug substance or via an Internal CofA for transfer of finished product.
The Internal CofA must not contain acceptance criteria for more than one market. If at the time of manufacture of the bulk finished product the final destination market is unknown the material should be supplied with an Internal CofA suitable for the country of the receiving packing site. Once the final destination is known and if the original Internal CofA is not suitable then a market specific Internal CofA should be requested.
The QA unit at the manufacturing site ensures manufacture has taken place according to GMP and regulatory license requirements. Confirmation of batch compliance is then given on the Raw Material CofA or the Internal CofA.
The product is suitable for use in all markets unless a market restriction applies. Any such restriction must be given on the Raw Material CofA or Internal CofA using either:
‘Suitable for use in ……..’
or
‘Marketing Authorization excludes supply to market(s)……..’
When an External CofA is required. The packing site attaches the Internal CofA to a document that links the manufacturing and packing steps. Primarily this is a document stating both the bulk batch number and the packed batch number.
Together the Internal CofA and the linking document make up the External CofA that is delivered to a customer.
5.5 Agreement of Market Specific Requirements
The market specific requirements are recorded in this guideline. The Supply Point Account Manager, the local site QA, and the local supply organizations should agree any deviation from this guideline
5.6 Generation and Delivery of Batch Specific Documentation
To facilitate the transmission of information between sites and to customers the BSD should be made available in Adobe Portable Document format PDF.
The QA/Compliance Unit should generate a PDF file version of the appropriate BSD for supply with the product. It may be necessary to also produce a hard copy version of the BSD. The BSD will be given to the supply organizations to forward the document to the customer. By prior agreement BSD may be sent directly to the identified customer by the QA function.
5.7 Content of Batch Specific Documentation
The guidance given here is to define the standard requirements for BSD. Any deviations from the information content shown in the templates should be avoided. BSD generated by sites within the European Union must include the name of the Qualified Person certifying the batch. The text suggested is ‘Qualified Person according to the requirements of Directive 2001/83/EC’
The different types of BSD are very similar with much of the information being the same on each document.
5.7.1 Certificate of Manufacture
The certificate must contain the following information:
* Title: Certificate of Manufacture.
* Market Specific Trade name, Strength, Dosage Form and Package Size.
* Batch number as printed on the pack.
* Date of manufacture and Expiry date, entered as Month Year or Year
* Month, with the year as four digits e.g., 07/2003 or 2003/07 or July 2003 are all acceptable.
* Name of Manufacturer, this is defined as the site carrying out the last manufacturing step e.g. packaging and therefore generating the Certificateand releasing . Using company letter headed paper and adding the name of the relevant company Legal Entity should normally meet this requirement.
* Address of the Manufacturer, this is defined as the site carrying out the last manufacturing step e.g. packaging and therefore generating the Certificate.
* GMP statement and conclusion.
* Name, title and full signature/date of person responsible for the release of the material. For certificates generated electronically from a validated Laboratory Information Management System the signature should be in the form of an electronic signature assigned as the document is produced.
* When the original document is generated manually then the signature should be hand written.
* Date of release entered as Day, Month, and Year e.g. 1st August 2003. If figures are used e.g. 01/08/2003 there is a danger of confusion between the USA and European conventions on date expression. Clarity is the objective.
* If appropriate a statement indicating that the document has been electronically signed.
* The Certificate of Manufacture should be in English.
5.7.2 External Certificate of Analysis Type I
(For external supply of Finished Product).
When all of the production activities have taken place at one site it will be possible to produce an External CofA without having to refer to an Internal CofA that has been generated by another site.
The external CofA will contain all of the information held on the Certificate of Manufacture but in addition:
Registered tests as stated under ‘specification tests’ in the relevant Regulatory Documentation (e.g. MAA, NDS, NDA) for the particular market.
Reference to the procedures used e.g. Strength by HPLC.
Acceptance criteria for each test as stated according to MAA/NDS/NDA with corresponding units and reference to pharmacopoeia as appropriate.
This includes the registered text for Description.
Numerical values and/or limits should be written with the corresponding units.
Results should be reported to the number of significant figures stated in the specification with the exception that degradation products should normally be reported to 2 decimal places.
For identification: reference should be made to the ‘Approved test(s)’.
Numerical results should apply whenever the specification is numerical (units are optional if stated under specifications). For tests measuring individual dosage units, e.g. content of uniformity, it is permissible to indicate the range and average of results.
For semi-quantitative tests, results should be reported as ‘less then x units’ or within a given interval.
For impurities, numerical results should be reported if applicable ‘< detection limit (numerical + units)’ should be reported.
Non numerical results should be reported as required e.g. complies, approved or conforms.
5.7.3 MRA Certificate of Analysis
(For supply to countries having an MRA)
When moving materials between countries that have a Mutual Recognition Agreement in place it is necessary to provide an External CofA with the following additional information:
* Product License/Marketing Authorization number of the importing country.
* Manufacturing Authorization / License Number.
* Importing country.
Additional specific information is required for BSD to supply Japan and Canada. Agreement on the exact content must be reached between the relevant QA units.
5.7.4 Internal Certificate of Analysis
(For Internal Shipment of Bulk Finished Product)
When bulk finished product is manufactured at one Operations Site for packaging at a second sister site it is necessary to provide an Internal CofA that contains the analytical results and a statement of batch compliance.
The Internal CofA is identical to the External CofA Type I except:
* There is no expiry date. Removal of this avoids an apparent conflict between the expiry dates for bulk finished product and finished pack stock. Expiry life information should be held separately.
* The batch compliance statement is generalized and does not make reference to specific Marketing Authorizations/Product Licenses.
A market restriction may apply. Any such restriction will be given on the Internal CofA using either:
* ‘Suitable for use in ’ Or
* ‘Marketing Authorization excludes supply to market(s) ’
When a batch of finished product is manufactured it is often not known to which market the product will be directed and this is not known until the batch has been allocated for packing. It can therefore be difficult for a CofA to be generated at the bulk finished product site that is relevant to the final destination market. In the first case the Internal CofA should be produced to fulfill the specification requirements of the country in which the receiving site is based. Subsequently the correct market specific Internal CofA should be requested by the receiving site from the bulk finished product site.
As remote access to BSD becomes available it will be possible for the packaging site to select for themselves the correct market specific CofA.
5.7.5 External Certificate of Analysis Type II
(for external supply when Bulk Finished Product has not been made at the Packaging Site)
If a market requires a CofA it is necessary to attach the Internal CofA with a linking document that certifies the final stage of manufacture.
The External CofA sent to the customer is then composed of two documents;
* External CofA Type II that links to the:
* Internal CofA (for bulk finished product).
The External CofA Type II is identical to the Certificate of Manufacture referred to in 5.8.1 but with fields for the bulk batch number and the packing batch number.
It is the responsibility of the QA/Compliance unit of the final release site to ensure that the product complies with the specification of the final destination country.
5.7.6 Raw Material Certificate of Analysis
(for API, Intermediate and Excipient).
This CofA complies with the requirements stated in ICH Q7a and is designed for internal use and for contractors. It is very similar to that used for internal transfer of bulk finished product but with the following differences:
* Intermediates may be named using an agreed trivial name.
* Excipients should be named as stated in the pharmacopoeia.
* Any deviations from this guideline should be justified.
5.8 Market Specific Requirements Database
MRAs are in place between the European Union and Australia, Switzerland, Japan, Canada and New Zealand. The MRA CofA therefore only applies to materials supplied between these countries and the EU. Without an MRA materials should be supplied with one of the other CofA as appropriate.