SOP on Preparation, Approval and Control of Technical Directions for Bulk Drug Preparation
Objective : To lay down a procedure for the preparation, approval and control of Technical Directions for manufacture of bulk drug preparation at contract manufacturing locations.
Scope : This Standard Operating Procedure is applicable for preparation and implementation of Technical Directions for all APIs manufactured at all plants.
Responsibility :Scientists, Process Development shall be responsible for preparation and checking of Technical Directions (manufacturing procedure).
Scientist, Packaging Development shall be responsible for preparation of the Technical Directions (packaging procedure) and Incharge, Packaging Development shall be responsible for checking.
Technical Directions shall be approved by respective department head or his/her designee of R&D, Production and Quality Assurance departments.
Abbreviations and Definitions
TDs: Technical Directions; It is a document, which describes complete set of approved instructions regarding manufacturing of the product starting from dispensing of raw materials, packaging materials, manufacturing and packaging operations including in-process checks and final dispatch for distribution, to get an appropriate quality of finished product. This document shall comprise of two separate parts- Technical Directions detailing Manufacturing procedure and Technical Directions detailing Packaging procedure. Technical Directions shall always be a part of BMR and shall be prepared with provision of recordings, which shall be done during manufacture of a product by the competent Production and Quality staff.
BMR: Batch Manufacturing Record; filled / unfilled controlled copy of Technical Directions along with other requisite forms/records, which reveals all the information of a batch of a product.
Procedure : The manufacturing or packaging procedures in the TDs shall be written in clear, easy to understand and unambiguous language.
TDs shall be generated on computer and shall be typed in font face ‘Times New Roman’ with font size ‘12’ (especially for the narrative text) printed on only one side of standard A-4 size white paper (with ‘landscape’ orientation) of appropriate quality in black ink.
TDs detailing manufacturing procedure shall comprise of : Cover Page – Manufacturing Instructions, Weighment Sheet ,Manufacturing Instructions.
TDs detailing packaging procedure shall comprise of : Cover Page – Packaging Instructions , Packaging Order ,Packaging Instructions.
Pages of the TDs i.e. Cover Page – Manufacturing Instructions, Weighment Sheet , Manufacturing Instructions , Cover Page – Packaging Instructions , Packaging Order and Packaging Instructions shall have the following information: Product Name: the brand name of the product shall be mentioned
‘Master Formula No.’; Master formula number is a unique number given by the concerned Scientist in the form as ‘Product Abbreviation-revision number batch size notation’ for TD of subsequent batch sizes e.g. For Location1 with batch size of 4,000 kg, the Master Formula No. shall be 1XXX-010-01A. For Location 2, with a batch size of 4000 kg, the master formula no. shall be 2XXX-010-01A. For Location 1 with batch size of 10,000 kg, the master formula no. shall be 1XXX-010-01B. For location 2 with batch size of 10,000 kg , the master formula no. shall be 2XXX-010-01B and so on.
Note: Also Refer SOP tilted ‘Assigning Master Formula Card Number, Master Formula Number and Packaging Formula Number to the Drug Products’ for assigning Master Formula Number and Packaging Formula Number in new TDs.
‘Supersedes’; the concerned scientist shall mention the superceded master formula number / packaging formula number against this column.
‘Effective Date’ is the date from which the implementation of Technical Directions shall commence. The effective date in Day-Month-Year (DD-MM-YY) format shall be given by Quality Assurance, by hand after approval of the Technical Directions.
‘Batch Size’; Batch size of the product shall be mentioned e.g. for a batch size of 400 kg of starting material, the batch size shall be written as 300 kg.
‘Batch No.’ (Batch Number); At the time of issuance of BMR, which is an unfilled controlled photocopy of Technical Directions along with relevant forms or attachments for recording purpose (Refer SOP titled ‘Issue, Receipt, Storage and Destruction of Batch Manufacturing Records’ of Quality Assurance department), Quality Assurance shall mention (by hand) the batch number of the product for which the technical directions are to be issued.
‘Batch started date and Batch Completed Date: Production shall fill the Batch started date and Batch Completed Date of the batch.
‘Pkg. Formula No.’; Packaging formula number is a unique number given by the Packaging Development Scientist to a Packaging Technical Directions in the form as ‘Product Abbr. (market code)-serial number which denotes pack size / batch size revision number notation.
‘Manufacturing Date’; Manufacturing date of the bulk drug preparation shall be date on which the process ends to give finished active material. The manufacturing date shall be put on the TD by Production department personnel after the end of processing steps.
‘Expiry Date’; the expiry date shall be the date during which the product is supposed to be within its approved specifications. The expiry date shall be put by the production department personnel.
‘Page No’ (Page number); page number shall be mentioned in a running format i.e. first page of seven page manufacturing instructions shall be written as 01 of 07 and second page of a three page weighment sheet shall be numbered as 02 of 03. The weighment sheets and manufacturing instructions shall be numbered separately, in case of manufacturing TDs and in case of Packaging TDs, Packaging Order and Packaging Instructions shall be numbered separately.
The designated persons or their designee from the mentioned department shall sign with name and date in the assigned columns as per responsibility mentioned in point 3.0
All entries (except Batch No., Effective Date, signatures with name and date of concerned persons for preparation, checking and approval, and Master Formula Number in Packaging Order and Packaging Instructions) shall be given by the scientist who is responsible for the preparation of TDs and hence shall be printed
Note: All the entries made in hand by the concerned personnel shall be in black ink. Weighment Sheet shall contain all the relevant information related to dispensing of raw materials. Following columns shall be printed (by the concerned scientist responsible for TDs’ preparation).
‘S.No’; Serial Number; each ingredient/ raw material shall be numbered.
‘Raw Material’; mention all the ingredients which shall be dispensed for use in manufacturing of the product. Raw material/ ingredient shall be written in such a way that these shall be dispensed as per their sequence of addition with respect to the quantity in the manufacturing process. The name of every ingredient shall be suffixed with its reference of specifications. Mention IP/BP/USP/USNF/Ph.Eur/IH, where IH stands for In-house specification e.g. in case of Lactose with IP specifications, write Lactose IP.
Note: Weighment sheet be prepared in such a way that it can accommodate the scope of multiple weighing’s against one ingredient for its quantity and for its availability at Stores as different Batch Numbers or (AR Nos.)
‘Item Code’; mention item code assigned to the ingredient/raw material.
‘Unit of Measurement’; Mention the unit in which the quantity shall be measured for dispensing e.g. kg, g, L, etc.
‘Qty per Batch’; Quantity per batch; It shall be a quantity required for the batch size. In case of dispensing the total batch quantity in lots, the same shall be mentioned in the weighment sheet e.g. if 40.0 kg of material is to be dispensed in 4 lots, the same shall be mentioned in column ‘Qty./batch’ as 4 x 10.0 kg. Following columns shall be filled (during the dispensing of raw materials by concerned person(s) of Production and Stores departments)
‘Quantity Dispensed’; Quantity dispensed shall be mentioned under Tare weight, Net weight and Gross weight notations.
‘AR No.’; Analytical Report Number of the dispensed batch of respective ingredient shall be mentioned.
Person responsible for dispensing of the material shall sign with date under the column ‘Dispensed by’ and person responsible for checking of dispensed material shall sign with date under the column ‘Checked by’
Note: If a batch is being processed in different lots then the provision of dispensing of raw materials using separate weighment sheets for every lot can be given during preparation of TDs.
Dispensing of raw material shall be carried out as per relevant SOP of Stores department.
‘Page No.’ on weighment sheet shall be in continuation with ‘Page No.’ on weighment sheet .
Manufacturing Instructions shall be covered under the following heads.
‘History’; mention ‘New’ for new TDs and in case of revision, the reason for revision from superseded version shall be mentioned in brief by the concerned scientist.
‘Precautions’; proper handling of raw materials and other process related precautions shall be mentioned, however stage wise precautions, if any can also be given.
While preparing TDs, Manufacturing Procedure shall be written with the interest of incorporating parallel information required/generating within the (execution of) TDs. Manufacturing procedure shall be detailed step by step giving reference of various SOPs or other reference documents, if available.
Mention the range of theoretical yield in percentage for relevant stage of manufacturing process. However for new products, the expected yield shall be based on knowledge of similar type of product. But after completion of five commercial scale batches, or first commercial campaign, the data shall be reviewed and if required, the necessary revision shall be made.
Packaging Order is for packaging materials. The packaging orders shall contain all the relevant dispensing information as specified in the respective formats, for packaging materials.
Packaging Instructions shall be covered under the following heads.
‘History’; mention ‘New’ for new TDs and in case of revision, the reason for revision shall be mentioned by the concerned scientist.
‘Precautions’; packaging operation related precautions shall be mentioned. Stage wise precautions, if any can also be mentioned in the TDs under this heading.
‘Checking of Quantities’; Packaging material(s) dispensed as per Packaging Order shall be checked against this column, by the production people.
‘Overprinting Instructions’, if any, required on the concerned packaging material shall be discussed under this heading.
While preparing TDs, Packaging Procedure shall be written with the interest of incorporating parallel information required/generating within the (execution of) TDs, in the specified format . Packaging procedure shall be detailed step by step giving reference of various SOPs or other reference documents covering various steps like primary packing, secondary packing tertiary packing, reconciliation of packaging materials and finished products including transfer of finished product to Quarantine Finished Goods Store and final yield, etc.
After preparing the TDs, a draft copy of the same shall be forwarded to QA for further evaluations/ review with respect to cGMP (Current Good Manufacturing Practices) standards, before finalization. Drafts shall be destroyed after finalization of TD.
While issuing BMR (unfilled regulated copy of TDs for packaging), QA shall enter Master Formula Number in the column ‘Master Formula No.’ along with the entry for Batch number in Packaging Order and Packaging Instructions.
No column or row in the technical directions shall be left blank and shall be appropriately filled by the production staff during recording against the defined procedure or instructions. Against no recording, write ‘NA’ or ‘Not Applicable’ in the relevant column and sign.
After approval of TDs, Head, QA or his / her designee shall put dates in ‘Effective Date’ column in DD-MM-YY format.
SOP titled ‘Document and Data Control’ shall be referred for preparation of Master copies and Controlled copies, distribution and retrieval of controlled copies, review and/ or revision of TDs.
All TDs shall be reviewed biennially i.e. once in two years. QA shall identify the TDs at least two months before approaching the end of two years from the effective date. QA shall initiate review process as per SOP titled ‘Document and Data Control’.