Preparation, Approval, Review, and Control of Technical Directions for the Manufacture of Drug Products
Objective
To lay down a procedure for the Preparation, Approval, Review, and Control of Technical Directions for Manufacture of Drug Products.
Scope
This Standard Operating Procedure is applicable for the preparation and implementation of Technical Directions for all products manufactured at all pharmaceutical formulation plants.
Responsibility
Scientists, FRD and Process Development or Scientist, Documentation Cell, shall be responsible for the preparation, and review of Technical Directions (manufacturing procedure).
Scientist, Packaging Development shall be responsible for the preparation of the Technical Directions (packaging procedure), and In-charge/designee, Packaging Development shall be responsible for reviewing the Technical Direction.
The head-R&D/Designee shall be responsible for approving the Technical Directions (Manufacturing and Packaging).
Head- Production/Contract manufacturing, or designee and Head-RA or designees shall be responsible for approval of Technical directions.
Head-QA shall be responsible for final approval of Technical directions.
The head QA and Plant Head shall be responsible for the implementation and compliance of this SOP.
The Head, of Contract Manufacturing shall be responsible for the implementation and compliance of the Technical Directions at the Contract Manufacturing Site during the manufacture of the product(s).
Abbreviations and Definitions
TDs: Technical Directions: Document, which reveals all approved instructions regarding the 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 two separate parts- Technical Directions detailing the Manufacturing procedure and Technical Directions detailing the Packaging procedure. Technical Directions shall always be a part of BMR and shall be prepared with a provision of recordings, which shall be done during the 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 a computer and shall be typed in font face ‘Times New Roman’ with font size ‘12’ (especially for the narrative text) and 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 :
Weighment Sheet.
Manufacturing Instructions.
TDs detailing packaging procedure shall comprise of :
Packaging Order.
Packaging Instructions.
All pages of the TDs i.e. Weighment Sheet, Manufacturing Instructions, Packaging Order, and Packaging Instructions shall have the following information:
In case, if product is manufactured within the plant, mention the address of the manufacturing site at the top center of all pages and if the product is manufactured from contract manufacturing, mention the name and address of the contract manufacturing site followed by ‘For Company name.’ at the top center of all pages.
‘Product Code’; a unique numerical code assigned to the product by Doc. Cell (R & D). In case of Technical Directions detailing manufacturing procedure, the three unique numeric characters (which shall always constitute the second, third, and fourth characters of 10 characters Finished Product Code assigned as per SOP titled ‘Assigning Item Codes to Raw Materials, Packaging Materials, In-process Materials and Finished Products’) suffixed with batch size notation shall be mentioned here. Batch size notation shall be given as ‘A’ for one batch size, ‘B’ for another batch size and so on e.g. in the case of a product with 010 unique numeric characters, 010A shall be mentioned for one batch size, and 010B for another batch size of the same product and likewise.
In the case of TD detailing the packaging procedure Finished Product Code (Refer to SOP titled ‘Assigning Item Codes to Raw Materials, Packaging Materials, In-process Materials and Finished Products’) shall be mentioned under the column ‘Product Code’.
‘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 ‘Location code – Product Code – Serial number which denotes pack size – Sales/Physician Samples etc.. – Market Code – Revision number’, Similarly ‘S’ shall be replaced by ‘G’ for Government Supply, ‘C’ for Clinical Trials, In packaging formula number, the market shall be coded as:
Note: A list of Market codes shall be prepared and maintained by R&D and its time-to-time circulation shall be made by R&D to different concerned departments, whenever required.
‘Supersedes’; the concerned scientist shall mention the superseded master formula number/packaging formula number against this column.
‘Master Formula No.’; Master formula number is a unique number given by the concerned Scientist in the form of ‘Location code – product code – batch size notation – revision number’.
Note: Also Refer to SOP for assigning Master Formula Number and Packaging Formula Number in new TDs.
‘Market’ for which the product shall be distributed.
‘Shelf Life’; the maximum assigned shelf life for the product in months shall be mentioned by the concerned scientist.
‘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. Technical directions shall be revised as and when required.
‘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 purposes, Quality Assurance shall mention (by hand/Machine) the batch number of the product for which the technical directions are to be issued, Batch Number shall be given as per SOP. In case of issuance of BMR for contract manufacturing, Batch Number shall be given as per SOP titled ‘Batch Numbering System at Contract Manufacturing Locations’.
‘Mfg. Date’ (Manufacturing date) and ‘Exp. Date’ (Expiry date); Production shall fill the manufacturing date/ expiry date of the batch under these columns as per SOP titled ‘Assigning Manufacturing and Expiry dates to the Finished products during Manufacturing’).
In the case of Packaging TDs, ‘Pack Size’ describes the type of pack and pack size e.g. Blister 10 x10’s, Glass Bottle 30 ml or PET Bottle 100 ml, etc.
‘Page No’ (Page number); page number shall be mentioned in a running format i.e. first page of eleven-page manufacturing instructions shall be written as 01 of 11 and the 10th page shall be written as 10 of 11. The weight sheets and manufacturing instructions shall be numbered separately, in case of manufacturing TDs, and case of Packaging TDs, Packaging Order and Packaging Instructions shall be numbered separately.
‘Product Name’; the brand name of the product shall be mentioned. In case of Packaging Order and for Packaging Instructions for the physician sample, the brand name ‘PS’ shall be written in parenthesis.
‘Generic Name’; the Generic name of the product shall be mentioned.
‘Label Claim’; the label claim of the product shall be mentioned against this column. In case a product contains seven to eight actives, then the label claim, if not getting accommodated in the provided space, can be mentioned in a separate page giving cross reference of this page in this column and this page shall be the last page of the TDs (manufacturing/ Packaging). In the case of tablets or other formulations, the color (s) used can be mentioned underneath the label claim.
“Standard Batch Size” in case of Packaging procedure describing that materials shall be dispensed as per the standard batch size of the dosage form.
Tablets:100, 000 tablets (no. of strips)
Capsules:100, 000 capsules (no. of strips)
Oral liquid:1000 liters liquid (no. of bottles)
Injections:100 liters of solution (no. of vials)
Granules:100 kg granules (no. of containers)
‘Actual Batch Size’, Batch size required for the packaging purpose.
Batch Size (In manufacturing procedure); the Batch size of the product shall be mentioned e.g. for a batch size of 3.0 lakh tablets, the batch size shall be written as 3 00,000 tablets.
The designated persons or their designee from the mentioned department shall signature with name and date in the assigned columns as per responsibility.
All entries (except Batch No., Mfg. Date, Exp. Date, 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 shall be made in hand by using a good quality ballpoint pen preferably in Black ink.
The Weighment Sheet shall contain all the relevant information related to the dispensing of raw materials.
The following columns shall be printed (by the concerned scientist responsible for TDs’ preparation).
‘S.No’; Serial Number; each ingredient/ raw material shall be numbered.
‘Ingredient’; mention all the ingredients starting with Active(s) which shall be dispensed for use in the manufacturing of the product. Raw material/ingredients shall be written in such a way that these shall be dispensed as per their sequence of addition concerning the quantity in the manufacturing process. The name of every ingredient shall be suffixed with its reference to specifications. Mention IP/BP/USP/USNF/Ph.Eur/IH, e.g. in case of Lactose with IP specifications, write Lactose IP.
Note: The weighment sheet shall be prepared in such a way that it can accommodate the scope of multiple weighing against one ingredient for its quantity and for its availability at Stores as different Batch Numbers
‘Item Code’; mention the item code assigned to the ingredient/raw material.
‘Qty/Unit (mg)’; Quantity per Unit in mg; this column head can be customized as per the requirement; mention as ‘Qty/cap’ or ‘Qty/tab’ or ‘Qty/5ml’ (in case of suspensions, etc.) or as ‘%w/w’ (in case of gelatin formula), etc.
‘Unit of Measurement’; Mention the unit in which the quantity shall be measured for dispensing e.g. kg, g, L, Nos. etc
‘Standard 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.
The following columns shall be filled (during the dispensing of raw materials by the concerned person(s) of the Production and Stores departments)
‘Required Quantity per batch to be dispensed’; after calculating the exact quantity of drug [active ingredient (s)], mention the quantity of active ingredient(s) to be dispensed along with other ingredients. If a quantity is being dispensed lot-wise, in case of processing in multiple lots, then lot-wise quantity (required) can be mentioned under this heading converting the title from ‘Required Qty/ batch’ to ‘Required Qty (Lot -1)’, in case of dispensing for first lot and likewise. All other ingredients, which shall not be dispensed in lots, can be written on separate weighment sheet(s) under the heading ‘Required Quantity per batch to be dispensed’.
‘Ingredient Batch No.’; It is the batch number of the ingredient which is to be dispensed.
‘Quantity Dispensed’; Quantity dispensed shall be mentioned under Tare weight, Net weight, and Gross weight notations.
The person responsible for dispensing the material shall sign with the date under the column ‘Dispensed by’ and the person responsible for checking of dispensed material shall sign with the 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 materials shall be carried out as per the respective SOP of the store department. In case of contract manufacturing, Dispensing of raw material shall be carried out under relevant Standard Operating Procedures available with a contract manufacturer.
‘Page No.’ on the weighment sheet shall be in continuation with ‘Page No.’ on the weighment sheet.
The Weighment Sheet shall be a sheet of calculations, which shall be done to evaluate the actual quantity of active ingredients to be dispensed. Calculation shall be done considering the Assay and Loss on Drying (LOD) or Water content of the Active Ingredient(s), in percentage. Due to changes in the quantity (ies) of Active Ingredient(s), the corresponding weight (batch weight) adjustments with another ingredient shall also be mentioned in this 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 the superseded version shall be mentioned in brief by the concerned scientist.
‘Precautions/ Instruction for manufacturing’; Proper handling of raw materials and other process-related precautions shall be mentioned, however, stage precautions, if any can also be given.
‘Checking of Weight/Volume’; The weight/ volume of all the ingredients shall be checked against this column, by the production personnel. (Refer to SOP titled ‘Requisition, Receiving, and Counter-checking of Issued Raw Materials’).
While preparing TDs, the Manufacturing Procedure shall be written with the interest of incorporating parallel information required/generating within the (execution of) TDs in the following manner. The manufacturing procedure shall be detailed step by step giving reference to various SOPs or other reference documents, if available. The manufacturing procedure or steps involving processing shall be written in the following manner (refer to the table given below).
| Manufacturing Procedure | Equipment/
Instrument Code |
Process Time | Done by | Checked by | |||
| Start | Over | Sign | Date | Sign | Date | ||
Note: If required, a list of SOPs or other requisite system documents and a list of equipment available at the Contract Manufacturing Site shall be provided to R&D by QA for the preparation of TDs for contract manufacturing accordingly
The following columns as defined in point no. 5.9.4, shall be filled during the manufacturing operations by the concerned production staff.
‘Equipment/ Instrument Code’; mention the Identity number or code of the equipment/ instrument used
‘Process Time’; time taken to perform operations like mixing, drying, etc. shall be mentioned preferably by considering the 24-hour clock.
Persons responsible for performing the operations as per TDs shall sign with the date in the columns ‘Done by’ and ‘Checked by’
Mention the range of expected yield in percentage for the relevant stage of the manufacturing process. However, for new products, the expected yield shall be based on knowledge of similar types of products. But after completion of five commercial scale batches or the first commercial campaign, the data shall be reviewed and if required, the necessary revision shall be made.
The ‘Packaging Order’ shall contain all the relevant dispensing information as specified in the respective format, for packaging materials.
Dispensing of packaging material shall be carried out per the relevant SOP In case of contract manufacturing, Dispensing of packaging material shall be carried out by the relevant Standard Operating Procedure available with a contract manufacturer.
Packaging Instructions shall be covered under the following heads.
‘History’; mention ‘New’ for new TDs and in case of revision, the reason for the 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 the Packaging Order shall be checked against this column, by the production people.
‘Overprinting Instructions’ required on the concerned packaging material shall be discussed under this heading.
While preparing TDs, the Packaging Procedure shall be written with the interest of incorporating parallel information required/generating within the (execution of) TDs, similarly as discussed in point no. 5.9.4, in the specified format. The 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 evaluation/ review concerning cGMP (Current Good Manufacturing Practices) standards, before finalization. In the case of contract manufacturing, after preparing the TDs, a draft copy of the same shall be forwarded to QA for evaluation/ review concerning cGMP (Current Good Manufacturing Practices) standards. The final draft of the TDs shall be forwarded to the Head, of Contract Manufacturing by QA for further evaluations concerning facilities available at the Contract Manufacturing Site. The head of the contract Manufacturing shall revert the draft copy of the TDs to QA with his/ her comments on it. Then, QA shall forward the same to R&D for necessary correction(s), if any. Draft copies shall be destroyed afterward.
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.
Note: The head of production (Contract Manufacturing) shall be responsible for guiding the production staff in recording/ filling the unfilled regulated TDs (BMR) at the contract manufacturing site during the manufacture of the product.
After approval of TDs, the Head, QA, or his / her designee shall put dates in the ‘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, and review and/ or revision of TDs.
All TDs shall be reviewed as and when required with change control procedure.
While issuing BMR (unfilled regulated copy of TDs for packaging) to Production, QA shall enter the 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.
R&D: Research and Development
Ph. Eur.: European Pharmacopoeia
USP: United States Pharmacopeia
BP : British Pharmacopoeia
IP : Indian Pharmacopoeia
RM: Raw Material
PM: Packaging Material
Prod.: Production
IH: In-House
USNF: United States National Formulary
FRD: Formulation Research & Development
Contract Acceptor: An organization responsible for doing job work for the contract giver.
Commercial: A set of production scale batches or commercial scale batches
Campaign: Taken together in tandem/ continuously during the manufacturing of a product.
Forms and Records
Specimen Format for Weighment Sheet (dispensing sheet) – Annexure-1
Specimen Format for Weighment Sheet (calculation sheet) – Annexure-2
Specimen Format for Manufacturing Instructions – Annexure-3
Specimen Format for Packaging Order – Annexure-4
Specimen Format for Packaging Instructions – Annexure-5
Distribution
Master Copy – Documentation Cell (Quality Assurance)
Controlled Copies – Documentation Cell (R&D), Production, Contract Manufacturing
