Topic 4 cgmp

• Bulk/Starting materials consist of:

  • API (active pharmaceutical ingredient): the active raw materials used in a drug that gives it the therapeutic effect
  • Inactive ingredient (Excipients - solids/liquids): ingredients that do not increase or affect the therapeutic action of the active ingredient
• Role of Excipients:

  • Supports maintaining the integrity of the drug during storage and transportation
  • Assists in the effectiveness and/or the delivery of drug use
  • Supports product identification and enhances attributes of overall safety
  • Protects, supports, and enhances stability, bioavailability, and patient acceptability
  • Aids in the processing of drug delivery system during the manufacturing process
• Materials are the physical starting point of drug manufacturing, especially critical for Parenteral products
• All materials must be suitably sourced, carefully inspected for purity and impurities, and obtained from approved suppliers with a certificate of analysis (CofA or COA)
• For liquids, containers/vessels must be thoroughly clean and supplied with cleaning certification to avoid mix-ups and aid materials tracking
• Materials identification by NIR linked to principal component analysis (PCA) or other identification systems like barcoding is required for appropriate QC testing
• Control strategies in materials purchasing include:

  • Purchasing starting materials directly from the manufacturer
  • Ensuring materials are suitably sourced from carefully selected suppliers
  • Evaluating suppliers through audit programs and survey assessments
• Raising a Materials Purchase Order involves preparing an official order with detailed instructions to the supplier, including item description, quantity required, shipping conditions, packaging details, and specific document requirements
• Materials Receipt Procedural Flow includes visual inspection, checking for external damages, correct identity, quantity ordered, expiry date, and comparing documents to the approved Purchase Order
• A Certificate of Analysis (COA) provides a summary of testing results on samples of products/materials for compliance to a stated specification
• Certificates of Analysis (CofA) are issued for each batch lot produced, with a unique batch lot number
• A valid CofA should include:

  • Clearly indicated laboratory or company issuing
  • Authorized signature by a competent person (can be electronically signed)
  • Tested by a specified individual
  • Specification tested against (e.g., USP/BP/Spec reference number)
  • Results showing compliance with the stated specification
  • Clearly stated: Materials Name/Code number, Batch/lot number, manufacturing date, and shelf life
• Certificate of Compliance (CofC) for Tankers:

  • Certificate of Cleaning/Compliance for tankers
  • Summarizes testing results on environmental sampling of tankers for compliance to a stated specification
  • Generated for non-dedicated tankers, especially for each cleaning
  • May be generated for dedicated tankers based on customer/product requirements
• Certificate of Compliance (CofC) for Packaging Materials:

  • Certifies that the product meets regulatory, technical, and safety requirements as required by the buyer
• Control Strategy: Materials Receipt Form:

  • Upon completion of visual inspection, acknowledged on Supplier’s Delivery Order Document
  • Fill up Company Materials Receipt Form (MRF) or Good Received Note (GRN)
  • Key information to be completed in the form includes supplier, raw material identity, item name, part number, lot/batch number, manufacturing/expiry date, date of receiving, quantity received, person receiving, signature & date, Supplier Delivery Order No, PO reference, visual inspection status (Accept/Reject)
• Confirming the receiving materials:

  • Visual inspection completed with the completion of the receipt form
  • For multi-container delivery, sort batches and segregate different supplier batches with a different internal lot number for each entered on the quarantine label
• Materials in Quarantine:

  • Pending QC Flow
  • Bring materials to the sampling room for QC testing
  • Ensure sampling tools, equipment, and containers are clean
  • Fill in sampling form
  • If QC test passed, sample containers as per pre-determined sampling plan
  • Materials ready for use in production (Follow FIFO)
• Quarantine Label:

  • Place a quarantine label on each container received in good condition
  • Include information like Materials Code, Material Name, Supplier Lot Batch, TPPL Lot Batch No., Date Received, Date Sampled, Sample By, Retest Date, Remarks
  • Recognized in-house style with company logo or name to avoid confusion with supplier label
• QC Labels after sampling test:

  • QC RELEASED label includes Materials Code, Material Name, TPPL Lot Batch No., Date Released, Authorized QC name & sign
  • QC REJECTED label includes Materials Code, Material Name, TPPL Lot Batch No., Date Rejected, Rejected by QC name & sign, Reject Note Ref, and remarks
  • Lock and forbid access to avoid mix-ups and protect inventory
• Materials storage:

  • Materials stored in accepted inventory with QC RELEASED label ready for production use
• In pharmaceutical production, "upstream" processes refer to material inputs for production, while "downstream" processes involve where products are produced and distributed
• Upstream processes in biopharma involve obtaining biological materials from an outside source or growing them in culture under controlled conditions, while downstream processes include harvesting, testing, purifying, and packaging the products
• The start and end of a production process depend on the scope of operations, which is defined in the company's Site Master File/Quality Manual
• GMP documentation like the Quality Manual/Site master file states the company's scope of quality system, which includes operations like production, packaging, labeling, storing, delivery, and shipping, depending on the company's business nature
• Critical process parameters in pharmaceutical manufacturing include materials production, packaging, labeling, storing, delivery, and shipping, which need to be identified to ensure the critical process parametres of the final medicinal products
• Line clearance is a control strategy in pharmaceutical production that involves performing clearance before and after production to ensure cleanliness and prevent mix-ups and cross-contamination
• Reconciliation is a control strategy performed after key production steps to compare the quantity theoretically and actually produced or used, ensuring all materials used for finished products are correctly accounted for
• Critical Process Parameters (CPP) are process parameters or measured variables that impact Critical Quality Attributes (CQA) and must be monitored or controlled within an acceptable range to ensure desired quality attributes are met
• Human error can occur in pharmaceutical production, highlighting the importance of following Good Manufacturing Practices (GMP) to guarantee the quality of pharmaceutical products
• Ineffective cleaning of equipment is a common cause of cross-contamination in pharmaceutical production, emphasizing the importance of following strict procedures to ensure product quality and purity