3 1 Assessing Batch Records Satish Mallya Quality

3 -1. Assessing Batch Records Satish Mallya Quality Workshop, Copenhagen May 18 -21, 2014 1| 20 -22, Satish Mallya January May 18 -21, 2014 2010

Outline l Focus on immediate release solid dosage forms l Design and content l Expectations l Case Studies 2| 20 -22, Satish Mallya January May 18 -21, 2014 2010

Documentation l Relevance: – Ensures uniformity, consistency and a common understanding of expectations; – Outlines the procedures for handling raw materials, manufacturing and control; – Facilitates decision making on release/quarantine/rejection of a batch; – Ensures accountability, traceability, and documentation trail that will permit investigation in the event of product recall; – Permits retrospective validation and periodic quality review throughout product lifecycle. 3| 20 -22, Satish Mallya January May 18 -21, 2014 2010

Documentation l Requirements: – Copies of the FPP master production documents should be provided for each proposed strength, commercial batch size and manufacturing site. – Master records should be in English, if not a translated version should be available. – Pilot batches should be manufactured by a procedure fully representative of and simulating that to be applied to a full production-scale batch. 4| 20 -22, Satish Mallya January May 18 -21, 2014 2010

Preliminary Verification l Ascertain that copies of the FPP master production documents are provided for each proposed strength, commercial batch size and manufacturing site. l Compare the blank master batch record with the executed batch record for the biolot to ensure that the proposed manufacturing process for the commercial product is representative of the process used to manufacture the biolot. l Verify that all pages of master and executed records have been submitted - each page will generally state the total number of pages (e. g. 1 of 40). Ensure that provision is made (e. g on page 1) for the following information and it is accurate: – Product name, product code, batch number, batch size and date of manufacture – Multiple signatures and dates recording chain of approval process and responsibilities 5| 20 -22, Satish Mallya January May 18 -21, 2014 2010

Preliminary Verification l Environmental Monitoring : Verify temperature, humidity and differential pressure are within acceptable limits, date and time are in chronological order. For photosensitive products ensure adequate lighting precautions are in place l Line Clearance Record - Alert: Previous product requires segregated facility – note to inspection l Cleaning Record for processing areas: May be several pages (not high risk for solid oral dosage forms -eyeball) 6| 20 -22, Satish Mallya January May 18 -21, 2014 2010

Manufacturing Methods WET GRANULATION DRY GRANULATION DIRECT COMPRESSION Milling/Screening Pre-blending Blending/lubrication Addition of binder Slugging/roller compaction Compression Screening of wet mass Dry screening Drying of the wet granules Blending of lubricant Screening of dry granules Compression Blending of lubricant (and disintegrant) Compression 7| January 20 -22, Satish Mallya. May 18 -21, 2014 2010

Manufacturing Equipment Ensure that all critical equipment have been identified at least by type and working capacity – check if all listed equipment are referenced in the manufacturing process 8| Sr. No. Name Capacity Make Model ID 1 Vibratory Sifter 20"/30" √ √ √ 2 Rapid Mixer Granulator 500 L √ √ √ 3 Fluid Bed Dryer 150 Kg √ √ √ 4 Conta Blender 500 L √ √ √ 5 Multi Mill various √ √ √ 6 Peristaltic pump N/A √ √ √ 7 Compression m/c 37 stations √ √ √ 8 Dedusting m/c N/A √ √ √ 9 Metal Detector N/A √ √ √ 10 Auto Coater 60" √ √ √ 20 -22, Satish Mallya January May 18 -21, 2014 2010

Detailed Assessment l Master formula: – Ensure batch formulation in line with unit formulation; – Check for overages of API and excipients; – Verify if provision is made for recording material codes and analytical report numbers; – Ascertain calculation(s) for API content is accurate 9| 20 -22, Satish Mallya January May 18 -21, 2014 2010

Calculating API content l When the amount of API is adjusted based on the assay results and/or on anhydrous basis - single lot of API – The total quantity of API + filler will be the same for every batch of the FPP – Quantity of filler required will vary with the assay and water content of the API lot Calculation for API = {Theoretical quantity of API required x 100} {% Assay of API x (100 -%water content)} Calculation for filler = {Theoretical quantity of API required + theoretical quantity of filler} – quantity of API 10 | 20 -22, Satish Mallya January May 18 -21, 2014 2010

Case Study 1 l Batch Size: 1000, 000 tablets Each tablet contains: 25 mg of API No. Ingredient RM Code AR No. Qty per unit (mg) % Qty per batch (Kg) 1 API AP-18 AR-2014 -1 25. 0# 2 Exp 1(filler) RM-12 RM- 2014 -2 60. 0@ 3 Exp 2 RM-18 RM 2014 -3 2. 00 2. 0 4 Exp 3 RM-07 RM 2014 -4 12. 0 5 Exp 4 RM-46 RM 2014 -5 1. 00 1. 0 l # actual quantity = A = [25 x 100]/ [%assay x (100 -% water content)] l @ actual quantity = (API + filler) – A = 85 -A l Assay = 98%, water content= 0. 5%, calculate the quantities of API and Exp 1 11 | 20 -22, Satish Mallya January May 18 -21, 2014 2010

Calculating API content When the amount of API is adjusted based on the assay results and/or on anhydrous basis - multiple lots of API If several lots of the API are used in the preparation of a single batch of the FPP, the total equivalent quantity of API on as is basis (∑E) determines the quantity of filler to be added in the batch Calculation of filler = {Theoretical quantity of API required + theoretical quantity of filler} – Total quantity of API (∑E) 12 | 20 -22, Satish Mallya January May 18 -21, 2014 2010

Case Study 2 l Calculation of quantity of API per batch: l Theoretical quantity of API [100% assay (anhydrous) and nil water] = 25 Kg Lot 1: Total available quantity (as is basis) (A) = 15. 50 Kg Actual assay (B) = 99. 0% ; Water content (C) = 0. 34% Qty of API equivalent to 100% assay and nil water (D) = A x B/100 x (100 -C)/100 = …… Kg Balance quantity of API required (100% assay and nil water) = …… Kg 13 | 20 -22, Satish Mallya January May 18 -21, 2014 2010 = 25 – …. . Kg

Case Study 2 (continued) Lot 2 Quantity of API required (100% assay and nil water) (D) = …… Kg Total available quantity (as is basis) (A) = 30. 00 Kg Actual assay (B) = 99. 4% Water content (C) = 0. 50% Equivalent quantity of API required from lot 2 = D x 100/B x 100/(100 -C) = ……. Kg 14 | 20 -22, Satish Mallya January May 18 -21, 2014 2010

Case Study 2 (contd) Theoretical quantity of API [100% assay (anhydrous) and nil water] = 25 Kg Lot No. Total available quantity (as is basis) (Kg) Assay (%) Water content (B) (% w/w) Actual Quantity used in FPP (C) (Kg) (A) 1 15. 50 99. 0 0. 34 2 30. 00 99. 4 0. 50 ∑ Quantity of Filler required (case study 1) = …………. Kg 15 | 20 -22, Satish Mallya January May 18 -21, 2014 2010

Detailed Assessment l Process parameters (e. g. mixing time, mixing speed, milling screen size, processing temperature range, granulation end-point, tablet machine speed); l In-process tests (e. g. loss on drying, weight variation, hardness, disintegration time, weight gain during coating); l Sampling plan at different stages (number of samples to be tested and frequency of testing during drying, lubrication, compression); l Holding times at intermediate stages; l Yield reconciliation (lubricated granules, core tablets, coated tablets). 16 | 20 -22, Satish Mallya January May 18 -21, 2014 2010

Case study # 3 l Tablets are manufactured by a wet granulation process. Intra-granular materials are sifted and mixed in a rapid mixer granulator. The granulating fluid is prepared separately and added to the blend. The end point of granulation is determined by the operator by pressing the wet mass in the palm to make a ball and then breaking it with the thumb - it should break in small lumps. The wet mass is sifted through a multimill and the granules thus formed are dried in a fluid bed dryer until the granules attain a LOD value of NMT 3%. The maximum processing time from dispensing to end of drying should not be more than 30 days. The dried granules are passed through a sieve, mixed with previously sieved extra-granular excipients and collected in drums. This blend can be stored for up to 30 days. Tablets are compressed on a rotary machine. Total compression time is 3 hours. Weight variation and DT are checked every hour during compression. The limit for average weight of 20 tablets is set at target weight + 5% and the limit for individual weight variation is set at target weight + 15%. The time elapsed between end of compression and beginning of coating should not exceed 90 days 17 | 20 -22, Satish Mallya January May 18 -21, 2014 2010

Thanks Questions ? 18 | 20 -22, Satish Mallya January May 18 -21, 2014 2010