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

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

3. Satish Mallya January 20-22, 2010 3 |3 | Documentation 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. May 18-21,2014

4. Satish Mallya January 20-22, 2010 4 |4 | Documentation 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. May 18-21,2014

5. Satish Mallya January 20-22, 2010 5 |5 | Preliminary Verification Ascertain that copies of the FPP master production documents are provided for each proposed strength, commercial batch size and manufacturing site. 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. 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 May 18-21,2014

6. Satish Mallya January 20-22, 2010 6 |6 | Preliminary Verification 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 Line Clearance Record - Alert: Previous product requires segregated facility – note to inspection Cleaning Record for processing areas: May be several pages (not high risk for solid oral dosage forms -eyeball) May 18-21,2014

7. Satish Mallya January 20-22, 2010 7 |7 | Manufacturing Methods DIRECT COMPRESSIONDRY GRANULATIONWET GRANULATION Milling/Screening Blending/lubricationPre-blending CompressionSlugging/roller compactionAddition of binder Dry screeningScreening of wet mass Blending of lubricantDrying of the wet granules CompressionScreening of dry granules Blending of lubricant (and disintegrant) Compression May 18-21,2014

8. Satish Mallya January 20-22, 2010 8 |8 | 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 Sr. No.NameCapacityMakeModelID 1Vibratory Sifter20"/30"√√√ 2Rapid Mixer Granulator500L√√√ 3Fluid Bed Dryer150Kg√√√ 4Conta Blender500L√√√ 5Multi Millvarious√√√ 6Peristaltic pumpN/A√√√ 7Compression m/c37 stations√√√ 8Dedusting m/cN/A√√√ 9Metal DetectorN/A√√√ 10Auto Coater60"√√√ May 18-21,2014

9. Satish Mallya January 20-22, 2010 9 |9 | Detailed Assessment 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 May 18-21,2014

10. Satish Mallya January 20-22, 2010 10 | Calculating API content 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 x 100} {% Assay of API x (100-%water content)} Calculation for filler = {Theoretical quantity of API required + theoretical quantity of filler} – quantity of API May 18-21,2014

11. Satish Mallya January 20-22, 2010 11 | Case Study 1 Batch Size: 1000,000 tabletsEach tablet contains: 25 mg of API # actual quantity = A = [25 x 100 x 100]/ [%assay x (100-% water content)] @ actual quantity = (API + filler) – A = 85-A Assay = 98%, water content= 0.5%, calculate the quantities of API and Exp 1 No.IngredientRM CodeAR No.Qty per unit (mg)%Qty per batch (Kg) 1APIAP-18AR-2014-125.0 25.0# 2Exp 1(filler) RM-12 RM- 2014-260.0 60.0@ 3Exp 2 RM-18 RM2014-32.002.0 4Exp 3 RM-07 RM2014-412.0 5Exp 4RM-46RM 2014-51.001.0 May 18-21,2014

12. Satish Mallya January 20-22, 2010 12 | 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) May 18-21,2014

13. Satish Mallya January 20-22, 2010 13 | Case Study 2 Calculation of quantity of API per batch: 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) = 25 – ….. Kg = …… Kg May 18-21,2014

14. Satish Mallya January 20-22, 2010 14 | 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 May 18-21,2014

15. Satish Mallya January 20-22, 2010 15 | 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) (A) Assay (%) (B) Water content (% w/w) (C) Actual Quantity used in FPP (Kg) 115.5099.00.34 230.0099.40.50 ∑ Quantity of Filler required (case study 1) = …………………….Kg May 18-21,2014

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

17. Satish Mallya January 20-22, 2010 17 | Case study # 3 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 May 18-21,2014

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