Development and Scale up in API Manufacture (Part 2 Quality Assurance Considerations) Tuesday 6 th October 2009 Dr. Claire Mc Donnell, D.I.T. 1
Contents Regulation of API Manufacture Comparison of API and finished drug production Process Stages involved in API synthesis Generation of Impurities Case study; therapeutic grade peptide synthesis at Kinerton Ltd Technology Transfer Summary Bibliography 2
Regulation of API Manufacture FDA applies cgmp regulations to bulk API manufacture Mutual recognition agreement is finalised (EU, Japan and USA are the 3 ICH regions) Inspections on API manufacturers carried out using ICH Guideline Q7A GMP Guide for Active Pharmaceutical Ingredients (August 2001) (www.fda.gov/cder/guidance/4286fnl.htm) API S regulated in EU according to Eudralex GMP guide, Annex 18 (July 2001/ (May 2004 (2004/27)). Same as ICH Q7A. (http://pharmacos.eudra.org/f2/eudralex/vol- 4/pdfs-en/v4an18.pdf ) 3
Comparison of API and Finished Drug Production API Manufacture Raw materials undergo some significant chemical change. Purification will be required to remove impurities, contaminants, solvents, unwanted crystalline / molecular forms etc. Purification achieved by various chemical, physical and / or biological processing steps. Effectiveness of the purification confirmed by chemical, biological and physical tests on the API 4
Comparison of API and Finished Drug Production cont d Finished Drug Product Production Quality of the drug ingredients and the care exercised in handling them predetermines purity of finished product. Purification steps not usually involved. 5
Types of API Manufacturing Process Chemical synthesis Natural product extraction Fermentation Enzymatic reactions Recombinant DNA technology 6
1. Reaction Process Stages Involved in API Chemical Synthesis (continuous/batch, multi-purpose/dedicated) 2. Separation (extraction/phase separation, centrifugation) 3. Purification (filtration, distillation, crystallisation, chromatography) 4. Drying (dryer, lyophiliser) 7
1. Reaction Reactor usually glass-lined steel with jacket and fixed agitator. - Need reactor vessel cleaning validation. Test to confirm removal of residues Usual Process Steps; Addition of raw materials and solvents. Mixing. Heating / Cooling. In-process monitoring. Carry out testing at maximum, middle and minimum of ranges quoted in SOP s 8
Reaction Stage - Purpose and Limitations Chemical transformation of raw materials to generate product/intermediate of specific molecular structure. Wide general application. Temperature range available usually 20 to 140 o C. Solid reagents can cause handling difficulties Effective sampling method required. Good reactor design will ensure an effective process that s in control. 9
2. Separation Extraction/phase separation extraction involving aqueous and organic phases separates inorganic and organic material. Some purification usually obtained. Rapid, effective phase separation required. Significant partition difference between product and impurities required. Centrifugation highly efficient and enclosed filtration system. Product then requires manual transfer to dryer however. 10
3. Purification Filtration used to remove residual solid impurities from a liquid or solution. Wide applications. Filter components must be appropriate to solvents / chemicals. Distillation commonly used purification /separation process for liquids. Requires b.p. difference of 15 o C and easily achievable pressure and temperature conditions. Won t separate mixture if an azetrope (constant boiling mixture) forms between starting composition and purity required. Can t separate compounds of very similar chemical structure. Sampling difficult under vacuum conditions. Energy costs can be significant. 11
3. Purification cont d Crystallisation common method for purification of solids. Cooling rate affects particle size. Consistent crystal morphology required from process. Requires filtration and washing; need efficient removal of mother liquor and washes. Chromatography very efficient purification. Dilute solutions necessary (large solvent volume and low throughput) specialised equipment high cost. Expensive technique on large scale. Only applicable to high value products. 12
4. Drying Dryer oven, vacuum, spray, fluid bed (many models / types available). Removal of residual solvent. Manual transfer often necessary exposure/degree of protection assessment. Organic vapours may be given off. Not applicable to heat-sensitive product. Lyophilisation freeze-drying. Used for heat-sensitive products. 13
Double drum dryer 14
Critical Steps in API Manufacture Design of API manufacturing plants traditionally like chemical manufacturing plants (traces of contaminants usually acceptable). Rigid controls may not be required or feasible in early processing steps. cgmp regulations apply to manufacture of drugs in their final dose form but FDA applies them to bulk API manufacture and to drug intermediate manufacture if the manufacture of the intermediate is a critical step. 15
Critical Steps in API Manufacture cont d Critical step affects part of the drug s characterisation (for example, its crystalline form) or impurity profile. Critical step must be controlled within predetermined criteria to ensure the API meets its specification. Step after which recovery from process malfunction or contamination is not possible. Not limited to final stage of API process. Can include intermediate steps that 1) Introduce essential molecular structure element or result in a major chemical transformation 2) Introduce significant impurities into the product 3) Remove significant impurities from the product 16
Critical Steps in API Manufacture cont d Therefore, a step can be critical due to its chemistry (control critical parameters) or with regard to contamination (control contamination sources such as operator procedures and environment). Critical parameter processing parameter which directly influences the drug characterisation or impurity profile of a drug in a critical step (e.g. temperature). Need to show have consistent control of critical parameters in critical processes. Instruments used to measure critical parameters require enhanced documentation (critical instruments). Reasonable acceptance criteria set between vendor claim and process requirement. 17
Critical Areas in Production of Product X Description Stage Process Step Agitation Rate Crystallization IV-A, C, H, J, P, Q, AE Temperature increase Hydrolysis Temperature increase Isolation III-O Temperature holding/maintaining Temperature holding/maintaining Temperature holding/maintaining Hydrolysis Crystallization Drying V-E Temperature Cooling Crystallization III-R, III-T ph Hydrolysis ph Crystallization IV-R, T, C, H, J, E, N, Q, R, S, V 18
Example of Manufacturing Scale Process Extract from Batch Log Sheet for Crystallisation 1.Adjust temperature to 40-50 o C 2.While maintaining the temperature at 40 50 o C, add 10% of the total charge of sulphuric acid. Note The sulphuric acid should be charged subsurface 3.Seed the mixture with 0.2 5% of Product X 4. Agitate the mixture at 40-50 o C for 30 minutes. 5. Add the remaining sulphuric acid over 2 to 3 hours while keeping the temperature at 40-50 o C 19
Regulatory Requirements At validation stage (3 batches), all parameters should be fixed and development complete (beyond experimental stage) DESIGN quality in, can t test it in. Post approval changes necessary due to continuous improvement requirement and changes in circumstances (raw material vendors, vegetable extracts instead of animal (BSE) etc.). 20
Post-Approval Changes SUPAC (scale up post approval changes) BACPAC (bulk actives post approval changes) CBE (changes being effected) Reporting categories - Major change (Prior Approval Supplement) - Moderate change (Supplement Changes Being Effected in 30 days or Supplement Changes Being Effected) - Minor change (next Annual Report) 21
Post Approval Changes Criteria used are potential for change to have effect on identity, strength, quality, purity or potency of the drug product. FDA Guidance Document Changes to an Approved NDA or ANDA, Nov 1999 (http://www.fda.gov/cder/guidance/2766fnl.htm) FDA Guidance Document BACPAC I : Intermediates in Drug Substance Synthesis, Feb 2001 (http://www.fda.gov/cder/guidance/3629fnl.htm) 22
Generation of Impurities Impurities - chemical (moisture, solvent, side-products), biological (endotoxin & microbial levels) and physical (particle size, homogeneity, specific bulk density outside specifications). Before defining critical steps in API manufacture, need to characterise the final drug substance including its impurity profile. (Identify impurities at > 0.1%) Impurity profile provides fingerprint for acceptance of each API batch. Recommended to submit relatively impure batch for safety/toxicology studies i.e. acceptance criteria that can readily be met and allow acceptable product quality. 23
Case Study; Therapeutic Grade Peptide Synthesis at Kinerton Ltd. Process Steps for A Specialised API Manufacturing Process BACKGROUND Ipsen Ltd produces synthetic peptides (10-12 amino acid sequences) which are API S. Applications cancer, diabetes, growth disorders Annual production ~ 20 Kg. Potent, high value API. Therapeutic delivery of peptides difficult due to short half-life (< 1 hour) and susceptibility to enzymatic degradation. Currently Ipsen s API is finished in sustained release formulation by a sister company in France. 24
Case Study; Therapeutic Grade Peptide Synthesis at Kinerton Ltd. Production of API separated into synthesis followed by purification and drying processes. SYNTHESIS Solid Phase Peptide Synthesis - Classical method (Merrifield, 1960 s) - Amino acids (a.a. s) can be assembled into a peptide of any desired sequence while one end of the a.a. chain is anchored to an insoluble support (resin). - 1 st a.a. attached to resin via linker, it s amino protecting group is removed and 2 nd a.a. is added. Amino protecting group of 2 nd a.a. removed and 3 rd a.a. added, etc - After desired sequence of a.a. s joined together on the support, cleave chain from support and finished peptide is liberated into solution. 25
Case Study; Therapeutic Grade Peptide Synthesis at Kinerton Ltd. - Critical requirement that carry out in process testing to ensure complete deprotection and then coupling (Kaiser-Ninhydrin test). - No isolation of intermediates. - Reactors used 50L glass with sintered glass frit at base. - Product dedicated, batch production. After cleavage, crude product extracted and precipitated. Then solubilised in dilute acetic acid. Tested to determine crude purity (50 70%) and yield. 26
Case Study; Therapeutic Grade Peptide Synthesis at Kinerton Ltd. PURIFICATION Preparative Scale HPLC - Very powerful technique, high reproducibility. - Expensive, high dilutions. - Chromatography distribution phenomenon between stationary (silica packing) and mobile phase (buffer/solvent system). All compounds spend same time in mobile phase but different times in stationary phase. - Purified product of > 99% (no impurities > 0.5%) obtained as solution in acetic acid buffer. NOTE - Potential of SMB (Simulated Moving Bed) Chromatography instead of Prep HPLC. 27
Prep Scale HPLC Systems 28
Case Study; Therapeutic Grade Peptide Synthesis at Kinerton Ltd. DRYING Lyophilisation - Solution of purified peptide freeze-dried to produce dry solid cake. - Critical parameters cycle used (temperatures, times, pressure), concentration of peptide solution affect drying and physical characteristics of product (e.g. SSA). -Exposure vertical laminar flow cleanroom (class 100) used for lyophilisation and packaging to protect API product. 29
Technology Transfer Overlap with Development and Scale up. Several pharmaceutical firms recently used SUPAC guidelines to move products that were former blockbuster drugs to contract manufacturers and renovated their vacated manufacturing sites for new blockbusters Subtle differences in processing equipment most overlooked area causing delays and failures in technology transfer (e.g. define pumping and spraying systems, mixer / homogeniser types, filter type and porosity for fluid bed) 30
Technology Transfer cont d Analytical methods transfer very important define equipment set-up and settings, calibration schedules, weighing and injection techniques and sample preparation methods (visits to new site) Equivalence of data between sites must be assured economic, compliance and regulatory aspects Stability programme requires consideration 31
Technology Transfer - Factors for Success Communication often difficult to achieve. Timely (mechanism?), Clear - nothing left to interpretation, Oral communications documented, All critical departments included. Quality Compliance with regulations, continuous evaluation, corporate culture Timeliness - Expectations clarified, critical milestones clearly identified Relationship - Cooperation and partnership approach, visits and meetings Robust process slight changes in operating parameters should give comparable results 32
Summary Are a series of usual process stages and a range of equipment usually employed in API manufacture Important to identify critical steps and parameters in process as soon as possible Specialised techniques and equipment may be employed if process will still be cost effective Post approval changes type of change determines reporting category Technology transfer communication and analytical data equivalence vital 33
Bibliography Change Control in the Pharmaceutical Industry, Lecture, Patricia Sheehan, Leo Labs, Nov 2000. ICH Guideline Q7A GMP Guidance for Active Pharmaceutical Ingredients, August 2001 (www.fda.gov/cder/guidance/4286fnl.htm) Chemical Development and Scale-Up in the Fine Chemical Industry, Course Notes from Trevor Laird, Scientific Update, 2000. Scale Up and Transfer with Manufacturing, Michael J. Valazza, Contract Pharma, Dec 1999. (http://www.contractpharma.com/dec992.htm) 34
FURTHER READING: Bibliography cont d Organic Process Research and Development, Journal (Amer Chem Soc / RSC). In DIT Kevin St. Pharmaceutical Technology Europe, Journal (Advanstar Publishing) - Accessible electronically on DIT library catalogue http://library.dit.ie/ or subscribe to for free at http://www.ptemag.com/pharmtecheurope/ 35
RSC Library and Information Centre 36