3. Quality Assurance and Principles of Testing Formulations

1. 3. Quality Assurance and Principles of Testing Formulations

2. Quality Assurance GMP: "Guide to Good Pharmaceutical Manufacturing Practice" The Secretary of State for Social Services (Sir Keith Joseph) (Hansard 7th March 1972) “I have to report with great regret to the House the deaths of five patients at the Devonport Hospital. The whole House will feel the deepest sympathy, as I do, towards those who have been so tragically bereaved. Last Saturday the doctors at the hospital confirmed their suspicion that these deaths might have a common link in that in each case an intravenous dextrose solution had been administered. These Solutions had all been from the same sub-batch from the Manufacturer, Evans Medical Ltd., of Speke.” DEVONPORT HOSPITAL (PATIENTS' DEATHS) Hansard 7th March 1972… http://hansard.millbanksystems.com/commons/1972/mar/07/devonport-hospital-patients-deaths#S5CV0832P0_19720307_HOC_244

3. 12th July: Clothier report The Committee concludes - in its own words in paragraph 79 – “that the fundamental cause of this disaster is to be found in human failings at Evans Medical, ranging from simple carelessness to poor management of men and plant.The Committee heard of no imminent technological advance in the field of production of intravenous fluids which will eliminate the need for skilful men devoted to their work. The Committee considers that too many people believe that sterilization of fluids is easily achieved with simple plant operated by men of little skill under a minimum of supervision, a view of the task which is wrong in every respect". The Government accept the report, and I have referred to the Medicines Commission a number of technical recommendations. These include consideration of the use of plastic containers, methods of identifying individual batches of dextrose, sterility testing methods, the possibility of incorporating bacterial filters and technical advice on the maintenance of autoclaves. There are also recommendations on prevention of contamination during cooling and after distribution”

4. New England Compounding Center (NECC) Preliminary Investigation Findings 23rd Oct 2012 • Final sterilization of product did not follow proper standards for autoclaving (sterilization through high pressure steam) pursuant to United States Pharmacopeia Standard 797 (USP 797) and NECC’s own Standard Operating Procedures: • Examination of NECC records indicated a systemic failure to keep products in the autoclave for the required minimum 20-minute sterilization period necessary to ensure product sterility. • NECC did not conduct proper validation of autoclaves pursuant to USP 797: • NECC failed to test their autoclaves to ensure proper function. • Visible black particulate matter was seen in several recalled sealed vials of methylprednisolone acetate from Lot 08102012@51. • Powder hoods, intended to protect pharmacists from inhaling substances during medication preparation, within the sterile compounding area were not thoroughly cleaned pursuant to USP 797. • Residual powder was visually observed within the hood during inspection. This contamination may subsequently lead to contamination of compounded medications. • Condition of “Tacky” mats, which are used to trap dirt, dust, and other potential contaminants from shoes prior to clean room entry, violated the USP 797. • Mats were visibly soiled with assorted debris. • A leaking boiler adjacent to the requisite clean room created an environment susceptible to contaminant growth: • A pool of water was visually observed around the boiler and adjacent walls, creating an unsanitary condition; the culture results of this potential contaminant are still pending. “...420 people sickened by potentially contaminated steroid injections that were prepared by a Massachusetts pharmacy. Thirty have died, with Tennessee on Monday reporting its 13th death — the most among the 19 states involved in the outbreak.” Duane Marsteller The Tennessean Tue Nov 6, 2012 8:40 PM

5. Good Manufacturing Practice “The Orange Guide: Rules and Guidance for Pharmaceutical Manufacturers and Distributors” Compiled by the Inspection and Standards Division, Medicines and Healthcare products Regulatory Agency (MHRA), London, UK European Commission Directive 2003/94/EC (the “GMP Directive”) sets out the requirements relating to the implementation of good manufacturing practice for medicinal products for human use (including Investigational Medicinal Products).

6. International Conference on Harmonisation (ICH)Quality GuidelinesPharmacopeias http://www.ich.org/products/guidelines/quality/article/quality-guidelines.html

7. Quality Control in Product Development • Product Design • Manufacture • Environmental Control • Sampling • Testing You can design but not test, quality in to a product Testing provides assurance that batch has been made correctly

8. Drug Product Quality Assurance • Design; composition/formulation & packaging • Control of in-put, raw materials • Manufacture: Has it been made correctly? • Equipment & process: • design, validation & maintenance • In-process controls • Environmental control: • eg cross-contamination, sterility, particulates, temp & humidity • Sampling: Are the samples representative? • Finished Product Testing: Assurance that batch has been made correctly? • Identity: Is it the right product? • Content: Does each dose contain the right amount of drug? • Purity: Control of related impurities, absence of un-related contamination? • Function: Does the dosage form work as intended? • eg dissolution rate; inhaled fine particle fraction

9. Identity: Is it the right product? • Active Pharmaceutical Ingredient • Proof of structure: NMR, mass spectroscopy etc. • Drug Product • Appearance • Two different methods, for example: • Infrared spectroscopy & HPLC • HPLC/UV diode array, HPLC/MS or GC/MS

10. Content: Does each dose contain the right amount of drug? European Pharmacopeia 2012: Assay : Specific for API 2.9.6 Uniformity of content of single-dose preparations: Test A: Tablets, powders for parenteral administration, ophthalmic inserts, suspensions for injection Determine the individual contents of active substance(s) of 10 dosage units taken at random. Complies : if each individual content is between 85% and 115% of the average Fails: if more than one individual content is outside these limits or if one individual content is outside the limits of 75% to 125% of the average. If one individual content is outside the limits of 85% to 115% but within the limits of 75% to 125%, determine the individual contents of another 20 dosage units taken at random. Complies: if not more than one of the individual contents of the 30 units is outside 85% to 115% of the average content and none is outside the limits of 75% to 125% of the average content. TEST B: Capsules, powders other than for parenteral administration, granules, suppositories, pessaries TEST C:Transdermal patches Alternatively 2.9.40. Uniformity of dosage units: Statistical Limits relating the individual & mean content to the label claim.

11. Purity: Control of related impurities, absence of un-related contamination? API • Organic impurities (process- and drug-related) • Starting materials; by-products; intermediates; degradation products; reagents and catalysts; wrong enantiomer • Inorganic impurities • Reagents and catalysts; Heavy metals or other residual metals; inorganic salts; other materials (e.g. filter aids, charcoal) • Residual solvents • Polymorphic form; hydrate; amorphous form • Micro-biological incl endotoxins and TSE risk (Transmissible Spongiform Encephalopathy) Drug Product • Micro-biological; foreign particulates; moisture; oxygen; extractables

12. Case study 2 Which route and batch should we use in our 6month Dog & Rat oncogenicity studies How and why did you make and justify your selection? Comparison of Route 1 and Route 2 impurity profiles (% area) A B C D E F G Tot R1.1 3.6 1.5 0.4 0.3 0.2 0.5 0.2 7.3 R1.2 1.3 0.5 0.1 0.1 0.6 1.7 0.3 5.0 R1.3 0.9 0.4 0.1 ND 0.1 1.6 0.2 3.2 R1.4 0.6 0.5 0.1 ND 0.1 1.5 0.2 3.0 R2.1 0.2 0.2 ND ND 0.2 ND 0.1 0.8 R2.2 0.3 0.3 ND ND 0.2 ND 0.1 0.9 Impurity Synthetic route and batch

13. Justification of ImpuritiesICH Q3A • The level of any impurity present in a new drug substance that has been adequately tested in safety and/or clinical studies would be considered qualified. • Impurities that are also significant metabolites present in animal and/or human studies are generally considered qualified. • A level of a qualified impurity higher than that present in a new drug substance can also be justified based on an analysis of the actual amount of impurity administered in previous relevant safety studies. • If data are unavailable to qualify the proposed acceptance criterion of an impurity, studies to obtain such data can be appropriate when the usual qualification thresholds given in Attachment 1 are exceeded.

14. Justification of Impurities ICH Q3AATTACHMENT 1 Thresholds 1 The amount of drug substance administered per day 2 Higher reporting thresholds should be scientifically justified 3 Lower thresholds can be appropriate if the impurity is unusually toxic

15. Function: Does the dosage form work as intended? Eg. disintegration time, dissolution rate, inhaled fine particle fraction QC test not a clinical prediction Percentage released Time (minutes)

16. Manufacture: in-process testing and Quality by Design • Tablet weight, thickness, crushing strength, friability, disintegration time • Filter integrity, temperature, time and pressure • Quality by Design; Control Strategy: “A planned set of controls, derived from current product and process understanding, that assures process performance and product quality. The controls can include parameters and attributes related to drug substance and drug product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control.” (ICH Q10: PHARMACEUTICAL QUALITY SYSTEM)

17. Change Control in Product Development • different formulations • API different physical form, salts, particle size • same formulation made by different process • same process at significantly different scale • In vivo tests: • Animal studies • Clinical trials • Bioequivalence:

18. Change Control in Product Development • Assumes PK/PD relationship, • if not; • Is clinical equivalence required? • in vitro equivalence • Is a bio-waiver available? • BCS class1: water soluble, • highly permeable compound Bio-equivalence: Which PK parameters are important? Plasma conc. Time

19. Categories of the BCS Classifies compounds based on their solubility and permeability characteristics Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System Issued in August 2000 by the FDA • http://www.fda.gov/cder/guidance/3618fnl.htm

20. BCS Definition of High Solubility • A drug substance is considered HIGHLY SOLUBLE when the highest dose strength is soluble in < 250 ml over a pH range of 1 to 7.5. • FDA also requires: • Enough test points to define this pH solubility curve (at least 5 - 7 test points) • Use of standard buffer solutions • A minimum of three replicate determinations at each test point • Use of a validated stability-indicating analytical method

21. BCS Definition of High Permeability • A drug substance is considered HIGHLY PERMEABLE when the extent of absorption in humans is determined to be > 90% of an administered dose, based on mass-balance or in comparison to an intravenous reference dose. • FDA indicates that permeability can be determined via: • Pharmacokinetic studies in humans • Based on Mass Balance studies • Absolute Bioavailability studies • Intestinal Permeability Methods • In vivo intestinal perfusion studies in humans • In vivo or in situ intestinal perfusion studies using suitable animal models • In vitro permeation studies using excised human or animal intestinal tissues • In vitro permeation studies across a monolayer of cultured epithelial cells. • Note: factors such as pre-absorptive degradation in the GI tract and active uptake or efflux also have some influence on the selection of an appropriate method for determining permeability.

22. Stability testing • Demonstrate that the product quality is retained during the shelf life of the product • Determine change in chemical and physical properties of dosage form on storage (up to 5 years) • In the packaging intended for the marketed product • Re-test at intervals against the release specification • Using stability indicating methods.

23. Basic stability programmeICH: Q1A(R2) *It is up to the applicant to decide whether long term stability studies are performed at 25 ± 2°C/60% RH ± 5% RH or 30°C ± 2°C/65% RH ± 5% RH. 1st year test at 3month intervals 2nd year test at 6month intervals >3rd year test at 12month intervals Includes guidance on Light stability Different climatic zones Bracketing product strengths Interpretation data ICH: Q1A(R2)

24. Analytical Method Development

25. Early analytical work What are you looking for? • Synthetic & Degradation chemistry • A detailed knowledge of the chemistry of the drug substance must be obtained • Establish the derivative effects of: • heat • light • water, oxygen, carbon dioxide (the atmosphere) • co-ingredients in the formulation • components in the packaging material

26. Method selection • Techniques for identification of impurities • NMR • Mass spectrometry • Chromatography • Infra-red & UV spectroscopy • Microscopy, sterility etc • Physical properties: eg polymorph, particle size • X-ray crystallography • Laser diffraction, image analysis etc. • Assay • HPLC with UV or Mass Spec detection • Function • Dissolution, cascade impaction etc.

27. Analytical Validation • Specificity • the ability to measure accurately and specifically the analyte in the presence of components expected to be present • Accuracy • the closeness of the test results obtained by the method to the true result • Precision • the degree of agreement between individual test results • Detection limit • the lowest amount of analyte which can be detected (but not necessarily quantified) under the defined experimental conditions • Quantitation limit • the lowest amount of analyte which can be quantified with acceptable precision and accuracy under the defined experimental conditions

28. Typical Specifications • Drug Substance • Identity • Description/ colour tests • Assay • Related Impurities • Optical rotation • Metals • Solvents • Water • Thermal analysis • Particle size • Tablet • Identity • Appearance • Impurity levels • Drug content • Dissolution rate • Sterile Solution • Identity • Appearance • Impurity levels • Drug content • pH • Sterility • Bacterial endotoxins • Foreign Particulate matter

29. Pharmaceutical Product Quality • Product Design • Manufacturing Process • Manufacturing Environment • Sampling Plan • Specification • Test method selection & validation You can design but not test, quality in to a product Testing provides assurance that batch has been made correctly