Pharmaceutical Development with Focus on Paediatric Formulations WHO/FIP Training Workshop Hyatt Regency Hotel Sahar Airport Road Andheri East, Mumbai, India 28 April 2008 – 2 May 2008
Pharmaceutical Development with Focus on Paediatric formulations Presented by: Name: Dr. János Pogány Contact details: firstname.lastname@example.org
Outline of presentation Regulatory issues on stability of APIs and FPPs • Introduction • Scientific approach to pharmaceutical stability • Introduction to the new WHO Stability guideline • Planning stability studies and reporting results • Evaluation of stability results • Risk-based inspection of stability studies • Main points again
Pharmaceutical Development with Focus on Paediatric formulations WHO working document QAS/06.179/Rev. DRAFTSTABILITY TESTING OF ACTIVE PHARMACEUTICAL INGREDIENTS AND PHARMACEUTICAL PRODUCTS INTRODUCTION
WHO guidelines „Stability of drug dosage forms” in 1990 initiated the global harmonization of regulatory stability requirements „Guidelines for stability testing of pharmaceutical products containing well established drug substances in conventional dosage forms” (1996) WHO amendment of the above guidelinein TRS 937 (2006) Working document QAS/06.179/Rev.2 – „Stability Testing of Active Pharmaceutical Ingredientsand Pharmaceutical Products” divides countries with tropical and subtropical moist climates into: • Zone IVA with long-term conditions: 30oC ± 2oC and 65% ± 5% RH • Zone IVB with long-term conditions: 30oC ± 2oC and 75% ± 5% RH, which is the worst case and the recommended long-term condition for the Prequalification Project Each individual Member State within the formerZone IV would need to indicate whether its territory should be classified asZone IVa or IVb
Selected definitions Re-test period After this period a batch of APIdestined for use in the manufacture of a pharmaceutical product should be re-tested for compliance with the specification and then used immediately. A batch of active pharmaceutical ingredient can be re-tested multiple times and a different portion of the batch used after each re-test, as long as it continues to comply with the specification. A retest period should be proposed on the basis of stability results and may be extended to five years (e.g., Ethambutol 2HCl, or Isoniazid) For most biotechnological/biological substances known to be labile, it is more appropriate to establish a shelf-life than a re-test period. The same may be true for certain antibiotics.
Selected definitions Shelf-life (also referred to as "expiration dating period“) The period of time during which a pharmaceutical product, if stored correctly, is expected to comply with the specification as determined by stability studies on a number of batches of the product. The shelf-life is used to establish the expiry date of each batch.
Pharmaceutical Development with Focus on Paediatric Formulations WHO working document QAS/06.179/Rev. DRAFTSTABILITY TESTING OF ACTIVE PHARMACEUTICAL INGREDIENTS AND PHARMACEUTICAL PRODUCTS STABILITY PROTOCOLS AND REPORTS
Protocol – regulatory requirement • The ongoing stability programme should be described in a written protocol and results formalized as a report. The protocol should extend to the end of the re-test period and should includeparameters illustrated in slide 12 • The stability protocol used for long-term studies for the stability commitment should be the same as that for the primary batches, unless otherwise scientifically justified.
Stability protocol - API The batches should be representative of the manufacturing process and should be manufactured from different batches of key intermediates.
Stability protocol – oral suspension The batches should be representative of the manufacturing process and should bemanufactured from different batches of APIs. Executed manufacturing records and certificates of analysis on the above batches should be submitted
Bracketing • Stability studies should be performed on each individual strength, dosage form and container size of the pharmaceutical product.If dosage form is the same, then bracketing can be applied to: • Different strengths (including FDC products) • have identical formulations (including FDC products) • are made with closely related formulations • Container-closure system is the same and either the container size or the fill size varies • Even when the container-closure system varies bracketing is possible with some justification. Such justification might be the demonstration that the product is not water sensitive,orthe discussion of the relative permeation rates of the closure systems.
Matrixing • Matrixing is the statistical design of a stability schedule . • Each storage condition should be treated separately under its own matrixing design • At a given time point (other than the initial or final ones) not every batch on stability needs to be tested • Full testing must be performed at the maximum storage period at the time of submission
A risk-based global stability protocol Source: Designing a globally acceptable registration stability protocol, Pharmaceutical Technology Europe, March 2007
Pharmaceutical Development with Focus on Paediatric Formulations WHO working document QAS/06.179/Rev. DRAFTSTABILITY TESTING OF ACTIVE PHARMACEUTICAL INGREDIENTS AND PHARMACEUTICAL PRODUCTS STRESS TESTING
Selected definitions • Stress testing – API Studies undertaken to elucidate the intrinsic stability of the active pharmaceutical ingredient. Such testing is part of the development strategy and is normally carried out under more severe conditions than those used for accelerated testing. • Stress testing – FPP Studies undertaken to assess the effect of severe conditions on the pharmaceutical product. Such studies include photostability testing and specific testing on certain products, (e.g. metered dose inhalers, creams, emulsions, refrigerated aqueous liquid products).
Stress testing • Tovalidate the stability indicating power of the analytical procedures. • To identify stability-affecting factors such as ambient temperature, humidity and light and to select packing materials, which protect the FPP against such effects. • To identify potential degradants of the API and assess if they can be formed during manufacture or storage of the FPP. • To select manufacturing process of the FPP
Increase in concentration of API During stability studies of Artesunate, the assay results were increasing. The hydrolysis yields artenimol and succinic acid. The formation of succinic acid justifies the increase in assay. The assay method is „stability indicating” but not specific. +
Stress stability testing • An optimal degradation pattern generated during stress testing would show only those degradation products observed at the end of shelf life in regulatory stability studies and those that might appear if the API or FPP if not manufactured, handled or packed properly. • Chromatograms thus obtained will be representative and not too complicated to evaluate, which may be the case if drastic conditions are applied and many second- and third-generation degradation products are formed.
Pharmaceutical Development with Focus on Paediatric Formulations WHO working document QAS/06.179/Rev. DRAFTSTABILITY TESTING OF ACTIVE PHARMACEUTICAL INGREDIENTS AND PHARMACEUTICAL PRODUCTS PRESENTATION AND EVALUATION OF RESULTS
Types of stability data • Three types of data can be collected during stability studies • reported as a single result such as assay, loss on drying, etc. • data with multiple results such as dissolution testing • third type is degradation product • Most analytical laboratories will not quantify the result if it falls below the LOQ. The value usually is reported as “˂ LOQ.” • A special situation arises when a new peak forms during the analysis.When a new peak forms during a stability study, one may expect that it should not exist and hence it would constitute a type of OoT. • If some of the results are below the LOQ value, if the assumption of normality is not reasonable, or if linearity cannot be assumed, then an attempt to identify OoT results using data from the same batch is not recommended
Stability reports • A systematic approach should be adopted in the presentation and evaluation of the stability information, which should include, as appropriate, results from the physical, chemical, biological and microbiological tests, including particular attributes of the dosage form • The results should be presented both as a table and as a graph and not as data sheets • The Applicant should evaluate the stability data
Evaluation – Best Case • Tabulate and plot stability data on all attributes at all storage conditions and evaluate each attribute separately. • No significant change at accelerated conditions within six (6) months. • Long-term data show little orno variability and little or no change over time.
Evaluation – Best Case • Accelerated data show little or no variability and little or no change over time. • Statistical analysis is normally unnecessary and providing a justification for the omission should be sufficient • Proposed retest period or shelf life = double of period covered by long-tem data (X) but NMT X + 12 months • A retest period or shelf life granted on the basis of extrapolation should always be verified by additional long-term stability data
Out-of-trend (OoT) results • An OoT result is a stability result that does not follow the expected trend, either in comparison with other stability batches or with respect to previous results collected during a stability study. • The identification of an OoT data point only notes that the observation is atypical: • within a batch • across historical stability batches • When an “odd-looking” stability pattern occurs, it is common to ask whether the pattern reflects an underlying mechanism (i.e., a “cause”) or is merely a normal process or analytical variation. • Any out of trend/out of specification (OoT/OoS) observations • “Do the data obtained so far indicate that the batch will go outside specification during its shelf life?”
Out-of-trend (OoT) results • Are all values above LOQ? • Are all values below LOQ? • Is a part of the data below LOQ? • What is the analytical and sampling variation and a measured characteristic's normal change over time? • Timeliness is especially important when an analytical error is suspected of causing OoT results
Significant change of FPPs • A 5% change in assay from its initial value. • Any degradation product exceeding its acceptance criterion. • Failure to meet the acceptance criteria for appearance, physical attributes, and functionality test (e.g., colour, phase separation, hardness). • As appropriate for the dosage form, e.g., failure to meet the acceptance criteria for dissolution for 12 dosage units.
Reporting results Result sheets must bear date and responsible person’s signature / QA approval
SOP requirements • A written stability-testing program to assess the stability characteristics of drug products • Review and investigation of OoT stability results • Written procedures for conducting a thorough investigation of any unexplained discrepancy • A review of the OoT alert procedures' performance might coincide with the annual product review • The depth of an investigation and the corrective measures taken may depend on the potential or implied risk to product quality
Evaluation – Change with Time • An approach for analysing data on a quantitative attribute that is expected to change with time is to determine the time at which the 95% one-sided confidence limit for the mean curve intersects the (lower) acceptance criterion (95% assay). • The majority of degradation processes results in an essentially linear line in this range of the label claim thus the method is generally applicable for the estimation of the expiry date at the studied storage conditions. • The hypothetical figure in the next slide illustrates that the extrapolated shelf life is 29months (25oC/60%RH) and there is only a 5% chance that this estimate will be high. Such a plot covers assay values from 105% down to 95%.
Evaluation – Change with Time* The hypothetical figure in the former slide illustrates that the shelf life is 24 months (at a given temperature). There is a 5% chance that this estimate will be high.Such a plot covers potency values from 100% down to 90%. *DRUG STABILITY — Principles and Practices Edited by Jens T. Carstensen and C. T. Rhodes Third edition, revised and expanded (2000) Marcel Dekker, Inc., 270 Madison Avenue, New York,
Evaluation – Change with Time • The hypothetical figuresin the former slides illustrate that the shelf life is 31-32months • (25oC/60%RH) and there is only a 5% chance that this estimate will be high. Such a plot covers degradant values from 0.6% up to 1.4%. • For FPPs in semipermeable containers, loss of vehicle can result in an increase in the API concentration. In such cases, the point where the upper 95% confidence bound intersects the 105% assay value will define the conformance period.
Stability results • A storage statement should be proposed for the labeling (if applicable), which should be based on the stability evaluation of the API. • A retest period should be derived from the stability information, and the approved retest date should be displayed on the container label. • An API is considered as stable if it is within the defined/regulatory specifications when stored at 30±2oC and 65±5% RH for 2 years and at 40±2oC and 75±5%RH for 6 months.
Additional or New Stability Data • Modifications affecting one or more steps of the same route of synthesis of an API • Change in the route of synthesis of an API • Change in composition of the FPP • Change in immediate packaging of the FPP
Main points again • Stability studies should be planned on the basis of pharmaceutical R+D and regulatory requirements. • Forced degradation studies reveal the intrinsic chemical properties of the API, while formal stability studies establish the retest date. • The shelf life (expiry date) of FPPs is derived from formal stability studies. • Variability and time trends of stability data must be evaluated by the manufacturer in order to propose a retest date or expiry date.