Chemical Aspects of Stability Evaluation

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Belinda Kennedy
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1 Chemical Aspects of Stability Evaluation 8 steps to generating stability data which speaks for itself Alan Doughty Chief Chemist Pty Ltd

2 Aim of a stability trial Obtain data which allows a definitive conclusion to be made about the stability of a product. Study carried out in a timely and predictable manner. Achieves objectives without the need for justifications, explanations and correspondence it speaks for itself.

3 Purpose of stability trial Product Development: Data for evaluation and optimisation of a formulation. Product Registration: Generation of data as part of a product registration dossier. Post Registration: On-going stability or validation of process changes. Data required to complete annual product review.

4 Steps to generating stability data 1. Start with the product specification. 2. Design your stability protocol to comply with regulations. 3. Establish competence in test methods before the initial timepoint. 4. Develop and implement validation protocols appropriate for the measurement. 5. Document methods thoroughly and reference consistently. 6. Aim to achieve mass balance. 7. Review data continually through the study. 8. Act immediately in response to OOS/OOT.

5 1. It starts with the product specification Before talking to the lab have your specifications worked out. For new products, this is will be a draft specification. Stability data will allow development of release specifications. Release Specifications: Tighter than product specifications, set so that the product is within specification at the end of shelf life. For a product where an active decomposes by 4% over shelf life, release specs may be % to ensure product spec of % is met over entire shelf life.

6 1. It starts with the product specification Specifications include: Assay specifications Limits for impurities and breakdown products. Other tests (ph, weight loss). Dosage specific tests (spray rate, dissolution). Effect of Packaging: Material leaching into product from container, and material moving from product into container.

7 1. It starts with the product specification Take care in setting specifications for appearance and other subjectives. Provide description (eg white to pale yellow liquid). Laboratory to report complies or does not comply to specification. This results in consistent reporting through the stability study.

8 2. Design stability protocol to comply with regulation. You need to consider: Number of type of batches on trial. Pack sizes. Dose levels. Storage conditions (real time/accelerated) Timepoints. Reference Documents: ICH Quality Guidelines Q1 parts A to F

9 3. Establish competence in test methods before the initial timepoint. Before the initial timepoint, rather than when the laboratory is performing the initial timepoint. You don t want your laboratory on training wheels when the most important timepoint is performed.

10 3. Establish competence in test methods before the initial timepoint. New products: Involve the lab as early as possible in the product development cycle. Optimisation of methodology occurs concurrent with optimisation of formulation. Ongoing stability: Consider the proposed stability lab testing batches in parallel with release testing. If expired batches are available provide these for testing with recent batches.

11 3. Establish competence in test methods before the initial timepoint. Consistent testing over time is a good prediction of performance of methods during a stability trial. Each time the method is run, method performance parameters will need to be met (%RSD of multiple standard injections, calibration checks, duplicates, chromatographic performance). Engaging a lab early gives you something to audit either paper audit or on site. Method validation is simulated method use, it won t always guarantee performance of methods in a trial. Horror story: During method validation recovery preparations made in glass, yielding excellent method performance. Real samples delivered in a manner allowing seed crystals to enter product when product was dispensed. Scary story: Validation for trace impurity completed after 4 weeks of intensive method development. During the trial, impurity peak initially didn t appear at all in samples or standards.

12 Will building a better simulator solve the problem?

13 4. Develop and implement validation protocols appropriate for the measurement. Method validation determines whether methods are fit for purpose. Can the results be used to determine if the product is within specification? Data is only valid if there is validation data to support it. Can methods be validated after the initial timepoint? If the product proves to be unstable, formulation may need to be changed requiring changes in analytical methodology. If the product proves to be stable, if method validation fails all data is invalid.

14 4. Develop and implement validation protocols appropriate for the measurement For assay methods: Assay must be stability indicating. Method must be specific for analyte in presence of its degradants. For impurity methods: Method must be able to detect the impurity and quantify it at the critical level.

15 4. Develop and implement validation protocols appropriate for the measurement Stress testing is a critical part of validating methods as stability indicating. Acid, base, oxidative and photolytic stress conditions.

16 4. Develop and implement validation protocols appropriate for the measurement Exposure to UV is important because different reaction pathways are possible. Reactions which are electron spin forbidden in the ground state may be spin allowed in the excited electronic state. Isomerisation reactions: No rotation is possible about a double bond (sigma bond) but excited state allows free rotation. hv Reference Document: ICH Guideline Q1B

17 4. Develop and implement validation protocols appropriate for the measurement Just tickle it!!!

18 4. Develop and implement validation protocols appropriate for the measurement Low extents of decomposition (<10%) give the most information on specificity, since under these conditions the primary decomposition products are formed. Primary products are: Closer match to real impurities which form during product decomposition. Chromatographically and spectroscopically more similar to the active material, therefore providing a greater challenge to the method.

19 4. Develop and implement validation protocols appropriate for the measurement

20 4. Develop and implement validation protocols appropriate for the measurement Solution allowed to stand for 15 minutes ph 11

21 No more training wheels and we are ready to go!

22 5. Document methods thoroughly and reference consistently. If methods are changed during a trial it complicates interpretation of the data. Generally require cross-validation. Conclusions may require extensive justification. Method validation is only relevant to the data if it can be shown unequivocally that the method validated is the same as the method used to generate the data.

23 5. Document methods thoroughly and reference consistently. Changes in a method reference can be as difficult to justify as changes to the test method. Particularly relevant where program management is carried out external to the testing laboratory. Very difficult to manage across multiple jurisdictions. Stability studies: Sample submission information links the laboratory to the stability study protocol. Release testing: Sample submission information links the laboratory to the marketing authorisations. Always state the method as part of sample submission.

24 6. Aim to achieve mass balance If a significant proportion of your active disappears you will need to find out where its gone. You will need to measure concentrations of decomposition products. Very much a risk based approached. Complementary medicines: Rarely if ever a requirement. Importance increases as the toxicity of breakdown products increases. Reference Document: ICH Guidelines Q3A and Q3B

25 6. Aim to achieve mass balance

26 6. Aim to achieve mass balance. Impurities listed in monographs will include both by-products from manufacture and decomposition products. Only decomposition products typically require profiling. At the end of shelf life, product must comply with specifications for all impurities. Benzoyl Peroxide Decomposition product Synthesis by-product

27 6. Aim to achieve mass balance Measuring Impurity Profiles: Without identification: GC-FID: area % method can achieve mass balance. HPLC-UV: area % is inaccurate as detector is not linear enough over the concentration range required. HPLC-UV: comparison of impurity areas with areas of a 1% solution of sample solution can achieve quantification. HPLC-UV: Accuracy is limited by differences in response of impurity to analyte. % impurity in sample area of impurity peak area of 1% dilution of sample

28 6. Aim to achieve mass balance Validation of Unknown Impurity Methods: Assume that your impurity behaves in a similar way to the active material (detection and chromatography). Carry out validation using the active material focussing on your critical level (maximum permissible level). Instrument linearity covering concentrations below and above the critical level. Instrument precision at critical level. Recovery measurements limited to confirming calibration, difficult to conduct realistic recovery measurements. Better alternative is to use an alternative compound to the active, such as an isomer or model compound. Realistic recovery measurement, requiring quantification of compound in the presence of a high concentration of active.

29 6. Aim to achieve mass balance. Impurity method validation the ideal situation Impurities are known, readily purchased, are plentiful and cheap. Method specific for the impurity, no assumptions required to interpret stability data. Validation protocol: Instrument linearity 50% to 200% of the critical level. Instrument precision at the critical level. Recoveries at 50, 100 and 200% of the critical level. Specificity is the unknown impurity easily resolved from active. No need to force degradation of the impurity. LOD/LOQ

30 6. Aim to achieve mass balance Developing validation acceptance criteria: At the LOQ, the %RSD of 6 instrument readings will be about 10%. At the LOD, the %RSD of 6 instrument readings will be about 30%. Recovery: typically % Remember below the LOQ the method will be less quantitative, so recovery limits will be more difficult to achieve. LOD verified using signal to noise ratio Specificity and sensitivity can be critically dependant on chromatographic conditions explore effect of column age and conditions as part of ruggedness.

31 7. Review data continually through the study Even if you don t have time to review it, at least look at it!!

32 7. Review data continually through the study The laboratory generating the data will review it as it is generated, but may not always be aware of implications, particularly if they are not managing the study.

33 8. Act immediately in response to OOS/OOT At the end of a study, individual timepoints can be replaced with retest results.

34 8. Act immediately in response to OOS/OOT You just need the right equipment!

35 8. Act immediately in response to OOS/OOT In most cases data can only be invalidated and revised immediately after it is first generated. After the study is complete, OOS/OOT points may be argued to be outliers but they remain part of the data and cannot be removed from the profile. A laboratory may recognise OOS, but not OOT if they are not managing the study.

36 Conclusion Management of a stability trial commences before the trial begins. Small investments in time and timely action can negate the need for lengthy explanations. The data will speak for itself!

Validation of Analytical Methods used for the Characterization, Physicochemical and Functional Analysis and of Biopharmaceuticals.

Validation of Analytical Methods used for the Characterization, Physicochemical and Functional Analysis and of Biopharmaceuticals. 1 Analytical Method Validation: 1..1 Philosophy: Method validation is