Preformulation Guide
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Formulation tools for pharmaceutical development - [image: https://www.facebook.com/#!/pages/Formulation-tools-for-pharmaceutical-development/802258473124226] I would like share with you my new Book *Form...
lunes, 30 de marzo de 2009
domingo, 29 de marzo de 2009
Out-of-Specification Results and Failure Investigations in current FDA Warning Letters
Even though the Final FDA Guidance for Industry for Out-of-Specification Results was published quite some time ago, in recent times there have increasingly been FDA warning letters dealing with this theme - improper dealing with OOS results and inadequate investigation of failures.
This is supported by examples of warning letters from 2008 and 2009, extracts of which can be read below.
In March 2008, the FDA wrote in a warning letter:
Investigations into out-of specification (OOS) results for Content Uniformity testing concluded that laboratory error had occurred and required test method changes and validation. However, drug products tested using the same method that caused the OOS results have not been evaluated to determine the lot quality using the newly-modified, valid method.
There is no assurance that any of the test results are accurate and reliable. Conclusions of error investigations are not specific enough to implement adequate corrections.... In addition, they are not always substantiated by sound scientific evidence.... Again, no rationale was provided to support the conclusions.
The test solution that generated the OOS result was discarded without explanation.
The Quality Control Unit allowed the reporting of only the passing results in the final certificate of analysis, thus disregarding the original failing results that could not be invalidated by the investigation. But the procedure stipulates that if the investigation is inconclusive, the original results and the retested results must be individually reported.
In another warning letter written in January 2009, the FDA stated:
Investigations into the failures of batches to meet specifications in response to out-of-specification (OOS) results were incomplete or not documented. In response to OOS results, the batches were remixed and then resampled to obtain passing results without performing adequate investigations into the root cause of your manufacturing problems. Further it was failed to expand investigations to determine if other batches were possibly affected. The OOS review stated only: "The batch was not mixed properly. The batch was remixed." After remixing a passing result was obtained. The OOS investigation was closed and the batch was released without conducting an investigation into the cause of the failure.
In the end the FDA underlined that it is the responsibility of the firm to investigate the cause of the failure of a batch of a drug product to meet its specifications and to include conclusions and follow-up measures to prevent recurrence of such manufacturing problems.
And in a warning letter from February 2009, the following reference was found after a CBER (Center for Biologics Evaluation and Research) inspection:
Your SOP entitled "Procedure for the handling of Out of Specification Results (OOS) " is inadequate, in that it allows for repeat testing of OOS results before notifying Quality Assurance (QA) of nonconformities. Quality Assurance was not notified when a lot failed to meet the licensed final release specifications. These lots were retested without QA investigation and approval. The results of the retesting met the specification, and the lots were released for distribution.
Furthermore a current case from February 2009 concerns the manufacturer of topical application forms. The stability investigations into different lots of different products (ointments and creams) already on the market showed OOS results:
The frequency of discrepancies in stability investigations is significant. There is no evidence that the drug products meet the standard of strength, quality and purity at the time of their use within the expiration period. The necessary field alert reports for stability failures of distributed products were not always reported to the FDA within three working days. When a marketing authorisation holder becomes aware of any such information he is required to report it to the FDA within three working days.
A detailed analysis of all Warning Letters was published just recently. To find more details about the results, please see here. You can order the complete report as "FDA Navigator with Warning Letters Report" here.
This is supported by examples of warning letters from 2008 and 2009, extracts of which can be read below.
In March 2008, the FDA wrote in a warning letter:
Investigations into out-of specification (OOS) results for Content Uniformity testing concluded that laboratory error had occurred and required test method changes and validation. However, drug products tested using the same method that caused the OOS results have not been evaluated to determine the lot quality using the newly-modified, valid method.
There is no assurance that any of the test results are accurate and reliable. Conclusions of error investigations are not specific enough to implement adequate corrections.... In addition, they are not always substantiated by sound scientific evidence.... Again, no rationale was provided to support the conclusions.
The test solution that generated the OOS result was discarded without explanation.
The Quality Control Unit allowed the reporting of only the passing results in the final certificate of analysis, thus disregarding the original failing results that could not be invalidated by the investigation. But the procedure stipulates that if the investigation is inconclusive, the original results and the retested results must be individually reported.
In another warning letter written in January 2009, the FDA stated:
Investigations into the failures of batches to meet specifications in response to out-of-specification (OOS) results were incomplete or not documented. In response to OOS results, the batches were remixed and then resampled to obtain passing results without performing adequate investigations into the root cause of your manufacturing problems. Further it was failed to expand investigations to determine if other batches were possibly affected. The OOS review stated only: "The batch was not mixed properly. The batch was remixed." After remixing a passing result was obtained. The OOS investigation was closed and the batch was released without conducting an investigation into the cause of the failure.
In the end the FDA underlined that it is the responsibility of the firm to investigate the cause of the failure of a batch of a drug product to meet its specifications and to include conclusions and follow-up measures to prevent recurrence of such manufacturing problems.
And in a warning letter from February 2009, the following reference was found after a CBER (Center for Biologics Evaluation and Research) inspection:
Your SOP entitled "Procedure for the handling of Out of Specification Results (OOS) " is inadequate, in that it allows for repeat testing of OOS results before notifying Quality Assurance (QA) of nonconformities. Quality Assurance was not notified when a lot failed to meet the licensed final release specifications. These lots were retested without QA investigation and approval. The results of the retesting met the specification, and the lots were released for distribution.
Furthermore a current case from February 2009 concerns the manufacturer of topical application forms. The stability investigations into different lots of different products (ointments and creams) already on the market showed OOS results:
The frequency of discrepancies in stability investigations is significant. There is no evidence that the drug products meet the standard of strength, quality and purity at the time of their use within the expiration period. The necessary field alert reports for stability failures of distributed products were not always reported to the FDA within three working days. When a marketing authorisation holder becomes aware of any such information he is required to report it to the FDA within three working days.
A detailed analysis of all Warning Letters was published just recently. To find more details about the results, please see here. You can order the complete report as "FDA Navigator with Warning Letters Report" here.
miércoles, 25 de marzo de 2009
Design Space
This presentation will provide you an verview in an easy way abut design space concept
Design Space
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domingo, 22 de marzo de 2009
Productos en Investigacion
EMEA publishes Questions and Answers on the Quality of IMPs
The European Medicines Agency (EMEA) has published new Q&As on the Guideline on the Requirements to the Chemical and Pharmaceutical Quality Documentation Concerning Investigational Medicinal Products in Clinical Trials (CHMP/QWP/185401/2004). Final reference is given for each question.
1. Question: Setting specifications for impurities
On which basis should specifications for related impurities be set?
Answer:
Safety considerations should be taken into account. The limits should be supported by the impurity profiles of batches of active substance used in non-clinical and clinical studies. Results between batches should be consistent (or the clinical batches should show better purity results than non-clinical and previous clinical batches).
Compliance with ICH requirements is not required, if proper justification is provided.
2. Question: Substantial amendments (Chapter 8)
How should industry notify amendments?
Answer:
The table in the Guideline on the Requirements to the Chemical and Pharmaceutical Quality Documentation Concerning IMPs in Clinical Trials (CHMP/QWP/185401/2004) gives examples of what should be notified as substantial amendments and of changes where a notification will not be necessary. The list is not exhaustive, and the Sponsor should decide on a case-by-case basis if an amendment is to be classified as substantial or not.
Substantial amendments should be notified using the Notification of Amendment Form. Relevant updated sections of the documentation should be submitted, not the entire Quality Investigational Medicinal Product Dossier (IMPD).
For non-substantial amendments the form should not be used. The relevant authorities should be informed about relevant amendments together with an overall IMPD update or a substantial amendment. Documentation should not be submitted, but the relevant documentation should be recorded within the company.
3. Question: Shelf life extensions
Which information should be included in the file in order to make shelf life extensions without notification of a substantial amendment?
Answer:
The criteria based on which it is intended to extend shelf life during an on-going study should be given. The information should include extension protocol limiting the maximum time period for extrapolation. In the case of any significant negative trend for stability data observed during long-term and accelerated testing, the sponsor should commit to notify any shelf life extension as a substantial amendment.
4. Question: Batch data
Are Certificates of Analysis needed?
Answer:
No, tabulated batch results are sufficient. Data for representative batches should be included in the batch analysis table of the IMPD. Results for batches controlled according to previous, (wider) specifications are acceptable if the results comply with the specification for the planned clinical trial. The results should cover the relevant strengths, but the batches do not need to be the same that will be used in the clinical trial.
Source: EMEA Inspections QWP Questions and Answers
The European Medicines Agency (EMEA) has published new Q&As on the Guideline on the Requirements to the Chemical and Pharmaceutical Quality Documentation Concerning Investigational Medicinal Products in Clinical Trials (CHMP/QWP/185401/2004). Final reference is given for each question.
1. Question: Setting specifications for impurities
On which basis should specifications for related impurities be set?
Answer:
Safety considerations should be taken into account. The limits should be supported by the impurity profiles of batches of active substance used in non-clinical and clinical studies. Results between batches should be consistent (or the clinical batches should show better purity results than non-clinical and previous clinical batches).
Compliance with ICH requirements is not required, if proper justification is provided.
2. Question: Substantial amendments (Chapter 8)
How should industry notify amendments?
Answer:
The table in the Guideline on the Requirements to the Chemical and Pharmaceutical Quality Documentation Concerning IMPs in Clinical Trials (CHMP/QWP/185401/2004) gives examples of what should be notified as substantial amendments and of changes where a notification will not be necessary. The list is not exhaustive, and the Sponsor should decide on a case-by-case basis if an amendment is to be classified as substantial or not.
Substantial amendments should be notified using the Notification of Amendment Form. Relevant updated sections of the documentation should be submitted, not the entire Quality Investigational Medicinal Product Dossier (IMPD).
For non-substantial amendments the form should not be used. The relevant authorities should be informed about relevant amendments together with an overall IMPD update or a substantial amendment. Documentation should not be submitted, but the relevant documentation should be recorded within the company.
3. Question: Shelf life extensions
Which information should be included in the file in order to make shelf life extensions without notification of a substantial amendment?
Answer:
The criteria based on which it is intended to extend shelf life during an on-going study should be given. The information should include extension protocol limiting the maximum time period for extrapolation. In the case of any significant negative trend for stability data observed during long-term and accelerated testing, the sponsor should commit to notify any shelf life extension as a substantial amendment.
4. Question: Batch data
Are Certificates of Analysis needed?
Answer:
No, tabulated batch results are sufficient. Data for representative batches should be included in the batch analysis table of the IMPD. Results for batches controlled according to previous, (wider) specifications are acceptable if the results comply with the specification for the planned clinical trial. The results should cover the relevant strengths, but the batches do not need to be the same that will be used in the clinical trial.
Source: EMEA Inspections QWP Questions and Answers
Investigation Medicinal Products
EMEA publishes Questions and Answers on the Quality of IMPs
The European Medicines Agency (EMEA) has published new Q&As on the Guideline on the Requirements to the Chemical and Pharmaceutical Quality Documentation Concerning Investigational Medicinal Products in Clinical Trials (CHMP/QWP/185401/2004). Final reference is given for each question.
1. Question: Setting specifications for impurities
On which basis should specifications for related impurities be set?
Answer:
Safety considerations should be taken into account. The limits should be supported by the impurity profiles of batches of active substance used in non-clinical and clinical studies. Results between batches should be consistent (or the clinical batches should show better purity results than non-clinical and previous clinical batches).
Compliance with ICH requirements is not required, if proper justification is provided.
2. Question: Substantial amendments (Chapter 8)
How should industry notify amendments?
Answer:
The table in the Guideline on the Requirements to the Chemical and Pharmaceutical Quality Documentation Concerning IMPs in Clinical Trials (CHMP/QWP/185401/2004) gives examples of what should be notified as substantial amendments and of changes where a notification will not be necessary. The list is not exhaustive, and the Sponsor should decide on a case-by-case basis if an amendment is to be classified as substantial or not.
Substantial amendments should be notified using the Notification of Amendment Form. Relevant updated sections of the documentation should be submitted, not the entire Quality Investigational Medicinal Product Dossier (IMPD).
For non-substantial amendments the form should not be used. The relevant authorities should be informed about relevant amendments together with an overall IMPD update or a substantial amendment. Documentation should not be submitted, but the relevant documentation should be recorded within the company.
3. Question: Shelf life extensions
Which information should be included in the file in order to make shelf life extensions without notification of a substantial amendment?
Answer:
The criteria based on which it is intended to extend shelf life during an on-going study should be given. The information should include extension protocol limiting the maximum time period for extrapolation. In the case of any significant negative trend for stability data observed during long-term and accelerated testing, the sponsor should commit to notify any shelf life extension as a substantial amendment.
4. Question: Batch data
Are Certificates of Analysis needed?
Answer:
No, tabulated batch results are sufficient. Data for representative batches should be included in the batch analysis table of the IMPD. Results for batches controlled according to previous, (wider) specifications are acceptable if the results comply with the specification for the planned clinical trial. The results should cover the relevant strengths, but the batches do not need to be the same that will be used in the clinical trial.
Source: EMEA Inspections QWP Questions and Answers
The European Medicines Agency (EMEA) has published new Q&As on the Guideline on the Requirements to the Chemical and Pharmaceutical Quality Documentation Concerning Investigational Medicinal Products in Clinical Trials (CHMP/QWP/185401/2004). Final reference is given for each question.
1. Question: Setting specifications for impurities
On which basis should specifications for related impurities be set?
Answer:
Safety considerations should be taken into account. The limits should be supported by the impurity profiles of batches of active substance used in non-clinical and clinical studies. Results between batches should be consistent (or the clinical batches should show better purity results than non-clinical and previous clinical batches).
Compliance with ICH requirements is not required, if proper justification is provided.
2. Question: Substantial amendments (Chapter 8)
How should industry notify amendments?
Answer:
The table in the Guideline on the Requirements to the Chemical and Pharmaceutical Quality Documentation Concerning IMPs in Clinical Trials (CHMP/QWP/185401/2004) gives examples of what should be notified as substantial amendments and of changes where a notification will not be necessary. The list is not exhaustive, and the Sponsor should decide on a case-by-case basis if an amendment is to be classified as substantial or not.
Substantial amendments should be notified using the Notification of Amendment Form. Relevant updated sections of the documentation should be submitted, not the entire Quality Investigational Medicinal Product Dossier (IMPD).
For non-substantial amendments the form should not be used. The relevant authorities should be informed about relevant amendments together with an overall IMPD update or a substantial amendment. Documentation should not be submitted, but the relevant documentation should be recorded within the company.
3. Question: Shelf life extensions
Which information should be included in the file in order to make shelf life extensions without notification of a substantial amendment?
Answer:
The criteria based on which it is intended to extend shelf life during an on-going study should be given. The information should include extension protocol limiting the maximum time period for extrapolation. In the case of any significant negative trend for stability data observed during long-term and accelerated testing, the sponsor should commit to notify any shelf life extension as a substantial amendment.
4. Question: Batch data
Are Certificates of Analysis needed?
Answer:
No, tabulated batch results are sufficient. Data for representative batches should be included in the batch analysis table of the IMPD. Results for batches controlled according to previous, (wider) specifications are acceptable if the results comply with the specification for the planned clinical trial. The results should cover the relevant strengths, but the batches do not need to be the same that will be used in the clinical trial.
Source: EMEA Inspections QWP Questions and Answers
European Recommendations on Dissolution Testing
In the July 2008 issue of PHARMEUROPA, the draft for a new general chapter 5.17.1 titled "Recommendations on Dissolution Testing" was published.
The following explanation precedes the chapter: "This chapter includes recommendations on dissolution testing. Currently, this text can be found at the end of chapter 2.9.3, Dissolution Testing for Solid Dosage Forms, the rest of which has been harmonised at international level. The part that will now contain the recommendations is exclusively Ph.Eur. text.
In order to clarify the status of this text, it has been decided to create a separate general chapter in the European Pharmacopoeia.
Right at the beginning of this new chapter 5.17.1., it is clarified once more that this chapter is not binding. It contains information on
dissolution testing,
recommended media for testing
and specifications for oral dosage forms
This chapter includes generally accepted parameters used in dissolution.
In addition, regarding the contents, the acceptance criteria were described in more concrete terms. With reference to dosage forms with conventional dissolution, e.g., the text says: "The acceptance criteria are at least 80 per cent of the active ingredient within a defined time, usually less than 45 minutes. This equals a Q value of 75%."
The following explanation precedes the chapter: "This chapter includes recommendations on dissolution testing. Currently, this text can be found at the end of chapter 2.9.3, Dissolution Testing for Solid Dosage Forms, the rest of which has been harmonised at international level. The part that will now contain the recommendations is exclusively Ph.Eur. text.
In order to clarify the status of this text, it has been decided to create a separate general chapter in the European Pharmacopoeia.
Right at the beginning of this new chapter 5.17.1., it is clarified once more that this chapter is not binding. It contains information on
dissolution testing,
recommended media for testing
and specifications for oral dosage forms
This chapter includes generally accepted parameters used in dissolution.
In addition, regarding the contents, the acceptance criteria were described in more concrete terms. With reference to dosage forms with conventional dissolution, e.g., the text says: "The acceptance criteria are at least 80 per cent of the active ingredient within a defined time, usually less than 45 minutes. This equals a Q value of 75%."
miércoles, 11 de marzo de 2009
New USP General Chapter on Residual Solvents - Implementation by the FDA?
On 1 July 2008, the USP implemented the new General Chapter <467> - "Residual Solvents", which replaces the former Chapter <467> - "Organic Volatile Impurities". Now, the new General Chapter <467> was also revised in the 1st supplement to USP 32. Since this changeover also affects many products placed on the American market, in August 2008 the FDA issued a Draft Guidance for Industry with the title "Residual Solvents in Drug Products Marketed in the United States".
This FDA guidance defines in which form holders of a marketing authorisation (NDA and ANDA) are meant to inform the FDA of modifications in connection with this changeover.
The FDA expects products with an official USP monograph that are sold on the American market to comply with the requirements of the revised General Chapter <467>.
The FDA also explicitly permits the use of other analytical procedures, apart from those mentioned in the revised Chapter <467>. However, this requires a complete description, validation and verification of the alternative test method.
The FDA starts from the assumption that in most cases where changes are made under NDAs and ANDAs it will be sufficient to report these changes in the Annual Report. Here, the marketing authorisation holder is not supposed to submit detailed data, but rather summaries. However, in case of an inspection, the complete data must be on hand.
The new USP chapter does not apply to medicinal products that do not have to comply with the USP. Here, the FDA refers to the ICH Guideline Q3C Impurities: Residual Solvents.
The complete FDA Draft Guidance document can be found here:
http://www.fda.gov/CDER/guidance/8179dft.pdf
Since in the meantime the implementation of the new USP chapter has caused confusion among ANDA holders, FDA's Office of Generic Drugs (OGD) had to clarify some unanswered questions as well. For this purpose, the document "Residual Solvents in ANDAs: Questions and Answers" was published in October 2008. This document gives answers to 12 frequently asked questions from the OGD's point of view. Examples are:
Which ANDAs and ANDA supplements have to comply with USP <467>?
Which pieces of information have to be submitted in order to demonstrate compliance with USP <467>?
Which data on residual solvents should be included in a statement by the excipient manufacturer?
How should acceptance criteria be laid down for residual solvents that are not listed in USP <467>?
In which cases is the use of a class-1 solvent permissible?
Can "loss on drying" be used to test for class-3 solvents even in the presence of class-2 solvents, provided that 0.5% are not exceeded by both classes?
Do the methods have to be validated or verified?
Can a high-purity solvent be used instead of the USP reference standard?
All questions and answers by FDA can be found following this link:
http://www.fda.gov/cder/ogd/residualsolvents.pdf
This FDA guidance defines in which form holders of a marketing authorisation (NDA and ANDA) are meant to inform the FDA of modifications in connection with this changeover.
The FDA expects products with an official USP monograph that are sold on the American market to comply with the requirements of the revised General Chapter <467>.
The FDA also explicitly permits the use of other analytical procedures, apart from those mentioned in the revised Chapter <467>. However, this requires a complete description, validation and verification of the alternative test method.
The FDA starts from the assumption that in most cases where changes are made under NDAs and ANDAs it will be sufficient to report these changes in the Annual Report. Here, the marketing authorisation holder is not supposed to submit detailed data, but rather summaries. However, in case of an inspection, the complete data must be on hand.
The new USP chapter does not apply to medicinal products that do not have to comply with the USP. Here, the FDA refers to the ICH Guideline Q3C Impurities: Residual Solvents.
The complete FDA Draft Guidance document can be found here:
http://www.fda.gov/CDER/guidance/8179dft.pdf
Since in the meantime the implementation of the new USP chapter has caused confusion among ANDA holders, FDA's Office of Generic Drugs (OGD) had to clarify some unanswered questions as well. For this purpose, the document "Residual Solvents in ANDAs: Questions and Answers" was published in October 2008. This document gives answers to 12 frequently asked questions from the OGD's point of view. Examples are:
Which ANDAs and ANDA supplements have to comply with USP <467>?
Which pieces of information have to be submitted in order to demonstrate compliance with USP <467>?
Which data on residual solvents should be included in a statement by the excipient manufacturer?
How should acceptance criteria be laid down for residual solvents that are not listed in USP <467>?
In which cases is the use of a class-1 solvent permissible?
Can "loss on drying" be used to test for class-3 solvents even in the presence of class-2 solvents, provided that 0.5% are not exceeded by both classes?
Do the methods have to be validated or verified?
Can a high-purity solvent be used instead of the USP reference standard?
All questions and answers by FDA can be found following this link:
http://www.fda.gov/cder/ogd/residualsolvents.pdf
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