Validation of USP Methods - Incorporation of ISO Terms!
In the first supplement of the USP 32, the revised, general chapter <1225> - Validation of Compendial Methods - was published. This chapter describes the requisite performance characteristics that should be considered to prove the validation of a method in the case of its submission to the Pharmacopoeia.
It is striking that terms coming from ISO standards have also been incorporated, although the wording in pharmaceutical surroundings was until now oriented towards the ICH Guidelines, especially ICH Q2(R1).
This was also the topic of the publication entitled "Making Sense of Trueness, Precision, Accuracy, and Uncertainty" in the Pharmacopoeial Forum of May-June 2008. This article reviews the differences between the terms when used in ICH and ISO. It also states that the terms "trueness" and "uncertainty" do not even exist in the ICH and the USP. The conclusions drawn in this article are as follows: The terms should be clarified in the USP. These clarifications could easily be added to the General Chapters <1010> und <1225>. In the longer term, the USP encourages continued harmonisation of terminology among the involved parties (ISO, ICH, VIM - International Vocabulary of Metrology) and other interested parties.
In the revised chapter <1225> of the first supplement to USP 32, these terms have now been incorporated from ISO 5725-1 and ISO 3534-1.
And the term "reportable value", established from the OOS discussions in recent years, is now also incorporated in this USP chapter.
The requisite performance characteristics to be considered in validation of the types of methods in order to prove their suitability for the USP (accuracy, precision, specificity, detection limit, quantitation limit, linearity, range and ruggedness) remained unchanged.
And when is it necessary to revalidate? Revalidation may become necessary when a revised analytical method is submitted to the USP or when an established, general method is to be used for a new product or for a new starting material.
jueves, 9 de abril de 2009
Validation Findings in FDA Warning Letters 2008
The GMP news from 18 February 2009 comprised information on the FDA Warning Letters Report 2008, including the Top 5 deficiencies.
It did not cover deficiencies regarding validation (validation/qualification/calibration) though. This is due to the fact that the findings are listed according to the paragraphs in the 21 CFR 210/211, which does not contain a separate paragraph addressing (process) validation. For that reason the following information does provide an individual validation issues analysis:
In the 22 Warning Letters in the fiscal year 2008 issues regarding validation were criticised 15 times. Top of the list were deficiencies relative to process validation (9 Warning Letters). Five of the letters referred to deficiencies concerning solid dosage forms, 2 concerned semi-solid forms, one addressed radio pharmaceuticals, and one product classification remained unclear.
Two Warning Letters per subject covered issues like inappropriate validation of the sterilisation process, filter validation, "smoke studies" and cleaning validation the authority issued like
Exemplary findings for the issues mentioned above are:
Exclusion of validation batches without providing reasons within a retrospective validation
Missing sampling details in the validation plan
It seems like you did not understand the meaning of a cleaning validation
The cleaning validation master plan does not contain any "scientific rationale" for specific products, sampling locations and acceptance criteria
Swab surfaces are too small
Not all loading patterns were mapped in the validation of the sterilisation process
Inadequate Air Flow Pattern
Further deficiencies concerned issues like
An inadequate calibration of thermocouples
A Media Fill not representing a commercial process
Undocumented removal of filled vials within Media Fills
Conclusion: Although the subject validation is not specifically listed in the 21 CFR 210/211, it still is among the top deficiencies in the Warning Letters issued. Almost 70% of all letters contained one or several findings relative to this subject. 41% were related to process validation.
It did not cover deficiencies regarding validation (validation/qualification/calibration) though. This is due to the fact that the findings are listed according to the paragraphs in the 21 CFR 210/211, which does not contain a separate paragraph addressing (process) validation. For that reason the following information does provide an individual validation issues analysis:
In the 22 Warning Letters in the fiscal year 2008 issues regarding validation were criticised 15 times. Top of the list were deficiencies relative to process validation (9 Warning Letters). Five of the letters referred to deficiencies concerning solid dosage forms, 2 concerned semi-solid forms, one addressed radio pharmaceuticals, and one product classification remained unclear.
Two Warning Letters per subject covered issues like inappropriate validation of the sterilisation process, filter validation, "smoke studies" and cleaning validation the authority issued like
Exemplary findings for the issues mentioned above are:
Exclusion of validation batches without providing reasons within a retrospective validation
Missing sampling details in the validation plan
It seems like you did not understand the meaning of a cleaning validation
The cleaning validation master plan does not contain any "scientific rationale" for specific products, sampling locations and acceptance criteria
Swab surfaces are too small
Not all loading patterns were mapped in the validation of the sterilisation process
Inadequate Air Flow Pattern
Further deficiencies concerned issues like
An inadequate calibration of thermocouples
A Media Fill not representing a commercial process
Undocumented removal of filled vials within Media Fills
Conclusion: Although the subject validation is not specifically listed in the 21 CFR 210/211, it still is among the top deficiencies in the Warning Letters issued. Almost 70% of all letters contained one or several findings relative to this subject. 41% were related to process validation.
miércoles, 25 de marzo de 2009
Pharmacy History
The pharmacy history
Pharmacy History 1 1226686818538034 9
View more presentations from Shujah A.r.
domingo, 22 de marzo de 2009
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
lunes, 9 de febrero de 2009
Quantitative Analysis-Instrumental Methods
In this video you can learn some topic related with Instrumental methods used at the Pharmaceutical Industry
Powder Characterization for Formulation and Processing
The current trend within the pharmaceutical industry toward more efficient development, manufacturing, and specification is fueling demand for analytical tools that provide highly relevant information. Effective powder characterization has a valuable role to play.
Tim Freeman
Pharmaceutical Technology
Freeman Technology
Despite advances in alternative methods, tablets remain the most widely used method of drug delivery. Well-manufactured tablets are extremely stable, provide excellent dose uniformity, and are well accepted by users. Formulation development is, however, challenging, with the apparent simplicity of a tablet belying the challenges of its manufacture.
Tablet production demands the transformation of a relatively free-flowing powder into a compressed solid form. Stability is a defining performance characteristic, but rapid dissolution is also essential for efficient in vivo delivery. Other properties such as taste, smoothness, and shape must also be taken into account. As a result, tablets are complex multicomponent blends of binders, glidants, lubricants, disintegrants, sweeteners, flavors, pigments and, of course, active pharmaceutical ingredients (APIs).
Tableting has a long history, and substantial experience has been gained over many decades. Processors and formulators have traditionally relied heavily on this experience, taking an empirical, as opposed to knowledge-based, approach. Now, with the introduction of quality by design, the situation is changing. There is recognition of the importance of more fundamental knowledge and of investing heavily in its development.
Taking tableting as an example unit operation, this article explores how modern powder characterization techniques can provide valuable information that enhances understanding. Measuring dynamic, bulk, and shear properties of powders allows identification of the parameters that best define product performance, both during processing and in final application. This knowledge underpins fast, successful formulation development and effective process control.
The demands of the tableting process
Direct-compression tableting is a common method of solid dosage form manufacture. With this approach, the constituents of the tablet are blended and are then fed directly to the press. In most cases, however, the formulation cannot be used without first completing several preprocessing steps such as a wet or dry granulation. Granulating the blend reduces problems such as segregation and improves flow behavior by densifying and increasing the size of particles.
Figure 1 shows a schematic of a single-sided rotary tablet press. Powder flows from the hopper or intermediate bulk container, down the transfer chute, and onto the table. The blend is distributed through the feeder and flows gravimetrically into the die. As the table rotates, excess powder is scraped away from the top of the die before the punches apply compression to create the tablet. The tablets are ejected before the dies reach the filling point again.
Because the aim is to produce tablets of defined weight, geometry, hardness, and composition, consistent flow from the hopper onto the table and through the feeder into the die is necessary. A free-flowing powder may avoid blockages and intermittent flow, but it also may be more prone to flooding or segregation (the separation of dissimilar-sized particles).
During the compression stage, the goal is to produce a stable form that can be cleanly ejected from the press with minimal force. Achieving this objective makes other aspects of powder behavior important. For example, if excess air is retained in the die and compressed along with the powder, then it may expand once the compression force is removed, causing the tablet to burst or cap. Blends that release air relatively easily are therefore preferred. Tablet strength also is directly affected by cohesivity—compressive strength. A blend with low cohesivity may form a weak, unstable tablet, while highly cohesive materials may adhere to the tablet press and cause variability in fill weight.
This brief analysis highlights some of the compromises involved in addressing just a few of the issues connected with processing and final product quality. Other performance criteria overlay additional and often conflicting priorities. For example, fines may be attractive to a formulator because they help achieve rapid dissolution and increase tablet-compression strength but are problematic during processing because they increase the risk of cohesive behavior and affect productivity. Balancing these variables is the formulator's art.
Experience-based formulation is possible, and indeed still common, but greater emphasis on effective processing and early definition of the design space is reducing the scope for error. Formulators need tools that provide relevant data at an early stage, thereby allowing rationalization of experience in terms of quantifiable parameters. This result gives insight and understanding, promoting a knowledge-based approach. Processors too require data to understand the reasons for both good and poor performance at the press. Such knowledge feeds back into formulation development and facilitates the successful processing of challenging blends.
See the article HERE
Tim Freeman
Pharmaceutical Technology
Freeman Technology
Despite advances in alternative methods, tablets remain the most widely used method of drug delivery. Well-manufactured tablets are extremely stable, provide excellent dose uniformity, and are well accepted by users. Formulation development is, however, challenging, with the apparent simplicity of a tablet belying the challenges of its manufacture.
Tablet production demands the transformation of a relatively free-flowing powder into a compressed solid form. Stability is a defining performance characteristic, but rapid dissolution is also essential for efficient in vivo delivery. Other properties such as taste, smoothness, and shape must also be taken into account. As a result, tablets are complex multicomponent blends of binders, glidants, lubricants, disintegrants, sweeteners, flavors, pigments and, of course, active pharmaceutical ingredients (APIs).
Tableting has a long history, and substantial experience has been gained over many decades. Processors and formulators have traditionally relied heavily on this experience, taking an empirical, as opposed to knowledge-based, approach. Now, with the introduction of quality by design, the situation is changing. There is recognition of the importance of more fundamental knowledge and of investing heavily in its development.
Taking tableting as an example unit operation, this article explores how modern powder characterization techniques can provide valuable information that enhances understanding. Measuring dynamic, bulk, and shear properties of powders allows identification of the parameters that best define product performance, both during processing and in final application. This knowledge underpins fast, successful formulation development and effective process control.
The demands of the tableting process
Direct-compression tableting is a common method of solid dosage form manufacture. With this approach, the constituents of the tablet are blended and are then fed directly to the press. In most cases, however, the formulation cannot be used without first completing several preprocessing steps such as a wet or dry granulation. Granulating the blend reduces problems such as segregation and improves flow behavior by densifying and increasing the size of particles.
Figure 1 shows a schematic of a single-sided rotary tablet press. Powder flows from the hopper or intermediate bulk container, down the transfer chute, and onto the table. The blend is distributed through the feeder and flows gravimetrically into the die. As the table rotates, excess powder is scraped away from the top of the die before the punches apply compression to create the tablet. The tablets are ejected before the dies reach the filling point again.
Because the aim is to produce tablets of defined weight, geometry, hardness, and composition, consistent flow from the hopper onto the table and through the feeder into the die is necessary. A free-flowing powder may avoid blockages and intermittent flow, but it also may be more prone to flooding or segregation (the separation of dissimilar-sized particles).
During the compression stage, the goal is to produce a stable form that can be cleanly ejected from the press with minimal force. Achieving this objective makes other aspects of powder behavior important. For example, if excess air is retained in the die and compressed along with the powder, then it may expand once the compression force is removed, causing the tablet to burst or cap. Blends that release air relatively easily are therefore preferred. Tablet strength also is directly affected by cohesivity—compressive strength. A blend with low cohesivity may form a weak, unstable tablet, while highly cohesive materials may adhere to the tablet press and cause variability in fill weight.
This brief analysis highlights some of the compromises involved in addressing just a few of the issues connected with processing and final product quality. Other performance criteria overlay additional and often conflicting priorities. For example, fines may be attractive to a formulator because they help achieve rapid dissolution and increase tablet-compression strength but are problematic during processing because they increase the risk of cohesive behavior and affect productivity. Balancing these variables is the formulator's art.
Experience-based formulation is possible, and indeed still common, but greater emphasis on effective processing and early definition of the design space is reducing the scope for error. Formulators need tools that provide relevant data at an early stage, thereby allowing rationalization of experience in terms of quantifiable parameters. This result gives insight and understanding, promoting a knowledge-based approach. Processors too require data to understand the reasons for both good and poor performance at the press. Such knowledge feeds back into formulation development and facilitates the successful processing of challenging blends.
See the article HERE
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