Pharmaceutical Technology (Johnny Aguilar)

WHO Publishes Guidelines on the Use of Quality Risk Management

noreply@blogger.com (J. Aguilar) — Mon, 27 Sep 2010 12:19:00 +0000

In August 2010, the WHO published a draft guideline on quality risk management (QRM). With its 24 pages divided into 6 chapters, it is a surprisingly detailed document.
In the introduction (Chapter 1), the WHO points out that it formerly considered the HACCP concept, which comes from the food sector, as a suitable risk management tool. Bit regard to the EU GMP Guide, ICH Q8 and the FDA's risk-based approach, the WHO now sees more pharma-specific concerning QRM. The draft guideline now describes the current WHO approach to QRM, which is now also based on ICH Q9. However, the text underlines the fact that risk management modules other than the one described in ICH Q9 can also be applied. Depending on the process in question, the WHO also sees the emphasis on the individual ICH-Q9 steps as quite different. Yet, the guideline requires that all of the elements from the QRM process of ICH Q9 be implemented. Interestingly, within the framework of QRM, the WHO also sees connections to GCP and GLP. An indirect requirement to use QRM also in those fields?
The second chapter describing QRM considerations for regulatory authorities is also highly interesting. Actually, the descriptions are hidden requirements on a QRM by regulatory authorities directed at marketing authorisation holders and manufacturers. 2.2.1 explicitly includes a checklist for inspecting a QRM, and 2.2.2 lays down the inspection of risk-based decisions.
Chapter 3, in turn, includes highly detailed requirements on QRM for pharmaceutical manufacturers. You can find specifications regarding the topic of training and education, on responsibilities detailed instructions for the initiation of a QRM process up to the establishment of corrective actions and the verification of the QRM plan. A separate part of this chapter is dedicated to the application of QRM in product development and during validation/qualification. Especially with regard to process validation, the guideline refers to the FDA draft on this topic. In a consistent way, dependent on the process knowledge through QRM coming from development, the number of validation or "conformance batches" is not fixed either. A deviation from the classical number three for validation runs is explicitly considered to be possible (e. g. in the validation of the manufacture of orphan drugs).
Chapter 4 is titled "Risk Management Tools". With reference to a document by the Product Quality Research Institute (PQRI), a probability-versus-impact matrix is published. This matrix is meant to facilitate the classification into low, medium or high risks. In this context, the QRM team shall define each status in advance. As a helpful tool, a "consequence table" is also published, giving examples for the classification of probabilities and impacts, e. g. what is marginal impact (no impact on the product). A separate table lists risk management tools and the cases in which they can potentially be applied. Here, the PQRI is also referenced as the source.
A glossary (Chapter 5) complements the other 4 chapters. A salient point is the contents' distinct reference to a Q&A paper by the MHRA on the topic of QRM (see our GMP News from 15 September 2010). Some of the passages were taken over verbatim. Like the MHRA paper, the draft requires a "risk register", too.
Conclusion: The draft shows an astonishing high level of detail and is therefore truly worth reading. It can give guidance also in the preparation for questions regarding the QRM within the framework of an official inspection. Likewise, it provides guidance for initiating a QRM. However, only time will tell whether pharmaceutical companies e. g. in emerging countries can also implement QRM so meticulously. But the document may still be changed within the framework of finalisation in order to facilitate its implementation. The document is said to be available on the WHO web page soon.

Source ECA

Johnny Aguilar, Encarna G, Pilar P, Ganadores del Acc. Concurso Real Academía de Farmacia de Catalunya 2008-2009: Premio Dr. Esteve

noreply@blogger.com (J. Aguilar) — Fri, 24 Sep 2010 07:10:00 +0000

El trabajo VALIDACIÓN DE LA INNOVADORA METODOLOGÍA SEDEM PARA SU USO COMO HERRAMIENTA DE PREFORMULACIÓN GALÉNICA SEGÚN LOS CRITERIOS DE CALIDAD POR DISEÑO (ICH-Q8) fue ganador del XXXVII Premio “DR. ESTEVE” 2008-2009 Organizado por la Real Academia de Farmacia de Cat- en Barcelona España

Autores: Johnny Aguilar Encarna García, Pilar P.

Este trabajo ha sido desarrollado en el Departamento de Tecnologia Farmacéutica de la Facultad de Farmacia Universidad de Barcelona constituyendo una parte de mi PhD.

Para acceder al summary del trabajo hacer click AQUI

Johnny Aguilar & Elias B. First Prize I-ISPE SPAIN AWARD

noreply@blogger.com (J. Aguilar) — Wed, 16 Jun 2010 12:14:00 +0000

Johnny Aguilar & Elias B. First Prize I-ISPE SPAIN AWARD

To access to this article click here

Johnny Aguilar and Elías Benito of Novartis BdV, winners of the I Prize ISPE Spain to the best technical article of pharmaceutical engineering The prize was given during IV the Congress of ISPE Spain, presided over by Sergio Torralbo. “Contribution to the design of a closed system of Wet granulation totally integrated with High Yields with analysis system online”, under this title hides the meticulous explanatory work developed by Johhny Aguilar, MST Manager and Elías Benito, Process Expert de Capsules of the plant of production of Novartis Barberà, that has made them of the I Prize ISPE Spain winning the best technical article of pharmaceutical engineering. “The article tries to contribute from an analysis of previous risk (ICHQ9) a guide of support in the design of lines of granulation that allows to obtain high performances and in addition on proposes the implementation of systems of integrated analyses line”, winners Johnny and Elias comment. The delivery of the prize was realised during IV the Congress of ISPE Spain that was celebrated the past in Madrid 19 of May

The jury of the I Prize ISPE Spain has evaluated the technical quality, the divulging capacity and the innovating component of presented/displayed articles

Unapproved Drug Warning Letters

noreply@blogger.com (J. Aguilar) — Thu, 16 Apr 2009 22:04:00 +0000

Apr 16, 2009
By: Angie Drakulich
ePT--the Electronic Newsletter of Pharmaceutical Technology

In late March 2009, the US Food and Drug Administration sent Warning Letters to nine companies asking them to stop manufacturing 14 unapproved narcotic drugs. Less than two weeks later, on Apr. 9, 2009, the agency amended those letters when it realized that one particular unapproved opioid (a high concentrate of morphine sulfate oral solution) is desperately needed by patients.

As part of FDA’s unapproved drugs initiative, launched in June 2006, the original Warning Letters went to: Boehringer Ingelheim Roxane (Columbus, OH), Cody Laboratories (Cody, WY), Glenmark Pharmaceuticals (Mahwah, NJ), Lannett Company (Philadelphia, PA), Lehigh Valley Technologies (Allentown, PA), Mallinckrodt Pharmaceuticals Group (St. Louis), Physicians Total Care (Tulsa, OK), Roxane Laboratories (Columbus, OH), and Xanodyne Pharmaceuticals (Newport, KY). The letters asked the companies to stop manufacturing and distributing unapproved products that included high-concentrate morphine sulfate oral solutions and immediate-release tablets containing morphine sulfate, hydromorphone, or oxycodone (oxycodone capsules were not included).

The original FDA press release about the nine Warning Letters stated, “FDA has determined that removal of the unapproved narcotic products will not create a shortage for consumers.” The agency had to backtrack when it received “concerns from patients and healthcare professionals in the palliative care community” that one of the affected opioid products (specifically 20 mg/mL morphine sulfate oral solution) is used to alleviate pain in terminally ill patients. FDA’s Apr. 9 release therefore stated, “The agency has determined that this dosage form is medically necessary, and should remain on the market until an approved alternative becomes available to the patients that need it.”

Companies manufacturing versions of high-concentrate morphine sulfate solution can now continue to do so, but only on an interim basis.

The very next day, Apr. 10, FDA announced permanent injunctions against contract manufacturer Neilgen Pharmaceuticals (Westminster, MD) and its parent company, Advent Pharmaceuticals (East Windsor, NJ), to prevent them from manufacturing and distributing any unapproved, adulterated, or misbranded drugs. An injunction was also filed against two of the companies’ officers, Bharat Patel and Pragna Patel. Neilgen, which operates as Unigen Pharmaceuticals, had been manufacturing unapproved prescription cough and cold products. The companies signed a consent decree to destroy their drug supply and to stop manufacturing and distributing any new drugs without FDA approval.

Read FDA’s guidance document on unapproved drugs.

Read a related blog post on PharmTech Talk.

EMEA Plans on Revising EC GMP Guide to Implement ICH Q10

noreply@blogger.com (J. Aguilar) — Thu, 09 Apr 2009 08:03:00 +0000

On 11 March 2009 the European Medicines Agency (EMEA) issued a so-called concept paper. In this paper the authority explains the problems in implementing the ICH Guideline Q10 "Pharmaceutical Quality System" in European legislation und thus proposes a revision of the EC GMP Guide. Following the approval of the ICH Guideline Q10 this transfer is mandatory for the EC.

The EMEA states that requirements regarding a pharmaceutical quality system are already implemented in the EC GMP Guide, and especially in chapter 1. For that reason the authority sees a potential risk for confusion in the regulatory requirements caused by a different terminology in the two documents. In addition to that, in EMEA's view the requirements defined in chapters 1 and 2 of the EC GMP Guide are not up to date any more. A revision is also necessary for the glossary as well as for the chapter 7 "Contract Manufacture and Analysis", as "Outsourcing" was emphasised in the final ICH Q10 version. Further issues to be addressed include:

"Clearer guidance on the handling and investigations of deviations, Corrective and Preventive action and change control.
Emphasising the role of senior management in ensuring that there is an effective Quality Management System to support GMP."
The first draft of the requirements is supposed to be published in July 2009 and is intended for finalisation within a year.

Validation of USP Methods - Incorporation of ISO Terms!

noreply@blogger.com (J. Aguilar) — Thu, 09 Apr 2009 08:02:00 +0000

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.

Validation Findings in FDA Warning Letters 2008

noreply@blogger.com (J. Aguilar) — Thu, 09 Apr 2009 08:00:00 +0000

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.

Preformulation Guide

noreply@blogger.com (J. Aguilar) — Tue, 31 Mar 2009 05:08:00 +0000

Preformulation Guide

View more documents from Vijayendrakumar.

Out-of-Specification Results and Failure Investigations in current FDA Warning Letters

noreply@blogger.com (J. Aguilar) — Sun, 29 Mar 2009 08:38:00 +0000

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.

Design Space

noreply@blogger.com (J. Aguilar) — Thu, 26 Mar 2009 06:34:00 +0000

This presentation will provide you an verview in an easy way abut design space concept

Design Space

View more presentations from elfoxy99.

Productos en Investigacion

noreply@blogger.com (J. Aguilar) — Sun, 22 Mar 2009 08:52:00 +0000

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

Investigation Medicinal Products

noreply@blogger.com (J. Aguilar) — Sun, 22 Mar 2009 08:50:00 +0000

European Recommendations on Dissolution Testing

noreply@blogger.com (J. Aguilar) — Sun, 22 Mar 2009 08:48:00 +0000

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%."

New USP General Chapter on Residual Solvents - Implementation by the FDA?

noreply@blogger.com (J. Aguilar) — Wed, 11 Mar 2009 20:15:00 +0000

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

HPLC Detectors

noreply@blogger.com (J. Aguilar) — Sat, 07 Mar 2009 11:12:00 +0000

wavelength, variable wavelength, diode array, laser, Nephelometry, Turbidimetry

Detectors and Detection Limits

The detector for an HPLC is the component that emits a response due to the eluting sample compound and subsequently signals a peak on the chromatogram. It is positioned immediately posterior to the stationary phase in order to detect the compounds as they elute from the column. The bandwidth and height of the peaks may usually be adjusted using the coarse and fine tuning controls, and the detection and sensitivity parameters may also be controlled (in most cases). There are many types of detectors that can be used with HPLC. Some of the more common detectors include: Refractive Index (RI), Ultra-Violet (UV), Fluorescent, Radiochemical, Electrochemical, Near-Infra Red (Near-IR), Mass Spectroscopy (MS), Nuclear Magnetic Resonance (NMR), and Light Scattering (LS).

Refractive Index (RI) detectors measure the ability of sample molecules to bend or refract light. This property for each molecule or compound is called its refractive index. For most RI detectors, light proceeds through a bi-modular flow-cell to a photodetector. One channel of the flow-cell directs the mobile phase passing through the column while the other directs only the mobile phase. Detection occurs when the light is bent due to samples eluting from the column, and this is read as a disparity between the two channels.

--Laser-Based RI Detectors

Ultra-Violet (UV) detectors measure the ability of a sample to absorb light. This can be accomplished at one or several wavelengths:

A) Fixed Wavelength measures at one wavelength, usually 254 nm
B) Variable Wavelength measures at one wavelength at a time, but can detect over a wide range of wavelenths
C) Diode Array measures a spectrum of wavelengths simulateneously

--[More on diode detectors]

UV detectors have a sensitivity to approximately 10-8 or 10 -9 gm/ml.

--Laser-based absorbance detectors

--Using Fourier Transform in UV Spectrometry.

Fluorescent detectors measure the ability of a compound to absorb then re-emit light at given wavelengths. Each compound has a characteristic fluorescence. The excitation source passes through the flow-cell to a photodetector while a monochromator measures the emission wavelengths.

Has sensitivity limit of 10-9 to 10-11 gm/ml.

--[More on fluorescent spectroscopy]

--Laser-based fluorescence detectors

Radiochemical detection involves the use of radiolabeled material, usually tritium (3H) or carbon-14 (14C). It operates by detection of fluorescence associated with beta-particle ionization, and it is most popular in metabolite research. Two detector types:

A) Homogeneous- Where addition of scintillation fluid to column effluent causes fluorescence.
B) Heterogeneous- Where lithium silicate and fluorescence caused by beta-particle emission interact with the detector cell.

Has sensitivity limit up to 10-9 to 10-10 gm/ml.

Electrochemical detectors measure compounds that undergo oxidation or reduction reactions. Usually accomplished by measuring gain or loss of electrons from migrating samples as they pass between electrodes at a given difference in electrical potential.

Has sensitivity of 10-12 to 10-13 gm/ml

6) Mass Spectroscopy (MS) Detectors- The sample compound or molecule is ionized, it is passed through a mass analyzer, and the ion current is detected. There are various methods for ionization:

A) Electron Impact (EI)- An electron current or beam created under high electric potential is used to ionize the sample migrating off the column.
B) Chemical Ionization- A less aggresive method which utilizes ionized gas to remove electrons from the compounds eluting from the column.
C) Fast Atom Bombarbment (FAB)- Xenon atoms are propelled at high speed in order to ionize the eluents from the column.

Has detection limit of 10-8 to 10-10 gm/ml.

7) Nuclear Magnetic Resonance (NMR) Detectors- Certain nuclei with odd- numbered masses, including H and 13C, spin about an axis in a random fashion. However, when placed between poles of a strong magnet, the spins are aligned either parallel or anti-parallel to the magnetic field, with the parallel orientation favored since it is slightly lower in energy. The nuclei are then irradiated with electromagnetic radiation which is absorbed and places the parallel nuclei into a higher energy state; consequently, they are now in "resonance" with the radiation. Each H or C will produce different spectra depending on their location and adjacent molecules, or elements in the compound, because all nuclei in molecules are surrounded by electron clouds which change the encompassing magnetic field and thereby alter the absorption frequency.

8) Light-Scattering (LS) Detectors- When a source emits a parallel beam of light which strikes particles in solution, some light is reflected, absorbed, transmitted, or scattered. Two forms of LS detection may be used to measure the two latter occurrences:

A) Nephelometry- This is defined as the measurement of light scattered by a particulate solution. This method enables the detection of the portion of light scattered at a multitude of angles. The sensitivity depends on the absence of background light or scatter since the detection occurs at a black or null background.

B) Turbidimetry- This is defined as the measure of the reduction of light transmitted due to particles in solution. It measures the light scatter as a decrease in the light that is transmitted through the particulate solution. Therefore, it quantifies the residual light transmitted. Sensitivity of this method depends on the sensitivity of the machine employed, which can range from a simple spectrophotometer to a sophisticated discrete analyzer. Thus, the measurement of a decrease in transmitted light from a large signal of transmitted light is limited to the photometric accuracy and limitations of the instrument employed.

--Laser-based scattering detectors

9) Near-Infrared Detectors- Operates by scanning compounds in a spectrum from 700 to 1100 nm. Stretching and bending vibrations of particular chemical bonds in each molecule are detected at certain wavelengths. This is a fast growing method which offers several advantages: speed (sometimes less than 1 second), simplicity of preparation of sample, multiple analyses from single spectrum, and nonconsumption of the sample (McClure, 1994).

Laser-Based Detectors

Linearity and detectors

McClure, W.F. Analytical Chemistry, 1994, Vol. 66, p. 44.

Return to applications page.

HPLC Mobile Phase

noreply@blogger.com (J. Aguilar) — Sat, 07 Mar 2009 11:08:00 +0000

The mobile phase in HPLC refers to the solvent being continuously applied to the column, or stationary phase. The mobile phase acts as a carrier for the sample solution. A sample solution is injected into the mobile phase of an assay through the injector port. As a sample solution flows through a column with the mobile phase, the components of that solution migrate according to the non-covalent interactions of the compound with the column. The chemical interactions of the mobile phase and sample, with the column, determine the degree of migration and separation of components contained in the sample. For example, those samples which have stronger interactions with the mobile phase than with the stationary phase will elute from the column faster, and thus have a shorter retention time, while the reverse is also true. The mobile phase can be altered in order to manipulate the interactions of the sample and the stationary phase. There are several types of mobile phases, these include: Isocratic, gradient, and polytyptic.

In isocratic elution compounds are eluted using constant mobile phase composition. The separation of compounds can be described using several equations:

(Snyder, 1983)
All compounds begin migration through the column at onset. However, each migrates at a different rate, resulting in faster or slower elution rate. This type of elution is both simple and inexpensive, but resolution of some compounds is questionable and elution may not be obtained in a reasonable amount of time (Snyder, 1983).

In gradient elution different compounds are eluted by increasing the strength of the organic solvent. The sample is injected while a weaker mobile phase is being applied to the system. The strength of the mobile phase is later increased in increments by raising the organic solvent fraction, which subsequently results in elution of retained components. This is usually done in a stepwise or linear fashion. There are several equations that describe gradient elution:
(Snyder, 1983)At the onset of sample introduction, the compounds are initially retained at the inlet of the column. As the solute capacity, or k', for the compound decreases, the compound begins to migrate through the stationary phase. Each of the other compounds in the sample subsequently migrate as their k' values decrease. Compared with isocratic elution, resolution and separation are improved, and bandwidths are nearly equal: (Snyder, 1983)

Isocratic Vs. Gradient Elution
The Knox equation describes column efficiency or plate number N in relation to certain experimental conditions, such as column length, column diameter, temperature, flow-rate, molecular weight, etc. (Equation). Plate number N is equal to plate height value H divided by particle diameter (dp). Plate height value H is in turn equal to column length L divided by N. Two of the Knox coefficients, B and C, depend on k' and size of the compound. In the equations above, k' in the isocratic equations is replaced with average k' in the gradient equations. In fact, this is the only difference in the bandwidth and resolution equations between the two. Thus, separation and height of the peak are dictated by the exact same conditions for both isocratic and gradient elution (Snyder, 1983).
>From the equation for capacity factor in gradient elution, it can be seen that average k' value depends on flow-rate, gradient time, and column dead volume. This differs in isocratic elution where k' is not dependent on time of separation, flow- rate, or column dimensions.

A special feature in gradient elution is linear-solvent strength (LSS) gradients. These give approximately equal values of average k' for samples eluting at different times during separation. This is the reason why gradient elution can yield constant bandwidths for different compounds and equal resolution for pairs of compounds which have similar alpha or separation factor values.

Polytyptic Mobile Phase, sometimes referred to as mixed-mode chromatography, is a versatile method in which several types of chromatographic techniques, or modes, can be employed using the same column. These columns contain rigid macroporous hydrophobic resins covalently bonded to a hydrophilic organic layer. SEC, IEC, hydrophobic or affinity chromatography are some of the methods that may be utilized. By changing the the mobile phase, the mode of separation is thereby changed which allows the chromatographer to achieve the desired selectivity in the separations.
Synder, L.R.; Stadalius, M.A.; Quarry, M.A. Analytical Chemistry, 1983, Vol. 55, pp. 1412-30.

HPLC Column

noreply@blogger.com (J. Aguilar) — Sat, 07 Mar 2009 11:05:00 +0000

Columns

There are various columns that are secondary to the separating column or stationary phase. They are: Guard, Derivatizing, Capillary, Fast, and Preparatory Columns.

Guard Columns are placed anterior to the separating column. This serves as a protective factor that prolongs the life and usefulness of the separation column. They are dependable columns designed to filter or remove: 1) particles that clog the separation column; 2) compounds and ions that could ultimately cause "baseline drift", decreased resolution, decreased sensitivity, and create false peaks; 3) compounds that may cause precipitation upon contact with the stationary or mobile phase; and 4) compounds that might co-elute and cause extraneous peaks and interfere with detection and/or quantification. These columns must be changed on a regular basis in order to optimize their protective function. Size of the packing varies with the type of protection needed.

Derivatizing Columns- Pre- or post-primary column derivatization can be an important aspect of the sample analysis. Reducing or altering the parent compound to a chemically related daughter molecule or fragment elicits potentially tangible data which may complement other results or prior analysis. In few cases, the derivatization step can serve to cause data to become questionable, which is one reason why HPLC was advantageous over gas chromatography, or GC (Brown, 1990). Because GC requires volatile, thermally stabile, or nonpolar analytes, derivatization was usually required for those samples which did not contain these properties. Acetylation, silylation, or concentrated acid hydrolysis are a few derivatization techniques.

Capillary Columns- Advances in HPLC led to smaller analytical columns. Also known as microcolumns, capillary columns have a diameter much less than a millimeter and there are three types: open-tubular, partially packed, and tightly packed. They allow the user to work with nanoliter sample volumes, decreased flow rate, and decreased solvent volume usage which may lead to cost effectiveness. However, most conditions and instrumentation must be miniaturized, flow rate can be difficult to reproduce, gradient elution is not as efficient, and care must be taken when loading minute sample volumes (Brown, 1990).
Microbore and small-bore columns are also used for analytical and small volumes assays. A typical diameter for a small-bore column is 1-2 mm. Like capillary columns, instruments must usually be modified to accommodate these smaller capacity columns (i.e., decreased flow rate). However, besides the advantage of smaller sample and mobile phase volume, there is a noted increase in mass sensitivity without significant loss in resolution (Simpson, 1987).--Capillary Electrophoresis

Fast Columns- One of the primary reasons for using these columns is to obtain improved sample throughput (amount of compound per unit time). For many columns, increasing the flow or migration rate through the stationary phase will adversely affect the resolution and separation. Therefore, fast columns are designed to decrease time of the chromatographic analysis without forsaking significant deviations in results. These columns have the same internal diameter but much shorter length than most other columns, and they are packed with smaller particles that are typically 3 µm in diameter. Advantages include increased sensitivity, decreased analysis time, decreased mobile phase usage, and increased reproducibility (DiCesare, 1987).

Preparatory Columns- These columns are utilized when the objective is to prepare bulk (milligrams) of sample for laboratory preparatory applications. A preparatory column usually has a large column diameter which is designed to facilitate large volume injections into the HPLC system.
Accessories important to mention are the back-pressure regulator and the fraction collector. The back-pressure regulator is placed immediately posterior to the HPLC detector. It is designed to apply constant pressure to the detector outlet which prevents the formation of air bubbles within the system. This, in turn, improves chromatographic baseline stability. It is usually devised to operate regardless of flow rate, mobile phase, or viscosity.The fraction collector is an automated device that collects uniform increments of the HPLC output. Vials are placed in the carousel and the user programs the time interval in which the machine is to collect each fraction. Each vial contains mobile phase and sample fractions at the corresponding time of elution. Packings for columns are diverse since there are many modes of HPLC. They are available in different sizes, diameters, pore sizes, or they can have special materials attached (such as an antigen or antibody for immunoaffinity chromatography). Packings available range from those needed for specific applications (affinity, immunoaffinity, chiral, biological, etc.) to those for all-purpose applications. The packings are attached to the internal column hull by resins or supports, which include oxides, polymers, carbon, hydroxyapatite beads, agarose, or silica, the most common type(Brown, 1990).

Caution regarding columns

Brown, P.R. Analytical Chemistry, 1990, Vol. 62, p. 995

.Brown, p. 996.

Simpson, R.C. and Brown, P.R.; J. Chromatogr., 1987, No. 400, p. 297.

DiCesare, J.L.; Dong, M.W.; Vandermark, F.L.; Am. Lab., 1981, No. 13, p. 52.

Brown, p. 998.

HPLC Column Efficiency

noreply@blogger.com (J. Aguilar) — Sat, 07 Mar 2009 11:02:00 +0000

Column efficiency refers to the performance of the stationary phase to accomplish particular separations. This entails how well the column is packed and its kinetic performance (Bidlingmeyer, 1984). The efficiency of a column can be measured by several methods which may or may not be affected by chromatographic anomalies, such as "tailing" or appearance of a "front." This is important because many chromatographic peaks do not appear in the preferred shape of normal Gaussian distribution. For this reason efficiency can be an enigmatic value since manufacturers may use different methods in determining the efficiency of their columns (Bidlingmeyer, 1984).

Calculation of column efficiency value:

All the following methods use this formula that measures N, or number of theoretical plates:
.

Inflection Method- Calculation is based upon inflection point which appears at 60.7% of the peak height for a normal Gaussian peak. At this point the width of the peak is equivalent to two standard deviation units. Any asymmetrical aspect of a peak should not affect this calculation since the width is measured above the anomalous occurance (i.e., tailing or fronting).
(Bidlingmeyer, 1984)

Half-peak height Method- As the name suggests, the measurement is based upon the width at 50% of peak height. For the same reason as inflection method, this measurement is not affected by asymmetry; however, this method is more reproducible from person to person since width at 50% peak height is less prone to be varied.
(Bidlingmeyer, 1984)

Tangent Method- Tangent lines are drawn on each side of the peak and the width is the distance between the two lines at the base of the peak. Therefore, it is more sensitive to asymmetrical peaks and variation in efficiency values is usually seen from user to user.
(Bidlingmeyer, 1984)

Sigma Methods- These methods measure peak width at decreasing levels of peak height. Thus, the three sigma method measures width at 32.4% of peak height, the four sigma method measures at 13.4%, and the five sigma method measures at 4.4%. The five sigma method is most sensitive to asymmetry because the width is measured at the lowest point.
(Bidlingmeyer, 1984)

Height/Area Method- This method utilizes the fact that the area of a peak is a function of its height and standard deviation. To determine efficiency, values for peak height and area are used in a different formula:
A computer is usually necessary to use this method in order to calculate the area and height.

Moment Method- This method entails disregarding peak shape and expresses parameters of the peak in statistical moments. The zero moment, µ0, is the peak area. The first moment, µ1, is the mean and occurs at the center of the peak (which is the maximum peak height in normal Gaussian peaks). The second moment, µ2, is the variance of the peak. This is a detailed method where appropriate data systems are needed. For a more detailed discussion, a reference is provided (Grubner, 1958).

These methods were evaluated by computer simulation based on efficiency values obtained on a series of synthetically modified Gaussian peaks (i.e., increasing the 'tailing') and compared to the actual value based on the moment method (which was determined to be the most accurate). Briefly, the results were as follows:

CALCULATION METHOD--ACCURACY(Bidlingmeyer, 1984).
Inflection Low
Half-peak height Low
Tangent Low
Height:Area ratio Medium
Four sigma Medium
Five sigma High
Asymmetry High
Bidlingmeyer, B.A. and Warren, F.V. Jr. Analytical Chemistry, 1984, Vol. 56, pp. 1583-96.Grubner, O. Advances in Chromatography, Giddings, J.C. and Keller, R.A. Eds.; Marcel Dekker: New York, N.Y., 1958, Vol. 6, pp. 173-209.

HPLC

noreply@blogger.com (J. Aguilar) — Mon, 16 Feb 2009 06:58:00 +0000

High Performance Liquid Chromatography (HPLC): A Users Guide

HPLC is a popular method of analysis because it is easy to learn and use and is not limited by the volatility or stability of the sample compound. The history section illustrates the HPLC's evolution from the 1970's to the 1990's. Modern HPLC has many applications including separation, identification, purification, and quantification of various compounds. It is important for those using HPLC to understand the theory of operation in order to receive the optimum analysis of their compounds. For those interested in purchasing or using an HPLC we have included a list of manufacturers, a troubleshooting guide, technical assistance, and a bibliography to help reduce your personal research and referencing time. Once you have completed the theory of operation, you will be qualified to take a quick quiz to test your understanding of HPLC systems.

Applications for HPLC

Preparative HPLC refers to the process of isolation and purification of compounds. Important is the degree of solute purity and the throughput, which is the amount of compound produced per unit time. This differs from analytical HPLC, where the focus is to obtain information about the sample compound. The information that can be obtained includes identification, quantification, and resolution of a compound.

Chemical Separations can be accomplished using HPLC by utilizing the fact that certain compounds have different migration rates given a particular column and mobile phase. Thus, the chromatographer can separate compounds (more on chiral separations) from each other using HPLC; the extent or degree of separation is mostly determined by the choice of stationary phase and mobile phase.

Purification refers to the process of separating or extracting the target compound from other (possibly structurally related) compounds or contaminants. Each compound should have a characteristic peak under certain chromatographic conditions. Depending on what needs to be separated and how closely related the samples are, the chromatographer may choose the conditions, such as the proper mobile phase, to allow adequate separation in order to collect or extract the desired compound as it elutes from the stationary phase. The migration of the compounds and contaminants through the column need to differ enough so that the pure desired compound can be collected or extracted without incurring any other undesired compound.
--HPLC of Proteins and Polynucleotides

Identification of compounds by HPLC is a crucial part of any HPLC assay. In order to identify any compound by HPLC a detector must first be selected. Once the detector is selected and is set to optimal detection settings, a separation assay must be developed. The parameters of this assay should be such that a clean peak of the known sample is observed from the chromatograph. The identifying peak should have a reasonable retention time and should be well separated from extraneous peaks at the detection levels which the assay will be performed. To alter the retention time of a compound, several parameters can be manipulated. The first is the choice of column, another is the choice of mobile phase, and last is the choice in flow rate. All of these topics are reviewed in detail in this document.

Identifying a compound by HPLC is accomplished by researching the literature and by trial and error. A sample of a known compound must be utilized in order to assure identification of the unknown compound. Identification of compounds can be assured by combining two or more detection methods.

Quantification of compounds by HPLC is the process of determining the unknown concentration of a compound in a known solution. It involves injecting a series of known concentrations of the standard compound solution onto the HPLC for detection. The chromatograph of these known concentrations will give a series of peaks that correlate to the concentration of the compound injected.(See picture 1)

Using the area of a triangle equation (A=1/2b x h) to calculate the area under each peak, a set of data is generated to develop a calibration curve. This is done by graphing peak area vs. the concentration of the sample solution. Most graphs can be generated using a computer software program such as Excel or Cricketgraph. From this graphing software, a best-fit line can be derived, and the equation of that line can be determined. This equation of a line, y=mx + b, generated by the data, is the calibration curve equation.

The equation of the line is then used in the following manner: A scientist injects a sample of unknown concentration x (x-axis of calibration curve) onto the HPLC; the chromatograph gives a peak output of area y (y-axis of the calibration curve). The area, y, is then in the equation of a line y=mx + b from the calibration curve, and the concentration is found by solving the equation for x.

Mass Spectrometry

noreply@blogger.com (J. Aguilar) — Mon, 09 Feb 2009 20:44:00 +0000

Introduction to the analythical technique of Mass Spectrometry

Validation

noreply@blogger.com (J. Aguilar) — Mon, 09 Feb 2009 20:35:00 +0000

Introduction to the amaizing world of Validation

Hope this video will be very usefull to understand the Validations Process

New Dimensions in Tablet Imaging

noreply@blogger.com (J. Aguilar) — Mon, 09 Feb 2009 20:27:00 +0000

Chemical imaging of solid dosage forms has become a powerful analytical tool for the development of solid dosage forms.

Mar 2, 2008
By: Maribel Rios
Pharmaceutical Technology
Volume 3, Issue 32

Like most of the world, the scientific community is now more than ever reliant on images to gain valuable information. When pixels replace pens, and the image of a new drug candidate can make or break a project, it becomes clear that a picture can be worth much more than 1000 words.

Uniting single-point spectroscopy and digital imaging, chemical imaging is slowly being adapted for the analysis of tablets and capsules. Advanced from traditional optical microscopy, which uses a material's refractive index among other material properties as the basis for generating image contrast, chemical imaging instead uses the underlying spectroscopy associated with the materials being analyzed at each spatial location as a means to produce image contrast. Multivariate analysis and chemometric software then translate this chemical image information into useful quantitative data.

The motivation for adapting chemical imaging lies primarily in the changing nature of today's dosage forms. "Definitely the business is moving in the direction of more complicated formulations, and the standard tools don't provide the information needed to characterize these products," says Linda Kidder, product manager, Chemical Imaging Systems, at Malvern Instruments, Inc. (Columbia, MD). "The single-point spectroscopies just can't do it, and HPLC [high-performance liquid chromatography] just can't do it. This is where the need is growing, and most of the companies working on advanced formulation, really understand this need."

Applications

The advantage of chemical imaging in solid-dosage form analysis is the ability determine the distribution and size of the active pharmaceutical ingredients (APIs) and excipients. The information is then correlated to optimize process operations and understand how ingredients interact within the tablet. "This information aids in quality control, trying to help understand how things dissolve, and their lifetimes with respect to shelf lives," says Richard Bormett, PhD, business manager at Renishaw (Hoffman Estates, IL). "Tableting processing can change the crystal form of the API, and being able to map where the API is and discriminate between its polymorphic forms is an important tool."

Previous methods of viewing the distribution didn't offer the quality that analysts needed. The time required to collect the data was long, making it not feasible, and high spatial-resolution mapping could take days. As Bormett observes, "If you looked at a whole tablet at a time, the spatial resolution of the probe became poorer and poorer so you had to look at larger and larger sections. If an API reached 5 to 1 microns, it wasn't always easy to see or determine its distribution."

Variations. The primary distinction between chemical imaging systems is the type of spectroscopic technique. Within the pharmaceutical industry, numerous spectroscopies have advanced, including Raman, mid-infrared (mid-IR), near-infrared (NIR) absorption–reflectance, UV–vis absorption–reflectance and luminescence. Each have been demonstrated useful for many applications.

Figure 1: Data processing software allows analysts to obtain quantitative information about a whole tablet or portions of a tablet.

Vibrational techniques such as Raman spectroscopy can pick up the unique chemical signatures for polymorphs of an API, which help analysts determine the cause of poor efficacy. Imaging with Raman spectroscopy is also useful in contamination identification. "In the world of tablet or capsule analysis, we often have the luxury of knowing what is present in the tablet based on a list of ingredients," says Matthew Nelson, PhD, director of application science at ChemImage (Pittsburgh, PA). "Often, this information allows us to develop a spectral library of the compounds that are present and to understand the chemical signatures for those components. We can collect data on small parts of a tablet, the whole tablet, or multiple tablets using chemical imaging.

See the article in full HERE

Tablet Technology

noreply@blogger.com (J. Aguilar) — Tue, 03 Feb 2009 06:35:00 +0000

Tablet Technology Presses On

By Matt Bundenthal
PFQ

Near infrared analysis methods can be used to check in-process quality on rotary tablet presses. Long considered to be somewhat recession-proof, the pharmaceutical industry has certainly faced its share of significant challenges in 2008. While it remains true that the use of pharmaceutical preparations tends to increase in stressful times, the manufacturers themselves are held in check by the growing domestic and global economic crisis.

Companies are subscribing more closely than ever before to the application of due diligence, and this certainly applies to their evaluation, selection, and purchase of developmental and manufacturing equipment. An ever-growing number of firms, both name brand and generic, are increasing the exploration and implementation of the concept of equipment standardization and are making more efficient use of existing assets as they make decisions to reduce the overall number of operating sites.

Many pharmaceutical equipment vendors have also felt the pinch as a result of the industry’s newfound reluctance to approve and spend capital. Tablet presses and related peripheral equipment represent one of the most critical investments that any developer of solid dose pharmaceutical products will make. Given the spending slowdown, and with users casting a more watchful eye upon equipment standardization, press vendors are engineering developmental solutions and features that greatly increase the likelihood of a successful handshake between research-specific designs and those intended to produce product in higher volumes. It is more important than ever for the press companies to demonstrate optimal flexibility with smaller units, as well as with other technologies that broaden the overall utilization capabilities of their equipment. The brief descriptions that follow will touch upon just a few of the more dynamic technologies that are being engineered and optimized by modern press manufacturers.

Software, Single-Tablet Compaction

Lower punches in raised position during the sampling cycle.Many tablet press manufacturers now offer a variety of research-based software packages and add-ons that facilitate the collection of useful data at the developmental stage. Going beyond the typical monitoring of preliminary and main compression and ejection forces, today’s systems for data retrieval and manipulation put greater power and versatility in the hands of the user. It is not at all uncommon for press research systems to allow for the measurement of upper and lower punch tightness, as well as the force required to remove a finished tablet from the die table surface via the take-off assembly.

Most of the data collected from the available research packages can be represented on an operator interface terminal both numerically and graphically; in most cases, it can be saved and downloaded in popular formats, including .xls and .pdf. While the power of each package varies from vendor to vendor, most of the more advanced modules place emphasis on the ability to create and analyze individual force profiles for many of the aforementioned parameters. When graphical compression force curves are created, for example, it is very useful to be able to superimpose the most recent one generated over previous curves measured at the same station on a press turret. The utility of such information can come in the form of determining how well (or poorly) a formulation compresses and whether or not there are content uniformity issues.

Some research systems also make provisions for the correlation of compression force data to other properties relating to the compression process, such as variable lubrication levels and optimal dwell times or peak compression times. Such ratios can then, in turn, provide valuable insight into key measurements affecting finished tablet criteria, including hardness, thickness, and friability.

There are also programs commercially available that create graphical representations of not only the amount of force required to compress a tablet but also the forces lost due to elasticity in the product itself and in the mechanical structure of the press. Ultimately, these graphs depict the net force that goes into compressing a tablet. Developmental personnel find this tool useful because it allows them to zero in on an optimal force, one that is substantial enough to produce a tablet to desirable specifications but not so significant as to damage the granules or cause premature wear on the press being utilized.

When graphical compression force curves are created, for example, it is very useful to be able to superimpose the most recent one generated over previous curves measured at the same station on a press turret. The utility of such information can come in the form of determining how well (or poorly) a formulation compresses and whether or not there are content uniformity issues.The ability to compress a single tablet on presses is not particularly novel. Pharmaceutical research personnel have been doing it for decades, typically on either a single-stroke machine with only one station or on a rotary press that has blank dies installed in all but one station. While both methods work in the most rudimentary sense, they fail to account for one physical phenomenon that is inescapable when developing product on a rotary press: centrifugal force.

Although its effects are largely speed-dependent, there certainly can be causality between centrifugal force and the ability to compress a product to a desired set of criteria. The key here, especially in the eye of the developer, should be how a product compresses at various turret speeds. Some press manufacturers now offer options that allow the user to make use of the single-station format on a rotary press more effectively.

Using only one station on the turret and filling the die cavity manually can tell the software the exact rotational speed at which the press should compress. The result is that in just one revolution, the turret can ramp up to the desired speed, compress and eject the tablet, and provide statistical data for analysis. This method not only increases the usefulness of collected data; it is also suitable for working with miniscule quantities of very expensive product.

Multi-Layer Technology
Whether driven by marketing-based ideas, capacity requirements, or simple physics, there are always unique factors to consider when developing a sound procedure for a repeatable manufacturing process. Certain dosage forms can drive formulators and manufacturers to distraction, and multi-layer tablets often do. The challenges associated with multi-layer tablets are myriad. Issues with how well the different layers bind to one another, concerns with cross-contamination, and a need for optional modes of layer sampling are just a few. Fortunately, modern tablet press manufacturers continue to streamline the processes and options related to this form of compression.

The most common multi-layer dosage form is the double-layer, or bi-layer, product, followed by the triple-layer form. A number of press companies now offer small multi-layer machines that allow pharmaceutical manufacturers to make much more efficient use of valuable product as they work at the developmental stage. There are many reasons for choosing a multi-layer form over a more conventional mono-layer tablet. These can include the desire to keep sustained-release formulations separate from those that offer more immediate bioavailability, aesthetic appeal for consumers, and product line extension. Whatever the reason for gravitating to the form, reliable, desirable results are more easily achievable than ever before.

Developmental equipment for multi-layer use is available in a variety of forms. There are benchtop models and free-standing presses. Some presses offer a more conventional design that makes use of separate feeder assemblies for each granulation that goes into a multi-layer tablet, and there are alternative systems that use an indexing feed system for each layer. Multi-layer compression at this scale is typically most valuable as a study of compression feasibility.

Wash-in-place (WIP) and containment presses. With WIP systems, the bulk of the cleaning will be handled by the equipment, with minimal manual cleaning.This type of compression can provide valuable insight into whether or not different layers bind together and the finished tablet offers the desired appearance, if that is deemed important. The potential drawback is that most developmental presses use turrets with a comparatively small pitch circle diameter. If dwell time is an important factor for finished tablet quality, then output is generally compromised.

New multi-layer presses at the larger scale definitely offer some distinct advantages, especially as pharmaceutical manufacturers adhere ever more closely to heightened quality. Many new presses offer features that are designed to mitigate the risk of compressing partial or single-layer tablets that may inadvertently make their way into a receptacle designated for acceptable tablets, especially during a first-layer sampling cycle.

Some press companies do this by moving the second-layer feeder back during this interval; some do so by physically moving the lower punches into a position during the sampling cycle in which their tips are almost flush with the die table surface as they pass under the feeder. The latter method ensures a "no-cavity" condition while at the same time reducing any risk associated with moving large components from their ideal set position. The sampling process itself has also been greatly optimized by some press manufacturers.

One new method makes use of a static sampling procedure in which the braking system on the machine stops the turret abruptly when a sample is called for. The turret moves slowly through the first-layer compression cycle, temporarily increasing the hardness so that the samples can be handled and tested, and then automatically returns to production settings. This method can be particularly advantageous, guaranteeing that the samples are filled in the same exact fashion as under production conditions and leading to more representative samples, less waste, and greater efficiencies.

Dealing With Potent Products
Reflection NIR as integrated with a tablet press offers a very different approach than that offered by transmission NIR technology. Installed on a press, a reflection NIR system allows for 100% inspection of tablet product continuity and serves as an in-line tool that can essentially check and verify a product’s chemical fingerprint.In recent years, the pharmaceutical industry has witnessed increasing numbers of potent products and compounds. The products themselves are becoming more powerful as formulators develop substances that are increasingly effective at providing desired physiological and therapeutic effects. Airborne particulate matter, more than many other substances, can represent a great risk to the equipment operator, particularly in cases in which a formulation contains a high percentage of a potent active drug substance. Historically, handling such compounds resulted in the use of positive-pressure respirators, full-body moon suits, and a variety of other types of personal protective equipment.

These issues led to a need for specifically engineered manufacturing equipment and systems that would offer far greater protection to individuals regularly working with potent compounds. Such systems would also, as a consequence of modern engineering capabilities, lead to the ability to clean the equipment more rapidly.

The marriage of these two issues has led to the creation by some press manufacturers of machines that combine high-containment features with those that fall under the banner of either wash-in-place (WIP) or clean-in-place (CIP). The generally accepted definition of WIP systems implies that the bulk of cleaning will be handled by the equipment itself, with minimal manual cleaning required to finish the process. CIP systems purportedly complete the entire cleaning process by themselves but in practice are often quite challenging to validate reliably.

Modern containment technology found on leading tablet presses will often make use of features—such as glove ports and rapid transfer ports—that allow the user to manipulate the press without breaching the integrity of containment prior to completing a batch (for example, stopping the press to examine or replace a faulty component or tool).

Press manufacturers now offer a variety of research-based software packages and add-ons that facilitate the collection of useful data to ensure quality.Additionally, it is not uncommon to find features on a WIP/ containment machine that allow the user to gain access to the compression area via the glove ports and make use of manual spray and vacuum wands. These, too, are engineered so that containment is assured at all times during their use. The WIP or CIP systems typically utilize a system of sparging valves and balls for the delivery of various cleaning media, and all parts that come in contact with these materials are generally manufactured from stainless steel. Alternative containment systems include machines that make use of removable compression compartments.

When selecting this type of press, it is imperative to work closely with the chosen vendor to accurately identify all critical criteria, such as the expected occupational exposure limits (OELs), that the system is designed to maintain. Toxicology studies determine the levels of exposure to a given substance that can lead to adverse health-related effects. Often, specific OELs are established only by the company producing a given product and are generally created with the assumption that they apply to healthy adults over an eight-hour workday.

Some tablet press vendors are able to provide proof that they have subjected their containment technology to rigorous surrogate testing, while others are not. When evaluating contained equipment, the prospective buyer should always ask the vendor whether or not it has performed such testing and, provided the vendor has, if the buyer can have a copy of the test results. Companies that do offer this type of technology have, in most cases, applied it to machines across their capacity range, covering both developmental and production sizes.

Analysis for Solid Dose Compression
Pharmaceutical manufacturers will always clamor for faster, more accurate methods of production with a goal of assuring their customers of better overall quality. Not long ago, many manufacturers were encouraged to begin closely evaluating what is known as PAT, or process analytical technology. First proposed by the United States Food and Drug Administration (FDA), PAT is defined by the FDA as "a system for designing, analyzing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes with the goal of ensuring final product quality." PAT is, therefore, essentially a framework under which a company develops faster, more accurate in- or on-line methodology for analyzing process results.

A major goal for any manufacturer today is to minimize, to the greatest possible degree, any risk of producing a product that does not meet stringent predefined parameters. Historically, mitigating this risk was achieved through the employment of rigorous end-of-process analytical work, which for a solid dosage form could include the measurement of weight, thickness, and hardness, as well as friability testing. While largely effective for ensuring that a quality product moves to the store shelves, these methods are perhaps not ideal for ensuring overall efficiencies. They are, after all, most often utilized after products are made, rather than during the production process.

A major goal for any manufacturer today is to minimize, to the greatest possible degree, any risk of producing a product that does not meet stringent predefined parameters.One emerging technology that shows the most promise when applied to in-process quality checking on a rotary tablet press makes use of near infrared (NIR) technology. NIR is a form of spectroscopy that utilizes light with a wavelength ranging from 800 to 2,500 nm. Molecular bands created by the use of NIR technology are typically very broad and therefore inherently complex, necessitating the employment of calibration techniques for multiple wavelengths. The technology is, however, very useful for different types of rapid analysis. Particular formulations will exhibit specific qualities when subjected to an NIR light source, creating a fingerprint that can later be used as a baseline for real-time quality analysis. Depending on the sample being analyzed, NIR light is generally measured in one of two ways, reflection or transmission.

Reflection NIR technology is a method in which light emitted from a source is reflected off of a sample and the resulting spectroscopy is read by an NIR sensor. Utilized on a high-speed rotary tablet press, this form of NIR measurement is suitable for 100% analysis due to its short cycle time. That very same speed, however, may limit the scope of its analytical potential to some degree.

The transmission method of NIR measurement occurs when light emitted from a source passes through a sample and is read by an appropriate sensor on the opposite side of the sample. While inherently slower than the reflection method, transmission can prove to be more accurate from a truly analytical perspective.

Following closely on the heels of the FDA’s suggestion that pharmaceutical manufacturers seriously consider the PAT initiative, some tablet press vendors soon embarked on various endeavors to create technologies embracing the opportunities presented by the use of NIR. It is important to note that some press vendors already offer potential solutions based on both forms of NIR measurement. Where the transmission method is desired, certain devices intended for the measurement of tablet weight, thickness, and hardness are fitted with an NIR measurement cell that can infer the percentage of active pharmaceutical ingredient (API) in finished tablet samples.

These devices deliver tablets chosen for NIR measurement in a rapid, highly controlled fashion, providing the user with comprehensive information about a tablet’s chemical and physical properties. Data recorded by the NIR cell is transferred to the user interface software for inclusion in summary batch reports; if necessary, the measured data can trigger in-process changes in the press for maintaining ideal product specifications.

Reflection NIR, as integrated with a tablet press, offers a very different approach than that offered by transmission NIR technology. Installed on a press, a reflection NIR system allows for 100% inspection of tablet product continuity and serves as an in-line tool that can essentially check and verify a product’s chemical fingerprint. Light information detected by the receiver can be compared to a baseline spectrum that is representative of that emitted by the product’s ideal composition when subjected to NIR radiation. The system allows for contact-free, non-destructive analysis of the content uniformity of active ingredients.

The modern tablet press market is extremely competitive, and the various manufacturers try hard to develop products that allow them to differentiate themselves from one another. Those who benefit the most from this competition are, of course, the end users. The leading press companies have made increasingly conscious efforts to engineer solutions in direct response to specific requests from their clients. Presses that allow a dizzying amount of flexibility for running a wide array of different products in highly variable quantities are now appearing on the market.

Much effort is focused on optimizing the safety and security of both the operator and the data generated by a machine, and the most reputable vendors offer more comprehensive assistance than ever before when it comes to the generation and customization of qualification documentation. Tablet presses play an integral role in modern pharmaceutical manufacturing, and their manufacturers seem poised to keep it that way.

Which Changes Have to Be Made to the Validation Strategy Due to the New FDA Process Validation Guide?

noreply@blogger.com (J. Aguilar) — Sat, 31 Jan 2009 18:23:00 +0000

Which Changes Have to Be Made to the Validation Strategy Due to the New FDA Process Validation Guide?
The new draft of the FDA Guidance Process Validation (see GMP News of 26 November 2008) calls for a "validation life cycle approach". The number of validation runs is not indicated any more. Revalidation is not mentioned any longer, instead the text uses the term "continued process verification". "Process understanding" - also with regard to statistical features - is the centre of attention. In place of DQ, IQ, OQ, the document refers to verification.
However, which concrete changes have to be made to the validation strategy?
The European regulations continue to include the 3-batch model of validation as well as revalidation and also qualification in the phases DQ, IQ, OQ, PQ. To reconcile this contradiction in a new validation strategy will be an important challenge faced by any globally acting enterprise for the next few months.
In order to help you with this task, we have developed a questionnaire addressing questions regarding implementation possibilities and also suggesting possible answers. On the whole, we have compiled 10 short questions for you. We will evaluate your answers and publish them on this website. Naturally, the questionnaire is anonymous. We will send the results to the FDA by the end of the commenting period, i. e. before 20 February 2009.
The survey can be found here. Just fill in the questionnaire and press "send" at the end. Thank you very much in advance for your commitment.

The Case of Blister-Filling and Packaging Systems

noreply@blogger.com (J. Aguilar) — Thu, 29 Jan 2009 22:15:00 +0000

Target Selection and Qualification: The Case of Blister-Filling and Packaging Systems
The authors propose an approach for qualification-target selection and show how it can be applied to blister-filling and packaging systems.
Jan 2, 2009By: Toyohiko Takeda, Hiroshi HirasawaPharmaceutical TechnologyVolume 33, Issue 1, pp. 72-80

Regulations that control the construction of facilities and equipment for medical-product manufacturing require qualification of the facilities and equipment. The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use defines the common principles of the qualification of ingredients, formulations, and packaging (1). However, it does not clearly define the methods for determining what must be qualified or for performing qualification.
In its guideline on commissioning and qualification (C&Q), the International Society for Pharmaceutical Engineering (ISPE) states that qualification practices are required after commissioning to provide supplementary assurance that good engineering practices (GEP) have been followed (2).
ISPE says that a system-impact assessment should be performed first to identify the systems that have a direct effect on the quality of the product. The components or devices of the direct-impact systems should then be classified as critical components, which have a direct effect on the quality of the product, and noncritical components, which do not. Qualification practices should only be applied to the critical components. Adherence to GEP is sufficient for indirect-impact systems and noncritical components.
ISPE's C&Q document, however, mentions an exceptionally broad range of criteria for identifying critical components. The document does not describe in detail how to determine which critical components must be qualified or how to qualify them. For these reasons, various methods for selecting targets and performing qualification have emerged. In many cases, components are qualified even when they are not required to be.
The Good Manufacturing Practice (GMP) Committee of the Japan Society of Pharmaceutical Machinery and Engineering has studied qualification practices for systems used in solid-dosage-form facilities, including pan-coating systems, blister-filling and packaging systems, and pillow-packaging systems (3, 4). On the basis of these studies, this article proposes a new approach to target selection and qualification and shows how the approach can be applied to blister-filling and packaging systems.
Selecting the targets of qualification
ICH's Q7 Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients states that appropriate qualification of critical equipment and ancillary systems should be completed before starting process-validation activities. This section will explain which components of the critical equipment and ancillary systems should be selected as targets of qualification.
Medical-product manufacturing systems have various functions that are performed by the systems' mechanism, shape, and material. Using a certain system to manufacture medical products entails executing the system's functions under prescribed, controlled conditions. In ordinary manufacturing processes, some system functions have a direct effect on the quality of the products and others have an indirect effect.
The authors believe that qualification of critical equipment and ancillary systems should be interpreted as qualification of system functions that have a direct effect on product quality. The article will apply this principle to qualification-target selection, using blister-filling and packaging systems as an example. First, the quality of the products should be explained. The quality of blister products can be defined in terms of protecting their contents (e.g., tablets) and display or identification. This article focuses on the former function. The authors define the thickness of the blister pocket web as a critical factor that directly affects product protection.
Blister-filling and packaging systems are direct-impact systems because they directly affect the quality of blister-package products. An examination of the systems' operating principles shows that the forming function and the speed-control function directly affect the thickness of the blister pocket web. Furthermore, a close examination of the system devices that affect the forming function shows that the heating device and the forming device directly affect the thickness of the blister pocket web.
Parts of the heating and the forming devices directly affect web thickness, and the functions of these critical parts should be identified. For example, manufacturers should determine the function of the heating device's heating plate and that of the forming device's forming die. In this case, the required function is that of assigning the appropriate quantity of heat or shape and size to the plastic film. Because the quantity of heat is usually difficult to measure or control, however, the temperature of the heating plate should be measured and controlled instead.
The temperature of the heating plate and the shape and size of the forming die are called direct factors. Qualification should be restricted to these direct factors.

See in detail this article here